Glucokinase activators

 

(57) Abstract:

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is non (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts. These compounds are activators of glucokinase, which increase insulin secretion in the treatment of diabetes type II. 4 C. 28 C. p. F.-ly.

Glucokinase (GK) is one of four hexokinase found in mammals (Colowick, S. P., in The Ensymes, volume 9 (P. Boyer, ed.) Academic Press, New York, NY, cc.1-48, 1973). Hexokinase catalyzes the first stage of glucose metabolism, namely the conversion of glucose into glucose-6-phosphate. Glucokinase is distributed in the cells is very limited, it is mainly concentrated in the cells of the pancreas and parenchymal liver cells. In addition, the group is an enzyme, which limits the rate of glucose metabolism in the cells of these two types, which is known to play a key role in glucose homeostasis throughout the body (Chipkin, S. R., Kelly, K. L., and Ruderman, N. B., Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, pieces Pennsylvania, cc.97-115, 1994). The glucose concentration at which the Ledger shows the half maximal activity, is approximately 8 mm. For the other three hexokinase saturation of the glucose draisma begins when the concentration of glucose in the blood rises from the fasting level (5 mm) to the level that occurs after a meal containing carbohydrates (10-15 mm) (Printz, R. G., Magnuson, M. A. and Granner, D. K., Ann. Rev. Nutrition volume 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.). Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993). More than ten years ago these results led to the emergence of the hypothesis, according to which GK acts as a glucose sensor in cells and hepatocytes (Meglasson, M. D., and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). Studies conducted in recent years, transgenic animals, confirmed that the group really plays a crucial role in glucose homeostasis throughout the body. Animals that are not expressed Ledger died from a severe form of diabetes in a few days after birth, whereas animals with superexpression of the Ledger showed improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. and others, Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F., and others, FASEB J., 10, 1213-1218, 1996). Increasing duration of exposure to glucose with the participation of SC increased insulin secretion in the cells, to increase the deposition of glycogen in hepatocytes and is likely to reduce the formation of glucose.

The fact that humans Ledger also functions as a glucose sensor, is confirmed by the fact that the loss of the ability etc., Biochem-J. 309, 167-173, 1995). Additional evidence of the important role of ha in the regulation of glucose metabolism in humans was obtained in the identification of patients that are characterized by the expression of mutant forms of ha with increased enzyme activity. These patients were found hungry hypoglycemia associated with non-compliant high insulin levels in plasma (Glaser, C., Kesavan, P., Heyman, M., and others, New England J. Med. 338, 226-230, 1998). Although mutation of the gene Ledger were not found in most patients with diabetes type II, compounds that activate the Ledger, and therefore increase the sensitivity of the sensor system Ledger, useful, apparently, in the treatment of hyperglycemia characteristic of all diabetes type II. Activators of glucokinase increase, apparently, the flow rate of glucose during its metabolism in cells and hepatocytes, which leads, perhaps, to increased insulin secretion. Such compounds can be used in the treatment of type II diabetes.

The present invention proposes a connection representing an amide of the formula I:

in which * denotes an asymmetric carbon atom;

R1and R2each independently represents a hydrogen atom or halogen,P>, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio-, PERFLUORO(ness.)allylthiourea, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl;

R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms;

R4denotes-C(O)or other unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom to the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist in place of a ring carbon atom other than adjacent to the connecting carbon atom, and Deputy selected from a range including (ness.)alkyl. halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8, -(CH2)n-OTHER6;

R40denotes a hydrogen atom, (ness.)alkyl, (ness.)alkenyl, /P>

R5denotes a hydrogen atom, (ness.)alkyl or PERFLUORO(ness.)alkyl;

R6, R7and R8each independently represents a hydrogen atom or (ness.)alkyl; and n denotes 0, 1, 2, 3 or 4;

or its pharmaceutically acceptable salt.

In the formula I compounds * denotes an asymmetric carbon atom in this compound. The compound of formula I can exist either in the form of the racemate or in the R configuration shows an asymmetric carbon atom. Preferred R-enantiomers.

It was found that the compounds of formula I in vitro activate glucokinase. Activators of glucokinase and can be used to enhance insulin secretion in the treatment of diabetes type II.

The object of the present invention is also a pharmaceutical composition comprising a compound of formula I, pharmaceutically acceptable carrier and/or adjuvant. Moreover, the object of the present invention is the use of such compounds in the preparation of medicines for the treatment of diabetes type II. The object of the present invention are methods of preparing compounds of formula I. in Addition, an object of the present invention is a method therape is ormula I.

Throughout this application the term "halogen atom" and "halo" in all cases, unless otherwise indicated, used to denote any of the four halogen atoms, i.e. fluorine, chlorine, bromine or iodine. The preferred halogen atom is a chlorine atom.

In the present description the term "(ness.)alkyl" used as covering as remotemachine and branched alkyl groups containing from 1 to 7 carbon atoms each, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. Related to R3it is preferred values are isopropyl and n-propyl. The term "halo(ness.)alkyl" used in this description to denote (ness.)alkyl group, one of the hydrogen atoms of which is substituted by halogen atom, listed above, and that the Deputy can be anywhere (ness.)of alkyl, including at the end. Preferred halo(ness.)alkyl group is chloroethyl. Similarly, "hydroxy(ness.)alkyl" means (ness.)alkyl group, one of the hydrogen atoms of which is substituted by hydroxyl anywhere, including at the end. Preferred hydroxy(ness.)alkyl groups include ethanol, isopropanol the group, all hydrogen atoms which is substituted or replaced by fluorine atoms. Among PERFLUORO(ness.)alkyl groups are preferred trifluoromethyl, pentafluoroethyl, heptafluoropropyl I. I.

In the present description the term "(ness.)alkylthio indicated (ness.)an alkyl group, as described above, where tighrope connected with the remainder of the molecule. Similarly the term "PERFLUORO(ness.)alkylthio indicated PERFLUORO(ness.)an alkyl group, as described above, where tighrope connected with the remainder of the molecule.

In the present description the term "(ness.)alkylsulfonyl" denotes (ness.)an alkyl group, as described above, where sulfonylurea group is associated with the remainder of the molecule. Similarly the term "PERFLUORO(ness.)alkylsulfonyl" denotes PERFLUORO(ness.)an alkyl group, as described above, where sulfonylurea group is associated with the remainder of the molecule.

In the present description the term "(ness.)alkylsulfonyl indicated (ness.)an alkyl group, as described above, where sulfonylurea group is associated with the remainder of the molecule.

In the present description the term "gidroksilaminopurina" denotes an amino group where one of the hydrogen atoms substituted by hydroxyl.

In the present description posttitle from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. Preferred cycloalkyl is cyclopentyl.

In the present description the term "(ness.)alkenyl indicated Allenova group containing from 2 to 6 carbon atoms with a double bond between any two adjacent carbon atoms of this group. Preferred (ness.)alkenylamine groups are allyl and crotyl.

The term "(ness.)alkoxy" in the present description are covered as remotemachine and branched alkoxygroup containing from 1 to 7 carbon atoms each, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy, ethoxy.

The term "aryl" in the present description are marked aryl monocyclic aromatic hydrocarbon groups such as phenyl, tolyl, etc. which may be unsubstituted or substituted in one or more positions by halogen atoms, the nitro-group, (ness.)alkyl or (ness.)alkoxysubstituted, and polycyclic aryl groups such as naphthyl, antril and tenantry, which can be unsubstituted or substituted by one or more of the aforementioned groups. Preferred areinitially" denotes an alkyl group, preferably, ness.)alkyl, in which one of the hydrogen atoms is substituted by an aryl group. Examples arylalkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-Chlorobenzyl, 4-methoxybenzyl etc.

The term "lower aliphatic acid" in the present description is used to denote the lower aliphatic acids containing from 2 to 7 carbon atoms each, such as propionic acid, acetic acid, etc., the Concept "(ness.)alkanoyl" is used to denote a monovalent alkanoyl groups containing from 2 to 7 carbon atoms each, such as propionyl, acetyl, etc., the Concept of "urologie acid" denotes arylaliphatic acid, in which aryl has the values listed above, and aliphatic residue contains from 1 to 6 carbon atoms. The concept of "aroyl" is used to denote arolovich acids, in which aryl has the values listed above, and the hydrogen group of the residue COOH removed. From rolnych groups preferred benzoyl.

Heteroaromatic ring in R4may be unsubstituted or monosubstituted five - or six-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from the series comprising oxygen atoms, the automatic ring contains the first nitrogen atom, adjacent to the connecting ring carbon atom, and in the case of other heteroatoms can be the atoms of sulfur, oxygen or nitrogen. These heteroaromatic rings include, for example, pyrazinyl, pyridazinyl, isoxazolyl, isothiazole and pyrazolyl. Among heteroaromatic rings are preferred include pyridinyl, pyrimidinyl, thiazolyl, oxazolyl and imidazolyl. The heteroaromatic ring, which we denote by R4through the ring carbon atoms are linked with amide group with the formation of the amides of formula I. the Ring carbon atom of the heteroaromatic ring, which is attached through amide bond with the formation of the compounds of formula I, any Deputy cannot maintain. When R4denotes unsubstituted or monosubstituted five-membered heteroaromatic ring, preferably those rings each of which contains nitrogen heteroatom adjacent to the connecting carbon atom, and the second heteroatom connected with it the connecting carbon atom or adjacent to the first-mentioned a heteroatom. Preferred five-membered heteroaromatic ring containing 2 or 3 heteroatoms, and especially preferred thiazolyl, imidazoline ring, this is the last through a ring carbon atom linked to the amino group, and one nitrogen heteroatom is adjacent to the connecting ring carbon atom. The preferred six-membered heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.

Before carrying out the reactions of various functional groups, such as the free carboxylic acid and hydroxyl groups, as a rule, protected by a conventional hydrolyzable ester or ether protective groups. In the present description the term "hydrolyzable ester or ether protective group" is used to denote the residue of any complex or simple esters, which are usually used to protect carboxylic acids or alcohols, which can be either hydrolyzed with formation of the corresponding hydroxyl or carboxyl groups. Examples of ester groups, which can be used for this purpose are those in which the acyl residues derivationally from (ness.)aliphatic, aryl(ness.)aliphatic or (ness.)aliphatic dicarboxylic acids. To those activated acids, which can be opolskie acids and bromohydrin acids, derivateservlet of aryl - or (ness.)aliphatic acids. Examples of anhydrides are anhydrides, derivateservlet of monocarboxylic acids, such as acetic anhydride, the anhydride of benzoic acid and anhydrides of lower aliphatic dicarboxylic acids, in particular succinic anhydride, and chloroformiate, in particular trichlorohydrin, and preferred ethylchloride. Acceptable ether protective groups for alcohols are, for example, remains tetrahydropyranyl ethers, such as 4-methoxy-5,6-dihydroxy-2H-peranovic esters. Others are roulettelive esters, such as benzyl, benzhydryl and treilly esters, or -(ness.)alkoxy-(ness.)alkalemia esters, for example methoxymethyl or allyl esters, or alkylsilane esters, such as trimethylsilyloxy ether.

The concept of "misamisaiwai group" refers to any conventional misamisaiwai group which can be split with a free amino group. Preferred protective groups are the usual misamisaiwai group used in the synthesis of peptides. Especially preferred are those misamisaiwai group, which can be chipped off in mild acidic conditions at a pH of about Biloxi (UNCCD) and the 9-fertilitycare (FMOC).

Used in the present description the term "pharmaceutically acceptable salts" embraces all salts with mineral and organic pharmaceutically acceptable acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid, etc., the Term "pharmaceutically acceptable salt" also includes all pharmaceutically acceptable basic salts such as amine salts, trialkylamine salt, etc., Such salts can be quite easily obtained by specialists in the art using standard methods.

One of the preferred options object of the present invention is a compound constituting the above amide of the formula I, in which R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxylamino-, cyano-, nitro-group, (ness.)alkyl, -OR, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio-, PERFLUORO(ness.)allylthiourea, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl, carbon atoms;

R4denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom to the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist in place of a ring carbon atom other than adjacent to the connecting carbon atom, and Deputy selected from a range including (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR SIG7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8, -(CH2)n-OTHER6;

n denotes 0, 1, 2, 3 or 4;

R5denotes a hydrogen atom, (ness.)alkyl or PERFLUORO(ness.)alkyl; and

R6, R7and R8independently from each other represent a hydrogen atom or (ness.)alkyl;

or its pharmaceutically acceptable salt.

According to another preferred variant, the object of the present invention is a connection, etc will mean a hydrogen atom or halogen, amino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, PERFLUORO(ness.)alkyl, (ness.)alkylthio-, PERFLUORO(ness.)allylthiourea, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl;

R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms;

R4denotes-C(O)other40;

R40denotes a hydrogen atom, (ness.)alkyl, (ness.)alkenyl, hydroxy(ness.)alkyl, halo(ness.)alkyl, -(CH2)n-C(O)OR5or-C(O)-(CH2)n-C(O)OR6;

R5and R6each denotes a hydrogen atom or (ness.)alkyl; and n denotes 0, 1, 2, 3 or 4;

or its pharmaceutically acceptable salt.

Preferred heteroaromatic residues in R4are unsubstituted or monosubstituted five - or six-membered heteroaromatic ring, selected from a range that includes thiazolyl, pyridinyl, imidazolyl, isoxazolyl, oxazolyl, pyridazinyl, pyrimidinyl and thiadiazolyl. Especially preferred unsubstituted thiazolyl, unsubstituted pyridinyl and pyridinyl, substituted by a halogen atom, (ness.)by alkyl, hydroxy(ness.)the alkyl or-C(O)OR5where R5means (NCDs is ness.)alkyl or (ness.)alkenyl.

Preferred in accordance with the present invention remains R1are hydrogen atoms and halogen, nitro and ceanography, more preferred hydrogen atoms or halogen.

Preferred in accordance with the present invention remains R2are a hydrogen atom, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, PERFLUORO(ness.)alkylsulfonyl, halogen atom or-OR5where R5means PERFLUORO(ness.)alkyl, more preferred halogen atom or (ness.)alkyl-sulfonyl.

Preferred in accordance with the present invention remains

R3are cyclopentyl, cyclohexyl or cycloheptyl, more preferred cyclopentyl.

In all cases, unless otherwise indicated, the following compounds R4denotes the group-C(O)other40where R40has the values listed above.

Some of these amide compounds R40denotes a hydrogen atom, (ness.)alkyl or (ness.)alkenyl. Such amides are preferred those in which R3denotes cyclopentyl, especially when amide characterized by the R configuration when shown an asymmetric carbon atom.

In some them amidon is 1-(3-cyclopen-Tyl-2-phenylpropionyl)-3-metalmachine. The other above-mentioned compounds one of R1and R2denotes a hydrogen atom and the other denotes a cyano or halogen atom. Examples of such amides are:

1-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[2-(4-bromophenyl)-3-cyclopentylpropionyl]-3-metalmachine.

Other amides as examples of the above compounds, R1and R2independently of one another denote halogen atom (preferably chlorine).

Examples of such amides are:

[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl] urea;

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-atilmotin

1-allyl-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl] urea;

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl] urea;

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-atilmotin;

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-from ntil-2-(3,4-differenl)propionyl]-3-metalmachine.

However, other amides as examples of the above compounds, one of R1and R2denotes a hydrogen atom or halogen and the other represents the nitrogroup. Examples of such amides are:

1-[2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(4-nitrophenyl)propionyl]-3-metalmachine.

Other amides as examples of the above compounds, one of R1and R2denotes a hydrogen atom, (ness.)alkylthio or PERFLUORO(ness.)alkylthio, and other means (ness.)alkylthio or PERFLUORO(ness.)alkylthio. Examples of such amides are:

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(4-methylsulfinylphenyl)propionyl]-3-metalmachine.

However, other amides as examples of the above compounds, one of R1and R2denotes a hydrogen atom or a PERFLUORO(ness.)alkylsulfonyl, and the other denotes a PERFLUORO(ness.)alkylsulfonyl. Examples of such amides are:

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(3-triftormetilfullerenov)propionyl]-3-metalmachine.< 2 means (ness.)alkylsulfonyl. In a preferred embodiment, one of R1and R2denotes a hydrogen atom or (ness.)alkylsulfonyl, and other means (ness.)alkylsulfonyl, and in a more preferred embodiment, R2means (ness.)alkylsulfonyl. Examples of such amides are:

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine;

1-{2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(4-ethanolgasoline)propionyl]-3-metalmachine;

1-[2-(3,4-bistanbulholiday)-3-cyclopentylpropionyl]-3-metalmachine.

Other amides as examples of the above compounds, at least one of R1and R2means (ness.)alkylsulfonyl, one of R1and R2denotes a cyano or halogen atom, and the other, preferably R2means (ness.)alkylsulfonyl. Examples of such amides are:

1-[2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionyl]-3-metalmachine;

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[what phenyl)-3-cyclopentylpropionyl]-3-atilmotin;

1-[2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine.

Other amides as examples of the above compounds, at least one of R1and R2means (ness.)alkylsulfonyl, one of R1and R2means PERFLUORO(ness.)alkyl, and the other, preferably R2means (ness.)alkylsulfonyl. An example of such amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionyl]-3-metalmachine. Other amides as examples of the above compounds, at least one of R1and R2means PERFLUORO(ness.)alkyl and the other represents a halogen atom. Examples of such amides are:

1-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionyl]-3-me-telecabina.

However, other amides as examples of the above compounds, at least one of R1and R2denotes the nitro-group and the other denotes (ness.)alkylsulfonyl. An example of such amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionyl]-3-metalmachine.

The amide compounds of the present invention, described below, compounds R40has the same value, and R3doesn't mean cyclopentyl.

Some of these compounds one of R1and R2denotes a halogen atom or hydrogen and the other denotes a hydrogen atom. An example of such amide is [2-(4-chlorophenyl)-4-methylpentanoic] urea. Thus, in particular, each of R1and R2may refer to a chlorine atom. Examples of such amides are:

[3-cyclopropyl-2-(3,4-dichlorophenyl)propionyl]urea;

[3-cyclobutyl-2-(3,4-dichlorophenyl)propionyl]urea;

R-[2-(3,4-dichlorophenyl)-4-methylpentanoic]urea;

1-[2-(3,4-dichlorophenyl)-4-methylpentanoic]-3-metalmachine;

1-[2-(3,4-dichlorophenyl)hexanoyl]-3-metalmachine.

In other such compounds, R40matter mentioned above, a R3refers to cyclohexyl. Some of these amides is one of R1and R2denotes a halogen atom or hydrogen and the other denotes a halogen atom. Examples of such amides are:

3-[cyclohexyl-2-(3,4-dichlorophenyl)propionyl] urea;

[3-cyclohexyl-2-(3,4-dichlorophenyl)propionyl-3-metalmachine. Other such compounds R has the values given above and R3means cycloheptyl. In the em halogen atom. An example of such amide is [3-cycloheptyl-2-(3,4-dichlorophenyl)propionyl] urea.

Some compounds of the present invention R40represents -(CH2)n-C(O)OR5or-C(O)-(CH2)n-C(O)OR6. Some of these compounds R3amide denotes cyclopentyl. In the preferred embodiment, each of R1and R2independently denotes a halogen atom. Examples of the above-mentioned amides are:

ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} propionic acid;

ethyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} acetic acid;

methyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} acetic acid;

methyl ester of 3-[3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido] propionic acid;

ethyl ester {3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]ureido} acetic acid;

ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}-3-oxopropanoic acid.

Some compounds of the present invention R40denotes hydroxy(ness.)alkyl or halo(ness.)alkyl. Some of these amide compounds R3

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxyethyl)urea;

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)urea;

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea;

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl) urea;

1-(2-chloroethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea;

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea.

In all cases, unless otherwise stated, the compounds described below, R denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom to the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen or nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting carbon atom, it monosubstituted heteroaromatic ring monogamist on ring carbon ash.)alkyl, halogen atom, nitro, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6-C(O)-C(O)OR8, -(CH2)n-OTHER6.

Some of these compounds R3denotes cyclopentyl (compound I-G). Variants of compound I-G are those compounds in which R4denotes an unsubstituted thiazole (compound I-G1). Different versions of the compounds I-1 include those compounds in which:

a) one of R1and R2denotes a hydrogen atom or halogen or PERFLUORO(ness.)alkyl and the other of these R1and R2denotes a halogen atom or a PERFLUORO (ness.) alkyl;

b) one of R1and R2denotes an amino, a nitro-group, halogen atom or hydrogen, and the other of these R1and R2denotes amino-, cyano - or nitro-group;

C) one of R1and R2means (ness.)alkylthio, PERFLUORO (ness.)alkylthio, halogen atom or hydrogen, and the other of these R1and R2means PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl or (ness.)alkylthio;

g) one of R1and R2means (ness.)alkylsulfonyl, a hydrogen atom, nitro-, cyano-, amino-, hydroxyamino, sulphonamido or Gai R2means (ness.)alkylsulfonyl, and the other of these R1and R2denotes halogroup or PERFLUORO(ness.)alkyl;

e) one of R1and R2means PERFLUORO(ness.)alkylsulfonyl or a hydrogen atom and the other of these R1and R2means PERFLUORO(ness.)alkylsulfonyl;

g) one of R1and R2means-OR5or-C(O)OR5and the other of these R1and R2denotes a hydrogen atom or-OR3where R3has the values specified above; and

C) one of R1and R2means-OR5and the other denotes halogroup. In accordance with another variant of implementation of the present invention, where R3denotes cyclopentyl, variants are those compounds in which R4represents monosubstituted the thiazole (compound I-G2). For different types of compounds I-D2 are those compounds in which monothelitism is the group-(CH2)n-OR, where n and R6have the values listed above (compounds I-D2(a)). Variants of the compounds I-D2(a) are those compounds in which:

a) one of R1and R2denotes a halogen atom, and the other of these R1and R2denotes a hydrogen atom or R and R2means (ness.)alkylsulfonyl or a hydrogen atom;

C) one of R1and R2denotes a hydrogen atom and the other of these R1and R2means (ness.)alkyl or PERFLUORO(ness.)alkyl.

In accordance with another variant implementation of the invention, where R3denotes cyclopentyl, and R4represents monosubstituted the thiazole (compound I-G2) are those compounds in which monothelitism is (ness.)alkyl; one of R1and R2denotes a hydrogen atom or halogen and the other of R1and R2denotes a halogen atom (compounds I-D2(b)).

Other variants of compounds I-G include those compounds in which monosubstituted the thiazole substituted by a group -(CH2)n-C(O)OR7in which n denotes 0 or 1, and R7denotes a hydrogen atom or (ness.)alkyl (compounds I-D2(in)). Variants of compounds of formula I-G2(V) are those compounds in which:

a) one of R1and R2denotes a hydrogen atom and the other of these R1and R2denotes halogroup;

b) each of R1and R2independently denotes halogroup;

C) one of R1and R2denotes nitro, amino groups is n of R1and R2means (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen atom or hydrogen, and the other of these R1and R2means (ness.) alkylsulfonyl.

In accordance with another variant of implementation of the present invention, where R3denotes cyclopentyl, and R4represents monosubstituted the thiazole (compound I-G2) are those compounds in which monosubstituted the thiazole substituted by a group-C(O)-C(O)OR8in which R8has the values listed above (compounds I-D2(g)). Variants of compounds I-D2(g) include those compounds in which:

a) one of R1and R2denotes a hydrogen atom and the other of these R1and R2denotes a nitro or amino group;

b) one of R1and R2denotes halogroup or PERFLUORO(ness.)alkyl and the other of these R1and R2means PERFLUORO(ness.)alkyl, halogen atom or hydrogen;

C) one of R1and R2denotes a hydrogen atom or halogen and the other of these R1and R2means (ness.)alkylsulfonyl.

In accordance with another variant of implementation of the present invention, where R3denotes cyclopentyl, and R4means monogamists the nitrogroup, one of R1and R2denotes a hydrogen atom or halogen and the other of R1and R2denotes a halogen atom or (ness.)alkylsulfonyl (compound of formula I-G2(l)).

In accordance with another alternative implementation of the present invention is offered to those compounds in which R stands for cyclopentyl (compound I-G), and R4denotes unsubstituted pyridine (compound I-G3). Variants of compound I-G3 include those compounds in which:

a) one of R1and R2denotes halogroup, PERFLUORO(ness.)alkyl or hydrogen atom, and the other of these R1and R2denotes halogroup, PERFLUORO(ness.)alkyl, amino-, cyano - or nitro-group;

b) one of R1and R2means (ness.)alkylthio, PERFLUORO(ness.)alkylthio or cyano, and the other denotes a hydrogen atom;

C) one of R1and R2means (ness.)alkylsulfonyl, halo-, cyano-, nitro-group or hydrogen atom, and the other of these R1and R2means (ness.)alkylsulfonyl;

g) one of R1and R2means PERFLUORO(ness.)alkylsulfonyl, (ness.)alkylsulfonyl or a hydrogen atom and the other of these R1and R2means PERFLUORO(ness.)alkyl3denotes cyclopentyl (compound I-G) are compounds where R4represents monosubstituted pyridine ring. Additional connection options with monosubstituted pyridine ring (compound I-G4) are offered to those compounds, where monothelitism is the group -(CH2)n-C(O)OR7in which n and R7have the values listed above (compound I-G4(a)). Variants of compounds I-G4(a) are those compounds in which:

a) each of R1and R2independently denotes halogroup,

b) one of R1and R2denotes a hydrogen atom and the other of these R1and R2indicates halo-, amino-, cyano - or nitro-group;

C) one of R1and R2means PERFLUORO(ness.)alkylsulfonyl, (ness.)alkylsulfonyl or a hydrogen atom and the other of these R1and R2means PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl.

Other variants of compounds of formula I-G4(b) are those compounds in which the pyridine ring is substituted by a group-(CH2)n-OR6where n and R6have the values listed above (compound I-G4(b)). Variants of compound I-G4(b) are those compounds in which:

b) one of R1and R2means (ness.)alkylsulfonyl or a hydrogen atom and the other of these R1and R2means (ness.)alkylsulfonyl.

Other variants of compounds, where R3denotes cyclopentyl, and R4represents monosubstituted pyridine ring, are those compounds in which the pyridine ring monogamist holography or PERFLUORO(ness.)alkyl Deputy, the compounds of formula I-G4(in). Variants of compounds of formula I-G4(C) are those compounds in which:

a) one of R1and R2denotes holograph or a hydrogen atom and the other denotes halogroup;

b) one of R1and R2indicates halo - or nitro-group or a hydrogen atom and the other denotes a PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl.

In accordance with another variant of implementation of the present invention provides compounds where R3denotes cyclopentyl, and R4represents monosubstituted pyridine, i.e., are offered to those compounds in which the pyridine monogamist nitrosubstituted (compound I-G4(g)). Variants of compound I-G4(g) include compounds in which one of R1and R2means galor

In accordance with another alternative implementation of the present invention provides compounds of formula I, where R3denotes cyclopentyl, and R4represents monosubstituted pyridine and monothelitism is (ness.)alkyl group (compound I-G4(d)). Variants of compound I-G4(d) are compounds in which one of R1and R2denotes halogroup or hydrogen atom, and the other of R1and R2denotes halogroup, PERFLUORO(ness.)alkyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl.

In accordance with another alternative implementation of the present invention provides compounds where R3denotes cyclopentyl, and R4represents monosubstituted pyridine, i.e. those compounds in which monothelitism is the group -(CH2)n-C(O)-OTHER6where n and R6have the values listed above (compound I-G4(f)). Variants of compound I-G4(f) include those compounds in which the value of one of R1and R2independently selected from a range that includes holograph and hydrogen atom, and the other of these R1and R2denotes halogroup or (ness.)alkylsulfonyl.

Another way to implement this izobratetalny imidazole (compound I-G5). Variants of compounds I-G5 are those compounds in which the value of one of R1and R2choose from a range that includes holograph and hydrogen atom, and the other of these R1and R2denotes halogroup or (ness.)alkylsulfonyl.

Another variation of the compounds of the present invention are those compounds in which R3denotes cyclopentyl, and R4means isoxazolidine ring (compounds I-G6). Variants of compounds I-G6 are those compounds in which isoxazolidine ring is unsubstituted or substituted, preferably monosubstituted. Among the substituents at monosubstituted compounds, the preferred substituent in isoxazoline ring is (ness.)alkyl. Option of compounds I-G6, which isoxazolidine ring is unsubstituted or substituted (ness.)alkyl Deputy, are those compounds, in which one of R1and R2denotes a halo-, nitro-group, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of R1and R2denotes a hydrogen atom or halogroup.

In another variant implementation of the present invention include compounds in which R3denotes cyclopentyl, prinny (ness.)alkyl group. Another option in respect of any of these compounds are those compounds in which one of R1and R2denotes a halo-, nitro-group, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of R1and R2denotes a hydrogen atom or halogroup.

According to another variant implementation of the present invention include compounds in which R3denotes cyclopentyl, are offered to those compounds in which R4denotes pyridazinyl, which is either unsubstituted or substituted (ness.)alkyl group (compounds I-G7). Variants of compounds I-G7 of the present invention comprise those compounds in which one of R1and R2denotes a halo-, nitro-group, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of R1and R2denotes a hydrogen atom or halogroup.

Another embodiment of the present invention, the compounds R3denotes cyclopentyl includes compounds in which R4denotes an unsubstituted pyrimidinyl. Variants of these compounds, in which R3denotes cyclopentyl, and R4denotes an unsubstituted pyrimidinyl, include those compounds in which one of R1and R2atom or halogroup.

Another embodiment of the present invention includes compounds in which R3denotes cyclopentyl and in which R4denotes unsubstituted thiadiazole ring. Options that relate to these compounds, in which R3denotes cyclopentyl, and R4denotes unsubstituted thiadiazolidine ring, cover those compounds in which one of R1and R2denotes a halo-, nitro-group, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of these R1and R2denotes a hydrogen atom or halogroup.

In accordance with other variants of execution of the present invention R3the compounds of formula I may designate cycloheptyl or cyclohexyl.

Variants of compounds of formula I, in which R3means cycloheptyl or cyclohexyl, include those compounds in which R4means thiazolyl, which can be monosubstituted or unsubstituted. Options that relate to these compounds, in which R3means cycloheptyl or cyclohexyl, and R4denotes unsubstituted thiazolyl encompass those compounds in which one of R1and R2denotes halogroup, (ness.)alkilany the>denotes halogroup, PERFLUORO(ness.)alkyl or a hydrogen atom.

Examples of compounds of formula I in accordance with the present invention, in which R4refers to heteroaromatic ring, are:

2-(3-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-bromophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(4-triptoreline)propionamide,

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triptoreline)propionamide,

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-ylpropionic,

2-(4-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(3-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-cyanophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-the evil-2-ylpropionic,

3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic,

2-(3-amino-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl)-N-thiazol-2-ylpropionic,

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-ethanolgasoline)-N-thiazol-2-ylpropionic,

2-(3,4-bistanbulholiday)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-sulfamoyl)-N-thiazol-2-ylpropionic,

2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic,

2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-[3-chloro-4-methanesulfonyl]-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triftormetilfullerenov)propionamide,

3-cyclopentyl-N-thiazol-2-yl-2-(4-trifloromethyl)propionamide,

3-cyclopentyl-2-(3-methoxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3-hydroxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-acid)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dihydroxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methoxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-hydroxyphenyl)-N-thiazol-2-ylpropionic,

methyl ester 4-[2-cyclopentyl-1-(thiazol-2-ylcarbonyl)ethyl]benzoic acid,

3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3-fluoro-4-hydroxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethylimidazole-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)thiazol-2-yl]-propionamide,

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethylimidazole-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethylimidazole-2-yl)propionamide,

3-cyclopentyl-N-(4-hydroxymethylimidazole-2-yl)-2-(4-methanesulfonyl-is,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylthiazole-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylthiazole-2-yl)propionamide,

ethyl ester {2-12-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl} acetic acid,

methyl ester [2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl] thiazol-4-yl} acetic acid,

methyl ester 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,

ethyl ester of 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,

ethyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl} acetic acid,

methyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,

ethyl ester of 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,

methyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl but]thiazol-4-yl] acetic acid,

{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl} acetic acid,

ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl} acetic acid,

2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazo,

methyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl} acetic acid,

methyl ester of (2R)-2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid,

methyl ester 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid,

ethyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid,

ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazol-4-yl} acetic acid,

methyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazol-4-yl} acetic acid,

methyl ester 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazole-4-carboxylic acid,

ethyl ester of 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazole-4-carboxylic acid,

methyl ether {2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]-thiazol-4-yl} acetic acid,

methyl ester 2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]-thiazole-4-carboxylic acid,

ethyl ester of [2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazole-4-carboxylic acid,

methyl ether {2-[3-cyclopentyl-2-(4-methanesulfonyl)the PCC shall ermatinger)propionamido]thiazol-4-yl) acetic acid,

methyl ester 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionamido]thiazole-4-carboxylic acid,

ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazol-4-yl}octoxynol acid,

ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-5-yl} octoxynol acid,

ethyl ether {2-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)~ propionamido]thiazol-4-yl} octoxynol acid,

ethyl ether {2-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]thiazol-4-yl} octoxynol acid,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitrothiazol-2-yl)propionamide,

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triptoreline)-2-propionamide,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triptoreline)propionamide,

2-(3-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-AMINOPHENYL)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-cyanophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic)-N-pyridin-2-ylpropionic,

2-(4-cyanophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide,

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl)-N-pyridin-2-ylpropionic,

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

3-cyclopentyl-2-(4-ethanolgasoline)-N-pyridin-2-ylpropionic,

2-(3,4-bistanbulholiday)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-pyridin-ylpropionic,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-carboxymethylamino)-2-ylpropionic,

methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide]nicotinic acid,

6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]nicotinic tx2">methyl ester of 6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid,

methyl ester of 6-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]nicotinic acid,

methyl ester of 6-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]nicotinic acid,

6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid,

6-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]nicotinic acid,

methyl ester of 6-[3-cyclopentyl-2-(4-triftormetilfullerenov)-propionamido]nicotinic acid,

6-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido]nicotinic acid,

methyl ester of 6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]nicotinic acid,

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxypyridine-2-yl)propionamide,

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)propionamide,

3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)-2-(4-methanesulfonyl)propionamide,

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-bromopyridin)ptx2">N-(5-bromopyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide,

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(4-triftormetilfullerenov)propionamide,

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-triftormetilfullerenov)propionamide,

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionamide,

2-(3-bromo-4-methanesulfonyl)-N-(5-bromopyridin-2-yl)-3-cyclopentylpropionate,

N-(5-bromopyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate,

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-(5-triptorelin-2-yl)propionamide,

N-(5-chloropyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitropyridine)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylpyridin)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylpyridin)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methylpyridin)-2-ylpropionic,

3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-triftormetilfullerenov)propionamide,

3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-(5-methylpyridin-2-yl)propionamide,

6-[3-cyclopentyl-2-(3,4-dynamic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylisoxazol-3-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-6-ylpropionic,

3-cyclopentyl-2-(4-nitrophenyl)-N-pyrimidine-4-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazole-2-ylpropionic,

2-[4-methanesulfonyl]-3-cyclohexyl-N-thiazol-2-ylpropionic and

2-[4-methanesulfonyl]-3-cycloheptyl-N-thiazol-2-ylpropionic.

Examples of compounds of formula I in accordance with the present invention, in which R4denotes the residue-C(O)other40, a R2has the values listed above are:

1-(3-cyclopentyl-2-phenylpropionyl)-3-metalmachine,

1-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-bromophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

[3-cyclopentyl-2-(3,4-dichlorophen clopotel-2(R)-(3,4-dichlorophenyl)propionyl]-3-atilmotin,

1-allyl-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea,

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-atilmotin,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-isopropylamino,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-proprotein

1-[3-cyclopentyl-2-(3,4-differenl)propionyl]-3-metalmachine,

1-[2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-nitrophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methylsulfinylphenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine,

1-{2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-ethanolgasoline)propionyl]-3-metabrom-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionyl]-3-metalmachine,

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-atilmotin,

1-[2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionyl]-3-metalmachine,

[2-(4-chlorophenyl)-4-methylpentanoic]urea,

[3-cyclopropyl-2-(3,4-dichlorophenyl)propionyl]urea,

[3-cyclobutyl-2-(3,4-dichlorophenyl)propionyl]urea,

R-[2-(3,4-dichlorophenyl)-4-methylpentanoic]urea,

1-[2-(3,4-dichlorophenyl)-4-methylpentanoic]-3-metalmachine,

1-[2-(3,4-dichlorophenyl)hexanoyl]-3-metalmachine,

3-[cyclohexyl-2-(3,4-dichlorophenyl)propionyl]urea,

[3-cyclohex the>P CLASS="ptx2">ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}propionic acid,

ethyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}acetic acid,

methyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}acetic acid,

methyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}propionic acid,

ethyl ester {3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-ureido}acetic acid,

ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}-3-oxopropanoic acid,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxyethyl)urea,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)urea,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)urea,

1-(2-chloroethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea.

It must be borne in mind that the compounds of formula I can be subjected to transformations in the place of functional groups with the floor is th, the scope of the present invention covers all physiologically acceptable equivalents of the compounds of formula I, which in vivo is able to be subjected to reverse transformation into the original connection.

The compound of the formula I can be obtained from compounds of formula V according to the following reaction scheme.

The scheme of reactions

in which R1, R2and R3have the meanings stated above, R42denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom to the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist in place of a ring carbon atom other than adjacent to the connecting carbon atom, and Deputy selected from a range including (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR SIG7, -(CH2)n-CCONHR6-C(O)-C(O)OR8, -(CH2 is achet hydrogen atom or (ness.)alkyl; and R41means (ness.)alkyl, (ness.)alkenyl, hydroxy(ness.)alkyl, halo(ness.)alkyl or -(CH2)n-C(O)OR5in which R5denotes a hydrogen atom or (ness.)alkyl, and n described above.

Carboxylic acids and their (ness.)alkalemia esters of the formula V in which one of R1and R2denotes nitro-, cyano-, thio-, amino group, chlorine atom, bromine or iodine, and the other denotes a hydrogen atom, technically available. In those cases where the only available carboxylic acid, using any conventional methods of esterification can be converted into the corresponding esters of the lower aliphatic alcohols. All appropriate reaction should be carried out with lower alkylamino esters of carboxylic acids of formula V. Eminememinem the compounds of formula V can be converted into compounds with other substituents before or after the conversion into compounds of formulas I-a, I-b, I-C or I-d. To this end, the amino group can be diisocyanate to obtain the corresponding diazonium compounds which can be in situ to enter into interaction with the target (ness.)alkylthio, PERFLUORO(ness.)alkylthiols (see, for example, Baleja, J. D. Synth-Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem.Soc.Chem.Comm. 1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. La-land metal with obtaining the corresponding compounds of formula V, where one of the substituents is (ness.)alkylthio, PERFLUORO(ness.)alkylthio or cinegroupe, and the other denotes a hydrogen atom. If necessary, after the connection with (ness.)alkylthio or PERFLUORO(ness.)alkylthio oxidation can be converted into the corresponding compounds of formula V, substituted (ness.)alkylsulfonyl or PERFLUORO(ness.)aciculiferum. The purpose of such transformation can be applied to any traditional method of oxidation of alkyldiethanolamine to sulfones.

If you need to obtain the compounds of formula V in which one of R1and R2means (ness.)alkyl or PERFLUORO(ness.)alkyl group, as the source materials you can use the corresponding glosemosen the compounds of formula V. in order to realize such a conversion can be applied by any conventional method for the conversion of aromatic halogroup to the corresponding alkyl group (see, for example, Katayama, T.; Umeno, M., Chem.Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. S.; Dua, S. S.; Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q-Y.; Duan, J.-X. J. Chem. Soc.Chem.Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, US 5113013). On the other hand, titlestyle can oxidize to groups getting sulfonamidnuyu substituent-S(O)2-NH2. If you want to obtain the compounds of formula V in which one of R1and R2or they both represent hydroxylamino, as the source material you can use the corresponding nitro compounds, and can be converted into the corresponding compounds where R1and/or R2denote hydroxylamino. To implement such a conversion can be applied by any conventional method to convert the nitro group to obtain compounds with the corresponding aromatic gidroksilaminopurina.

Carboxylic acid and (ness.)alkalemia esters of the formula V, in which both R1and R2represent chlorine atoms or fluorine, are technically accessible. In those cases where the only available carboxylic acid, using any conventional methods can be converted into the corresponding esters of the lower aliphatic alcohols. To obtain the compounds of formula V, in which both R1and R2denote nitro, as the source material can be used 3,4-dinitrotoluene. This compound can be transformed to obtain the corresponding 3,4-dinitrophenoxy acid. This transformation can be done either before or after transformation of compounds foretelling group to the remainder of the corresponding akriluksusnoy acid (see, for example, the work of Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. C.; Souchet, M, Synthesis, 1991, 871). The compounds of formula V where both Deputy R1and R2are amino groups, can be obtained from the corresponding above dinitrosobenzene formula V. in order to realize such a transformation can be applied to any traditional recovery method of nitro group to amino group. The compound of formula V where both R1and R2denote amino groups, can be used to obtain the corresponding compounds of formula V where both R1and R2denote the atoms of iodine or bromine, by reaction of diazotization. To implement this transformation can be applied by any conventional method for converting the amino group in the iodine or bromine group (see, e.g., Lucas, N. J.; Kennedy, R. E. Org.Synth.Coll., volume II 1943, 351).

If you need to obtain the compound of formula V, in which both R1and R2denote (ness.)alkylthio or Peter(ness.)allylthiourea, as the source material may be used a compound of the formula V, in which each of R1and R2denotes the amino group. For this conversion you can use any traditional method of turning killingray in alltoallw group. Priel or PERFLUORO(ness.)alkylsulfonyl, as source material, you can use the corresponding compounds of formula V, where each of R1and R2means (ness.)alkylthio or PERFLUORO(ness.)alkylthio. In order to realize such a transformation can be applied by any conventional method for the oxidation of alkyldiethanolamine to sulfones.

If you need to obtain the compounds of formula V where both R1and R2substituted (ness.)alkyl or PERFLUORO(ness.)alkyl groups in the starting materials can be used appropriate glosemosen the compounds of formula V. in order to realize such a transformation can be applied by any conventional method for the conversion of aromatic halogroup in the appropriate alkyl or PERFLUORO(ness.)alkyl group.

If you need to obtain the compounds of formula V in which one of R1and R2or they are both substituted sulfonamidnuyu groups, as the source materials you can use the corresponding compound where one of R1and R2or they are both substituted by the nitro group. In order to realize such a transformation can be applied to any standard method of turning nitroaniline connection to the appropriate sulfonatophenyl will soedinenie the nitrogroup, and the other denotes halogroup, are those which are known from the literature (in terms of 4-chloro-3-nitrophenylarsonic acid, see Japan patent 71-99504, issued in the name Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S., Chemical Abstracts 80:59716; for 4-nitro-3-chlorophenylalanine acid, see Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org.Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be converted into the corresponding (ness.)alkalemia esters with any of the conventional methods of esterification. For example, if necessary, to obtain the compound of formula V where one of R1and R2denotes the nitro-group and the other denotes (ness.)alkylthiol PERFLUORO(ness.)allylthiourea, as the source material, you can use the corresponding compound in which one of R1and R2denotes the nitro-group and the other represents a chlorine atom. When carrying out this reaction it is possible to apply any of the traditional method of nucleophilic substitution of the chlorine groups of the aromatic ring (ness.)alkylthiols (see, for example, Singh, P.; Batra, M. S.; Singh, H. J. Chem.Res. -S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem.Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W, US 5169951). After the connection is tor(ness.)allylthiourea, be available, conventional oxidation methods can be converted into the corresponding compounds of formula V where one of R1and R2denotes the nitro-group and the other denotes (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl.

If you need to obtain the compounds of formula V where one of R1and R2denotes the amino group and the other denotes (ness.)alkylthio or PERFLUORO(ness.)alkylthio, as starting materials can be used, the corresponding compound where one of R1and R2denotes the nitro-group and the other denotes (ness.)alkylthio or PERFLUORO(ness.)alkylthio. To implement this transformation can be applied by any conventional method for recovering aromatic nitro group to amino group.

If you want to obtain the compounds of formula V where one of R1and R2means (ness.)alkylthio, and the other denotes a PERFLUORO(ness.)alkylthio, as starting materials can be used, the corresponding compound where one of R1and R2denotes the amino group and the other denotes (ness.)alkylthio or PERFLUORO(ness.)alkylthio. To implement this transformation can be applied to any ASS="ptx2">If you want to obtain the compounds of formula V where one of R1and R2means (ness.)alkylsulfonyl, and the other denotes a PERFLUORO(ness.)alkylsulfonyl, or as raw materials can be used, the corresponding compound where one of R1and R2means (ness.)alkylthio, and the other denotes a PERFLUORO(ness.)alkylthio. To implement this transformation can be applied by any conventional method of oxidizing aromatic thioester group to the corresponding sulfonic group.

When it is necessary to obtain the compounds of formula V where one of R1and R2denotes halogroup, and other means (ness.)alkylthio or PERFLUORO(ness.)alkylthio, as starting materials can be used, the corresponding compound where one of R1and R2denotes the amino group and the other denotes (ness.)alkylthio or PERFLUORO(ness.)alkylthio. To implement this transformation can be applied by any conventional method of diazotization of aromatic amino group and its transformation in situ in the aromatic halide.

When it is necessary to obtain the compounds of formula V where one of R1and R2denotes halogroup, and other means (ness.)archstudio connection where one of R1and R2denotes halogroup, and other means (ness.)alkylthio or PERFLUORO(ness.)alkylthio. To implement this transformation can be applied by any conventional method of oxidizing aromatic tiefere to the corresponding sulfone. If you need to obtain the compounds of formula V with different combinations (ness.)alkyl and PERFLUORO(ness.)alkyl groups as the source materials you can use the corresponding glosemosen the compounds of formula V. in order to realize this transformation can be applied by any conventional technique for making aromatic halogroup to the corresponding alkyl group.

If it is desired to obtain a compound of formula V where one of R1and R2denotes the nitro-group and the other denotes the amino group, the source material may be used a compound of formula V where one of R1and R2denotes the nitro-group and the other represents a chlorine atom. Perchloric substituent in the phenyl ring can be converted into iodine substituent (see, for example, work Bunnett, J. F.; Conner, R. M.; Org. Synfh. Coll volume V, 1973, 478; Clark, J. H.; Jones, C. W. J. Chem. Soc. Chem. Comm.un. 1987, 1409), which in turn can enter into interaction with the transfer agent, 3, 1765). This azide is possible to restore the traditional way using a reducing agent, which is usually used for the conversion of azides to amines, to obtain the amine substituent (see, for example, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis, 1987, 48).

To obtain the compounds of formula V where one of R1and R2denotes cyano, and the other denotes the amino group, as the source material, you can use the compound of formula V where one of R1and R2denotes the nitro-group and the other denotes the amino group. The amino group is transformed into a cyano through the usual means of turning killingray in killerapp, for example by diazotization using agent migration cyanide groups, such as cyanide monovalent copper. The nitro-group is converted into the amino group as described above.

If technically available connection, you need to turn in the compounds of formula V where one of R1and R2denotes cyano, and the other refers to any other target Deputy, as described above, in the source material, you can use the compound of formula V where one of R1and R2denotes the nitrogroup, and the other is the turn in the target substituent R1or R2.

If you need to obtain the compound of formula V where both R1and R2denote ceanography, it can be obtained as set forth above, of the compounds, where R1and R2denote amino groups, by diazotization and reaction with the agent migration cyanide groups, such as cyanide monovalent copper.

When it is necessary to obtain the compound of formula V in which one of R1and R2denotes-C(O)OR5this connection can be obtained from the corresponding compounds where each of R1and R2denotes the amino group, by conversion of the amino group in the remainder of the diazonium salt by reaction of the diazonium salt with kaleidotrope acid to obtain the corresponding halide, and then the reaction of the halide with a Grignard reagent to obtain the corresponding acid, which can be atrificial. On the other hand, if it is desired to obtain a compound of formula V where both R1and R2denote carboxyl group, this compound can be obtained as described above from the corresponding compounds of formula V where both R1and R2denote amino groups. Similarly, the amino group is connected to the BA R1and R2represent-OR5by simple reaction of the amino group with sodium nitrate in sulfuric acid by conversion of the amino group in the hydroxyl group and subsequent esterification, if necessary, this hydroxyl group.

Substituents, which are the fragments of R1and R2can be attached to the ring after the conversion of compounds of formula XII compounds of formulas I-a, I-b, I-C and I-d. Therefore, all described reactions produce different substituents R1and R2the compounds of formula I, can also be carried out with the participation of the compounds of formulas I-a, I-b I-C and I-d.

In the first stage of this scheme of reactions are reaction alkylhalogenide formula VI with the compound of the formula V to obtain the compounds of formula VII. If in the course of carrying out this reaction, each of R1or R2the compounds of formula V denotes the amino group, before conducting the alkylation reaction with alkylhalogenide formula VI such an amino group (-group) you want to protect. The amino group can be protected any normal group, cycloeucalenol group, for example tert-butyloxycarbonyl group (see Bodanszky, M. Principles of Peptide Chemistry, Springer-Verlag, New York, 1984, S. 99). After obtaining the appropriate connections FOH amines. The compound of formula V is an organic acid containing alpha-carbon atom, and the compound of formula VI is alkylhalogenide, resulting alkylation takes place on an alpha-carbon atom of this carboxylic acid. This reaction is carried out using any conventional means alkylation of alpha-carbon atom (ness.)Olkiluoto ether carboxylic acid. Usually during such alkylation reactions alkylhalogenide interacts with the anion formed by any ether acetic acid. The formation of this anion can be called using a strong organic base, such as diisopropylamide lithium, n-utility, as well as other organic lithium base. When carrying out this reaction as a solvent used low-boiling ethers, such as tetrahydrofuran, it is conducted at low temperatures, preferably from -80 to about -10°C. However, the process can be conducted at any temperature from -80°C to room temperature.

Compound of formula VII can be converted into a compound of formula XII by any traditional method of turning ether carboxylic acids into acid. Further, the compound of formula XII can condensive the formula I-d. In order to realize such a transformation when carrying out this reaction it is possible to use any conventional method of condensing a primary amine with a carboxylic acid. Required aminoheterocycles the compounds of formula VIII technically available or can be obtained as described in the published literature. Heteroaromatic compounds of the formula VIII, in which one of the substituents is-(CH2)nR7where n denotes 0, 1, 2, 3 or 4, can be obtained from the corresponding carboxylic acid. For the conversion of low molecular weight carboxylic acids in its heavier homologues may be used any conventional carbon homologation (see, for example, work Skeean, R. W.; Goel, O. P. Synthesis, 1990, 628), then using any conventional methods of esterification can be converted into the corresponding (ness.)alkalemia esters. Heteroaromatic compounds of the formula VIII, in which one of these substituents represents -(CH2)nOR, where n denotes 0, 1, 2, 3 or 4, can be obtained from the corresponding carboxylic acid. For the conversion of low molecular weight carboxylic acids in its heavier homologues may be used any of these esters can be converted into the corresponding alcohols. Heteroaromatic compounds of the formula VIII, in which one of the substituents represents-COCOOR8can be obtained from the corresponding halogenated compounds. For the conversion of aromatic or heteroaromatic halogenated compounds in their low molecular weight ether derivatives octoxynol acids may be used any conventional acylation methods (see, e.g., Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895).

On the other hand, the carboxylic acid of formula XII can be converted into amide of formula IX. This reaction is carried out with conventional means of turning the acid of formula XII in the acid chloride acid and subsequent treatment of the carboxylic acid or ammonia to form ammonium compound, such as hexamethyldisilazane. When implementing this method, you can create conditions that are common during the conversion of the acid into the acid chloride acid. Further, the acid chloride of the acid in normal conditions enter into reaction with ammonia to obtain, as above, the amide of formula IX. In the interaction of the compounds of formula IX with alkyl, alkenyl - or -(CH2)nC(O)OR SIG5the isocyanate of the formula X is formed product of the merger of urea of the formula I-A. D. the Il - or -(CH2)nC(O)OR5isocyanate with Amida education macewindow connection.

When the compounds of formula I-a R41means (ness.)alkenylphenol group, this group of compounds can be converted into the corresponding hydroxy(ness.)alkyl group ordinary gidroborudovaniya place olefinic group with obtaining the corresponding hydroxyl group. If necessary, the hydroxyl group can be converted into halogroup. In accordance with the present invention can be applied to any method of haloiding hydroxyl group.

On the other hand, if necessary, to obtain the compound of formula I-b in the beginning, the compound of formula XII is transformed into methyl ester compounds of the formula XI, after which it enter into interaction with urea, receiving the compound of formula I-b. This reaction is carried out using traditional means of the reaction of the methyl ester with urea, receiving the appropriate product of condensation.

The compound of the formula I-s, i.e. the compound of formula I, in which R4denotes the group-C(O)other40, a R40represents-CO-(CH2)n-OR6receive from a monobasic carboxylic acid XIII as monoether appropriate dicarbon is completed using the standard combination methods.

Compound of formula VII contains an asymmetric carbon atom through which the associated group-CH2R3and Vice-amide acid. In accordance with the present invention the preferred stereoconfiguration this group is R-configuration.

If you need to get the R - or S-isomer of compounds of formula I is the compound can be divided into its isomers by any ordinary chemical means. For the preferred chemical agents include the reaction of the compound of formula XII with an optically active base. For such a separation process may be used any conventional optically active base. To the preferred optically active bases are optically active amine base, such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha methylnaphthalene. During this separation process, you can apply any of the traditional methods of separation of organic acids with optically active organic amine bases.

At the stage of separation conduct the reaction of the compound of formula XII with an optically active base in an inert organic restorationhardware and pressure of the critical value have no and the salt formation can occur at room temperature and under atmospheric pressure. R - and S-salt can be divided by any conventional method such as fractional crystallization. After crystallization of each of the salts can be converted into the corresponding compounds of formula XII in the form of R - and S-configuration by hydrolysis with acid. Among the preferred acids dilute aqueous acid, i.e., aqueous acid concentration of from about 0,001 to N. 2n., such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of the compounds of formula XII, which is obtained by this method of separation is maintained during the reduction reactions of the whole scheme of obtaining the target R - or S-isomer of compounds of formula I. the separation of R - and S-isomers can also be achieved by enzymatic ester hydrolysis of any (ness.)aliphatic esters, the corresponding compounds of formula XII (see, for example, work Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), resulting in formation of the corresponding chiral acid and chiral esters. Ester and acid can be divided by any conventional method of separating acids from complex ester. The preferred method of separation of racemates of compounds of the formula XII is to get the ACC is but to get a reaction mix of carboxylic acids of the formula XII with a chiral alcohol or chiral amine. This reaction can be performed using any conventional method of combining the carboxylic acid with an alcohol or amine. Further relevant diastereoisomer the compounds of formula XII can be divided using any conventional method of separation. The resulting net diastereoisomeric esters or amides can hydrolyze the corresponding pure R - or S-isomers. The hydrolysis reaction can be carried out by customary known methods of hydrolysis of ester or amide without racemization.

All the compounds of formula I which include compounds shown in the examples, when carrying out the experiment of example And activated in vitro glucokinase. Thanks to this, they increased the flux of glucose metabolism, which causes increased insulin secretion. Therefore, the compounds of formula I are activators of glucokinase, effectively enhancing insulin secretion.

Were tested following compounds and it was found that in accordance with these tests, which are described in example B, when administered orally they showed in vivo excellent ability to activate glucokinase:

3-cyclopentyl-2-(4-methanol is d;

3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide;

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic;

methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide]nicotinic acid;

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide;

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide;

3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-triftormetilfullerenov) propionamide;

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide;

methyl ester of 6-[3-cyclopentyl-2-(4-triftormetilfullerenov)-propionamido]nicotinic acid;

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-ylpropionic;

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide;

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic;

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic;

2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic;

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic;

N-(5-bromopyridin-2-and until-N-thiazol-2-ylpropionic;

(2R)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic;

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic;

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic;

3-cyclopentyl-2-(4-ethanolgasoline)-N-thiazol-2-ylpropionic;

3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic and

N-(5-bromopyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate.

In addition, were tested following compounds and it was found that in accordance with these tests, which are described in example B, when administered orally, they showed excellent ability to activate in vivo glucokinase:

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-atilmotin;

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine;

1-13-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine;

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine;

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea;

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine;

1-[2-(3-enyl)-3-cyclopentylpropionyl]-3-metalmachine.

Given their ability to activate glucokinase, the compounds of formula I can be used as medicines for the treatment of diabetes type II. Thus, as mentioned above, an object of the present invention are also medicinal product containing a compound of formula I, as well as the method of preparation of such medicines, which includes making one or more compounds of formula I, as well as, if necessary, one or more other therapeutically active substances in the form of medicines, prepared according to the officially approved recipe for introduction into the body.

The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Perhaps rectal administration, such as suppositories, topical or percutaneous introduction, for example with the use of ointments, creams, gels or solutions; or parenteral, for example intravenous, intramuscular, subcutaneous, intrathecal or transdermal using, for example, solutions for injection. In addition, it is possible sublingual introduction or paustenbach capsules of the compounds of the present invention can be mixed with pharmaceutically inert, inorganic or organic fillers. So, for example, fillers suitable for manufacture of tablets, coated tablets or hard gelatin capsules include lactose, corn starch and its derivatives, talc, stearic acid and its salts. Acceptable for use in hard gelatin capsules fillers include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc., depending on the nature of the active components is possible, however, the case of soft gelatin capsules filler may not be necessary. It is suitable for the preparation of solutions and syrups fillers may include, for example, water, polyols, saccharose, invert sugar and glucose. Fillers that can be used in solutions for injection include, for example, water, a monohydroxy alcohols, polyols, glycerine and vegetable oils. Fillers that can be used in the preparation of suppositories, the local application or percutaneous introduction, include, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols.

Pharmaceutical compositions may also include preservatives, solubilizing additives, stabilizers, wetting agents, emulsifying agents, sweetening Ti and antioxidants. As mentioned above, they may also include other therapeutically active funds. A necessary requirement is that the toxicity of all adjuvants used for the preparation of drugs.

Preferred applications are intravenous, intramuscular and oral administration, most preferably oral administration. Dose, in which the compounds of the formula I is administered to achieve the effect, depend on the nature of the particular active component, age, needs of the patient and route of administration. Usually interest a dose of about 1 to 100 mg/kg of body weight per day.

The essence of the present invention more clear from the following examples, which are illustrative and not as limiting the scope of invention defined by the attached claims.

Example 1

(A) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic:

A solution of 2.0 g (of 6.96 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38), to 4.62 g (10,44 mmol) benzotriazol-1-yloxytris(dimethylamino)fosfodiesterasa and 1.05 g (10,44 mmol) of 2-aminothiazole in 50 ml of methylene chloride at 25°With the handle of 2.9 ml (Wade and was extracted with 3 portions of 10 ml of methylene chloride. The combined organic layers are successively washed with 1 portion in 10 ml of water, 1 portion of 10 ml of 1N. an aqueous solution of sodium hydroxide, 1 portion of 10 ml of 1N. an aqueous solution of hydrochloric acid and 1 portion of 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 2,48 g (yield: 96%) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic; tPL: 143,5-145,5°C; EI-HRMS m/e Rasch. for C17H18Cl2N2OS (M+): 368,0516, detect.: 368,0516.

(C) Similarly received:

(a) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and ethyl ester of 2-(aminothiazol-4-yl)octoxynol acid: ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl]octoxynol acid as a white solid: tPL: 134-136°C; FAB-HRMS m/e Rasch. for C21H22CL2O4S (M+H)+: 469,0755, detect.: 469,0746;

(b) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and ethyl ester of 2-(aminothiazol-5-yl)octoxynol acid: ethyl ether {2-[3-cyclo is l: 129-131°C; FAB-HRMS m/e Rasch. for C21H22CL2N2ABOUT4S (M+H)+: 469,0755, detect.: 469,0765;

(C) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and ethyl ether (2-aminothiazol-4-yl)-acetic acid: ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl} acetic acid as a yellow solid: tPL: 138-139°C; FAB-HRMS m/e Rasch. for C21H24Cl2N2O3S (M+H)+: 455,0963, detect.: 455,0960;

(g) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and 2-amino-5-methylthiazole: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylthiazole-2-yl)propionamide in the form of a white solid: tPL: 142-143°C; EI-HRMS m/e Rasch. for C18H20Cl2N2OS (M+): 382,0673, detect.: 382,0679;

(d) from 3-cyclopentyl-2-(3,4-dichlorophenyl) propionic acid and 2-amino-4-methylthiazole: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylthiazole-2-yl)propionamide in the form of a white foam: tPL: 151-152°C; FAB-HRMS m/e Rasch. for C18H20Cl2N2OS (M+H)+: 383,0751, detect.: 383,0758;

(e) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and ethyl ester of 2-aminothiazol-4-carboxylic acid: ethyl ester of 2-[3-cyclopentyl-2-(3,4-diclofenac. for C20H22CL2N2O3S (M+H)+: 441,0807, detect.: 441,0808;

(W) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and ethyl ester of 2-aminothiazol-5-carboxylic acid: ethyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid as a pale yellow solid: tPL: 136-137°C; FAB-HRMS m/e Rasch. for C18H22Cl2N2O3S (M+H)+: 441,0807, detect.: 441,0803;

(C) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and 2-amino-5-nitrothiazole: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitrothiazol-2-yl)propionamide as an orange solid: tPL: 67-71°C; FAB-HRMS m/e Rasch. for C17H17Cl2N3O3S (M+H)+: 414,0446, detect.: 414,0442;

(and) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and amide 2-aminothiazol-4-carboxylic acid: amide 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid as a pale orange solid: tPL: 120-122°C; EI-HRMS m/e Rasch. for C18H19Cl2N3O2S (M+): 411,0575, detect.: 411,0572.

Example 2

2-(4-bromophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

Example 3

(A)

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic

A solution of 3.3 ml (23.5 mmol) of Diisopropylamine in 50 ml of dry tetrahydrofuran and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in nitrogen atmosphere was cooled to -78°C and then was treated with 2.35 ml (23.5 mmol) of a 10 M solution of n-utility in hexano. The yellow reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution of 2.40 g (of 11.2 mmol) 4-methylsulfinylphenyl-luxusni acid in a small amount of dry tetrahydrofuran. After about half an hour was added 4-methylsulfonylmethane acid in dry tetrahydrofuran, was formed precipitate. When you next add the remaining 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture had become a thick consistency. After adding 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture became very thick and barely resisted mixing. This thick reaction mixture was added an additional, what about after which was added dropwise of a solution of 2.35 g (of 11.2 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 100 ml of water and the resulting yellow reaction mixture was concentrated under vacuum removal of tetrahydrofuran. Using conc. hydrochloric acid aqueous residue was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white solid substance was obtained of 1.80 g (yield: 52%) of 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 152-154°C; EI-HRMS m/e Rasch. for C15H20O4S (M+): 296,1082, detect.: 296,1080.

The solution 4,91 g (16,56 mmol) 3-cyclopentyl-2-(4-methanesulfonyl)-propionic acid and of 6.52 g (24,85 mmol) of triphenylphosphine in 41 ml of methylene chloride was cooled to 0°C and then was treated by adding small portions 5,01 g (28,16 mmol) of N-bromosuccinimide. The color of the reaction mixture changed from light yellow to dark yellow, and the cost is 25°C. Next, the brown reaction mixture was treated to 4.98 g (49,69 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 19 h Then the reaction mixture was concentrated under vacuum removal of methylene chloride. Received the black residue was diluted with 400 ml of 10% aqueous hydrochloric acid solution and then was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate, then 1/1 hexane/ethyl acetate) as a white solid substance was obtained of 4.49 g (yield: 72%) of 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic: tPL: 216-217°C; EI-HRMS m/e Rasch. for C18H22N2ABOUT3S2(M+): 378,1072, detect.: 378,1071. (B) Similarly received:

(a) from 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and methyl ester 2-aminothiazol-4-carboxylic acid, methyl ester 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazole-4-carboxylic acid as a yellowish brown solid: tPL"ptx2">(b) from 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and ethyl ester of 2-aminothiazol-4-carboxylic acid: ethyl ester of 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazole-4-carboxylic acid as a pale yellow solid: tPL: 101-103°C; EI-HRMS m/e Rasch. for C21H26N2O5S2(M+): 450,1283, detect.: 450,1284;

(C) from 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and methyl 2-amino-4-thiazoleacetate: methyl ester of 2-[3-cyclopentyl-2-(4-methanesulfonyl) propionamido] thiazol-4-yl}acetic acid as a yellow solid: tPL: 63-65°C; EI-HRMS m/e Rasch. for C21H26N2O5S2(M+): 450,1283, detect.: 450,1294;

(g) from 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and ethyl-2-amino-4-thiazoleacetate: ethyl ester of 2-[3-cyclopentyl-2-(4-methane-sulfanilyl)propionamido]thiazol-4-yl}acetic acid as a pale yellow solid: tPL: 61-63°C; EI-HRMS m/e Rasch. for C22H28N2ABOUT5S2(M+): 464,1440, detect.: 464,1431.

Example 4

2-(4-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic

A solution of 345 mg (1.0 mmol) 3-cyclo is 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas under a pressure of 60 pounds per square inch at 25°C for 6 hours and Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum to obtain a yellow solid 288,3 mg (yield: 91.4 per cent) of 2-(4-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-yl-propionamide: tPL: 102-107°C; EI-HRMS m/e Rasch. for C17H21N3OS (M+): 315,1405, detect.: 315,1401.

Example 5

2-(3-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic

A solution of 5.0 g (27.6 mmol) of (3-nitrophenyl) acetic acid in 50 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 48 hours and Then the reaction mixture was concentrated under vacuum. The residue was dissolved in 50 ml of methylene chloride and washed with 2 portions of 25 ml of saturated aqueous sodium bicarbonate solution, 1 portion of 50 ml of water and 1 portion of 50 ml of a saturated aqueous solution of sodium chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a pale yellow solid at 5.27 g (in the SUB>NO4(M+): 195,0531, detect.: 195,0532.

The solution of their diisopropylamide lithium (43,3 ml, 0.3 M source solution, 12,99 mmol), cooled to -78°C, treated of 2.45 g (12,56 mmol) methyl ether (3-nitrophenyl) acetic acid in 32 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes Then added 2,78 g (13,23 mmol) iodomethylpropane in 2,78 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and the mixture was stirred at -78°C for 3 hours, the Reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise 25 ml of a saturated aqueous solution of ammonium chloride and concentrated under vacuum. The residue was diluted with 50 ml water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed with 2 portions of 25 ml of saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow oil was obtained 1.63 g (yield: 46,8%) methyl ester 3-cyclopentyl-2-(3-nitrophenyl) propio is 0.55 g (2.0 mmol) of methyl ester of 3-cyclopentyl-2-(3-nitrophenyl) propionic acid in 10 ml of tetrahydrofuran/water (in the ratio 3:1) was treated with 185 mg (4.40 mmol) of lithium hydroxide. The reaction mixture was stirred at 25°C for 48 hours and Then under vacuum, remove the tetrahydrofuran. The residue was diluted with 25 ml water and was extracted with 1 portion in 20 ml of diethyl ether. The aqueous layer was acidified to pH 2 3 N. aqueous solution of hydrochloric acid. The product was extracted with 3 portions of 25 ml of methylene chloride, washed with 2 portions of 25 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellowish-brown solid of 0.48 g (yield: 91,9%) 3-cyclopentyl-2-(3-nitrophenyl)propionic acid: tPL: 95-99°C; EI-HRMS m/e Rasch. for C14H17NO4(M+): 263,1157, detect.: 263,1156.

A solution of 432 mg (1,64 mmol) 3-cyclopentyl-2-(3-nitrophenyl)propionic acid in 16 ml of methylene chloride was cooled to 0°C and then was treated to 0.90 ml (1,80 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 1,2 hours Then the reaction mixture was treated with a solution 361,4 mg (3.61 mmol) of 2-aminothiazole in 16 ml of tetrahydrofuran and 0.70 ml (3.93 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at 25°With during the ica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a yellowish brown solid was obtained 409,3 mg (yield: 72.2 per cent) 3-cyclopentyl-2-(nitrophenyl) - N-thiazol-2-Elpro-Piramida: tPL: 171-174°C; EI-HRMS m/e Rasch. for C17H19N3O3S (M+): 345,1147, detect.: 345,1153.

The solution 327,8 mg (0.95 mmol) of 3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-ylpropionic in 25 ml of ethyl acetate was treated with 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas under a pressure of 60 pounds per square inch at 25°C for 3 hours and Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum obtaining in the form of a white solid substance 310 mg (yield: 100%) of 2-(3-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 158-160°C; EI-HRMS m/e Rasch. for C17H21N3OS (M+): 315,1405, detect.: 315,1405.

Example 6

2-(3-chlorophenyl) -3-cyclopentyl-N-thiazol-2-ylpropionic

6,03 g (0.03 mol) of (3-chlorophenyl) acetic acid was dissolved in 37,7 ml of ethanol and was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 12 hours the us/ethyl acetate) in the form of a clear oil was obtained 6,10 g (yield: 86.8% of) ethyl ester (3-chlorophenyl) acetic acid: EI-HRMS m/e Rasch. for C10H11lO2(M+): 198,0448, detect.: 198,0442.

The solution of their diisopropylamide lithium (23 ml, 0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.28 g (6,48 mmol) ethyl ester (3-chlorophenyl) acetic acid 16,1 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.50 g (7,13 mmol) iodomethylpropane in 1 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 h, the Reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours Then the reaction in the reaction mixture was suppressed by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. This mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a yellow oil was obtained 1.70 g (yield: 93%) of ethyl ester of 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21lO2(M+):islote and 673 mg (remaining 9.08 mmol) of metallocene 17.3 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 12.1 mmol) was boiled under reflux at 100°C for 6 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained 149,1 mg (yield: 8%) 1-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine: tPL: 52-55°C; EI-HRMS m/e Rasch. for C16H21ClN2O2(M+): 308,1292, detect.: 308,1287. Methyl ester starting material of the reaction mixture were isolated by interesterification.

A mixture of 113 mg (0.42 mmol) of the methyl ester of 2-(3-chlorophenyl)-3-cyclo-interprovincial acid and 84 mg (0.84 mmol) of 2-aminothiazole 2.4 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 1,69 mmol) was boiled under reflux at 100°C for 20 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 87 mg (yield: 53%) of 2-(3-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 138,8-141,2°C; EI-HRMS m/e Rasch. for C17H19ClN2OS (M+): 334,0906, detect.: 334,0907.

Example 7

2-(4-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

PL: 39-41°C; EI-HRMS m/e Rasch. for C10H11ClO2(M+): 198,0448, detect.: 198,0452.

The solution of their diisopropylamide lithium (23,0 ml, 0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.28 g (6,48 mmol) ethyl ester (4-chlorophenyl) acetic acid 16,1 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.50 mg (7,13 mmol) iodomethylpropane in 1 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 h, the Reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours Then the reaction in the reaction mixture was suppressed by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. This mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. ORGANICA (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a yellow oil was obtained of 1.65 g (yield: 90.9 per cent) ethyl ester 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21Cl2O2(M+): 280,1230, detect.: 280,1227.

A mixture of 1.65 g (of 5.89 mmol) ethyl ester 2-(4-chlorophenyl)-3-cyclopentylpropionic acid and 654 mg (8,83 mmol) of metallocene 16.9 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 11,78 mmol) was boiled under reflux at 100°C for 6 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained to 105.3 mg (yield: 5,8%) 1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine: tPL: 145-147°C; EI-HRMS m/e Rasch. for C16H21ClN2O2(M+): 308,1292, detect.: 308,1291. Methyl ester starting material of the reaction mixture were isolated by interesterification.

A mixture of 648 mg (2,43 mmol) methyl ester of 2-(4-chlorophenyl)-3-cyclopentylpropionic acid and 487 mg (a 4.86 mmol) of 2-aminothiazole in of 14.0 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 9,72 mmol) was boiled under reflux at 100°C for 20 hours Then the reaction mixture of concentra solids received 286 mg (yield: 35%) of 2-(4-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: of 156.6-159,8°C; EI-HRMS m/e Rasch. for C17H19ClN2OS (M+): 334,0906, detect.: 334,0910.

Example 8

3-cyclopentyl-N-thiazol-2-yl-2-(4-triptoreline)propionamide

The solution of their diisopropylamide lithium (23 ml, 0,31 M source solution, 7,13 mmol), cooled to -78°C, cultivated 693 mg (3.4 mmol (4-triptoreline)acetic acid in 8.5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 30 minutes Then added 784 mg (3.7 mmol of iodomethylpropane in 1 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours then the reaction in the reaction mixture was suppressed by adding dropwise 10 ml of a saturated aqueous solution of ammonium chloride. Under vacuum, remove the excess solvent. 1H. aqueous solution of hydrochloric acid, the residue was acidified to pH 1. Then the mixture was poured into 150 ml of water and was extracted with 3 portions of 100 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/etilize is islote: tPL: 94-95°C; EI-HRMS m/e Rasch. for C15H17F3ABOUT2(M+): 309,1079, detect.: 309,1072.

A solution of 185 mg (0.64 mmol) of 3-cyclopentyl-2-(4-triptoreline)propionic acid and 6.5 ml of methylene chloride was cooled to 0°C and treated with 0.35 ml (0.71 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 142 mg (1,42 mmol) of 2-aminothiazole in 3,23 ml of tetrahydrofuran and 0.27 ml (1.55 mmol) of N,N-diisopropylethylamine. The solution was stirred at 25°C for 5 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 127 mg (yield: 53.3 per cent) 3-cyclopentyl-N-thiazol-2-yl-2-(4-triptoreline)propionamide: tPL: 210-212°C; EI-HRMS m/e Rasch. for C18H19F3N2OS (M+): 368,1175, detect.: 368,1170.

Example 9

3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic

A solution of 3.2 ml (23,16 mmol) Diisopropylamine in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1(23,16 mmol) of a 10 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution 2,01 g (11,03 mmol) of 4-(methylthio)phenylacetic acid in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 1 h and after this time was added dropwise a solution of 2.55 g (12,13 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at -78°C for 30 min and then it was heated to 25°C, after which it was stirred for 24 h the Reaction in the reaction mixture extinguished with water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was acidified to pH 2 10% aqueous solution of hydrochloric acid and then was extracted with 200 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.01 g (yield: 35%) 3-cyclopentyl-2-(4-methylsulfinylphenyl)propionic acid: tPL: 91-93°C; EI-HRMS m/is lipantil-2-(4-methylsulfinylphenyl)-propionic acid and 198 mg (from 0.76 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated by adding small portions 150 mg (0.84 mmol) of N-bromosuccinimide. After adding N-bromosuccinimide the reaction mixture for 30 min was heated to 25°C. Next, the reaction mixture was treated with 160 mg (1,60 mmol) of 2-aminothiazole and the resulting reaction mixture was stirred at 25°C for 15 hours and Then the reaction mixture was concentrated under vacuum removal of methylene chloride. The residue was diluted with water and ethyl acetate. In the future, the organic layer washed with 1 N. aqueous solution of hydrochloric acid, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) in the form of a yellow solid was obtained crude 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic. By recrystallization from hexanol/ethyl acetate in a ratio of 2/1 in the form of a white solid substance was obtained 114 mg (yield: 44%) of pure 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic: tPL: 195-196°C; EI-HRMS m/e Rasch. for C18H22N2O2OS (M+): 346,1174, detect.: 346,1171.

Example 10

3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide

A solution of 2.4 ml (Ls 16.80 was ladli to -78°C in nitrogen atmosphere and then treated of 6.7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 1.89 g (8,00 mmol) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after this time was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was acidified to pH 2 10% aqueous solution of hydrochloric acid and then was extracted with 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-trifluoromethyl-sulfanilyl)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17Fsulfanilyl)propionic acid, 49.4 mg (0,19 mmol) of triphenylphosphine in 471 μl of methylene chloride was cooled to 0°C and then was treated by adding small portions 36,9 mg (0.21 mmol) of N-bromosuccinimide. After adding N-bromosuccinimide the reaction mixture for 30 min was heated to 25°C. Next, the bright orange reaction mixture was treated to 39.6 mg (0.40 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 18 h Then the reaction mixture was concentrated under vacuum removal of methylene chloride. The residue was diluted with 50 ml ethyl acetate. The organic layer was washed 1 portion 50 ml of 10% aqueous hydrochloric acid solution, washed with 1 portion 50 ml saturated aqueous sodium bicarbonate solution, washed with 1 portion 50 ml of water, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a white foam was obtained (to 49.9 mg, yield: 66%) 3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide: tPL: 58-60°C; EI-HRMS m/e Rasch. for C18H19F3N2OS2(M+): 400,0890, detect.: 400,0895.

Example 11

(A) 3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 1.89 g (8,00 mmol) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after this time was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was acidified to pH 2 10% aqueous solution of hydrochloric acid and then was extracted with 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15His-2-(4-trifloromethyl-(renel)propionic acid in 10 ml of methanol was treated with gradual addition of 4 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 36 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1052.

A solution of 1.14 g (3,43 mmol) methyl ester 3-cyclopentyl-2-(4-tri-formatterconverter)propionic acid 8.6 ml of methylene chloride was treated with 2.00 g of 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 9,26 mmol). The reaction mixture was stirred at 25°C for 17 h, after this time the data thin-layer chromatography showed the presence of two new products with reduced mn is niteline 2,00 g 3-chloroperoxybenzoic acid and the resulting reaction mixture was stirred at 25°C for 3 days. The reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 3 portions of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.19 g (yield: 95%) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0965.

The solution 708,2 mg (1.94 mmol) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 2.4 ml of tetrahydrofuran was treated with 3.6 ml (2,92 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 h and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous layer was acidified to pH 2 10% aqueous solution of hydrochloric acid and then was extracted with 2 portions of 100 ml of ethyl acetate. The combined organic layers were washed 1 portion in 100 ml of n is the Aquum with getting a cream solid. This solid was purified by rubbing the powder in diethyl ether/petroleum ether to obtain a white solid 527,0 mg (yield: 77%) of pure 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL:: 143-145°C; EI-HRMS m/e Rasch. for C15H17F3O4S (M+): 350,0800, detect.: 350,0816.

The solution 164,0 mg (0.47 mmol) of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and 184,2 mg (0.70 mmol) of triphenylphosphine in 1.2 ml of methylene chloride was cooled to 0°C and then was treated by adding small portions 141,6 mg (0.80 mmol) of N-bromosuccinimide. After adding N-bromosuccinimide the reaction mixture was heated to 25°C, after which it was stirred for 1 h Then the reaction mixture was treated 140,6 mg (1,40 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 22 h Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid substance was obtained by 47.9 mg (yield: 24%) 3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide: tPL: 189-191°C; EI-HRMS m/e Rasch. for C18H19F3N2O3Tyl-2-(4-triftormetilfullerenov)propionic acid and methyl ester 2-aminothiazol-4-carboxylic acid, methyl ester 2-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido]thiazole-4-carboxylic acid as a gray solid: tPL: 122-125°C; EI-HRMS m/e Rasch. for C20H21F3N2O5S2(M+): 490,0844, detect.: 490,0844;

(b) from 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and ethyl ester of 2-aminothiazol-4-carboxylic acid: ethyl ester of 2-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido]thiazole-4-carboxylic acid as a white solid: tPL: 132-134°C; EI-HRMS m/e Rasch. for C21H23F3N2O5S2(M+): 504,1000, detect.: 504,0988;

(C) from 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and methyl 2-amino-4-thiazoleacetate: methyl ester of 2-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido]thiazol-4-yl} acetic acid as a yellow foam: tPL: 48-52°C; EI-HRMS m/e Rasch. for C21H23F3N2O5S2(M+): 504,1000, detect.: 504,0998.

Example 12

2-[3-chloro-4-methanesulfonyl]-3-cyclopentyl-N-thiazol-2-ylpropionic

The anhydrous solution of 5.00 g (37,50 mmol) of aluminum chloride in 15 ml of chloroform was cooled to 0°C and was stirred for 30 min in nitrogen atmosphere. Next was added 5 ml of a solution 3,91 g (28,64 mmol) acrocallosal in 5 ml of the reaction mixture was gradually added to the solution 4,08 g (25,58 mmol) of 2-chloroanisole in 20 ml of chloroform. The solution has bought the red color and slowly over a 30 minute period was retinoid. Thereafter, the resulting reaction mixture was stirred for an additional 3.5 h, and during this period the reaction mixture was heated to 25°C. Next, the reaction in the reaction mixture was suppressed by the addition of 25 ml of water. The aqueous layer was extracted with 3 portions of 25 ml of chloroform. The combined organic layers were concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 4,32 g (yield: 65.3 per cent) ethyl ester (3-chloro-4-methylsulfinylphenyl)octoxynol acid.

The solution 3,93 g (15,19 mmol) ethyl ester (3-chloro-4-methylsulfinylphenyl)octoxynol acid in 30 ml of methanol was cooled to 0°C and then was treated 530,9 mg (14,03 mmol) sodium borohydride. The reaction mixture was changed, turning from yellow to colorless. The mixture was stirred for 15 min and then the reaction extinguished 10 ml of 1 N. aqueous solution of hydrochloric acid. Next, the resulting reaction mixture was extracted with 2 portions of 30 ml of methylene chloride. The combined organic layers were washed 1 portion 30 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered the Etat) in the form of a white solid substance was obtained of 1.43 g (yield: 38%) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)hydroxyoctanoic acid: tPL: 56-57°C; EI-HRMS m/e Rasch. for C11H13ClO3S (M+): 260,0273, detect.: 260,0276.

A solution of 1.43 g (5,49 mmol) ethyl ester (3-chloro-4-methylsulfinylphenyl)hydroxyoctanoic acid in 2 ml of pyridine was treated with 2 ml of acetic anhydride and 50 mg (0.41 mmol) of 4-dimethylaminopyridine. The reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 100 ml of methylene chloride. The organic layer was washed with 2 portions of 30 ml of 1 N. aqueous solution of hydrochloric acid, washed with 1 portion 30 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.51 g (yield: 91%) of ethyl ether acetoxy(3-chloro-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C13H15ClO4S (M+): 302,0379, detect.: 302,0387.

A solution of 1.47 g (4,87 mmol) of ethyl ether acetoxy(3-chloro-4-methylsulfinylphenyl) acetic acid 7.2 ml hexamethylphosphoramide and 20 ml of methanol was treated with 146 ml (14.6 mmol) of 0.1 M solution of samarium iodide in tetrahydrofuran. The reaction mixture was stirred at 25°C in nitrogen atmosphere in those who offer was diluted with 150 ml of water and then was extracted with 3 portions of 100 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a pale yellow oil was obtained 0.71 g (yield: 60%) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C11H13lO2S (M+): 244,0324, detect.: 244,0332.

A solution of 457 μl, (3,26 mmol) Diisopropylamine in 5 ml of tetrahydrofuran was cooled to -78°C in nitrogen atmosphere and then was treated with 1.3 ml (3,26 mmol) of a 2.5 M solution of n-utility in hexano. The mixture was stirred at -78°C for 30 min, after this time the reaction mixture was slowly added a solution of 0.67 g (2,75 mmol) ethyl ester (3-chloro-4-methylsulfinylphenyl) acetic acid in 8 ml of tetrahydrofuran. The color of the reaction mixture became dark yellow. Next, the reaction mixture was additionally stirred at -78°C for 30 min, after this time with a syringe was added a solution of 0.65 g (3,09 mmol) iodomethylpropane in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. Then the reaction mixture was heated to 25°C, after which it was stirred for 16 hours During this time period the reaction mixture acquired balali 20 ml of water. Next, the reaction mixture was extracted with 3 portions of 20 ml of methylene chloride. The combined organic layers were washed 1 portion in 25 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a pale yellow oil was obtained 0.50 g (yield: 56%) of ethyl ester of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentylpropionic acid.

A solution of 0.45 g (1,39 mmol) ethyl ester of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 3 ml of ethanol was treated with 2 ml of 10% aqueous solution of potassium hydroxide. The reaction mixture was stirred in nitrogen atmosphere at 25°C for 16 hours Then the reaction mixture was acidified with 5 ml of 1 N. aqueous solution of hydrochloric acid. Then the reaction mixture was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid substance of 0.29 g (yield: 70%) of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H19ClO2S (M+): 298,0794, detect.: 298,0798.

The solution is 0, sulfanilyl)-3-cyclopentylpropionic acid in 10 ml of methylene chloride was treated with 500 μl (2,87 mmol) of N,N-diisopropylethylamine and 140 mg (1,27 mmol) of 2-aminothiazole. The mixture was stirred in nitrogen atmosphere at 25°C for 14 h Then the reaction mixture was washed 1 portion 15 ml 6N. an aqueous solution of hydrochloric acid and washed with 1 portion of 25 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a white solid substance was obtained 0.26 g (yield: 71%) of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: EI-HRMS m/e Rasch. for C18H21ClN2OS2(M+): 380,0783, detect.: 380,0792.

A solution of 187 mg (0.49 mmol) of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic in 10 ml of methylene chloride was cooled to 0°C in nitrogen atmosphere and then treated 456,8 mg (in terms of 50% purity) 3-chloroperoxybenzoic acid. The reaction mixture was stirred for 3 h and during this period the temperature was raised to 25°C. Then the reaction mixture was diluted with 50 ml of methylene chloride. The organic layer was washed 1 portion 20 ml of a saturated aqueous solution of sodium carbonate, washed with 1 portion 20 ml of a saturated aqueous solution of sodium chloride, dried over sulatycky/ethyl acetate) as a white solid substance was obtained 102 mg (yield: 50%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: EI-HRMS m/e Rasch. for C18H21ClN2O3S2(M+): 412,0682, detect.: 412,0674.

Example 13

(2R)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic

The solution 43,63 g (0,204 mol) of 4-(methanesulfonyl)phenyl acetic acid in 509 ml of methanol was treated by slow addition of 2 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 19 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The residue was diluted with 800 ml ethyl acetate. The organic phase is washed with 1 portion 200 ml saturated aqueous sodium bicarbonate solution, washed with 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 1/1 hexane/ethyl acetate) as a yellow oil, which upon standing at 25°With over time hardened with education is painted in a cream color solid was obtained of 45.42 g (yield: 98%) of methyl ester of 4-(methanesulfonyl) phenylacetic acid: tPL: 78-80°C; EI-HRMS m/e Rasch. for C10H12O4S (M+): 228,045 ü) Diisopropylamine in 186 ml of dry tetrahydrofuran and 62 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C and then processed by 83.4 ml (0.21 mol) of a 2.5 M solution of n-utility in hexano. The yellow-orange reaction mixture was stirred at -78°C for 35 min and then was treated by slow addition of a solution 45,35 g (0.20 mol) of methyl ester of 4-(methanesulfonyl)phenylacetic acid in 186 ml of dry tetrahydrofuran and 62 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture acquired a dark color. Next, the reaction mixture was stirred at -78°C for 50 min, after this time was gradually added to the solution 50,08 g (0.24 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Then the reaction mixture was stirred at -78°C for 50 min, after which it was heated to 25°C with subsequent stirring for 36 h Reaction in the reaction mixture extinguished 100 ml of water and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 1.5 l of ethyl acetate. The organic phase is washed with 1 portion in 500 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a yellow viscous oil was obtained 41,79 g (yield: 68%) of methyl ester of 3-cyclopentyl-2-(4-means/P>

The solution 50,96 g (0.16 mol) of methyl ester of 3-cyclopentyl-2-(4-methane-sulfanilyl)propionic acid in 410 ml of methanol was treated with 345 ml (0.35 mol) 1 N. aqueous sodium hydroxide solution. The reaction mixture was stirred at 25°C for 24 h the Reaction mixture was concentrated under vacuum to remove methanol. The resulting aqueous residue was acidified to pH 2 with concentrated hydrochloric acid and then was extracted with 5 portions of 200 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid, which was used without further purification, 43,61 g (yield: 90%) of pure 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 152-154°C; EI-HRMS m/e Rasch. for C15H20O4S (M+): 296,1082, detect.: 296,1080.

Simultaneously conducted two separate reactions: (1) the solution to 3.67 g (20,73 mmol) of (R)-(+)-4-benzyl-2-oxazolidinone in 35 ml of dry tetrahydrofuran was cooled to -7 8°C and then was treated with 7.9 ml (19,86 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then it was heated to 25°C, after which it was stirred for 1, the CSO of tetrahydrofuran, was cooled to 0°C and then was treated with 2.8 ml (19,86 mmol) of triethylamine. The reaction mixture was stirred at 0°C for 10 min and then treated by adding dropwise 2.6 ml (20,73 mmol) trimethylacetylchloride. The resulting reaction mixture was stirred at 0°C for 2 h and then was cooled to -78°to add their chiral oxazolidinone. Next, this reaction mixture, containing oxazolidinone was added to a chilled (-78°C) mixed anhydrous solution. The resulting reaction mixture was stirred at -78°C for 1 h and slowly warmed up to 25°C. Then the reaction mixture was stirred at 25°C for 3 days. The reaction in the resulting reaction mixture was suppressed 100 ml of water and then concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted with 600 ml ethyl acetate. The organic layer was washed 1 portion 300 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Thin-layer chromatography using hexanol/ethyl acetate in the ratio 13/7 as a solvent for the display showed the presence of two products. The value of Rfmore mobile-chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 9/1, then the 13/7 hexane/ethyl acetate) received two products: (1) a product with a large value of Rf- (4R,2'S)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]oxazolidin-2-he (2,12 g, yield: 54%) as a white foam: tPL: 62-64°C; []23589=+6,3° (=0,24, chloroform); EI-HRMS m/e Rasch. for C25H29NO5S (M+): 455,1766, detect.: 455,1757; (2) a product with a smaller value of Rf- (4R,2'R-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]oxazolidin-2-he (3.88 g, yield: 99%) as a white foam: tPL: 59-61°C; []23589=-98,3° (C=0,35, chloroform); EI-HRMS m/e Rasch. for C25H29NO5S (M+): 455,1766, detect.: 455,1753. The total mass of the two selected products amounted to 6.00 g, so that the degree of conversion during the reaction was 76%.

The mixture solution 707,3 mg (16,86 mmol) of anhydrous powdered lithium hydroxide in 5,27 ml of water from 3.44 ml (33,71 mmol) of 30% aqueous hydrogen peroxide solution has been freshly prepared aqueous solution of lithium hydroperoxide. This freshly prepared aqueous solution of lithium hydroperoxide was cooled to 0°C and then slowly added to a chilled (0°C) a solution of 3.84 g (8,43 mmol) (4R,2'R)-4-benzyl-3-[3-cyclopentyl-2-(4-metalcore 0°C for 1.5 hours Next, the reaction in the reaction mixture extinguished 25 ml of 1.5 N. aqueous solution of sodium sulfite. Then the reaction mixture was diluted with 300 ml of water. The resulting aqueous layer was continuously extracted with diethyl ether until until thin layer chromatography showed the absence of a water layer selected chiral oxazolidinone. Then the aqueous layer was acidified to pH 2 10% aqueous solution of hydrochloric acid and was extracted with 300 ml of ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid substance of 2.23 g (yield: 89%) of (2R)-3-cyclopentyl-2-(4-methanesulfonyl)propionic acid, which was used without further purification. To obtain a purified sample for the analytical data used Express chromatography (Silica gel 60 Merck, 70-230 mesh, 30/1 methylene chloride/methanol, then 10/1 methylene chloride/methanol), resulting in the form of a white foam was obtained pure (2R)-3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 62-64°C (foam ultinationals); []23589=-50,0° (=0,02, chloroform); EI-HRMS m/e Rasch. for C15H20O4S (M+): 296,1082, detect.: 296,1080.

The solution to 3.35 g (12,79 mmol) of triphenylphosphine in,79 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min, during this period of time the color of the reaction mixture changed from light yellow to dark yellow, and then to purple. Further chilled purple reaction mixture was treated of 2.23 g (7,52 mmol) of (2R)-3-cyclopentyl-2-(4-methanesulfonyl)propionic acid. In further formed reaction mixture for 45 min was heated to 25°C and then, after this period the reaction mixture was treated with 1.88 g (18,81 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 12 hours then the reaction mixture was concentrated under vacuum removal of methylene chloride. Received the black residue was diluted with 300 ml of ethyl acetate and then thoroughly washed with 2 portions of 100 ml of 10% aqueous hydrochloric acid solution, 3 portions of 100 ml of 5% aqueous sodium bicarbonate solution and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1, 3/1 and then 11/9 hexane/ethyl acetate) as a white foam was obtained of 2.10 g (yield: 74%) of (2R)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ilps. for C18H22N2O3S2(M+): 378,1072, detect.: 378,1081.

Example 14

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst®15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then filtered, removing the ion-exchange resin Amberlyst®15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C and then was treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition during the course the m number of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate sodium 3 m, the resulting formed a brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

The solution 865 mg (2,43 mmol) methyl ester 3-cyclopentyl-2-(4-meth-insulter-3-nitrophenyl)propionic acid in 6 ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted 25 water and then was treated with 10 ml of 1N. an aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. United orgia (Silica gel 60 Merck, 230-400 mesh mesh, 1/4 hexane/ethyl acetate) as a white foam was obtained 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl) propionic acid. Analytical data indicated the presence of small amounts of impurities, but this 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid was used in the subsequent reactions without further purification.

A solution of 138 mg (of 0.53 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated by slow addition of small portions 94 mg (of 0.53 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 150 mg (0.44 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. The resulting reaction mixture was stirred at 0°C for 5 min, and then it was heated to 25°C, after which it was stirred for 25 minutes Then the reaction mixture was treated with 97 mg (0.97 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 hours This crude mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale yellow solid 96 mg (yield: 52%) of 3-cyclopentyl-2-(4-metasolv the 5S2(M+N)+424,1001, detect.: 424,1000.

Example 15

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethylimidazole-2-yl)propionamide

A solution of 110 mg (0.25 mmol) of the ethyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid (obtained in example 1 (B) (W)), in 2 ml of diethyl ether at 0°C was treated by slow addition of 12 mg (0.31 mmol) of lithium aluminum hydride. The resulting reaction mixture continued to stir at 0°C and it was gradually heated to 25°C. Next, the reaction mixture was stirred at 25°C for 14-hour period. The reaction in the reaction mixture slowly snuffed out by adding dropwise 5 ml of water. The resulting reaction mixture was separated between water and ethyl acetate. For the destruction of the emulsion was added a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a pale yellow solid was obtained 52,9 mg (yield: 53%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethylimidazole-2-yl)propionamide: tPL: 128-130°C; EI-HRMS m/e Rasch. for C18H20Cl2N2O

A solution of 129 mg (0.28 mmol) of ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl} acetic acid (obtained in example 1 (B) (C)) in 1.4 ml of tetrahydrofuran at 25°C was treated by slow addition of 22.5 mg (0.59 mmol) of sodium borohydride. The resulting reaction mixture was stirred at 25°C for 10 h after 10 h of treatment at 25°With was still a significant amount of source material. In the reaction mixture was added an additional amount of powdered sodium borohydride (21,4 mg, or 0.57 mmol) and the reaction mixture is boiled under reflux for 14 hours the Reaction mixture was allowed to cool to 25°C, and then the reaction slowly snuffed out by adding dropwise water. The resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The obtained residue was diluted with 100 ml ethyl acetate and washed with 1 portion 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1, then 1/1 hexane/ethyl acetate) as a white foam was obtained to 68.1 mg (yield: 58%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxy S (M+N)+: 413,0858, detect.: 413,0838.

Example 17

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethylimidazole-2-yl)propionamide

A solution of 200 mg (0.45 mmol) of the ethyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid (obtained in example 1(B)(e)) in 3 ml of tetrahydrofuran at 25°C was treated by slow addition to 26.0 mg (of 0.68 mmol) sodium borohydride. The reaction mixture is boiled under reflux for 48 hours the Reaction mixture was allowed to cool to 25°C and then the reaction it extinguished slowly adding dropwise water. The resulting reaction mixture was separated between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white solid substance was obtained to 44.9 mg (yield: 25%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethylimidazole-2-yl)propionamide: tPL: 88-90°C; EI-HRMS m/e Rasch. for C18H20Cl2N2O2S (M+): 398,0623, detect.: 398,0631.

Example 18

{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl}acetic acid

The solution 198,1 mg n in example IB) (in)), 2.2 ml of absolute ethanol was treated 910 μl (of 0.91 mmol) 1 N. aqueous sodium hydroxide solution. The reaction mixture is boiled under reflux for 2 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum removal of absolute ethanol. The remainder 10% aqueous solution of hydrochloric acid acidified to pH 2 and was extracted with 1 portion 150 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. The obtained white residue thoroughly washed with cold water and dried to obtain a white solid of 150 mg (yield: 81%) {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl}acetic acid: tPL: 100-102°C; FAB-HRMS m/e Rasch. for C19H20Cl2N2O3S (M+H)+: 427,0650, detect.: 427,0633.

Example 19

2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid

A solution of 1.0 g of 2.27 mmol) ethyl ester 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid (obtained in example KB) (W)) in 10 ml of absolute ethanol was treated 4,77 the receive 15 PM The reaction mixture was allowed to cool to 25°C and then concentrated under vacuum removal of absolute ethanol. The yellow residue with concentrated hydrochloric acid was acidified to pH 2 and extracted with 2 portions of 75 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. By recrystallization from ethyl acetate as white solid substance was obtained 210 mg (yield: 22%) of 2-[3-cyclopentyl-2-(3,4-dichlorophen-yl)propionamido]thiazole-5-carboxylic acid: tPL: 269-270°C; FAB-HRMS m/e Rasch. for C18H18Cl2N2O3S (M+H)+: 413,0493, detect.: 413,0483.

Example 20

2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid

A solution of 600 mg (1,36 mmol) ethyl ester 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid (obtained in example 1(B)(e)) in 6 ml of absolute ethanol was treated to 2.85 ml (2,85 mmol) 1 N. aqueous sodium hydroxide solution. The reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum removal of absolute ethanol. The yellow octadecene organic layers were dried over magnesium sulfate, was filtered and concentrated under vacuum. Deposition from hexanol/ethyl acetate in a ratio of 1/1 in the form of a white solid substance was obtained 399 mg (yield: 71%) of 2-[3-cyclopen-Tyl-2-(3,4-dichlorophenyl)propionamide] thiazole-4-carboxylic acid: tPL: 285-287°C; FAB-HRMS m/e Rasch. for C18H18Cl2N2O3S (M+H)+: 413,0493, detect.: 413,0481.

Example 21

(A) Methyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl}acetic acid

The solution of 95.4 mg (0,223 mmol) {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionamido]thiazol-4-yl} acetic acid (obtained in example 18) 1.1 methanol was treated with 1 drop of concentrated sulfuric acid. The reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was diluted with 100 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow viscous oil was obtained for 77.2 mg (yield: 78%) met the20H22Cl2N2O3S (M+H)+: 441,0807, detect.: 441,0804.

(B) Similarly received:

(a) from 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid (obtained in example 20): methyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid as a white solid: tPL: 153 to 155°C; FAB-HRMS m/e Rasch. for C19H20Cl2N2O3S (M+H)+: 427,0650, detect.: 427,0659;

(b) from 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid (obtained in example 19): methyl ester of 2- [3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide] thiazole-5-carboxylic acid as a white solid: tPL: 150-151°C; FAB-HRMS m/e Rasch. for C19H20Cl2N2O3S (M+H)+: 427,0650, detect.: 427,0650.

Example 22

(A) 3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-ylpropionic

Solution (430,55 ml, 0.3 M source solution, 129,16 mmol) of their diisopropylamide lithium cooled to -78°C, cultivated 26,32 g (125,83 mmol) ethyl ester (4-nitrophenyl)acetic acid in 312,5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). Forming the 27,75 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise to 250 ml of a saturated aqueous solution of ammonium chloride. The mixture was concentrated, diluted with 250 ml of water and was extracted with 3 portions of 300 ml of ethyl acetate. The organic material was washed with 2 portions of 250 ml of saturated aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 98/2 hexane/ethyl acetate) as a yellow oil was obtained 28,30 g (yield: 77.2 percent) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: EI-HRMS m/e Rasch. for C16H21NO4(M+): 291,1470, detect.: 291,1470.

A solution of 14.1 g (48,06 mmol) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid in 300 ml of tetrahydrofuran/water (in the ratio 3:1) was treated with 4.35 g (103,67 mmol) of lithium hydroxide. The reaction mixture was stirred at 25°C for 21 hours Then under vacuum, remove the tetrahydrofuran. The residue was diluted with 75 ml of water and was extracted with 3 portions of 75 ml of diethyl ether. The aqueous layer was acidified to pH 1 3 N. water restorewindow aqueous solution of sodium chloride, was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain a yellow solid of $ 11.97 g (yield: 93,6%) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: tPL: 119-125°C; EI-HRMS m/e Rasch. for C14H17NO4(M+): 263,1157, detect.: 263,1162.

A solution of 131 mg (0.5 mmol) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid in 5.0 ml of methylene chloride was cooled to 0°C and then was treated with 1.0 ml (2.0 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 110 mg (1.0 mmol) of 2-aminothiazole in 5 ml of tetrahydrofuran and 0.28 ml (0.55 mmol) of N,N-diisopropylethylamine. The solution was stirred at 25°C for 24 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a yellow solid was obtained 38 mg (yield: 22.4 percent) 3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-ylpropionic: tPL: 186-187°C; EI-HRMS m/e Rasch. for C17H19N3O3S (M+): 345,1147, detect.: 345,1148.

(B) in a Similar way the ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl}octoxynol acid (yield: 57,5%) as a white solid: tPL: 134-136°C; FAB-HRMS m/e Rasch. for C21H23N3O6S (M+N)+: 446,1400, detect.: 446,1386.

Example 23

Ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl} acetic acid

The solution 263,0 mg (1.0 mmol) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid (obtained in example 22A) in 10 ml of N,N-dimethylformamide was treated 379 mg (1.0 mmol) of hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea, 279 mg (1.5 mmol) of ethyl ether (2-aminothiazol-4-yl)acetic acid and 0.34 ml (2.0 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at 25°C for 5 hours Then the reaction mixture was poured into 25 ml of 2 N. aqueous solution of hydrochloric acid and was extracted with 3 portions of 25 ml of ethyl acetate. The organic layers were combined and washed with 1 portion in 75 ml of water, 1 portion 75 ml saturated aqueous sodium bicarbonate solution and 3 portions of 75 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a pale yellow oil was obtained 70.0 mg (yield: 39,4%) of ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionovoj.: 432,1595.

Example 24

Methyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl}acetic acid

A solution of 160 mg (from 0.37 mmol) of ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl}acetic acid (obtained in example 23) in 10 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 68 hours, the Reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a pale yellow oil was obtained which was 82.3 mg (yield: 53.3 per cent) methyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl] acetic acid: FAB-HRMS m/e Rasch. for C20H23N3O5S (M+N)+: 418,1436, detect.: 418,1424.

Example 25

Methyl ether {2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]thiazol-4-yl} acetic acid

The solution 75,3 mg (0.18 mmol) of the methyl ester [2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl} acetic acid (obtained in example 24) in 25 ml of ethyl acetate was treated with 10% palladium on charcoal. The reaction mixture was stirred in the atmosphere of hazoor what Oskanian through the layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum obtaining in the form of a yellowish-brown oil of 64.5 mg (yield: 93,3%) methyl ether {2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]thiazol-4-yl}acetic acid: EI-HRMS m/e Rasch. for C20H25N3O3S (M+): 387,1616, detect.: 387,1612.

Example 26

Methyl ester 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazole-4-carboxylic acid

A solution of 135 mg (0.32 mmol) of the ethyl ester of 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazole-4-carboxylic acid (obtained in example 39 (B) (b)) in 10 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 68 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a pale yellow solid was obtained and 71.4 mg (yield: 54.8 per cent) methyl ester 2-[3-cyclopentyl-2-(4-nitrophe-nil)propionamido]thiazole-4-carboxylic acid: EI-HRMS m/e Rasch. for C19H21N3O5S (M+): 403,1201, detect.: 403,1188.

Example 27

Methyl ester 2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]thiazole-4-carboxylic what ylamino]thiazole-4-carboxylic acid (obtained in example 26) in 25 ml of ethyl acetate was treated with 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas under a pressure of 60 pounds per square inch at 25°C for 4.5 h Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum obtaining in the form of a pale yellow oil with 61.3 mg (yield: 100%) methyl ester 2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid: EI-HRMS m/e Rasch. for C19H23N3O3S (M+): 373,1460, detect.: 373,1454.

Example 28

(A) Ethyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl] thiazol-4-yl}acetic acid

The solution of their diisopropylamide lithium (141,3 ml of 0.32 M source solution of 45.0 mmol), cooled to -78°C, were treated to 3.41 g (20.0 mmol) of (3-chlorophenyl)acetic acid in 49,7 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting reaction solution was stirred at -78°C for 1 h and Then added with 4.64 g (22,08 mmol) iodomethylpropane in with 4.64 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours th acid. The product was extracted with 1 portion 150 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) in the form of a yellow solid was obtained 3,68 g (yield: 72,9%) of 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: tPL: 70-72°C; EI-HRMS m/e Rasch. for C14H17ClO2(M+): 252,0917, detect.: 252,0915.

A solution of 252 mg (1.0 mmol) of 2-(3-chlorophenyl)-3-cyclopentylpropionic acid in 10 ml of methylene chloride was cooled to 0°C and then was treated with 0.6 ml (1.2 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 2 h Then the reaction mixture was treated 409 mg (2.2 mmol) of ethyl ether (2-aminothiazol-4-yl)acetic acid and 0.5 ml (2.4 mmol) of N,N-diisopropylethylamine. The resulting solution was stirred at 25°C for 48 hours, after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 254 mg (yield: 60.3 per cent) ethyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl is UP>+): 420,1274, detect.: 420,1268.

(B) Similarly received:

(a) of the ethyl ester of 2-aminothiazol-4-carboxylic acid and 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: ethyl ester of 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid as a white solid: tPL: 167-168°C; EI-HRMS m/e Rasch. for C20H23lN2O3S (M+): 406,1117, detect.: 406,1103;

(b) from 2-amino-pyridine and 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: 2-(3-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic in the form of a clear oil: EI-HRMS m/e Rasch. for C19H21lN2O2S (M+): 328,1342, detect.: 328,1333;

(C) of the methyl ester of 6-aminonicotinic acid and 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: methyl ester of 6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid as a colorless oil: EI-HRMS m/e Rasch. for C21H23lN2O3(M+): 386,1397, detect.: 386,1398.

Example 29

Methyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl}acetic acid

The solution 177,2 mg (0.42 mmol) of ethyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-Yves sulfuric acid. The reaction mixture is boiled under reflux for 40 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) in the form of a clear oil was obtained 104,4 mg (yield: 60,9%) methyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl}acetic acid: EI-HRMS m/e Rasch. for C20H23lN2O3S (M+): 406,1117, detect.: 406,1118.

Example 30

Methyl ester 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid

A solution of 94.5 mg (0.23 mmol) of ethyl ester 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid (obtained in example 28 (B) (a)) in 15 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 40 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained to 36.8 mg (yield: 40.3 per cent) methyl ester 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid: tPL: 95-98°C; EI-HRMS m/e Rasch. for C19H21lN-3-cyclopentylpropionyl]thiazol-4-yl}acetic acid

The solution of their diisopropylamide lithium (78,0 ml of 0.91 M source solution, 70,98 mmol), cooled to -78°C, cultivated 5,76 g (33.8 mmol) (4-chlorophenyl)acetic acid in 84 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 1 h Then was added 7,45 g (35,49 mmol) iodomethylpropane in 2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. This solution was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours then the reaction in the reaction mixture was suppressed by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. Under vacuum, remove the excess solvent. The remainder of 1 N. aqueous hydrochloric acid solution was acidified to pH 1. Next, the mixture was poured into 150 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) in the form of a yellow solid was obtained 6,76 g (yield: 79,1%) of 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: tPL: 82-84°With: EI-HRMS m/e Rasch. for C1 is interprovincial acid in 10 ml of methylene chloride was cooled to 0°C and then was treated with 0.55 ml (1.1 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and then at 25°C for 1.5 hours Then the reaction mixture was treated 409 mg (2.2 mmol) of ethyl ether (2-aminothiazol-4-yl)acetic acid and 0.5 ml (2.4 mmol) of N,N-diisopropylethylamine. This solution was stirred at 25°C for 24 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) as a pale yellow oil was obtained 183,3 mg (yield: 43,5%) of ethyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl] acetic acid: EI-HRMS m/e Rasch. for C21H25lN2O3S (M+): 420,1274, detect.: 420,1272.

(B) Similarly received:

(a) of the ethyl ester of 2-aminothiazol-4-carboxylic acid and 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: ethyl ester of 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid as a white solid: tPL: 114-116°C; EI-HRMS m/e Rasch. for C20H23lN2O3S (M+): 406,1117, detect.: 406,1119;

(b) from 2-amino-pyridine and 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: 2-(4-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic in the form of the transparent is delovogo ether 6-aminonicotinic acid and 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: methyl ester of 6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid as a white foam: EI-HRMS m/e Rasch. for C21H23lN2O3(M+): 386,1397, detect.: 386,1384.

Example 32

Methyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid

A solution of 105 mg (0.25 mmol) ethyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid (obtained in example 31 (B) (a)) in 10 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 68 hours, the Reaction mixture was concentrated under vacuum. Liquid chromatography under high pressure (product Chromegasphere SI-60, 10 μm, 60 , 25 cm × 23 cm (inner diameter), 75/25 heptane/ethyl acetate) as a white solid substance was obtained 41.3 mg (yield: 40.7 per cent) methyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid: tPL: 156-157°C; EI-HRMS m/e Rasch. for C19H21lN2O3S (M+): 392,0961, detect.: 392,0956.

Example 33

Methyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl}acetic acid

The solution 76,1 mg (0.18 mmol) of ethyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazol-4-yl}acetic KIS the lots. The reaction mixture is boiled under reflux for 72 hours, the Reaction mixture was concentrated under vacuum. Liquid chromatography under high pressure (product Chromegasphere SI-60, 10 μm, 60 , 25 cm × 23 cm (inner diameter), 75/25 heptane/ethyl acetate) as a colourless oil was obtained 21,5 mg (yield:

29,2%) methyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl]acetic acid: EI-HRMS m/e Rasch. for C20H23lN2O3S (M+): 406,1117, detect.: 406,1114.

Example 34

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethylimidazole-2-yl)propionamide

The solution of 127.7 mg (0.31 mmol) of methyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid (obtained in example 32) in 0.4 ml of tetrahydrofuran was injected at 0°C in a suspension of 15.0 mg (0,39 mmol) of lithium aluminum hydride 2.24 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 2 h Then the reaction was suppressed by adding dropwise water. Then the reaction mixture was diluted with an additional 25 ml of water and was extracted with 3 portions of 25 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express-chromatography is) 2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethylimidazole-2-yl)propionamide: tPL: 115-117°C; EI-HRMS m/e Rasch. for C18H21ClN2O2S (M+): 364,1012, detect.: 364,1004.

Example 35

3-cyclopentyl-N-(4-hydroxymethylimidazole-2-yl)-2-(4-methanesulfonyl)propionamide

A solution of 130 mg (0.29 mmol) of the ethyl ester of 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazole-4-carboxylic acid (obtained in example 3(B) (b)) in 2 ml of diethyl ether was cooled to 0°C and then was treated by slow addition of 17 mg (0.44 mmol) of lithium aluminum hydride. The reaction mixture was heated to 25°C, after which it was stirred for 4 h after 4 h of exposure at 25°With the data thin-layer chromatography indicated the presence of starting material. In the reaction mixture was added an additional amount of lithium aluminum hydride (11 mg, 0.29 mmol) and the reaction mixture was stirred at 25°C for 15 h Then the reaction in the reaction mixture extinguished slowly adding dropwise water. The resulting mixture was divided between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, ethyl acetate) as a white solid substance was obtained 55 mg (output m/e Rasch. for C19H24N2O4S2(M+): 408,1178, detect.: 408,1164.

Example 36

3-cyclopentyl-N-[4-(2-hydroxyethyl)thiazol-2-yl]-2-(4-meanswhen-ylphenyl) propionamide

A solution of 120 mg (0.26 mmol) of the ethyl ester of 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazol-4-yl} acetic acid (obtained in example 3(B)(d)) in 500 µl of diethyl ether was cooled to 0°C and then was treated by slow addition of 15 mg (0,39 mmol) of lithium aluminum hydride. The reaction mixture was heated to 25°C, after which it was stirred for 1 h After exposure for 1 h at 25°With the data thin-layer chromatography indicated that all were still present ethyl ester 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazol-4-yl] acetic acid. In the reaction mixture was added an additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) and the reaction mixture was stirred at 25°C for 1 h Then the reaction in the reaction mixture extinguished slowly adding dropwise 10 ml of water. The resulting mixture was divided between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 f is Teal)thiazol-2-yl]-2-(4-methanesulfonyl)propionamide: tPL: 84-87°C; EI-HRMS m/e Rasch. for C20H26N2O4S2(M+): 422,1334, detect.: 422,1335.

Example 37

Methyl ester of (2R)-2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid

A solution of 164 mg (0,63 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C and then was treated by adding small portions 112 mg (0,63 mmol) of N-bromosuccinimide. The resulting orange reaction mixture was stirred at 0°C for 20 min and then was treated with 150 mg (0.52 mmol) of (2R)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 54). The reaction mixture was stirred at 0°C for another 15 min and then it was heated to 25°C. Next, the reaction mixture was treated with 181 mg (1.15 mmol) of methyl ester of 2-aminothiazol-4-carboxylic acid. The resulting reaction mixture was stirred at 25°C for 15 hours the Crude reaction mixture was subjected to direct cleaning Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) to give the crude methyl ester (2R)-2-[3-cyclopentyl-2-(3,4-dichlorophen-yl)propionamido]thiazole-4-carboxylic acid. This crude product was diluted with ethyl acetate, and then trevali and concentrated under vacuum obtaining in the form of a white solid 92 mg (yield: 41%) of pure methyl ester (2R)-2-[3-cyclopentyl-2-(3,4-dichlorophenyl) propionamide]thiazole-4-carboxylic acid: tPL: 143-144°C; []23589=-10,2° (C=0,98, chloroform); EI-HRMS m/e Rasch. for C19H20Cl2N2O3S (M+): 426,0572, detect.: 426,0562.

Example 38

(A) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic:

The solution 28,80 g (109,8 mmol) of triphenylphosphine and 14.9 g (219,6 mmol) of imidazole in 160 ml of methylene chloride was cooled to 0°C and then was treated by slow addition of 27,87 g (109,8 mmol) of iodine. Next, the reaction mixture was treated by the addition dropwise of a solution of 10.0 g (99,8 mmol) cyclopentylmethyl in 10 ml of methylene chloride. The resulting reaction mixture was heated to 25°C, after which it was stirred for 4 h Then the reaction mixture was diluted with 50 ml water and the reaction mixture was additionally extracted with 3 portions of 20 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum at 25°C. the Obtained solid was washed with 4 portions of 50 ml of pentane and filtered by passing through a layer of silica gel. The filtrate was concentrated under vacuum at 25°with the receipt in the form of a colorless transparent liquid 18,48 g (yield: 88%) of iodomethylpropane: EI-HRMS m/e Rasch. for C6H11I1PL: 74,5-76,9°C; EI-HRMS m/e Rasch. for C14H16Cl2O2(M+): 286,0527, detect.: 286,0534.

A solution of 114 mg (0,39 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionate the ion and the mixture was processed to 0.22 ml (0.44 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of 78 mg (0.83 mmol) of 2-aminopyridine and 0.16 ml (0.95 mmol) of N,N-diisopropylethylamine in 2 ml of tetrahydrofuran. The resulting reaction mixture was stirred at 25°C for 14 h and Then the reaction mixture was diluted with 10 ml water and was extracted with 2 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, hexane, then hexane/ethyl acetate in ratios from 19/1 to 4/1) as a white foam was obtained 58 mg (yield: 50%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic: EI-HRMS m/e Rasch. for C19H20Cl2N2O2(M+): 362,0953, detect.: 362,0955.

(B) Similarly received:

(a) from 2-amino-5-nitropyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitropyridine)-2-ylpropionic in the form of a yellow-orange foam: EI-HRMS m/e Rasch. for C19H19Cl2N3O3(M+): 407,0803, detect.: 407,0799;

(b) from 2-amino-5-carboxymethylamino and 3-cyclopentyl-2-(3,4-di-chlorophenyl)propionic acid: 3-cyclopentyl-2-(3,4-di 2N2O3(M+): 420,1007, detect.: 420,0994;

(C) from 4-aminopyrimidine and 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-6-ylpropionic in the form of a white foam: EI-HRMS m/e Rasch. for C18H19Cl2N3O (M+): 363,0905, detect.: 363,0910;

(g) from 2-amino-5-methylpyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylpyridin)-2-ylpropionic in the form of a white solid: EI-HRMS m/e Rasch. for C20H22Cl2N2O (M+): 376,1109, detect.: 376,1119;

(d) from 2-amino-4-methylpyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylpyridin)-2-ylpropionic in the form of a white solid: EI-HRMS m/e Rasch. for C20H22Cl2N2O (M+): 376,1109, detect.: 376,1106;

(e) from 2-amino-6-methylpyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methylpyridin)-2-ylpropionic in the form of a light yellow solid: EI-HRMS m/e Rasch. for C20H22Cl2N2O (M+): 376,1109, detect.: 376,1107;

(g) from 2-amino-5-chloropyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-prop. the La C19H19Cl3N2O (M+): 396,0563, detect.: 396,0564;

(C) from 2-amino-5-bromopyridine and 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-bromopyridin)-2-ylpropionic in the form of a white solid: EI-HRMS m/e Rasch. for C19H19Cl2N2O (M+): 440,0058, detect.: 440,0066.

Example 39

(A) 3-cyclopentyl-2-(4-nitrophenyl)-N-pyridin-2-ylpropionic

A solution of 263 mg (1.0 mmol) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid (obtained in example 22) in 5 ml of methylene chloride was cooled to 0°C and then was treated with 0.6 ml (1.2 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and then at 25°C for 1 h Then the reaction mixture was treated with a solution of 207 mg (2.2 mmol) of 2-aminopyridine in 5 ml of tetrahydrofuran and 0.42 ml (2.5 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at 25°C for 24 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 110,2 mg (you>H21N3ABOUT3(M+): 339,1582, detect.: 339,1581.

(B) Similarly received:

(a) from 4-aminopyrimidine and 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: 3-cyclopentyl-2-(4-nitrophenyl)-N-pyrimidine-4-ylpropionic in the form of a white solid: Tmelt: 152-153°C; EI-HRMS m/e Rasch. for C18H20N4ABOUT3(M+): 340,1535, detect.: 340,1533.

(b) of the ethyl ester of 2-aminothiazol-4-carboxylic acid and 3-cyclopentyl-2-(4-nitrophenyl) propionic acid: ethyl ester of 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazole-4-carboxylic acid as a pale yellow solid: tPL: 110-115°C; EI-HRMS m/e Rasch. for C20H23N3ABOUT5S (M+): 417,1358, detect.: 417,1346.

Example 40

3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylpropionic

A solution of 3.2 ml (23,16 mmol) Diisopropylamine in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,b-tetrahydro-2(1 h)-pyrimidinone was cooled to-78°C in nitrogen atmosphere and then was treated with 2.3 ml (23,16 mmol) of a 10 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by adding dropwise racetraitor-2 (1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 2.55 g (12,13 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at -78°C for 30 min and then was heated to 25°C, after which it was stirred for 24 h the Reaction in the reaction mixture extinguished with water and then the mixture was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous solution of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 200 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.01 g (yield: 35%) 3-cyclopentyl-2-(4-methylsulfinylphenyl)propionic acid: tPL: 91-93°C; EI-HRMS m/e Rasch. for C15H20ABOUT2S (M+): 264,1184, detect.: 264,1177.

A solution of 200 mg (from 0.76 mmol) 3-cyclopentyl-2-(4-methylsulfinylphenyl)-propionic acid and 198 mg (from 0.76 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then the-bromosuccinimide the reaction mixture for 30 min was heated to 25°C. Next, the orange reaction mixture was treated with 151 mg (1,60 mmol) of 2-aminopyridine and the resulting reaction mixture was stirred at 25°C for 15 hours and Then the reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was separated between water and ethyl acetate. The organic layer was washed 1 N. aqueous solution of hydrochloric acid, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a white solid substance was obtained 83 mg (yield: 32%) 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylpropionic: tPL: 127-128°C; EI-HRMS m/e Rasch. for C20H24N2OS (M+): 340,1609, detect.: 340,1611.

Example 41

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then treated of 6.7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at-alucase acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after that time, it was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water, and then it was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3ABOUT2S (M+): 318,0901, detect.: 318,0912.

The solution to 59.6 mg (0,187 mmol) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and 49,1 mg (0,187 mmol) of triphenylphosphine in 460 ml of methylene chloride was cooled to 0°C and then was treated dobavlennuju the mixture for 30 min was heated to 25°C. Next, the orange reaction mixture was treated 35.2 mg (0,374 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 50 ml ethyl acetate. The organic layer was washed 1 portion 50 ml of 10% aqueous hydrochloric acid solution, washed with 1 portion 50 ml saturated aqueous sodium bicarbonate solution, washed with 1 portion 50 ml of water, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) in the form of a cream solid was obtained 25.0 mg (yield: 34%) 3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide: tPL: 101-102°C; EI-HRMS m/e Rasch. for C20H21F3N2OS (M+): 394,1327, detect.: 394,1321.

Example 42

3-cyclopentyl-2-(4-methanesulfonyl)-N-pyridin-2-ylpropionic

A solution of 95 mg (1.01 mmol) of 2-aminopyridine in 2 ml of acetonitrile was treated with 250 mg (0.84 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl) propionic acid (obtained in example 3(A)), 243 mg (0,93 mmol) of triphenylphosphine, 350 ál (2,53 mmol) three is. the cozy reaction mixture was diluted with water, and then extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) was obtained crude 3-cyclopentyl-2-(4-methanesulfonyl)-N-pyridin-2-ylpropionic. By recrystallization from hexanol/methylene chloride in the form of a white solid substance was obtained 170 mg (yield: 54%) of pure 3-cyclopentyl-2-(4-methanesulfonyl)-N-pyridin-2-ylpropionic: tPL: 172-173°C; EI-HRMS m/e Rasch. for C20H24N2O3S (M+): 372,1508, detect.: 372,1498.

Example 43

(A) 3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to-7 8°C in nitrogen atmosphere and then treated of 6.7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 1.89 g (8,00 mmol) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran IO after this time was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3O2S (M+): 318,0901, detect.: 318,0912.

A solution of 1.33 g (4,18 mmol) 3-cyclopentyl-2-(4-trifloromethyl-phenyl)propionic acid in 10 ml of methanol was treated with gradual addition of 4 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 36 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The residue was diluted with 200 ml atieli 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. For C16H19F3O2S (M+) 332,1058, detect.: 332,1052.

A solution of 1.14 g (3,43 mmol) methyl ester 3-cyclopentyl-2-(4-tri-formatterconverter)propionic acid 8.6 ml of methylene chloride was treated with 2.00 g of 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 9,26 mmol). The reaction mixture was stirred at 25°C for 17 h, after this period these thin-layer chromatography showed the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added optional 2.00 g of 3-chloroperoxybenzoic acid and the resulting reaction mixture was stirred at 25°C for 3 days. The reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 3 portions of 100 sodium chloride, was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.19 g (yield: 95%) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0965.

The solution 708,2 mg (1.94 mmol) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 2.4 ml of tetrahydrofuran was treated with 3.6 ml (2,92 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 h and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous layer with 10% aqueous hydrochloric acid solution was acidified to pH 2 and then extracted with 2 portions of 100 ml of ethyl acetate. The combined organic layers were washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to obtain a cream solid. This solid was purified by rubbing the powder in diethyl ether/petroleum ether to obtain a white solid vedastus; EI-HRMS m/e Rasch. for C15H17F3O4S (M+): 350,0800, detect.: 350,0816.

The solution 118,9 mg (0.34 mmol) of 3-cyclopentyl-2-(4-triftorbyenzola-ylphenyl)propionic acid and 133,5 mg (0.51 mmol) of triphenylphosphine in 848 μl of methylene chloride was cooled to 0°C and then was treated by adding small portions 102,7 mg (of 0.58 mmol) of N-bromosuccinimide. After adding N-bromosuccinimide the reaction mixture was heated to 25°C, after which it was stirred for 45 minutes Then the reaction mixture was processed for 95.8 mg (1,02 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 22 h Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 5/1 hexane/ethyl acetate) as a light yellow solid substance was obtained by 37.1 mg (yield: 26%) 3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)propionamide: tPL: 151-153°C; EI-HRMS m/e Rasch. for C20H21F3N2O3S (M+): 426,1225, detect.: 426,1220.

(B) Similarly received:

(a) from 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and 2-amino-5-chloropyridine: N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(4-triptorelin the H20ClF3N2O3S (M+): 460,0835, detect.: 460,0846;

(b) from 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and 2-amino-5-methyl pyridine: 3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-triftormetilfullerenov)propionamide in the form of a pale yellow solid: tPL: 155-157°C; EI-HRMS m/e Rasch. for C21H23F3N2O3S (M+): 440,1381, detect.: 440,1376;

(C) from 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and methyl ester of 6-aminonicotinic acid: methyl ester of 6-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido] nicotinic acid as a yellow foam: tPL: 58-62°C; EI-HRMS m/e Rasch. for C22H23F3N2O5S (M+): 484,1280, detect.: 484,1274.

Example 44

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-ylpropionic

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C and then filtered to remove the ion exchange resin Amberlyst® 15. The filtrate is e yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to-78°C and then was treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The remainder of resbala is whether over magnesium sulfate, was filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml of DMSO was kept at 130°C for 5 hours Then the black reaction mixture was poured into 20 g of ice, which formed the brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+-nitrophenyl)propionic acid in 6 ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted 25 water, and then was treated with 10 ml of 1N. an aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/4 hexane/ethyl acetate) as a white foam was obtained 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. Analytical data indicated the presence of small amounts of impurities, but this 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid was used in the subsequent reactions without further purification.

A solution of 138 mg (of 0.53 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated by slow addition of small portions 94 mg (of 0.53 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 150 mg (0.44 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl) propionic acid. The resulting reaction with the 25 minutes Next, the reaction mixture was treated with 91 mg (0.97 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 hours the resulting crude mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to give a white foam 106 mg (yield: 58%) 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-ylpropionic: tPL: 92-95°C (foam ultinationals); FAB-HRMS m/e Rasch. for C20H23N3O5S (M+N)+: 418,1436, detect.: 418,1430.

Example 45

Methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide] nicotinic acid

A mixture of 4.0 g (of 28.9 mmol) 6-aminonicotinic acid, 75 ml of methanol and 4 ml of concentrated hydrochloric acid was boiled under reflux for 16 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to remove methanol. The obtained solid was treated with 20 ml of water and sodium bicarbonate in a quantity sufficient to bring the pH to 8. The resulting solution was extracted with 3 portions of 25 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum with 7H8N2O2(M+): 152,0586, detect.: 152,0586.

A solution of 1.23 g (4,69 mmol) of triphenylphosphine in 15 ml of methylene chloride was cooled to 0°C, and then processed 947 mg (5,32 mmol) of N-bromosuccinimide. The resulting brown-purple solution was stirred at 0°C for 5 min and then was treated with 900 mg (3,13 mmol) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionic acid (obtained in example 54). The reaction mixture was stirred at 0°C, and then for 45 min was heated to 25°C. Next, the reaction mixture was treated with 620 mg (4.07 mmol) of methyl ester of 6-aminonicotinic acid and 0.38 ml (4.7 mmol) of pyridine and the reaction mixture was stirred at 25°C for 20 hours the Resulting reaction mixture was diluted with 15 ml of water and then was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) as a white foam was obtained 1.10 g (yield: 84%) of methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide] nicotinic acid: []23589=-68,0° (C=0,128, chloroform); FAB-HRMS m/e Rasch. for C21H22Cl2N2O3(M+H)+

A solution of 50 mg (0.12 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-carboxymethylamino)-2-ylpropionic (obtained in example 38(B)(b)) in 10 ml of ethanol at 25°C was treated with a solution of 20 mg (0.36 mmol) of potassium hydroxide in 2 ml of water. The reaction mixture was stirred at 25°C for 2 hours after this time the reaction mixture was diluted with 5 ml of water. Under vacuum, remove the ethanol. Next, the aqueous layer was acidified to pH 2 1 N. aqueous solution of hydrochloric acid. This solution was extracted with 3 portions of 10 ml of methylene chloride. The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate with acetic acid) as a white foam received 34 mg (yield: 71%) of 6-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide] nicotinic acid: EI-HRMS m/e Rasch. for C20H20CL2N2ABOUT3(M+): 406,0851, detect.: 406,0852.

Example 47

6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid

Solution and 62.6 mg (0.16 mmol) of the methyl ester of 6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid (obtained in example 31 (B) (C)) and 0.40 ml of tetrahydrofuran (THF)/the complete mixture was stirred at 25°C for 24 hours Next, the reaction mixture was poured into water and was extracted with 2 portions of 30 ml of chloroform. Then 1 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 1. The product was extracted with 3 portions of 25 ml of chloroform/methanol (ratio 9:1), dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate with acetic acid) in the form of a white solid substance was obtained of 17.0 mg (yield: 31,5%) 6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid: tPL: 206-208°C; EI-HRMS m/e Rasch. for C20H21ClN2O2(M+): 372,1240, detect.: 372,1244.

Example 48

6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]nicotinic acid

A solution of 100 mg (0.23 mmol) of the methyl ester of 6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido] nicotinic acid (obtained in example 53(B)(a)) in 500 μl of tetrahydrofuran was treated with 300 μl (0.23 mmol) of 0.8 M aqueous solution of lithium hydroxide. The solution was stirred at 25°C for 4 h Then the reaction mixture was purified directly by column chromatography. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 methanol/atilano] nicotinic acid: tPL: 191-193°C; FAB-HRMS m/e Rasch. for C21H24N2O5S (M+H)+: 417,1484, detect.: 417,1484.

Example 49

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide

A solution of 398 mg (0.95 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-carboxymethylamino)-2-ylpropionic (obtained in example 38(B)(b)) in 30 ml of diethyl ether, cooled to 0°C, and treated with 54 mg (1.4 mmol) of lithium aluminum hydride. The resulting suspension was slowly heated to 25°C. the Reaction mixture was stirred at 25°C for 16 hours after this time the reaction was suppressed with 10 ml water and was extracted with 3 portions of 15 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white foam was obtained 131 mg (yield: 35%) 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide: EI-HRMS m/e Rasch. for C20H22Cl2N2O2(M+): 392,1058, detect.: 392,1062.

Example 50

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)propionamide

The solution of 83.3 mg (0.21 mmol) of the methyl ester of 6-[2-(4 the furan was injected into a cooled (0°C) suspension of 12.0 mg (0.32 mmol) of lithium aluminum hydride 1.54 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 2.5 h Then the reaction was suppressed by adding dropwise 25 ml of water. After the reaction mixture was diluted with water and then was extracted with 3 portions 35 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a white solid substance was obtained 12.5 mg (yield: 16,1%) of 2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)propionamide: tPL: 60-62°C; EI-HRMS m/e Rasch. for C20H23ClN2O2(M+): 358,1448, detect.: 358,1443.

Example 51

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxypyridine-2-yl)propionamide

A solution of 183 mg (0,63 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38) in 6,37 ml of methylene chloride was cooled to 0°C, and then treated with 0.35 ml (0.7 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and then at 25°C for 30 minutes Then the reaction mixture was treated 281 mg (1.4 mmol) of 5-benzyloxypyridine-2-ylamine and 0.26 ml (1.5 mmol) of N,N-diisopropyl the offer was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) in the form of a yellow solid was obtained 150 mg (yield: 50.0%) were N-(5-benzyloxypyridine-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide: tPL: 47-49°C; EI-HRMS m/e Rasch. for C26H26Cl2N2O2S (M+): 469,1449, detect.: 469,1455.

The solution 145,3 mg (0.3 mmol) of N-(5-benzyloxypyridine-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide 5.1 ml of methanol was treated with 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas at 25°C for 16 hours Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum obtaining in the form of a yellowish-brown solid 92,2 mg (yield: 78.5 per cent) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxypyridine-2-yl)propionamide: tPL: 79-81°C; EI-HRMS m/e Rasch. for C19H20Cl2N2O2(M+): 378,0896, detect.: 378,0890.

Example 52

3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)-2-(4-methanesulfonyl) propionamide

A solution of 110 mg (0.26 mmol) of the methyl ester of 6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido] nick is Wali by slow addition of 15 mg (0.38 mmol) of lithium aluminum hydride. The reaction mixture was stirred at 0°C for 30 min, and then heated to 25°C. After 1 h exposure at 25°With the data thin-layer chromatography still indicated the presence of starting material. In the reaction mixture was added an additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) and the reaction mixture was stirred at 25°C for 1 h Then the reaction in the reaction mixture was suppressed by adding dropwise 10 ml of water. The resulting mixture was divided between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a yellow foam was obtained 60 mg (yield: 57%) 3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)-2-(4-methanesulfonyl)propionamide: tPL: 74-77°C; EI-HRMS m/e Rasch. for C21H26N2O4S (M+): 402,1613, detect.: 402,1617.

Example 53

(A) 3-cyclopentyl-2-(4-methanesulfonyl)-N-(5-methylpyridin-2-yl)propionamide

A solution of 177 mg (of 0.68 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C, and then treated by adding small portions 132 mg (0,74 mmol) of N-bromosuccinimide. The reaction mixture is in technoboy acid (obtained in example 3 (A)). The reaction mixture was stirred at 25°C for 30 min and then was treated with 154 mg (1,42 mmol) 2-amino-5-methylpyridine. The resulting reaction mixture was stirred at 25°C for 1 h the Crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to give a red solid of the crude 3-cyclopentyl-2-(4-methanesulfonyl)-N-(5-methylpyridin-2-yl)propionamide. This crude product was further purified by precipitation from hexanol/ethyl acetate in a ratio of 1/1 with obtaining as not quite white solid, 80 mg (yield: 31%) of pure 3-cyclopentyl-2-(4-methanesulfonyl)-N-(5-methylpyridin-2-yl)propionamide: tPL: 184-185°C; EI-HRMS m/e Rasch. for C21H26N2O3S (M+): 386,1664, detect.: 386,1664.

(B) Similarly received:

(a) from 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and methyl ester of 6-aminonicotinic acid: methyl ester of 6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido] nicotinic acid as a yellow foam: tPL: 82-85°C; EI-HRMS m/e Rasch. for C22H26N2O5S (M+): 430,1562, detect.: 430,1571.

Example 54

23589=+87,5° (C=0,160, chloroform); EI-HRMS m/e Rasch. for C20H25CL2NO3(M+): 397,1211, detect.: 397,1215 and (2) in the form of a white solid 1.88 g (yield: 28%) of 3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-4(S)-isopropylacetanilide-2-it: tPL: 71,9-74,6°C; []23589=-27,6° (C= 0,188, chloroform); EI-HRMS m/e Rasch. for C20H25CL2NO3(M+): 397,1211, detect.: 397,1212.

A solution of 1.88 g (4,72 mmol) 3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionyl]-4(S)-isopropylacetanilide-2-it in 73 ml of tetrahydrofuran and 22 ml of water, cooled to 0°C, and treated with 2.1 ml of 30% aqueous hydrogen peroxide solution and 394 mg (9.4 mmol) of lithium hydroxide. The reaction mixture was stirred at 0°C for 1 h, after this time the reaction was suppressed by adding 16 ml of a saturated aqueous solution of sodium sulfite followed by adding 50 ml of 0.5 N. aqueous sodium bicarbonate solution. Next, under vacuum, remove the tetrahydrofuran. The residue was diluted with 40 ml water and was extracted with 3 portions of 20 ml of methylene chloride. Then the aqueous layer 5 Ago the combined organic layers were dried over sodium sulfate, was filtered and concentrated under vacuum obtaining in the form of a white solid 928 mg (yield: 70%) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionic acid: tPL: 75,1-78,3°C; []23589=-50,3° (C=0,100, chloroform); EI-HRMS m/e Rasch. for C14H16CL2O3(M+): 286,0527, detect.: 286,0535.

A solution of 344 mg (1,31 mmol) of triphenylphosphine in 10 ml of methylene chloride, cooled to 0°C, cultivated 263 mg (1.48 mmol) of N-bromosuccinimide. The reaction solution was stirred at 0°C for 5 minutes after this time was added 250 mg (0.87 mmol) of 3-cyclopentyl-2-(R)-(3,4-dichlorophenyl)propionic acid. The reaction mixture slowly over 45 min was heated to 25°C. after this time the reaction mixture was added 145 mg (1.13 mmol) of 5-chloro-2-aminopyridine and 0.11 ml (1,31 mmol) of pyridine. The reaction mixture was stirred at 25°C for 20 hours, after this time the reaction mixture was diluted with 10 ml water and was extracted with 3 portions of 10 ml of methylene chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a white solid substance was obtained 289 mg (yield: 84%) N76; (C=0,16, chloroform); EI-HRMS m/e Rasch. for C19H19Cl3N2O (M+): 396,0563, detect.: 396,0565.

(B) Similarly received:

(a) from 2-aminopyridine and 3-cyclopentyl-2-(R)-(3,4-dichlorophenyl)-propionic acid: 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic in the form of a white foam: []23589=-56,2° (C=0,153, chloroform); EI-HRMS m/e Rasch. for C19H10Cl3N2O (M+): 362,0953, detect.: 362,0952;

(b) from 2-aminothiazole and 3-cyclopentyl-2-(R)-(3,4-dichlorophenyl)propionic acid: 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic in the form of a white solid: tPL: 133,4 TO 136.5°C; []23589=-66,0° (C=0,106, chloroform); EI-HRMS m/e Rasch. for C17H18Cl2N2OS (M+): 368,0517, detect.: 368,0519;

(C) of the ethyl ester of 2-(aminothiazol-5-yl)octoxynol acid and 3-cyclopentyl-2-(R)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid: ethyl ester of (2R)-{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-5-yl}octoxynol acid as a pale yellow foam: tPL: 117-120°C; FAB-HRMS m/e Rasch. for C21H22Cl2N2O4S (M+N)+: 469,0755, detect.: 469,0753;

(g) from glyoxylate ethyl-2-amino-4-thiazole and 3-cycloparaphenylene]thiazol-4-yl}octoxynol acid as a white solid: EI-HRMS m/e Rasch. for C21H22Cl2N2O4S (M+): 468,0677, detect.: 468,0677.

Example 55

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)propionamide

A solution of 200 mg (0.70 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38), 310 mg (0.70 mmol) of hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium, 244 μl (1,40 mmol) of N,N-diisopropylethylamine and 140 mg (1.05 mmol) of 2-iminoimidazolidine in 5 ml of dry N,N-dimethylformamide was stirred at 25°C in nitrogen atmosphere for 15 hours, the Reaction mixture was separated between water and ethyl acetate. The organic layer was washed 1 N. aqueous solution of hydrochloric acid, washed with water and washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white solid substance was obtained at 81.4 mg (yield: 33%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)propionamide: tPL: 58-60°C; EI-HRMS m/e Rasch. for C17H19Cl2N3O3(M+): 351,0905, detect.: 351,0901.

Example 56

3-cyclopentyl-2-(3,4-dichlorophenyl)nil)propionic acid (obtained in example 38) in 215 ml (2,46 mmol) oxalicacid was cooled to 0°C and then was treated with 1 drop of dry N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 30 min, and then stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum to obtain the product as a yellow oil. This product is in the form of a yellow oil was dissolved in a small amount of methylene chloride and then was gradually added into the solution to 48.3 mg (0.49 mmol) of 3-amino-5-methylisoxazole and 68 ml (0.49 mmol) of triethylamine and 1.2 ml of methylene chloride. The resulting reaction mixture was stirred at 25°C for 14 h, the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 100 ml of ethyl acetate and then washed with 10% aqueous solution of hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow glassy material was obtained to 78.3 mg (yield: 87%) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylisoxazol-3-yl)propionamide: tPL: 84-86°C.; FAB-HRMS m/e Rasch. for C18H20Cl2N2O2(M+N)+: 367,0981, detect.: 367,0982.

Example 57

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-ylpropionic

RA is pentyl-2-(3,4-di-chlorophenyl)propionic acid (obtained in example 38), 73 μl (0.42 mmol) of N,N-diisopropylethylamine and 27 mg (0.31 mmol) 2-aminoanisole in 1 ml of dry N,N-dimethylformamide was stirred at 25°C in nitrogen atmosphere for 15 hours, the Reaction mixture was separated between water and ethyl acetate. The organic layer was washed for 1H. aqueous solution of hydrochloric acid, washed with water and washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white solid substance was obtained to 34.9 mg (yield: 47%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-ylpropionic: tPL: 134-136°C; EI-HRMS m/e Rasch. for C17H18Cl2N2O2(M+): 352,045, detect.: 352,0750.

Example 58

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-ylpropionic

The solution 652,2 mg (2,18 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (obtained in example 38), 908,3 mg (2,39 mmol) hexaphosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea, 1.1 ml (6,53 mmol) of N,N-diisopropylethylamine and 310,6 mg (3,27 mmol) 3-aminopyridazine in 11 ml of dry N,N-dimethylformamide was stirred at 25°C in nitrogen atmosphere in techaisle 200 ml of ethyl acetate. The organic layer is washed with 10% aqueous hydrochloric acid and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white foam was obtained 493,8 mg (yield: 62%) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-PI-ridazin-3-ylpropionic: tPL: 70-71°C; EI-HRMS m/e Rasch. for C18H19Cl2N3O (M+): 363,0905, detect.: 363,0908.

Example 59

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylpropionic

A solution of 100 mg (0.35 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38) in 1 ml of methylene chloride was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0°C, and then treated by adding dropwise 34 ml (0,39 mmol) oxalicacid. The reaction mixture was stirred at 0°C for 10 min, and then stirred at 25°C for 2 h, the Reaction mixture was concentrated under vacuum. The obtained residue was dissolved in a small amount of methylene chloride and slowly added to a chilled (0°C) a solution of 67 mg (0.70 mmol) of 2-aminopyrimidine in Bali at 25°C for 2 hours The reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with water and was extracted with 3 portions of 50 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white solid substance was obtained with 85.4 mg (yield: 67%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylpropionic: tPL: 103-105°C; EI-HRMS m/e Rasch. for C18H19Cl2N3O (M+): 363,0905, detect.: 363,0915.

Example 60

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-pyrimidine-6-ylpropionic

A solution of 200 mg (0.69 mmol) of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (obtained in example 54 (A)) in 5 ml of methylene chloride was treated with 1 drop of N,N-dimethylformamide and then was cooled to 0°C. Next, the reaction mixture was treated 0,52 ml (1.04 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of 131 mg (1.38 mmol) of 4-aminopyrimidine in 10 ml of tetrahydrofuran and 0.28 ml (the mixture was diluted with 10 ml water and was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/2 hexane/ethyl acetate) as a white solid substance was obtained 147 mg (yield: 60%) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-pyrimidine-4-ylpropionic: tPL: KZT 166.5-169,3°C; EI-HRMS m/e Rasch. for C18H19Cl2N3O (M+): 363,0905, detect.: 363,0909.

Example 61

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic

A solution of 3.2 ml (23,16 mmol) Diisopropylamine in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated with 2.3 ml (23,16 mmol) of a 10 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution 2,01 g (11,03 mmol) of 4-(methylthio)phenylacetic acid in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 1 h, after this time was treated by the addition dropwise of a solution of 2.55 g (12,13 mmol) iodomethylpropane in small quantity is up to 25°C then was stirred for 24 h the Reaction in the reaction mixture extinguished with water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 200 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.01 g (yield: 35%) 3-cyclopentyl-2-(4-methylsulfinylphenyl)propionic acid: tPL: 91-93°C; EI-HRMS m/e Rasch. for C15H20O2S (M+): 264,1184, detect.: 264,1177.

A solution of 200 mg (from 0.76 mmol) 3-cyclopentyl-2-(4-methylsulfinylphenyl)-propionic acid and 198 mg (from 0.76 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated with gradual addition of 150 mg (0.84 mmol) of N-bromosuccinimide. After adding N-bromosuccinimide the reaction mixture for 30 min was heated to 25°C. Next, the reaction mixture was treated with 160 mg (1,60 mmol) of 2-aminothiazole and the resulting reaction mixture AC is Yes. The obtained residue was diluted with water and ethyl acetate. The organic layer was washed 1 N. aqueous solution of hydrochloric acid, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) in the form of a yellow solid was obtained crude 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic. By recrystallization from hexanol/ethyl acetate in a ratio of 3/1 in the form of a white solid substance was obtained 114 mg (yield: 44%) of pure 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic: tPL: 195-196°C; EI-HRMS m/e Rasch. for C18H22N2O2S2(M+): 346,1174, detect.: 346,1171.

A solution of 75 mg (0,216 mmol) 3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic in 1 ml of methylene chloride was treated with 50 mg (0,216 mmol) 3-chloroperoxybenzoic acid (75% of grade). Immediately after this, the reaction mixture was analyzed by thin-layer chromatography, the results of which indicated no by this time the source material. The reaction mixture was separated between water and methylene chloride and then washed with saturated aqueous was restartable and concentrated under vacuum. By recrystallization from hexanol/ethyl acetate in a ratio of 1/1 in the form of a white solid substance was obtained 25 mg (yield: 32%) 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic: tPL: 170-173°C; EI-HRMS m/e Rasch. for C18H22N2O2S2(M+): 362,1123, detect.: 362,1121.

Example 62

Ethyl ether {2-[3-cyclopentyl-2-(4-triftormetilfullerenov)-propionamido]thiazol-4-yl}acetic acid

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then treated of 6.7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 1.89 g (8,00 mmol) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after that time, it was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, policewoman remove tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3O2S (M+): 318,0901, detect.: 318,0912.

A solution of 1.33 g (4,18 mmol) 3-cyclopentyl-2-(4-cryptomelane-ylphenyl)propionic acid in 10 ml of methanol was slowly treated with 4 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 36 hours the Reaction mixture was allowed to cool to 25°C and then it was concentrated under vacuum to remove methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over self the rck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-trifloromethyl-phenylphenyl)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1052.

A solution of 1.14 g (3,43 mmol) methyl ester 3-cyclopentyl-2-(4-tri-formatterconverter)propionic acid 8.6 ml of methylene chloride was treated with 2.00 g of 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 9,26 mmol). The reaction mixture was stirred at 25°C for 17 h, after this time the data thin-layer chromatography showed the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added optional 2.00 g of 3-chloroperoxybenzoic acid and the resulting reaction mixture was stirred at 25°C for 3 days. The reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 3 portions of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of chlorite is matography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.19 g (yield: 95%) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0965.

The solution 708,2 mg (1.94 mmol) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 2.4 ml of tetrahydrofuran was treated with 3.6 ml (2,92 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 h and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous layer with 10% aqueous hydrochloric acid solution was acidified to pH 2 and then extracted with 2 portions of 100 ml of ethyl acetate. The combined organic layers were washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to obtain a cream solid. This solid was purified by rubbing the powder in diethyl ether/petroleum ether to obtain a white solid 527,0 mg (yield: 77%) of pure 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 143-145°C; EI-HRMS m/e Rasch. for CPL: 48-51°C; EI-HRMS m/e Rasch. for C22H25F3N2O5S2(M+): 518,1157, detect.: 518,1157.

Example 63

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-triftormetilfullerenov)propionamide

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then treated of 6.7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction I) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after that time, it was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water, and then it was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3O2S(M+): 318,0901, detect.: 318,0912.

A solution of 1.33 g (4,18 mmol) 3-cyclopentyl-2-(4-trifloromethyl-phenyl)propionic acid in 10 ml of methanol was slowly treated by adding 4 drops of concentrated sulfuric acid. Formed is then concentrated under vacuum to remove methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1052.

A solution of 1.14 g (3,43 mmol) methyl ester 3-cyclopentyl-2-(4-tri-formatterconverter)propionic acid 8.6 ml of methylene chloride was treated with 2.00 g of 3-chloroperoxybenzoic acid (80-85% of whom varieties, in terms of 80% of the basic substance, 9,26 mmol). The reaction mixture was stirred at 25°C for 17 h, after this time the data thin-layer chromatography showed the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added optional 2.00 g of 3-chloroperoxybenzoic acid and the resulting reaction is of milenaria. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 3 portions of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.19 g (yield: 95%) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0965.

The solution 708,2 mg (1.94 mmol) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 2.4 ml of tetrahydrofuran was treated with 3.6 ml (2,92 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 h and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous layer with 10% aqueous hydrochloric acid solution was acidified to pH 2 and then extracted with 2 portions of 100 ml of ethyl acetate. The combined organic layers were washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, female grinding into powder in diethyl ether/petroleum ether to obtain a white solid 527,0 mg (yield: 77%) of pure 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 143-145°C; EI-HRMS m/e Rasch. for C15H17F3O4S (M+): 350,0800, detect.: 350,0816.

A solution of 206 mg (0,785 mmol) of triphenylphosphine in 4 ml of methylene chloride was cooled to 0°C, and then slowly worked the addition of 140 mg (0,785 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min, and then was treated with 250 mg (0,710 mmol) 3-cyclopentyl-2-(4-triftormetilfullerenov) propionic acid. The resulting reaction mixture was stirred at 0°C for 10 min, and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 271 mg (1.57 mmol) of 2-amino-5-bromopyridine. The resulting reaction mixture was stirred at 25°C for 15 hours Then this reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) as a yellow foam was obtained 226 mg (yield: 63%) of N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-triftormetilfullerenov)propionamide: tPL: 130-132°C; EI-HRMS m/e Rasch. for C20H20BrF3N2O3S (M+) 504,0330, detect.: 504,0325.

Example 64

2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C and then was treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise restou the mixture was stirred at -78°C and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 260 mg (0,834 mmol) methyl ester of 2-(4-chloro-3-nitrogen-yl)-3-cyclopentylpropionic acid in 3 ml of tetrahydrofuran was treated with 1.25 ml (1.00 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 15 hours the Resulting reaction mixture was divided between 50 ml water and 50 ml of ethyl acetate and then was treated with 10 ml of 1 N. aqueous solution of hydrochloric acid. The layers were shaken and separated. Next, the aqueous layer was extracted with 50 ml ethyl acetate. Obyedinenny the IDA yellow solid, which was used without further purification, 243 mg (yield: 98%) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: tPL: 112-115°C; FAB-HRMS m/e Rasch. for C14H16ClNO4(M+H)+: 298,0847, detect.: 298,0851.

A solution of 105 mg (0,403 mmol) of triphenylphosphine in 1 ml of methylene chloride was cooled to 0°C and then was treated with gradual addition of 72 mg (0,403 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 20 min and then was treated with 100 mg (0,336 mmol) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 10 min and then was heated to 25°C, after which it was stirred for 20 minutes Then the reaction mixture was treated with 74 mg (0,739 mmol) of 2-aminothiazole.

The resulting reaction mixture was stirred at 25°C for 15 hours the Crude reaction mixture was treated with 2 ml of hexanol/ethyl acetate (ratio 3:1) and then purified Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate). In the form of a pale yellow foam was obtained 93 mg (yield: 73%) of pure 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 68-72°C (foam ultinationals); EI-HRMS m/e">2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C, and then treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of those who ü stirred at -78°C for 1 h, after this period of time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 260 mg (0,834 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid in 3 ml of tetrahydrofuran was treated with 1.25 ml (1.00 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 15 hours the Resulting reaction mixture rasstraivay and shared. Next, the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain a yellow solid which was used without further purification, 243 mg (yield: 98%) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: tPL: 112-115°C; FAB-HRMS m/e Rasch. for C14H16ClNO4(M+H)+: 298,0847, detect.: 298,0851.

A solution of 105 mg (0,403 mmol) of triphenylphosphine in 1 ml of methylene chloride was cooled to 0°C and then was treated with careful addition of 72 mg (0,403 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 20 min and then was treated with 100 mg (0,336 mmol) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 10 min and then it was heated to 25°C, after which it was stirred for 20 minutes Then the reaction mixture was treated with 70 mg (0,739 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 hours the Crude reaction mixture was treated with 2 ml of hexanol/ethyl acetate (ratio 3:1) and then purified Express chromatography (Silica gel 60 Merck, 230-400 mesh m is opentel-N-pyridine-2-ylpropionic: tPL: 48-52°C (foam ultinationals); EI-HRMS m/e Rasch. for C19H20ClN3O3(M+): 373,1193, detect.: 373,1185.

Example 66

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionamide

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C, and then treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 CSOs ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml dimetilan which formed a brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

The solution 865 mg (2,43 mmol) methyl ester 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid in b ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted with 25 ml of water and then was treated with 10 ml of 1 N. aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and cabelas foam received 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. Analytical data indicated the presence of small amounts of impurities, but this 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid was used in the subsequent reactions without further purification.

A solution of 212 mg (0.81 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C, and then slowly treated with 144 mg (0.81 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 250 mg (0.73 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. The resulting reaction mixture was stirred at 0°C for 5 min, and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated 279 mg (1,61 mmol) 2-amino-5-bromopyridine.

The resulting reaction mixture was stirred at 25°C for 15 hours the resulting crude mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) to give a white foam 121 mg (yield: 33%) of N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionamide: tPL: 80-83°C (foam ultinationals); FAB-HRMS m/e Rasch. for C20H22BrN3O5S (M+N)+: 496,0542, propionamide

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C, and then treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purpuro the seed was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml of DMSO was kept at 130°C for 5 hours Then the black reaction mixture was poured into 20 g of ice, which formed the brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further EXT the rum sodium chloride, was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

The solution 865 mg (2,43 mmol) methyl ester 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid in 6 ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted 25 water and then was treated with 10 ml of 1 N. aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/4 hexane/ethyl acetate) as a white foam was obtained 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl) propionic acid. Analytical data indicated a new acid was used in the subsequent reactions without further purification.

A solution of 138 mg (of 0.53 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated with gradual addition of 94 mg (of 0.53 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 150 mg (0.44 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. The resulting reaction mixture was stirred at 0°C for 5 min, and then it was heated to 25°C, after which it was stirred for 25 minutes Then the reaction mixture was treated with 97 mg (0.97 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 hours the Crude mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale yellow solid 96 mg (yield: 52%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic: tPL: 121-124°C; FAB-HRMS m/e Rasch. for C18H21N3O5S2(M+H)+424,1001, detect.: 424,1000.

A solution of 150 mg (0,354 mmol) 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic in 3 ml of methanol was treated with 50 mg of 10% palladium on charcoal. The reaction mixture was stirred under high d is the mash was filtered by passing through a layer of brownmillerite and this layer brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 20/1 methylene chloride/methanol) as a white solid substance was obtained 85 mg (yield: 59%) 3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl)N-thiazol-2-ylpropionic: tPL: 124-126°C; EI-HRMS m/e Rasch. for C18H23N3O4S2(M+): 409,1130, detect.: 409,1131.

Example 68

2-(3-amino-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetragonia of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cycle is SS="ptx2">A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml of DMSO was kept at 130°C for 5 hours Then the black reaction mixture was poured into 20 g of ice, which formed the brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

The solution 865 mg (2,43 mmol) methyl ester 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid in 6 ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours, the Reaction mixture of kontsentrirovanii 10 ml of 1N. an aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/4 hexane/ethyl acetate) as a white foam was obtained 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. Analytical data indicated the presence of small amounts of impurities, but this 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid was used in the subsequent reactions without further purification.

A solution of 138 mg (of 0.53 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated with gradual addition of 94 mg (of 0.53 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 150 mg (0.44 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. The resulting reaction mixture was stirred at 0°C for 5 min, and then it was heated to 25°C, after which it was stirred for 25 minutes Then the reaction mixture was treated with 97 mg (0.97 mmol) of 2-aminothiazole. The resulting reaction mixture peremeci-400 mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale yellow solid 96 mg (yield: 52%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic: tPL: 121-124°C; FAB-HRMS m/e Rasch. for C18H21N3O5S2(M+N)+424,1001, detect.: 424,1000.

A solution of 100 mg (0,236 mmol) 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic in 2 ml of methanol was treated with a solution of 27 mg (0,500 mmol) of ammonium chloride in 200 ml of water. Next, the reaction mixture was treated with 151 mg (2,31 mmol) of zinc dust. The reaction mixture is boiled under reflux for 2 hours the Reaction mixture was allowed to cool to 25°C, and then it was filtered by passing through a layer of brownmillerite. This layer brownmillerite thoroughly washed with methanol. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white solid substance was obtained 40 mg (yield: 43%) of 2-(3-amino-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide: tPL: 207-209°C; EI-HRMS m/e Rasch. for C18H23N3O3S2(M+): 393,1181, detect.: 393,1180.

Example 69

3-cyclopentyl-N-thiazol-2-yl-2-(3-triftormetilfullerenov)Anola slowly treated by adding 10 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 18 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to remove methanol. The residue was diluted with 100 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum obtaining in the form of a pale yellow oil which was used without additional purification, 5,28 g (yield: 99%) of methyl ester of (3-triftormetilfullerenov)acetic acid: EI-HRMS m/e Rasch. for C10H9F3O2S (M+): 250,0275, detect.: 250,0274.

A solution of 1.5 ml (10.5 mmol) of Diisopropylamine in 27 ml of dry tetrahydrofuran and 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled in a nitrogen atmosphere to -78°C, and then processed to 4.2 ml (10.5 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 2.50 g (10.0 mmol) of methyl ether (3-triftormetilfullerenov) acetic acid in a small amount of tetrahydrofuran. The reaction mixture was stirred at -78°C in the course is the amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 50 ml of water, and then divided between 75 ml of water and 75 ml of ethyl acetate. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 8/1 hexane/ethyl acetate) as a colourless oil was obtained 2,95 g (yield: 89%) of methyl ester of 3-cyclopentyl-2-(3-Cryptor-methylsulfinylphenyl)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1047.

A solution of 2.75 g (of 8.27 mmol) of methyl ester of 3-cyclopentyl-2-(3-tri-formatterconverter)propionic acid in 30 ml of methylene chloride was treated 4,28 g 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 20,67 mmol). The reaction mixture was stirred at 25°C for 6 h, after this time the data thin-layer chromatography showed the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added addition of 4.00 g of 3-chloroperoxybenzoic acid and the resulting Rea is ranged between 100 ml of water and 100 ml of methylene chloride. The layers were shaken and separated. The organic phase is twice washed with saturated aqueous sodium bicarbonate, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/methylene chloride) in the form of a colorless oil was obtained 2,07 g (yield: 69%) of methyl ester of 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0947.

A solution of 1.28 g (3,52 mmol) methyl ester 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid in 12 ml of tetrahydrofuran was treated with 4.9 ml (3.88 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 24 h, and then concentrated under vacuum removal of tetrahydrofuran. The resulting product in the form of a yellow oil was divided between 50 ml water and 50 ml of ethyl acetate and then was treated with 1H. aqueous solution of hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a viscous yellow oil, which upon standing senil)propionic acid: tPL: 86-88°C; EI-HRMS m/e Rasch. for C15H17F3O4S (M+): 350,0800, detect.: 350,0792.

A solution of 194 mg (0,74 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C, and then processed by the gradual addition of 132 mg (0,74 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 15 min and then was treated with 200 mg (or 0.57 mmol) 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid. The resulting reaction mixture was stirred at 0°C for 5 min and then for 30 min, it was heated to 25°C. Next, the reaction mixture was treated with 143 mg (1,43 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 hours Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) to obtain in the form of a light yellow foam 178 mg (yield: 72%) of pure 3-cyclopentyl-N-thiazol-2-yl-2-(3-triftormetilfullerenov)propionamide: tPL: 61-64°C (foam was ultinationals); EI-HRMS m/e Rasch. for C18H19F3N2O3S2(M+): 432,0789, detect.: 432,0790.

Example 70

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-thiazol-2-ylpropionic

atively 4 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C and then it was concentrated under vacuum to remove methanol. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a colourless oil was obtained 2.58 g (yield: 97%) of methyl ester of (3-fluoro-4-triptoreline)acetic acid: EI-HRMS m/e Rasch. for C10H8F4O2(M+): 236,0460, detect.: 236,0457.

A solution of 1.5 ml (10,67 mmol) Diisopropylamine in 24 ml of dry tetrahydrofuran and 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated with 4.3 ml (10,67 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 45 min and then treated by the addition dropwise of a solution of 2.40 g (10,16 mmol) methyl ether (3-fluoro-4-triptoreline) acetic acid in a small amount of tetrahydrofuran. The reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 2.24 g (10,67 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, the pic is Orica ammonium and then shared between 75 ml of water and 75 ml of ethyl acetate. The layers were shaken and separated. The aqueous layer was additionally extracted with 1 portion in 75 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 5/1 hexane/ethyl acetate) as a colourless oil was obtained 2,69 g (yield: 83%) of methyl ester of 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H18F4O2(M+): 318,1243, detect.: 318,1250.

A solution of 1.80 g (5,69 mmol) methyl ester 3-cyclopentyl-2-(3-fluoro-4-triptoreline) propionic acid in 15 ml of tetrahydrofuran was treated with 7.1 ml (5,69 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 15 hours, the Reaction mixture was concentrated under vacuum. The obtained residue was diluted with 100 ml of ethyl acetate, and then washed with 5% aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) in the form of a white solid is#176;C; FAB-HRMS m/e Rasch. for C15H16F4O2(M+H)+: 305,1165, detect.: 305,1175.

A solution of 312 mg (1,19 mmol) of triphenylphosphine in 5 ml of methylene chloride was cooled to 0°C and then slowly treated 212 mg (1,19 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min and then was treated with 300 mg (0,99 mmol) 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid. The resulting reaction mixture was stirred at 0°C for 15 min and then was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 218 mg (2,18 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 3 days. Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) to obtain in the form of a white solid substance 243 mg (yield: 64%) 3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-thiazol-2-ylpropionic: tPL: 194-195°C; EI-HRMS m/e Rasch. for C18H18F4N2OS (M+): 386,1076, detect.: 386,1076.

Example 71

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-ylpropionic

A solution of 2.50 g (of $ 11.25 mmol) 3-fluoro-4-(triflate. The resulting reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C and then it was concentrated under vacuum to remove methanol. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a colourless oil was obtained 2.58 g (yield: 97%) of methyl ester of (3-fluoro-4-triptoreline)acetic acid: EI-HRMS m/e Rasch. for C10H8F4O2(M+): 236,0460, detect.: 236,0457.

A solution of 1.5 ml (10,67 mmol) Diisopropylamine in 24 ml of dry tetrahydrofuran and 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated with 4.3 ml (10,67 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 45 min and then treated by the addition dropwise of a solution of 2.40 g (10,16 mmol) methyl ether (3-fluoro-4-triptoreline) acetic acid in a small amount of tetrahydrofuran. The reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 2.24 g (10,67 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it Perea was then divided between 75 ml of water and 75 ml of ethyl acetate. The layers were shaken and separated. The aqueous layer was additionally extracted with 1 portion in 75 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 5/1 hexane/ethyl acetate) as a colourless oil was obtained 2,69 g (yield: 83%) of methyl ester of 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H18F4O2(M+): 318,1243, detect.: 318,1250.

A solution of 1.80 g (5,69 mmol) methyl ester 3-cyclopentyl-2-(3-fluoro-4-triptoreline) propionic acid in 15 ml of tetrahydrofuran was treated with 7.1 ml (5,69 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 15 hours, the Reaction mixture was concentrated under vacuum. The obtained residue was diluted with 100 ml of ethyl acetate, and then washed with 5% aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) in the form of a white solid is#176;C; FAB-HRMS m/e Rasch. for C15H16F4O2(M+N)+: 305,1165, detect.: 305,1175.

A solution of 312 mg (1,19 mmol) of triphenylphosphine in 5 ml of methylene chloride was cooled to 0°C and then slowly worked the addition of 212 mg (1,19 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min and then was treated with 300 mg (0,99 mmol) 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid. The resulting reaction mixture was stirred at 0°C for 15 min and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 205 mg (2,18 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 3 days. Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) to obtain in the form of a pale yellow foam 171 mg (yield: 45%) 3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-ylpropionic: tPL: 40-44°C (foam ultinationals); EI-HRMS m/e Rasch. for C20H20F4N2O (M+): 380,1512, detect.: 380,1519.

Example 72

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

Rahl concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 3 days. The reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H12O2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. The reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction with who I am. The reaction mixture was concentrated under vacuum removal of carbon tetrachloride. The resulting aqueous layer was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H11BrO2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 6,10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfinylphenyl) acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 5,59 Ali to 25°C after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution b is, was filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 1,09 g (yield: 94%) of methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

A solution of 1.62 g (4,16 mol) methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid in 10 ml of methanol was treated with 8.7 ml (a total of 8.74 mol) 1 N. aqueous sodium hydroxide solution. The reaction mixture was stirred at 25°C for 27 hours, the Reaction mixture was concentrated under vacuum to remove methanol. The resulting aqueous residue 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 400 ml of ethyl acetate. The organic layer was washed 1 portion 300 ml of water and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid, which was used without additional purification, 1.39 g (yield: 89%): 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid tPL: 149-150°With the eh) of triphenylphosphine in 3 ml of methylene chloride, was cooled to 0°C and then slowly worked the addition of 114 mg (0.64 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 200 mg (of 0.53 mmol) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 5 min and then was heated to 25°C, after which it was stirred for 25 minutes Then the reaction mixture was treated with 117 mg (1,17 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain a yellow solid 214 mg (yield: 88%) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 106-107°C; EI-HRMS m/e Rasch. for C18H21BrN2O3S2(M+): 456,0177, detect.: 456,0175.

Example 73

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic

The solution 21,21 g (116,38 mmol) of 4-(methylthio)phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. Formed reacts is so concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H12O2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. The reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum, removing tetrachloride plerre over sodium sulfate, was filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H11BrO2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 6,10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfinylphenyl) acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 5.59 in (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and zatrzyma 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

A solution of 1.62 g (4,16 mol) methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid in 10 ml of methanol was treated with 8.7 ml (a total of 8.74 mol) 1 N. aqueous sodium hydroxide solution. The reaction mixture was stirred at 25°C for 27 hours, the Reaction mixture was concentrated under vacuum to remove methanol. The resulting aqueous residue 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 400 ml of ethyl acetate. The organic layer was washed 1 portion 300 ml of water and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid, which was used without additional purification, 1.39 g (yield: 89%): 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid tPL: 149-150°C; FAB-HRMS m/e Rasch. for C15H19BrO4S (M+H)+: 375,0266, detect.: 375,0274.

A solution of 168 mg (0.64 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C and then slowly worked the addition of 114 mg (0.64 mmol) of N-bromosuccinimide. The reaction mixture peremeshivaemogo acid. The resulting reaction mixture was stirred at 0°C for 5 min and then was heated to 25°C, after which it was stirred for 25 minutes Then the reaction mixture was treated with 110 mg (1,17 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to give a white foam 175 mg (yield: 73%) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic: tPL: 99-101°C; FAB-HRMS m/e Rasch. for C20H23BrN2O2S (M+N)+: 451,0692, detect.: 451,0689.

Example 74

2-(3-bromo-4-methanesulfonyl)-N-(5-bromopyridin-2-yl)-3-cyclo-pantypooping

The solution 21,21 g (116,38 mmol) of 4-(methylthio)phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 3 days. The reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of n is I. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H12O2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. The reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum removal of carbon tetrachloride. The resulting aqueous layer was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express-chromatographia ether (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H11BrO2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 6,10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfinylphenyl) acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 5.59 in (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sulfate is Sana'a/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 1,09 g (yield: 94%) of methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

A solution of 1.62 g (4,16 mol) methyl ester of 2-(3-bromo-4-meanswhen-ylphenyl)-3-cyclopentylpropionic acid in 10 ml of methanol was treated with 8.7 ml (a total of 8.74 mol) 1H. water rastvoro under vacuum to remove methanol. The resulting aqueous residue 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 400 ml of ethyl acetate. The organic layer was washed 1 portion 300 ml of water and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid, which was used without additional purification, 1.39 g (yield: 89%): 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid tPL: 149-150°C; FAB-HRMS m/e Rasch. for C15H19BrO4S (M+H)+: 375,0266, detect.: 375,0274.

A solution of 154 mg (0.59 mmol) of triphenylphosphine in 3 ml of methylene chloride was cooled to 0°C and then slowly worked the addition of 104 mg (0.59 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 200 mg (of 0.53 mmol) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 5 min and then was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 203 mg (1,17 mmol) 2-amino-5-bromopyridine. The reaction mixture is displaced is th (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) to give a white foam 164 mg (yield: 58%) of 2-(3-bromo-4-methanesulfonyl)-N-(5-bromopyridin-2-yl)-3-cyclopentylpropionate: tPL: 83-86°C (foam ultinationals); FAB-HRMS m/e Rasch. for C20H22Br2N2O2S (M+H)+: 528,9796, detect.: 528,9783.

Example 75

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

The solution 21,21 g (116,38 mmol) of 4-(methylthio) phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 3 days. The reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) the thief of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. The reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum removal of carbon tetrachloride. The resulting aqueous layer was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H11BrO2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting p is equal to 6.10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfinylphenyl) acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 5.59 in (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). Reaction is inflorida. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 1,09 g (yield: 94%) of methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

The mixture 990,0 mg (2.54 mmol) of the methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid and 273,3 mg (3,05 mmol) of copper cyanide(1) in 2.5 ml of dry N,N-dimethylformamide was heated under reflux for 4 hours the Reaction mixture was allowed to cool to 25°C and the crude reaction mixture was purified directly without additional chemical treatment. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanol, then 3/1 hexane/ethyl acetate) as a very pale yellow oil was obtained 646,5 mg (yield: 76%) of methyl ester of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. DL 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid in 25 ml of tetrahydrofuran was treated with 27 ml (21.6 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 2.5 h, the Reaction mixture was separated between water and ethyl acetate and then 10% aqueous solution of hydrochloric acid acidified to pH 2. The layers were shaken and separated. The obtained organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a pale yellow oil, which was hardened in becoming pale yellow solid, 3.80 g (yield: 82%) of crude 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid. The sample for analysis was obtained by recrystallization from ethyl acetate to obtain a white solid of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid: tPL: 180-181°C; EI-HRMS m/e Rasch. for C16H19NO4S (M+):321,1034, detect.: 321,1039.

A solution of 98 mg (from 0.37 mmol) of triphenylphosphine in 1 ml of methylene chloride was cooled to 0°C and then slowly treated with added 67 mg (from 0.37 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 15 min and then was treated with 100 mg (0.31 mmol) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid. The resulting reaction Smin. Next, the reaction mixture was treated with 68 mg (of 0.68 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to give a white solid 117 mg (yield: 93%) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide: tPL: 145-148°C; EI-HRMS m/e Rasch. for C19H21N3O3S2(M+): 403,1024, detect.: 403,1023.

Example 76

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic

The solution 21,21 g (116,38 mmol) of 4-(methylthio)phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 3 days. The reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer is odorou used without further purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H12O2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. The reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum removal of carbon tetrachloride. The resulting aqueous layer was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. the Amin in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 6,10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfinylphenyl)acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 5.59 in (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+ilointernational acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 1,09 g (yield: 94%) of methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

The mixture 990,0 mg (2.54 mmol) of the methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid and 273,3 mg (3,05 mmol) of copper cyanide(1) in 2.5 ml of dry N,N-dimethylformamide was heated under reflux for 4 hours the Reaction mixture was allowed to cool to 25°C and the crude reaction mixture was purified directly without additional chemical treatment. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanol, then 3/1 is unsulfonated)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C17H21NO4S (M+): 335,1191, detect.: 335,1185.

The solution 4,84 g (14.4 mol) methyl ester of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid in 25 ml of tetrahydrofuran was treated with 27 ml (21.6 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 2.5 h, the Reaction mixture was separated between water and ethyl acetate and then 10% aqueous solution of hydrochloric acid acidified to pH 2. The layers were shaken and separated. The obtained organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a pale yellow oil, which was hardened in becoming pale yellow solid, 3.80 g (yield: 82%) of crude 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid. The sample for analysis was obtained by recrystallization from ethyl acetate emitting in the form of a white solid of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid: tPL: 180-181°C; EI-HRMS m/e Rasch. for C16H19NO4S (M+): 321,1034, detect.: 321,1039.

A solution of 98 mg (from 0.37 mmol) of triphenylphosphine in 1 ml of methylene chloride was cooled to 0°C and#176;C for 15 min and then was treated with 100 mg (0.31 mmol) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 5 min, and then heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 64 mg (of 0.68 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain as a yellow foam of 94.5 mg (yield: 76%) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic: tPL: 87-90°C; (foam was ultinationals); EI-HRMS m/e Rasch. for C21H23N3O3S (M+): 397,1460, detect.: 397,1460.

Example 77

3-cyclopentyl-2-(4-ethanolgasoline)-N-thiazol-2-ylpropionic

The mixture 72,35 g (0.54 mol) of aluminium chloride in 181 ml of chloroform was cooled to 0°C and stirred to dissolve the solids. Next, the reaction mixture was slowly treated with added 61 ml (0.54 mol) of heterocalixarenes and the resulting reaction mixture was stirred at 0°C for 30 minutes and Then the reaction mixture was slowly treated with adding 25,00 g (0.18 mol) of ethylvinylacetate. The solution has gained a deep red coloration of 2 hours The reaction mixture was slowly poured into a large amount of ice/water. The resulting aqueous layer was extracted with 3 portions of 200 ml of chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexane/ethyl acetate) as a yellow oil was obtained 23,64 g (yield: 55%) of ethyl ester (4-ethylsulfanyl)octoxynol acid. This material was used in subsequent reactions without further purification and characterization.

The solution 4,60 g (21,89 mmol) iodomethylpropane and grade of 5.74 g (21,89 mmol) of triphenylphosphine in 22 ml of acetonitrile was heated under reflux for 2 weeks. The reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to obtain an orange solid. This orange solid was ground into powder in diethyl ether, and then filtered. The solid material is thoroughly washed with diethyl ether until then, until thin layer chromatographic analysis of wash fluids showed no iodomethylpropane and triphenylphosphine. The solid was left to dry in air to produce in the form of a light-HRMS m/e Rasch. for C24H26P (M+N)+345,1772, detect.: 345,1784.

Suspension 24,48 g (51,82 mmol) cyclopentadienylsodium in 100 ml dry tetrahydrofuran was cooled to 0°C, and then treated by adding dropwise 52 ml (51,82 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran. The bright orange reaction mixture was stirred at 0°C for 1 h Then the reaction mixture was treated to 9.50 g (39,87 mmol) ethyl ester (4-ethylsulfanyl)octoxynol acid. The resulting reaction mixture was heated to 25°C, after which it was stirred for 20 hours the Reaction mixture was concentrated under vacuum, removing the tetrahydrofuran and then diluted with 300 ml of water. The aqueous layer was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexane/ethyl acetate) was obtained between 6.08 g (yield: 50%) of ethyl ester of 3-cyclopentyl-2-(4-ethylal-phenylphenyl)acrylic acid in the form of a yellow oil, containing a mixture of isomers (E) and (Z) in the ratio is 1.82:1; FAB-LRMS m/e Rasch. for C

The solution 5,76 g (18,92 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethyl-sulfanilyl)acrylic acid (isomers (E) and (Z) in the ratio is 1.82:1) in 47 ml of methylene chloride was slowly processed the addition of 11.45 g of 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 37,83 mmol). The reaction mixture was stirred at 25°C for 1 h, the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 4,89 g (yield: 77%) of ethyl ester of 3-cyclopentyl-2-(4-ethanal-phenylphenyl)acrylic acid. The product was a mixture of isomers (E) and (Z) in the ratio 3:1, which was used without further purification and characterization.

The solution 4,89 g (14,53 mmol) of ethyl ester of 3-cyclopentyl-2-(4-(ethane-sulfanilyl)acrylic acid (isomers (E) and (Z) in the ratio 3:1) in 36 ml of e is od high pressure gaseous hydrogen (balloon) at 25°C and under atmospheric pressure for 44 PM Next, the catalyst was filtered by passing through a layer of brownmillerite and this layer brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless viscous oil was obtained 3.50 g (yield: 71%) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid: FAB-LRMS m/e Rasch. for C18H26O4S (M+H)+the mass in the form of an integer: 338, detect.: 339.

A solution of 2.50 g (7,39 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid in 30 ml of tetrahydrofuran was treated to 11.1 ml (8,86 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 hours the Resulting reaction mixture was divided between 75 ml of water and 75 ml of ethyl acetate, and then was treated with 15 ml of 1 N. aqueous solution of hydrochloric acid. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 2.20 g (yield: 96%) of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid as a white solid, which was used without further purification: tPL: 137-138°C; FAB is refinishing in 5 ml of methylene chloride was cooled to 0°C and then slowly treated 189 mg (1.06 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 20 min and then was treated with 300 mg (0.97 mmol) of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid. The resulting reaction mixture was stirred at 0°C for 10 min and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 213 mg (2,13 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale yellow solid 330 mg (yield: 87%) of 3-cyclopentyl-2-(4-ethanolgasoline)-N-thiazol-2-ylpropionic: tPL: 178-179°C; EI-HRMS m/e Rasch. for C19H24N2O3S2(M+): 392,1228, detect.: 392,1230.

Example 78

3-cyclopentyl-2-(4-ethanolgasoline)-N-pyridin-2-ylpropionic

The mixture 72,35 g (0.54 mol) of aluminium chloride in 181 ml of chloroform was cooled to 0°C and stirred to dissolve the solids. Next, the reaction mixture was slowly treated with added 61 ml (0.54 mol) of heterocalixarenes and the resulting reaction mixture was stirred at 0°With those who the thief was acquired dark red colour and gradually became a retinoid. Then the resulting reaction mixture was stirred at 0°C for 2 h, the Reaction mixture was slowly poured into a large amount of ice/water. The resulting aqueous layer was extracted with 3 portions of 200 ml of chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexane/ethyl acetate) as a yellow oil was obtained 23,64 g (yield: 55%) of ethyl ester (4-ethylsulfanyl)octoxynol acid. This material was used in subsequent reactions without further purification and characterization.

The solution 4,60 g (21,89 mmol) iodomethylpropane and grade of 5.74 g (21,89 mmol) of triphenylphosphine in 22 ml of acetonitrile was heated under reflux for 2 weeks. The reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to obtain an orange solid. This orange solid was ground into powder in diethyl ether, and then filtered. The solid material is thoroughly washed with diethyl ether until then, until thin layer chromatographic analysis of wash fluids showed no iodomethylpropane and triphenylphosphine g (yield: 86%) of cyclopentadienylsodium: tPL: 195-198°C; FAB-HRMS m/e Rasch. for C24H26R (M+N)+345,1772, detect.: 345,1784.

Suspension 24,48 g (51,82 mmol) cyclopentadienylsodium in 100 ml dry tetrahydrofuran was cooled to 0°C, and then treated by adding dropwise 52 ml (51,82 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran. The bright orange reaction mixture was stirred at 0°C for 1 h Then the reaction mixture was treated to 9.50 g (39,87 mmol) ethyl ester (4-ethylsulfanyl)octoxynol acid. The resulting reaction mixture was heated to 25°C, after which it was stirred for 20 hours the Reaction mixture was concentrated under vacuum, removing the tetrahydrofuran and then diluted with 300 ml of water. The aqueous layer was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexane/ethyl acetate) as a yellow oil was obtained between 6.08 g (yield: 50%) of ethyl ester of 3-cyclopentyl-2-(4-ethylsulfanyl)acrylic acid, containing a mixture of isomers (E) and (Z) with the P>

The solution 5,76 g (18,92 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethyl-sulfanilyl)acrylic acid (isomers (E) and (Z) in the ratio is 1.82:1) in 47 ml of methylene chloride was slowly processed the addition of 11.45 g of 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 37,83 mmol). The reaction mixture was stirred at 25°C for 1 h, the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 4,89 g (yield: 77%) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)acrylic acid. The product was a mixture of isomers (E) and (Z) in the ratio 3:1, which was used without further purification and characterization.

The solution 4,89 g (14,53 mmol) of ethyl ester of 3-cyclopentyl-2-(4-(ethane-sulfanilyl)acrylic acid (isomers (E) and (Z) in the ratio 3:1) in 36 ml ethanolblended pressure of hydrogen gas (balloon) at 25°C and under atmospheric pressure for 44 PM Next, the catalyst was filtered by passing through a layer of brownmillerite and this layer brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless viscous oil was obtained 3.50 g (yield: 71%) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid: FAB - LRMS m/e Rasch. for C18H24O4S (M+H)+the mass in the form of an integer: 338, detect.: 339.

A solution of 2.50 g (7,39 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid in 30 ml of tetrahydrofuran was treated to 11.1 ml (8,86 mmol) 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 23 hours the Resulting reaction mixture was divided between 75 ml of water and 75 ml of ethyl acetate, and then was treated with 15 ml of 1 N. aqueous solution of hydrochloric acid. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 2.20 g (yield: 96%) of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid as a white solid, which was used without further purification: tPL: 137-138°C; FA in 5 ml of methylene chloride was cooled to 0°C. and then slowly treated 189 mg (1.06 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 20 min and then was treated with 300 mg (0.97 mmol) of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid. The resulting reaction mixture was stirred at 0°C for 10 min and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 200 mg (2,13 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale orange solid 185 mg (yield: 50%) 3-cyclopentyl-2-(4-ethanolgasoline)-N-pyridin-2-ylpropionic: tPL: 144-145°C; EI-HRMS m/e Rasch. for C21H26N2O3S (M+): 386,1664, detect.: 386,1660.

Example 79

2-(3,4-bistanbulholiday)-3-cyclopentyl-N-thiazol-2-ylpropionic

A solution of 5.00 g (29,05 mmol) of 3,4-dipertanyakan acid in 73 ml of methanol was treated by slow addition of 4 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 65 hours, the Reaction mixture was allowed to cool to 25°C and ZAT aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 5,38 g (yield: 99%) of methyl ether (3,4-differenl)acetic acid as a yellow oil which was used without further purification.

The solution to 6.39 g (86,69 mmol) timelocked sodium in 72 ml of dimethylsulfoxide was treated 5,38 g (28,89 mmol) methyl ether (3,4-differenl) acetic acid. The reaction mixture was stirred at 25°C for 2 h, then kept at 70°C for 15 min, after that time the data thin-layer chromatography indicated the absence of starting material and the presence of highly polar of a new product. The reaction was shown that by heating the ether hydrolizable to acid. The resulting reaction mixture was allowed to cool to 25°C. Next, the reaction mixture was treated with 200 ml of 10% aqueous hydrochloric acid solution and then was extracted with 3 portions of 200 ml of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain the substance in the form of a yellow oil. This substance is in the form of a yellow oil was dissolved in 100 ml of methanol and then slowly treated with 5 ml of concentrated sulfuric chislett up to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was slowly diluted with 300 ml saturated aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil with 4.65 g (yield: 75%) do not separate the isomeric mixture of methyl ether (3-fluoro-4-methylsulfinylphenyl)acetic acid methyl ester (4-fluoro-3-methylsulfinylphenyl)acetic acid which was used without further purification and characterization.

A solution of 4.44 g (20,72 mmol) not divided isomeric mixture of methyl ether (3-fluoro-4-methylsulfinylphenyl)acetic acid methyl ester (4-fluoro-3-methylsulfinylphenyl)acetic acid in 103 ml of methylene chloride was slowly treated with adding 13,80 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 45,59 mmol). The reaction mixture was stirred at 25°C for 4 h the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 1 portion 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 serving of 200 ml saturated aqueous rastvoratee (Silica gel 60 Merck, 70-230 mesh, 20/1 methylene chloride/ethyl acetate) was obtained and 3.31 g (yield: 65%) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl)acetic acid methyl ester (4-fluoro-3-methanesulfonyl)acetic acid as colorless liquid, which was used without further purification and characterization.

A solution of 2.28 g (9,26 mmol) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl)acetic acid methyl ester (4-fluoro-3-methanesulfonyl)acetic acid, 23 ml of dimethylsulfoxide was treated to 1.37 g (holds 18.52 mmol) timelocked sodium. The reaction mixture was stirred at 25°C for 4 h and then the reaction was suppressed 10% aqueous solution of hydrochloric acid. The aqueous layer was extracted with 1 portion in 400 ml of chloroform, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/2 hexane/ethyl acetate) received 2,19 g (yield: 86%) do not separate the isomeric mixture of methyl ether (3-methanesulfonyl-4-methylsulfinylphenyl) acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl) acetic acid as a yellow liquid which was used without further purification and is a (3-methanesulfonyl-4-methylsulfinylphenyl)acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl) acetic acid in 20 ml of methylene chloride was slowly treated with adding 6,41 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 31,93 mmol). The reaction mixture was stirred at 25°C for 5 h and then the reaction it slowly extinguished 1,5 N. aqueous solution of sodium sulfite. The resulting reaction mixture was extracted with 300 ml of methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 10/1 methylene chloride/ethyl acetate) as a white solid substance was obtained 1.89 g (yield: 77%) of methyl ether (3,4-bistanbulholiday) acetic acid: tPL: 157-158°C; EI-HRMS m/e Rasch. for C11H14O6S2(M+): 306,0232, detect.: 306,0234.

The solution 951 ál (6,79 mmol) Diisopropylamine in 6 ml of dry tetrahydrofuran and 2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in a nitrogen atmosphere, and then was treated with 2.5 ml (6,79 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution of 1.89 g (6,17 mmol) methyl ether (3,4-bistanbulholiday) acetic acid in 12 ml of dry tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Produced reactio(7.40 mmol) of iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 64 hours, the Reaction in the reaction mixture extinguished 150 ml of water and then concentrated under vacuum removal of tetrahydrofuran. Further, the obtained residue was diluted with 100 ml of water and then was extracted with 1 serving of 250 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained of 1.61 g (yield: 67%) of methyl ester of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C17H24O6S2(M+): 388,1014, detect.: 388,1014.

A solution of 1.17 g (a 3.01 mmol) of the methyl ester of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid in 12 ml of tetrahydrofuran was treated with 5.6 ml (to 4.52 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Resulting reaction mixture was divided between 75 ml of water and 75 ml of ethyl acetate and then was treated with 10 ml of 1 N. aqueous solution of hydrochloric acid. The layers were shaken and separated. The organic layer sushi is wltnylfj)-3-cyclopentylpropionic acid as a white foam, which was used without further purification: tPL: 64-68°C (foam ultinationals); FAB-HRMS m/e Rasch. for C16H22O6S2(M+H)+: 375,0936, detect.: 375,0932.

A solution of 154 mg (0.59 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then slowly treated with 105 mg (0.59 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 200 mg (of 0.53 mmol) of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 5 min and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 118 mg (1.18 mmol) of 2-aminothiazole. The resulting reaction mixture was stirred at 25°C for 15 h and Then the crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) to obtain in the form of a pale yellow foam 150 mg (yield: 61%) of 2-(3,4-bistanbulholiday)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 104-107°C; EI-HRMS m/e Rasch. for C19H24N2ABOUT5S3(M+): 456,0847, detect.: 456,0846.

Example 80

2-(3,4-bistanbulholiday)-3-Ziloti in 73 ml of methanol was treated by slow addition of 4 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 65 hours, the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was slowly diluted with 300 ml saturated aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 5,38 g (yield: 99%) of methyl ether (3,4-differenl) acetic acid as a yellow oil which was used without further purification.

The solution to 6.39 g (86,69 mmol) timelocked sodium in 72 ml of dimethylsulfoxide was treated 5,38 g (28,89 mmol) methyl ether (3,4-differenl) acetic acid. The reaction mixture was stirred at 25°C for 2 h, then kept at 70°C for 15 min, and after this time the data thin-layer chromatography indicated the absence of starting material and the presence of highly polar of a new product. The reaction was shown that by heating the ether hydrolizable to acid. The resulting reaction mixture was allowed to cool to 25°C. Next, the reaction mixture was treated with 200 ml of 10% aqueous solution of hydrochloric sour magnesium, was filtered and concentrated under vacuum to obtain the substance in the form of a yellow oil. This substance is in the form of a yellow oil was dissolved in 100 ml of methanol and then slowly treated with 5 ml of concentrated sulfuric acid. The reaction mixture is boiled under reflux for 3 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was slowly diluted with 300 ml saturated aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil with 4.65 g (yield: 75%) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methylsulfinylphenyl)acetic acid methyl ester (4-fluoro-3-methylsulfinylphenyl)acetic acid which was used without further purification and characterization.

A solution of 4.44 g (20,72 mmol) not divided isomeric mixture of methyl ether (3-fluoro-4-methylsulfinylphenyl)acetic acid methyl ester (4-fluoro-3-methylsulfinylphenyl) acetic acid in 103 ml of methylene chloride was slowly treated with adding 13,80 g 3 chloroperoxybenzoic the ri 25°C for 4 h The reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 1 portion 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 20/1 methylene chloride/ethyl acetate) was obtained and 3.31 g (yield: 65%) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl) acetic acid methyl ester (4-fluoro-3-methanesulfonyl)acetic acid as colorless liquid, which was used without further purification and characterization.

A solution of 2.28 g (9,26 mmol) not divided isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl)acetic acid methyl ester (4-fluoro-3-methanesulfonyl) acetic acid, 23 ml of dimethylsulfoxide was treated to 1.37 g (holds 18.52 mmol) timelocked sodium. The reaction mixture was stirred at 25°C for 4 h and then the reaction was suppressed 10% aqueous solution of hydrochloric acid. The aqueous layer was extracted with 1 portion in 400 ml of chloroform, dried over magnesium sulfate is ylacetic) received 2,19 g (yield: 86%) of pratdesaba isomeric mixture of methyl ether (3-methanesulfonyl-4-methylsulfinylphenyl) acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl) acetic acid as a yellow liquid, which was used without further purification and characterization.

The solution 2,19 g (7,98 mmol) pratdesaba isomeric mixture of methyl ether (3-methanesulfonyl-4-methylsulfinylphenyl) acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl)acetic acid in 20 ml of methylene chloride was slowly treated with adding 6,41 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 31,93 mmol). The reaction mixture was stirred at 25°C for 5 h and then the reaction it slowly extinguished 1,5 N. aqueous solution of sodium sulfite. The resulting reaction mixture was extracted with 300 ml of methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 10/1 methylene chloride/ethyl acetate) as a white solid substance was obtained 1.89 g (yield: 77%) of methyl ether (3,4-bistanbulholiday) acetic acid: tPL: 157-158°C; EI-HRMS m/e Rasch. for C11H14ABOUT6S2(M+): 306,0232, detect.: 306,0234.

The solution 951 ál (6,79 mmol) Diisopropylamine in 6 ml of dry tetrahydrofuran and 2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°Her reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution of 1.89 g (6,17 mmol) methyl ether (3,4-bistanbulholiday) acetic acid in 12 ml of dry tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution of 1.56 g (7.40 mmol) of iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 64 hours, the Reaction in the reaction mixture extinguished 150 ml of water and then concentrated under vacuum removal of tetrahydrofuran. Further, the obtained residue was diluted with 100 ml of water and then was extracted with 1 serving of 250 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained of 1.61 g (yield: 67%) of methyl ester of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C17H24ABOUT6S2(M+): 388,1014, detect.: 388,1014.

A solution of 1.17 g (3,01 mm is probatively 5.6 ml (to 4.52 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Resulting reaction mixture was divided between 75 ml of water and 75 ml of ethyl acetate and then was treated with 10 ml of 1 N. aqueous solution of hydrochloric acid. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 1.10 g (yield: 98%) of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid as a white foam, which was used without further purification: tPL: 64-68°C (foam ultinationals); FAB-HRMS m/e Rasch. for C16H22ABOUT6S2(M+H)+: 375,0936, detect.: 375,0932.

A solution of 154 mg (0.59 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then slowly treated with 105 mg (0.59 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 10 min and then was treated with 200 mg (of 0.53 mmol) of 2-(3,4-bismuthinite-Neil)-3-cyclopentylpropionic acid. The resulting reaction mixture was stirred at 0°C for 5 min and then it was heated to 25°C, after which it was stirred for 30 minutes Then the reaction mixture was treated with 110 mg (1.18 mmol) of 2-aminopyridine. The resulting reaction mixture was stirred at 25°C for 15 h/1 hexane/ethyl acetate) to obtain in the form of a pale yellow foam 117 mg (yield: 49%) of 2-(3,4-bistanbulholiday)-3-cyclopentyl-N-pyridine-2-ylpropionic: tPL: 107-110°C; EI-HRMS m/e Rasch. for C21H26N2ABOUT5S2(M+): 450,1283, detect.: 450,1282.

Example 81

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazine-3-ylpropionic

A solution of 400 mg (1,40 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38) in 5 ml of dry pyridine was treated with 316 mg (1.53 mmol) of 1,3-dicyclohexylcarbodiimide. The reaction mixture was stirred at 25°C for 3.5 h, and then processed 296 mg (is 3.08 mmol) 3-amino-1,2,4-triazine and an additional amount of pyridine (1 ml). The reaction mixture was stirred at 100°C for 20 hours the Reaction mixture was concentrated under vacuum to remove pyridine. The obtained residue was diluted with ethyl acetate, and then filtered. The filtrate was washed for 1H. aqueous solution of hydrochloric acid and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 ethyl acetate/hexane) as a yellow-orange solid was obtained of 40.9 mg (yield: 8%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazine-3-ylpropionic: tPL: 81-83°C; EI-HRMS m/e Rasch. for C17H18Cl2N4

A solution of 3.3 ml (23.5 mmol) of Diisopropylamine in 50 ml of dry tetrahydrofuran and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in nitrogen atmosphere was cooled to -78°C and then was treated with 2.35 ml (23.5 mmol) of a 10 M solution of n-utility in hexano. The yellow reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution of 2.40 g (of 11.2 mmol) 4-methylsulfonylmethane acid in a small amount of dry tetrahydrofuran. After about half an hour was added 4-methylsulfonylmethane acid in dry tetrahydrofuran, was formed precipitate. When you next add the remaining 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture had become a thick consistency. After adding 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture became very thick, and with difficulty were amenable to mixing. This thick reaction mixture was added an additional amount of dry tetrahydrofuran (20 ml) and the reaction mixture was stirred at -78°C for 45 min, after which was added dropwise a solution of 2.35 g (of 11.2 mmol) iodomethylpropane in the sky for 15 hours The reaction in the reaction mixture extinguished 100 ml of water and the resulting yellow reaction mixture was concentrated under vacuum removal of tetrahydrofuran. Using conc. hydrochloric acid aqueous residue was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white solid substance was obtained of 1.80 g (yield: 52%) of 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 152-154°C; EI-HRMS m/e Rasch. for C15H20ABOUT4S (M+): 296,1082, detect.: 296,1080.

The solution 4,91 g (16,56 mmol) 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and of 6.52 g (24,85 mmol) of triphenylphosphine in 41 ml of methylene chloride was cooled to 0°C and then was treated by adding small portions 5,01 g (28,16 mmol) of N-bromosuccinimide. The color of the reaction mixture changed from light yellow to dark yellow and then to brown. After adding N-bromosuccinimide the reaction mixture for 30 min was heated to 25°C. Next, the brown reaction mixture was treated to 4.98 g (49,69 mmol) of 2-aminothiazole. Formed realties of methylene chloride. Received the black residue was diluted with 400 ml of 10% aqueous hydrochloric acid solution and then was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 1/3 hexane/ethyl acetate, then 1/1 hexane/ethyl acetate) as a white solid substance was obtained of 4.49 g (yield: 72%) of 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic: tPL: 216-217°C; EI-HRMS m/e Rasch. for C18H22N2ABOUT3S2(M+): 378,1072, detect.: 378,1071.

The solution 559 μl (3,99 mmol) Diisopropylamine in 1.2 ml of dry tetrahydrofuran was cooled to -78°C in nitrogen atmosphere and then was treated with 1.6 ml (3,99 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was allowed to warm to 0°C and then was treated by adding small portions 463,1 mg (1,22 mmol) 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic. The color of the reaction mixture gave way to orange. Next, the reaction mixture was heated to 25°C, after which it was stirred for 30 minutes After 30 m the ora tributylamine in tetrahydrofuran. The resulting reaction mixture was stirred at 0°C for 10 min, then it was heated to 25°C. the Reaction mixture was stirred at 25°C for 30 min and then boiled under reflux for 20 hours, the Reaction mixture was cooled to 0°C, then was treated with 3 ml of water, after which 702,5 mg (8,56 mmol) of sodium acetate, and then, finally, 484,2 mg (4,28 mmol) hydroxyamine-O-sulfonic acid. The resulting reaction mixture was stirred at 0°C for 30 min, after which it was heated to 25°C and further stirred for 44 hours, the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted with 150 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/2 hexane/ethyl acetate) as a white solid substance was obtained 191,8 mg (yield: 72%) of 3-cyclopentyl-2-(4-sulfamoyl)-N-thiazol-2-ylpropionic: tPL: 179-181°C; EI-HRMS m/e Rasch. for C17H21N3ABOUT2S2(M+

A solution of 200.0 mg (0.70 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38), 316,9 mg (0.84 mmol) of hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea, 365 ml (2,09 mmol) of N,N-diisopropylethylamine and 140,8 mg (1,39 mmol) 2-amino-1,3,4-thiadiazole in 2 ml of dry N,N-dimethylformamide was stirred at 25°C in nitrogen atmosphere for 20 hours the Reaction mixture was concentrated under vacuum, removing N,N-dimethylformamide. The obtained residue was diluted with 100 ml of ethyl acetate. The organic layer was washed 1 portion 50 ml saturated aqueous sodium bicarbonate solution, 1 portion of 100 ml of 10% aqueous hydrochloric acid solution and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) as a white foam was obtained 197,3 mg (yield: 77%) of 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazole-2-ylpropionic: tPL: 90-91°C; EI-HRMS m/e Rasch. for C16H17Cl2N3OS (M+) 369,0469, detect.: 369,0476.

Example 86

(A) 2-(4-cyanophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

15H19O2Br (M+): 310,0568 the detection.: 310,0564.

A solution of 500 mg (1,60 mmol) methyl ester of 2-(4-bromophenyl)-3-cyclopentyloxy is 170°C for 1 h After this time the reaction mixture was cooled to 25°C and was poured into 5 ml of an aqueous solution of ammonium hydroxide. The solution was diluted with 25 ml water and was extracted with 3 portions 35 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) in the form of a clear oil was obtained 65,6 g (yield: 15.8 percent) methyl ester of 2-(4-cyanophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19NO2(M+): 257,1415 the detection.: 257,1406.

A solution of 65.0 mg (0.25 mmol) of the methyl ester of 2-(4-cyanophenyl)-3-cyclopentylpropionic acid in 2.5 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) was treated with 0.27 ml (0.27 mmol) of 1H. an aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 6 hours after that time 1H. aqueous solution of hydrochloric acid, the reaction mixture was acidified to pH 1 and extracted with 3 portions of 25 ml of chloroform/methanol (ratio 9:1). The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white TV;; EI-HRMS m/e Rasch. for C15H17NO2(M+): 243,1259 the detection.: 243,1268.

A solution of 33.0 mg (0.13 mmol) of 2-(4-cyanophenyl)-3-cyclopentylpropionic acid of 1.36 ml of methylene chloride was cooled to 0°C and then was treated 0,07 ml (0.14 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 30.0 mg (0.29 mmol) 2-aminothiazole and 0.05 ml (0.32 mmol) N,N-diisopropylethylamine in of 0.67 ml of tetrahydrofuran. This solution was stirred at 25°C for 3 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained to 44.1 mg (yield: 100%) of 2-(4-cyanophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic: tPL: 64-66°C; EI-HRMS m/e Rasch. for C18H19N3OS (M+): 325,1248 the detection.: 325,1247.

(B) Similarly received:

(a) from 2-aminopyridine and 2-(4-cyanophenyl)-3-cyclopentylpropionic acid: 2-(4-cyanophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic in the form of a white solid: tPL: 61-63°C; EI-HRMS m is interprovincial acid and methyl ester of 6-aminonicotinic acid: methyl ester of 6-[2-(4-cyanophenyl)-3-cyclopentylpropionyl] nicotinic acid as a white solid: tPL: 62-64°C; EI-HRMS m/e Rasch. for C22H23N3O3(M+): 377,1739, detect.: 377,1736.

Example 87

(A) 3-cyclopentyl-N-pyridin-2-yl-2-(4-triptoreline)propionamide

23 ml of a solution of their diisopropylamide lithium (0,31 M source solution, 7,13 mmol), cooled to -78°C, cultivated 693 mg (3.4 mmol) (4-triptoreline) acetic acid in 8.5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 30 minutes Then added 784 mg (3.7 mmol) of iodomethylpropane in 1 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours then the reaction mixture was suppressed by adding dropwise 10 ml of a saturated aqueous solution of ammonium chloride. Under vacuum, remove the excess solvent. The remainder of 1 N. aqueous hydrochloric acid solution was acidified to pH 1. The mixture was poured into 150 ml of water and was extracted with 3 portions of 100 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 95/5 hexane/ethyl acetate) in which you: tPL: 94-95°C; EI-FAB m/e Rasch. for C15H17F3O2(M+Na)+: 309,1079, detect.: 309,1072.

A solution of 170 mg (0.38 mmol) of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium, 100 mg (0.34 mmol) of 3-cyclopentyl-2-(4-triptoreline)propionic acid and 36 mg (0.38 mmol) of 2-aminopyridine 1.75 ml of N,N-dimethylformamide was treated to 0.12 ml (0.73 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at 25°C for 18 hours after this time the reaction mixture was poured into 50 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The combined organic layers were washed 1 portion 50 ml of 1 N. aqueous solution of hydrochloric acid, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a white resin was obtained 127 mg (yield: 53.3 per cent) 3-cyclopentyl-N-pyridin-2-yl-2-(4-triptoreline) propionamide: EI-HRMS m/e Rasch. for C20H21F3N2O (M+): 362,1605, detect.: 362,1592.

(B) Similarly received:

(a) of the methyl ester of 6-aminonicotinic acid and 3-cyclopentyl-2-(4-triptoreline)propionic: methyl ester of 6-[3-cyclopentyl-2-(4-triptoreline)ro>3(M+): 420,1660, detect.: 420,1661.

Example 88

(A) 2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentyl-N-thiazol-2-ylpropionic

430,55 ml solution (0.3 M source solution, 129,16 mmol) of their diisopropylamide lithium cooled to -78°C, cultivated 26,32 g (125,83 mmol) ethyl ester (4-nitrophenyl) acetic acid (obtained in example 22) in 312,5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes Then add 27,75 g (132,1 mmol) iodomethylpropane in 27,75 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise to 250 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was concentrated under vacuum. The residue was diluted with 250 ml of water and was extracted with 3 portions of 300 ml of ethyl acetate. The organic fraction was washed with 2 portions of 250 ml of saturated aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 98/2 exponaval acid: EI-HRMS m/e Rasch. for C16H21NO4(M+): 291,1470, detect.: 291,1470.

The solution 7,37 mg (to 25.3 mmol) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl) propionic acid 316 ml of ethyl acetate was treated with 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas under a pressure of 60 pounds per square inch at 25°C for 18 hours Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a yellow oil was obtained to 3.52 mg (yield: 53.3 per cent) ethyl ester of 2-(4-AMINOPHENYL)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H23NO2(M+): 261,1729 the detection.: 261,1727.

A mixture of 0.38 ml of concentrated hydrochloric acid and 380 mg of ice, cooled to 0°C, cultivated 497 mg (1,90 mmol) ethyl ester of 2-(4-AMINOPHENYL)-3-cyclopentylpropionic acid. After 5 min the reaction mixture was added a solution of 139 mg (for 2.01 mmol) of sodium nitrite in 0,31 ml of water. The resulting solution was stirred at 0°C for 5 minutes, after this time the solution was added to a solution of 0.23 ml (2,20 mmol) n-butylmercaptan the reaction mixture was diluted with 50 ml water and was extracted with 3 portions of 50 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product as a brown oil (588 mg) 8.8 ml of methylene chloride was cooled to 0°C and was treated with 1.5 g of 3-chloroperoxybenzoic acid (80-85% grade, 8,78 mmol). The reaction mixture was stirred at 25°C for 18 hours after this time the reaction mixture was diluted with 75 ml of water and was extracted with 2 portions of 30 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a yellow oil was obtained 144,3 mg (yield: 20.7 per cent) ethyl ester 2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C20H30O4S (M+): 366,1865 the detection.: 366,1858.

A solution of 140 mg (0.38 mmol) of ethyl ester of 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentylpropionic acid 0.95 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) was treated 0,76 ml (from 0.76 mmol) 1H. an aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 6 hours after this time 1 N. aqueous solution of hydrochloric acid, the reaction mixture was acidified to pH 1 and extrastriatal under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 chloroform/methanol) in the form of a clear oil was obtained of 88.3 mg (yield: 68,4%) 2-[4-(butane-1-sulfonyl) phenyl]-3-cyclopentylpropionic acid: FAB-HRMS m/e Rasch. for C18H26O4S (M+H)+: 339,1631 the detection.: 339,1638.

A solution of 99 mg (from 0.37 mmol) of triphenylphosphine and 76 mg (0.42 mmol) of N-bromosuccinimide 1.26 ml of methylene chloride, cooled to 0°C, was treated with 85 mg (0.25 mmol) 2-[4-(butane-1-sulfonyl) phenyl]-3-cyclopentylpropionic acid in methylene chloride. The reaction mixture was stirred at 25°C for 45 minutes after this time the reaction mixture was treated with 33 mg (0.32 mmol) of 2-aminothiazole and 0.03 ml (from 0.37 mmol) of pyridine. The reaction mixture was stirred at 25°C for 18 h Then the reaction mixture was concentrated under vacuum removal of methylene chloride. After the reaction mixture was diluted with 50 ml water and was extracted with 3 portions of 50 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 50/50 hexane/ethyl acetate) in the form of not quite white solid substance was obtained 69,3 mg(65,6%) 2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentyl-N-thiazol-ylpropionic.: 420,1535.

(B) Similarly received:

(a) from 2-aminothiazole and 3-cyclopentyl-2-[4-(propane-1-sulfonyl)phenyl] propionic acid: 3-cyclopentyl-2-[4-(propane-1-sulfonyl)phenyl]-N-thiazol-2-ylpropionic as a yellow oil: EI-HRMS m/e Rasch. for C20H26N2O3S2(M+): 406,1385 the detection.: 406,1389.

Example 89

(A) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-thiazol-2-ylpropionic

35,3 ml solution of their diisopropylamide lithium (0,31 M source solution, 10,95 mmol), cooled to -78°C, cultivated 1,11 g (5.0 mmol) of (4-fluoro-3-triptoreline)acetic acid in 12,42 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 1 h and Then added to 1.16 g (5,52 mmol) iodomethylpropane in 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 24 h In the further reaction of this solution extinguished gradual addition of the reaction mixture in 50 ml of 2n. an aqueous solution of hydrochloric acid. The product was extracted with 1 portion 300 ml of ethyl acetate and listed under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 1.28 g (yield: 84.3 percent) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: tPL: 65-68°C; EI-HRMS m/e Rasch. for C15H16F4O2(M+) 305,1165, detect.: 305,1174.

A solution of 304 mg (1.0 mmol) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid in 10 ml of methylene chloride was cooled to 0°C and then was treated with 0.6 ml, 1.2 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 24 h Then the reaction mixture was treated with 175 mg (1,75 mmol) of 2-aminothiazole and 0.4 ml (2,41 mmol) of N,N-diisopropylethylamine. This solution was stirred at 25°C for 48 hours, after this time the reaction mixture was concentrated under vacuum. In the liquid chromatography under high pressure (product Chromegasphere SI-60, 10 μm, 60 , 25 cm×23 cm (inner diameter), 60/40 heptane/ethyl acetate) as a pale yellow solid was obtained 326 mg (yield: 84,5%) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-thiazol-2-ylpropionic: tPL: 125-127°C; EI-HRMS m/e Rasch. for C18CLASS="ptx2">(a) of ethyl-2-amino-4-ceasalpinaceae and 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: ethyl ester {2-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionamido]thiazol-4-yl}octoxynol acid as a pale yellow solid: tPL: 155-158°C; FAB-HRMS m/e Rasch. for C22H22F4N2O4S (M+H)+: 487,1314, detect.: 487,1319;

(b) from 5-methyl-2-aminopyridine and 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: 3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-(5-methylpyridin-2-yl)propionamide in the form of a white solid: tPL: 132-133°C; EI-HRMS m/e Rasch. for C21H22F4N2O (M+): 392,1668, detect.: 392,1669;

(C) from 2-aminopyridine and 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: 3-cyclopentyl-2-(4-fluoro-3-triptoreline)N-pyridine-2-ylpropionic in the form of a light yellow oil: EI-HRMS m/e Rasch. for C20H20F4N2O (M+): 380,1511, detect.: 380,1521.

Example 90

3-cyclopentyl-N-thiazol-2-yl-2-(3-triptoreline)propionamide

35.32 per ml solution of their diisopropylamide lithium (0,31 M source solution, 10.9 mmol), cooled to -78°C, was treated with 1.0 imaginon (in the ratio 3:1). The resulting solution was stirred at -78°C for 3 hours Then added to 1.16 g (5,52 mmol) iodomethylpropane in to 1.16 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours In the further reaction of this solution extinguished gradual addition of the reaction mixture in 50 ml of 2 N. aqueous solution of hydrochloric acid. The product was extracted with 3 portions of 100 ml of ethyl acetate and 1 portion of 50 ml of diethyl ether. The organic fraction was washed with 2 portions of 100 ml of a saturated aqueous solution of lithium chloride and 1 portion 150 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate with acetic acid) in the form of not quite white solid substance was obtained of 1.16 g (yield: 80.5 per cent) 3-cyclopentyl-2-(3-triptoreline)propionic acid: tPL: 64-65°C; EI-HRMS m/e Rasch. for C15H17F3O2S (M+Na+) 309,1079, detect.: 309,1084.

A solution of 286 mg (1.0 mmol) 3-cyclopentyl-2-(3-triptoreline)-propionic acid in 10 ml of the stands and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 1.25 hours Then the reaction mixture was treated with a solution of 175 mg (1,75 mmol) of 2-aminothiazole and 0.42 ml (2,41 mmol) of N,N-diisopropylethylamine in 10 ml of tetrahydrofuran. This solution was stirred at 25°C for 24 hours after this time the reaction mixture was concentrated under vacuum. In the liquid chromatography under high pressure (product Chromegasphere SI-60, 10 μm, 60 , 25 cm × 23 cm (inner diameter), 60/40 heptane/ethyl acetate) as a pale yellow solid was obtained 299,2 mg (yield: 81.4 per cent) 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)propionamide: tPL: 134-136°C; EI-HRMS m/e Rasch. for C18H19F3N2OS (M+): 368,1170, detect.: 368,1165.

Example 91

(A) 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic

35,3 ml solution of their diisopropylamide lithium (0,31 M source solution, 10.9 mmol), cooled to -78°C, cultivated 1,11 g (5.0 mmol) of (4-fluoro-3-triptoreline) acetic acid in 12,42 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°With during the,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours In the further reaction of this solution extinguished gradual addition of the reaction mixture in 50 ml of 2n. an aqueous solution of hydrochloric acid. The product was extracted with 3 portions of 100 ml of ethyl acetate and 1 portion of 50 ml of diethyl ether. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate with acetic acid) in the form of a white solid substance was obtained 1.28 g (yield: 84.3 percent) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: tPL: 65-68°C; EI-HRMS m/e Rasch. for C15H16F4O2(M+) 305,1165, detect.: 305,1174.

The solution to 7.77 g (to 25.3 mmol) 3-cyclopentyl-2-(4-fluoro-3-triptoreline) propionic acid in 50 ml of methanol was slowly treated with 0.01 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 24 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. The residue was dissolved in 75 ml ethyl acetate and washed 1 portgo aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil 8,48 g (yield: 87,5%) of methyl ester of 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H18F4O2(M+): 318,1243, detect.: 318,1240.

A solution of 7.0 g (21.9 mmol) of methyl ester of 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid in 50 ml of N,N-dimethylformamide was treated 2,61 g (33.0 mmol) methanolate sodium. Next, the reaction mixture was stirred at 100-110°C for 24 hours after this time the reaction mixture was poured into 100 ml of a mixture of ice and 2n. an aqueous solution of hydrochloric acid. The resulting mixture was extracted with 3 portions of 75 ml of ethyl acetate and 1 portion of 50 ml of diethyl ether. Then the organic fraction was washed for 1 portion in 75 ml of water and 3 portions of 100 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) as a pale yellow oil was obtained 2,48 g (yield: 35.5 per cent) methyl ester 3-cyclopentyl-2-(4-matilal is: 346,1214, the detection. 346,1212.

A solution of 2.36 g (for 6.81 mmol) of methyl ester of 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid in 75 ml of methylene chloride at 25°With the processed RS 9.69 g of 3-chloroperoxybenzoic acid (80-85% grade, to 40.1 mmol). The reaction mixture was stirred at 25°C for 16 hours after this time the reaction mixture was diluted with 75 methylene chloride. The solution was washed with 2 portions of 50 ml of a saturated aqueous solution of sodium bisulfite, 1 portion of 50 ml of water, 3 portions of 75 ml of a saturated aqueous solution of sodium chloride, 1 portion 75 ml saturated aqueous sodium bicarbonate solution and 3 portions of 75 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a clear oil 2,88 g of methyl ester of 3-cyclopentyl-2- (4-methanesulfonyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C17H21F3O4S (M+): 378,1112 the detection.: 378,1116.

A solution of 395 mg (1.04 mmol) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid and 209 mg (1.38 mmol) of 2-aminothiazole 2.09 ml of a solution of magnesium methoxide in Mroveli under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 256,7 mg (yield: 55.1 per cent) 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic: tPL: 95-100°C; EI-HRMS m/e Rasch. for C19H21F3N2O3S2(M+): 446,0946, detect.: 446,0944.

(B) Similarly received:

(a) of the methyl ester (2-aminothiazol-4-yl)acetic acid and 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid: methyl ether {2-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionamido]thiazol-4-yl}acetic acid as a white solid: tPL: 81-86°C; FAB-HRMS m/e Rasch. for C22H25F3N2O5S2(M+N)+: 518,1157, detect.: 518,1161;

(b) methyl ester of 2-aminothiazol-4-carboxylic acid and 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid, methyl ester 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionamido]thiazole-4-carboxylic acid as a white solid: tPL: 117-121°C; FAB-HRMS m/e Rasch. for C21H23F3N2O5S2(M+N)+: 504,1000, detect.: 504,1000.

141,28 ml solution of their diisopropylamide lithium (0,31 M source solution that 43.8 mmol), cooled to -78°C, cultivated 4.44 g (20.0 mmol) of (4-fluoro-3-triptoreline) acetic acid in 49,68 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution with 4.64 g (22,09 mmol) iodomethylpropane 4.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and stirred at 25°C for 48 hours In the further reaction of this solution extinguished gradual addition of the reaction mixture in 2 N. aqueous solution of hydrochloric acid. The product was extracted with 3 portions of 400 ml of ethyl acetate and 1 serving of 200 ml of diethyl ether. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate with acetic acid) in the form of a white solid substance was obtained 3,37 g (yield: 55.4 per cent) of 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic 4.

A solution of 1.52 g (5.0 mmol) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid in 10 ml of N,N-dimethylformamide was treated 0,59 g (7.5 mmol) methanolate sodium. Next, the reaction mixture was stirred at 100-110°C for 14 hours after this time the reaction mixture was poured into 25 mixture of ice and ml 2n. an aqueous solution of hydrochloric acid.

The resulting mixture was extracted with 3 portions 35 ml of ethyl acetate and 1 portion in 25 ml of diethyl ether. Then the organic fraction was washed for 1 portion 50 ml of water and 3 portions of 75 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.36 g (yield: 83.4% of) 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1057.

A solution of 1.29 g (to 3.89 mmol) 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid in 25 ml of ethanol was slowly treated with 0.01 ml of concentrated sulfuric acid. The resulting reaction mixture is boiling the Ali under vacuum. The residue was dissolved in 35 ml of ethyl acetate and washed with 1 portion 15 ml saturated aqueous sodium bicarbonate solution, 1 portion 15 ml of water and 3 portions of 20 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil of 1.39 g (yield: 94,8%) of ethyl ester of 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C18H23F3O2S (M+): 360,1370, detect.: 360,1370.

A solution of 1.32 g (3,69 mmol) of ethyl ester of 3-cyclopentyl-2-(4-methyl-effect-free remedy 3-triptoreline)propionic acid in 50 ml of methylene chloride at 25°C was treated with 4.8 g of 3-chloroperoxybenzoic acid (80-85% grade, to 19.8 mmol). The reaction mixture was stirred at 25°C for 4 days. After this time the reaction mixture was diluted with 25 ml of methylene chloride. The resulting solution was washed with 1 portion 50 ml of a saturated aqueous solution of sodium bisulfite, 1 portion of 50 ml of water, 1 portion 50 ml saturated aqueous sodium bicarbonate solution, 1 portion of 50 ml of water and 3 portions of 50 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried n is(Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate with acetic acid) in the form of a clear oil was obtained 1.28 g (yield: 89,0%) of ethyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C18H23F3O4S (M+): 392,1269 the detection.: 392,1268.

A solution of 707 mg (1,80 mmol) of ethyl ester of 3-cyclopentyl-2-(4-methane-sulfonyl-3-triptoreline)propionic acid in 24 ml of tetrahydrofuran/water (in the ratio 3:1) was treated with 166 mg (of 3.97 mmol) of lithium hydroxide. The reaction mixture was stirred at 25°C for 24 hours after this time the reaction mixture was concentrated under vacuum. The residue was diluted with 25 ml water and was extracted with 1 portion 15 ml of diethyl ether. 2 N. an aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 1 and extracted with 3 portions of 25 ml of chloroform. The organic fraction was washed for 1 portion in 25 ml of water, 3 portions of 25 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid 426,7 mg (yield: 65%) 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid: tPL: 122-123°C; EI-HRMS m/e Rasch. for C16H19FPL: 86-89°C; EI-HRMS m/e Rasch. for C21H23F3N2O3S (M+): 440,1383, detect.: 440,1381.

Example 93

3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)-N-thiazol-2-ylpropionic

A solution of 1.52 g (5.0 mmol) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid (obtained in example 89) in 10 ml of N,N-dimethylformamide was treated 593 mg (7.5 malmani the reaction mixture was cooled to 25°C was poured into 25 ml of 1 N. aqueous solution of hydrochloric acid and was extracted with 3 portions of 25 ml of ethyl acetate and 1 portion in 25 ml of diethyl ether. Then the organic fraction was washed for 1 portion 50 ml of water and 3 portions of 75 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 82,4%) 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1057.

A solution of 188 mg (0.42 mmol) of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium and 94 mg (0.28 mmol) of 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid in 5 ml of N,N-dimethylformamide was treated with 150 μl (0.85 mmol) of N,N-diisopropylethylamine and 42.5 mg (0.42 mmol) 2-aminothiazole. The mixture was stirred at 25°C for 48 hours, after this time the reaction mixture was poured into 25 ml of cold water containing 50 ml of 1 N. aqueous solution of hydrochloric acid, and was extracted with 2 portions of 75 ml of ethyl acetate and 1 portion in 25 ml of diethyl ether. Gave the reed sodium, was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a clear oil was obtained 50.5 mg (43,1%) 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)-N-thiazol-2-ylpropionic: FAB-HRMS m/e Rasch. for C19H21F3N2OS2(M+H)+: 415,1125, detect.: 415,1123.

Example 94

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic

A solution of 34.8 g (261,4 mmol) trichloride aluminum in 120 ml of chloroform in an argon atmosphere was cooled to 0°C and then was treated by adding dropwise to 18.7 ml (167,5 mmol) of a solution of ethylchloroformiate in 120 ml of chloroform. Next, the mixture was stirred at 0°C for 30 minutes, after this time, the above mixture at 0°C was added dropwise a solution of 25.0 g (156,5 mmol) of 2-chloroanisole in 120 ml of chloroform, and the mixture was bought by red color. It was heated to 25°C and was stirred for another 3.5 hours the Reaction was suppressed by slow addition of 500 ml of water.

The colour of the solution changed, becoming yellow, then it was transferred into a separating funnel and was extracted with 3 portions at Xpress-chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a yellow oil was obtained 31,37 g (yield: 77%) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)octoxynol acid.

A solution of 725 mg (1.53 mmol) of cyclopentanetetracarboxylic in 10 ml of tetrahydrofuran was cooled to 0°C. To this cooled solution was added and 2.14 ml (1.0 M solution in THF, 2.14 mmol) of bis(trimethylsilyl)amide, sodium and the reaction mixture was bought by red color. It was stirred at 0°C for 45 min, and then was slowly added a solution of 355 mg (1.37 mmol) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)octoxynol acid in 5 ml of tetrahydrofuran. The reaction mixture was heated to 25°C and was stirred for 20 hours, the Reaction mixture was diluted with 50 ml water, transferred into a separating funnel and was extracted with 3 portions of 25 ml of diethyl ether. The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 12M, 80/20 hexane/ethyl acetate) as a yellow oil was obtained 267 mg (yield: 60%) of the ethyl ester of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylacetic acid (mixture of E - and Z-isomers in the ratio 2:1), which was used without characterization.

A solution of 1 ml of methylene chloride, cooled to 0°C, cultivated 157 mg 3-chloroperoxybenzoic acid (80%, advanced 0.729 mmol) and was stirred for 3.5 hours the Reaction mixture was diluted with 25 ml of methylene chloride, was transferred to a separating funnel and washed with 2 portions of 10 ml of a saturated aqueous solution of sodium carbonate and 2 portions of 10 ml of brine. The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 12M, 80/20 hexane/ethyl acetate) as a colourless oil was obtained 95 mg (yield: 86%) of the ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid (mixture of E - and Z-isomers in the ratio 2:1), which was used without characterization.

A mixture of 1.04 g (only 2.91 mmol) of E - and Z-isomers of ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid, 69 mg (0.29 mmol) of uranyl chloride Nickel and 25 ml of methanol in an argon atmosphere were loaded into the flask. Then in the resulting green solution in small portions slowly added 221 mg (5.83 mmol) of sodium borohydride, using an ice bath if necessary to maintain the temperature at 20°C. the Solution was obtained a black color, and after addition of sodium borohydride was formed t the operating mixture was filtered by passing through brownmillerite and washed with methanol. The filtrate and washing liquid were combined and concentrated under vacuum, reducing the volume. Next, the residual solution was diluted with 15 ml water and was extracted with 3 portions of 15 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a clear colorless oil was obtained 937 mg of a mixture of methyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclo-interprovincial acid and ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (in these reaction conditions proceeded transesterification, subsequently the mixture was used without characterization, because it was a mixture of esters).

937 mg of a mixture of methyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid obtained in the above was dissolved in 30 ml of ethanol and allowed to dissolve. Next to this solution was added a solution of 733 mg (13,1 mmol) of potassium hydroxide in 7 ml of water. Then the yellow solution was stirred for 3 h at 25°C. It was concentrated under vacuum to remove ethanol and satcharita. Then the organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate plus 1% acetic acid) in the form of a white solid substance was obtained 787 mg of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (total yield in two stages: 82%): tPL: 123,9-126,2°C; FAB-HRMS m/e Rasch. for C15H19O4SCl (M+H)+: 331,0771, detect.: 331,0776.

238 mg (of 0.91 mmol) of triphenylphosphine were dissolved in 10 ml of methylene chloride and cooled to 0°C. To this solution was added 183 mg (1,03 mmol) of N-bromosuccinimide and stirred at 0°C to complete its dissolution; the mixture has acquired a light purple color. Next to it was added 200 mg (0.61 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and stirred at 0°C for 20 min, and then heated to 25°C and was stirred for 30 minutes after this time was added 85 mg (of 0.91 mmol) of 2-aminopyridine and 0,088 ml (1,09 mmol) of pyridine and stirred at 25°C for 16 h Then the reaction mixture was diluted with 10 ml of water followed by extraction with 3 portions of 15 ml of methylene chloride. Further organic layers were United by the company Merck, 230-400 mesh mesh, 60/40 hexane/ethyl acetate) as a colourless oil was obtained 210 mg (yield: 85%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic: EI-HRMS m/e Rasch. for C20H23N2O3SCl (M+): 406,1118, detect.: 406,1120.

Example 95

N-(5-bromopyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to complete dissolution of the added substance; the mixture has acquired a light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 94) and it was stirred at 0°C for 20 min, and then heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 157 mg (of 0.91 mmol) 2-amino-5-bromopyridine and 0,088 ml (1,09 mmol) pyridine and the reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml of water followed by extraction with 3 portions of 15 ml of methylene chloride. The combined organic gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a white foam was obtained 245 mg (yield: 83%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-(5-bromopyridin-2-yl)propionamide: EI-HRMS m/e Rasch. for C20H22BrClN2O3S (M+): 484,0223, detect.: 484,0222.

Example 96

N-(5-chloropyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to complete dissolution of the added substance; the mixture has acquired a light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 94) and it was stirred at 0°C for 20 min, and then heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 117 mg (of 0.91 mmol) 2-amino-5-chloropyridine and 0,088 ml (1,09 mmol) pyridine and the reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml of water followed by extraction with 3 portions of 15 ml of methylene chloride. The combined organic gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a yellow foam was obtained 110 mg (yield: 41%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-(5-chloropyridin-2-yl)propionamide: EI-HRMS m/e Rasch. for C20H22Cl2N2O3S (M+): 440,0728, detect.: 440,0728.

Example 97

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-(5-triptorelin-2-yl)propionamide

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to complete dissolution of the added substance, the mixture has acquired a light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 94) and it was stirred at 0°C for 20 min, and then heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 147 mg (of 0.91 mmol) 2-amino-5-triptoreline and 0,088 ml (1,09 mmol) pyridine and the reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml of water followed by extraction with 3 portions of 15 ml of methylene chloride. press chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 60/40 hexane/ethyl acetate) as a white foam was obtained 122 mg (yield: 43%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N(5-triptorelin-2-yl)propionamide: EI-HRMS m/e Rasch. for C20H22ClF3N2O3S (M+): 474,0992, detect.: 474,0990.

Example 98

Ethyl ether {2-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]thiazol-4-yl}octoxynol acid

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to complete dissolution of the added substance, the mixture has acquired a light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 94) and it was stirred at 0°C for 20 min, and then heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 182 mg (of 0.91 mmol) of the ethyl ester of 2-(aminothiazol-4-yl)octoxynol acid and 0,088 ml (1,09 mmol) pyridine and the reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml of water with p the m sodium was filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a colourless oil was obtained 208 mg (yield: 67%) of ethyl ether {2-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]thiazol-4-yl}octoxynol acid: EI-HRMS m/e Rasch. for C22H25Cl2N2O6S2(M+): 513,0921, detect.: 513,0919.

Example 99

2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic

The mixture 6,07 g (18,35 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclo-interprovincial acid (obtained in example 94), 2.83 g (15,96 mmol) of (R)-(+)-4-benzyl-2-oxazolidinone and (6,68 ml, 47,71 mmol) of triethylamine in 50 ml of toluene kept at 80°C in an argon atmosphere before the formation of a homogeneous solution. Next, the reaction mixture was treated with 3.55 ml (28,81 mmol) trimethylacetylchloride in 10 ml of toluene, the reaction mixture was bought yellow and sediment build-up. Then the reaction mixture was stirred at 80°C for 36 h, the Reaction mixture was cooled to 25°C and then under vacuum to remove the toluene. The residue was diluted with 150 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of 1 N. aqueous solution aqueous solution of sodium chloride. After that, the organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/5/5 methylene chloride/hexane/ethyl acetate) received (1) of 2.08 g (yield: 23%) 4(R)-benzyl-3-[2(S)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]oxazolidin-2-it is in the form of a white foam: []23589=+10,4° (C=0,144, chloroform); FAB-HRMS m/e Rasch. for C25H28ClNO5S (M+N)+: 490,1455, detect.: 490,1457 and (2) 2.20 g (yield: 25%) 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]oxazolidin-2-it is in the form of a white foam: []23589=-93,9° (C =0,165, chloroform); FAB-HRMS m/e Rasch. for C25H28ClNO5S (M+N)+: 490,1455, detect.: 490,1443.

A solution of 215 mg (9.0 mmol) of lithium hydroxide in 2.8 ml of water was treated with 2.0 ml (18 mmol) of 30% aqueous hydrogen peroxide solution. Further, this freshly prepared solution of lithium hydroperoxide was cooled to 0°C and then slowly added to a chilled (0°C) a solution of 2.20 g (4.5 mmol) 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]oxazolidin-2-it in 18 ml of tetrahydrofuran and 5.8 ml of water. After 1.5 h of exposure at 0°With the reaction in the reaction mixture extinguished 25 ml of 1.5 N. aqueous solution of sodium sulfite Hilali 1H. aqueous solution of hydrochloric acid to pH 2 and was extracted with 3 portions of 50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate with 1% acetic acid) in the form of a white solid substance was obtained 1.26 g (yield: 85%) 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid: tPL: 106,1-108,8°C; []23589=-43,0° (C=0,172, chloroform); EI-HRMS m/e Rasch. for C15H19ClO4S (M+): 330,0692, detect.: 330,0690.

A solution of 248 mg (0,94 mmol) of triphenylphosphine in 9 ml of methylene chloride was cooled to 0°C and then was treated with 190 mg (1.07 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to its complete dissolution, the mixture was bought light purple color. Next, the reaction mixture was treated with 208 mg (0,63 mmol) of 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid. The reaction mixture was stirred at 0°C for 20 min and then was heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 95 mg (0,94 mmol) of 2-aminothiazole and 0,092 ml (1.13 mmol) of pyridine and the reaction mixture plumage is produced in 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica 65/35 hexane/ethyl acetate) as a white foam was obtained 210 mg (yield: 81%) 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide: []23589=-54,3° (=of 0.081, chloroform); EI-HRMS m/e Rasch. for C18H21ClN2O3S2(M+): 412,0682, detect.: 412,0679.

Example 100

2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C until its complete dissolution, the mixture was bought light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 99). The reaction mixture was stirred at 0°C for 20 min and then was heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 85 mg (of 0.91 mmol) of 2-aminopyridine and 0,088 ml (1.09 m is ml of water, then was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica, 60/40 hexane/ethyl acetate) as a white foam was obtained 202 mg (yield: 81,5%) 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic: []23589=-41,8° (C=0,098, chloroform); EI-HRMS m/e Rasch. for C20H2ClN2O3S (M+): 406,1118, detect.: 406,1119.

Example 101

N-(5-bromopyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate

A solution of 238 mg (of 0.91 mmol) of triphenylphosphine in 10 ml of methylene chloride was cooled to 0°C and then was treated with 183 mg (1,03 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to its complete dissolution, the mixture was bought light purple color. Next, the reaction mixture was treated with 200 mg (0.61 mmol) of 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 99). The reaction mixture was stirred at 0°C for 20 min and then was heated to 25°C, after which it was stirred for 30 minutes after this time the reaction is at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml of water, then was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica, 60/40 hexane/ethyl acetate) in the form of not quite white foam was obtained 222 mg (yield: 76%) of N-(5-bromopyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate: []23589=-48,6° (C=0,105, chloroform); EI-HRMS m/e Rasch. for C20H22BrClN2O3S (M+): 484,0223, detect.: 484,0223.

Example 102 N-(5-cyano-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide

A solution of 253 mg (1,16 mmol) bromide, Nickel(II) and 1.15 g (4,39 mmol) of triphenylphosphine and 113 mg (1,73 mmol) of zinc dust in 11 ml of acetonitrile was stirred in an argon atmosphere at 60°C for 1 h, the Reaction mixture had become dark brown in color. After this time the reaction mixture was treated 578 mg (11,8 mmol) of sodium cyanide and 2.00 g (11.6 mmol) of 2-amino-5-bromopyridine and the reaction mixture was stirred at 60°C for 16 hours Then the reaction mixture was cooled to 25°C, diluted with 50 ml of ethyl acetate and then filtered carrying capacity is k, 230-400 mesh mesh, 100% ethyl acetate) as a white solid substance was obtained 577 mg (yield: 42%) of 6-aminonicotinamide: tPL: 156,8-158,5°C; EI-HRMS m/e Rasch. for C6H5N3(M+): 119,0483, detect.: 119,0480.

A solution of 1.23 g (4,70 mmol) of triphenylphosphine in 26 ml of methylene chloride was cooled to 0°C and then was treated 948 mg (5.33 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to its complete dissolution, the mixture was bought light purple color. Next, the reaction mixture was treated with 900 mg (3,13 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38). The reaction mixture was stirred at 0°C for 20 min and then was heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated with 560 mg (4,70 mmol) of 6-aminonicotinamide and 0.46 ml (5,64 mmol) of pyridine and the reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 25 ml water, then was extracted with 3 portions of 25 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) in the form of a pink the I C20H19Cl2N3O (M+): 387,0905, detect.: 387,0905.

Example 103

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-triptorelin-2-yl)propionamide

A solution of 200 mg (0.69 mmol) of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionic acid (obtained in example 54) in 10 ml of methylene chloride and one drop of N,N-dimethylformamide was cooled to 0°C and then was treated at 0.42 ml (0.84 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. Immediately began the evolution of gas. The reaction mixture was slowly heated to 25°C, after which it was stirred for 30 minutes after this time the reaction mixture was treated by adding one portion of a solution of 0.24 ml (1,39 mmol) of N,N-diisopropylethylamine and 150 mg (0,905 mmol) of 5-trifluoromethyl-2-aminopyridine in 4 ml of tetrahydrofuran. The resulting reaction mixture was stirred at 25°C for 16 hours after this time the reaction mixture was diluted with 15 ml water and was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a white solid substance was obtained 77 mg ( m/e Rasch. for C20H19Cl2F3N2O (M+): 430,0826, detect.: 430,0835.

Example 104

6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide]nicotinic acid

A solution of 188 mg (0.45 mmol methyl ester 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl) propionamide]nicotinic acid (obtained in example 45) in 3 ml of tetrahydrofuran was treated with 3 ml of 3 N. aqueous solution of hydrochloric acid. The resulting reaction mixture is boiled under reflux at 60°C for 4 h, after this time the reaction mixture was cooled to 25°C, diluted with 5 ml of water and then was extracted with 3 portions of 20 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate with 1% acetic acid) in the form of a white solid substance was obtained 8 mg (yield: 4%) of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide]nicotinic acid: []23589=-41,4° (C= 0,099, chloroform); FAB-HRMS m/e Rasch. for C20H20Cl2N2O3(M+H)+: 407,0930, detect.: 407,0928.

Example 105

6-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamido]-N-IU the] nicotinic acid (obtained in example 46), 0.10 ml (0.61 mmol) of N,N-diisopropylethylamine and 142 mg (0.32 mmol) of hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium in 15 ml of N,N-dimethylformamide at 25°With handle added dropwise 0.16 ml (0.32 mmol) of a 2.0 M solution of methylamine in tetrahydrofuran. The resulting reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml water and was extracted with 3 portions of 10 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 83 mg (yield: 64%) of 6-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamido]-N-nicotine amide: tPL: 229,1-231,7°C; FAB-HRMS m/e Rasch. for C21H23Cl2N3O2(M+N)+: 420,1245, detect.: 420,1247.

Example 106

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrazin-2-ylpropionic

A solution of 100 mg (0.35 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 38) in 5 ml of methylene chloride and one drop of N,N-dimethylformamide was cooled to 0°C and then was treated to 0.20 ml (0,39 mmol) of a 2.0 M solution of oxalicacid in Metalist this time the reaction mixture was treated by adding one portion of a solution of 0.15 ml (0.84 mmol) of N,N-diisopropylethylamine and 69 mg (0.73 mmol) of aminopyrazine in 4 ml of tetrahydrofuran. The resulting reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml water and was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) in the form of a yellow solid was obtained 38 mg (yield: 30%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrazin-2-ylpropionic: tPL: 46,5-51,3°C; EI-HRMS m/e Rasch. for C18H19Cl2N3O (M+): 363,0905, detect.: 363,0907.

Example 107

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl) propionamide

A solution of 411 mg (1.57 mmol) of triphenylphosphine in 15 ml of methylene chloride was cooled to 0°C and then was treated with 316 mg (1.78 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C to its complete dissolution, the mixture was bought light purple color. Next, the reaction mixture was treated with 300 mg (1.05 mmol) of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionic acid (obtained in example 54). The reaction mixture was stirred at 0°C for 20 min, and then heated to 25°C, after which it was stirred for 30 min. At p is pyridine. The resulting reaction mixture was stirred at 25°C for 16 hours Then the reaction mixture was diluted with 10 ml water and was extracted with 3 portions of 15 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a white solid substance was obtained 448 mg (yield: 97%) of N-(5-bromopyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide: tPL: 107,3-109,9°C; []23589=-66,7° (C=0,084, chloroform); EI-HRMS m/e Rasch. for C19H19BrCl2N2O (M+): 440,0058, detect.: 440,0056.

Example 108

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide

A solution of 398 mg (0.95 mmol) of the methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide]nicotinic acid (obtained in example 45) in 30 ml diethyl ether was cooled to 0°C and then was treated by adding one portion 54 mg (1.4 mmol) of lithium aluminum hydride. Immediately began the evolution of gas. The reaction mixture was slowly heated to 25°C and was stirred at 25°With 16 hours after this time the reaction mixture was diluted with 10 ml of water and then ek is trevali and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a white foam was obtained 131 mg (yield: 35%) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide: FAB-HRMS m/e Rasch. for C20H22Cl2N2O2(M+N)+: 392,1058, detect.: 392,1062.

Example 109

3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic

The mixture to 4.81 g (200 mmol) of metallic magnesium and 10 ml of dry tetrahydrofuran in an argon atmosphere was treated with a solution of 0.94 g (5 mmol) of 1,2-dibromethane in 5 ml of dry tetrahydrofuran. The resulting reaction mixture to activate the magnesium metal was stirred for 10 min. Then the reaction mixture was treated by the addition dropwise of a solution of 17.7 g (100 mmol) of cycloheptylamine in 30 ml of dry tetrahydrofuran (one-fifth portions over a 5 minute period). To initiate an exothermic reaction the reaction mixture was stirred for 5-10 minutes and Then the remaining part of the solution cycloheptylamine was added dropwise, simultaneously adjusting the temperature inside the reactor below 50°C. After complete addition the solution was stirred for 1 h, and then diluted with 80 ml dry the aqueous at 130°C under high vacuum for 3 h) and 8,96 g (100 mmol) of copper cyanide(I) in 110 ml of dry tetrahydrofuran was stirred at 25°With in an argon atmosphere for 10 minutes to obtain a transparent solution. The reaction mixture was cooled to -70°C and then slowly worked their cycloheptylamine. After the addition the reaction mixture was allowed to warm to -10°C, after which it was stirred for 5 minutes the Resulting reaction mixture was again cooled to -70°C and then was treated EUR 7.57 g (90 mmol) methylpropionate. The reaction mixture was stirred for 15 h at a temperature of from -70 to -50°C, and then slowly treated with a solution of 34.3 g (135 mmol) of iodine in 30 ml of dry tetrahydrofuran, maintaining the temperature from -70 to -60°C. After adding a solution of iodine cooling bath was removed and the reaction mixture was heated to 25°C, after which it was stirred for 2 h Then the reaction mixture was poured into a solution, containing 400 ml of a saturated aqueous solution of ammonium chloride and 100 ml of ammonium hydroxide and the organic compound was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic extracts are then washed 1 portion 400 ml of a saturated aqueous solution of sodium thiosulfate and 1 portion 400 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. As a result, the colored oil was obtained 17,86 g (yield: 64%) of methyl ester of (E)-3-cycloheptyl-2-iodically acid: EI-HRMS m/e Rasch. for C11H17IO2(M+): 308,0273, detect.: 308,0273.

A mixture of 2.6 g (40 mmol) of zinc dust (Aldrich company, with a particle size of -325 mesh) and 3 ml of dry tetrahydrofuran in an argon atmosphere was treated to 0.38 g (2 mmol) of 1,2-dibromethane. Next, a suspension of zinc was heated by the apparatus for drying a stream of warm air to a rapid boil, let it cool down and re-heated. This process was repeated three times to ensure activation of the zinc dust. Then the suspension of activated zinc dust was treated with 220 mg (2 mmol) of tributyltinchloride and the suspension was stirred for 15 min at 25°C. After the reaction mixture was treated by adding dropwise within 10 min solution 6,16 g (20 mmol) of methyl ester of (E)-3-cycloheptyl-2-iodically acid in 5 ml of dry tetrahydrofuran. Then the reaction mixture was stirred at 40 to 45°C for 1 h, followed by stirring overnight at 25°C. further, the reaction mixture was diluted with 10 ml of dry tetrahydrofuran and stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask 270 mg (0.5 mmol) of bis (dibenzylideneacetone) palladium (0) and 520 mg (2 mmol) of triphenylphosphine in 25 ml of dry Tetra is romanistische and their connection zinc in tetrahydrofuran. Received a brick-red solution was kept at 50°C for 24 h, the Reaction mixture was cooled to 25°C, and then poured into 150 ml of a saturated aqueous solution of ammonium chloride and the organic compound was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic extracts were washed 1 portion 300 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, hexane/acetate in a ratio of from 4/1 to 1/1) as a viscous yellow oil was obtained 6,01 g (yield: 99%) of methyl ester of (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid: EI-HRMS m/e Rasch. for C18H24O4S (M+): 336,1395, detect.: 336,1395.

A solution of 7.8 mg (0,033 mmol) of uranyl chloride Nickel(II) and 111 mg (0.33 mmol) of the methyl ester (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid in 3 ml of methanol was cooled to 0°C and then was treated with two portions of 25 mg (0.66 mmol) of sodium borohydride. After adding the black reaction mixture was stirred for 15 min at 0°C, and then it was heated to 25°C, after which it was stirred for 15 hours With the help of filter and under vacuum and the residue was diluted with 25 ml water and 25 ethyl acetate. Both layer was isolated and the aqueous layer was extracted with 1 portion 15 ml of ethyl acetate. The combined organic extracts were washed 1 portion 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a colorless oil 101 mg (yield: 91%) of racemic methyl ester 3-cycloheptyl-2-(4-methanesulfonyl)propionic acid: EI-HRMS m/e Rasch. for C18H26O4S (M+): 338,1552, detect.: 338,1555.

A solution of 95 mg (0.28 mmol) of methyl ester of 3-cycloheptyl-2-(4 - methanesulfonyl)propionic acid in 2 ml of ethanol was treated with 1.5 ml 1N. an aqueous solution of sodium hydroxide. The solution was kept at 45 to 50°C for 15 h, after this time the data thin-layer chromatographic analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated under vacuum to remove ethanol. The residue was diluted with 10 ml water and was extracted with 1 portion in 20 ml of diethyl ether to remove neutral impurities. Next, the aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with 2 portions of 15 ml of ethyl acetate. United organhation magnesium, was filtered and concentrated under vacuum obtaining in the form of a white solid substance 78 mg (yield: 86%) of 3-cycloheptyl-2-(4-methanesulfonyl)propionic acid: EI-HRMS m/e Rasch. for C17H24O4S (M+H)+: 325,1474, detect.: 325,1478.

A solution of 116 mg (0.44 mmol) of triphenylphosphine in 2 ml of methylene chloride was cooled to 0°C and then was treated with 78 mg (0.44 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of 72 mg (0.22 mmol) of 3-cycloheptyl-2-(4-methanesulfonyl)propionic acid in 2 ml of methylene chloride. A clear solution was stirred for 10 min at 0°C, and then heated to 25°C, after which it was stirred for 1.5 hours Then the reaction mixture was treated with 66 mg (0.66 mmol) of 2-aminothiazole and the resulting suspension was stirred for 20 h at 25°C. Then the reaction mixture was concentrated under vacuum removal of methylene chloride, and the residue was diluted with 30 ml ethyl acetate and 30 ml of 1 N. aqueous solution of hydrochloric acid. Both layer was isolated and the aqueous layer was extracted with 1 portion in 10 ml of ethyl acetate. The combined organic extracts are then washed 1 portion 20 ml of a saturated aqueous solution of sodium bicarbonate and 1 on the and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica, hexane/acetate in a ratio of from 4/1 to 1/1) as an amorphous solid was obtained 68 mg (yield: 76%) of 3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic: EI-HRMS m/e Rasch. for C20H26N2O3S2(M+): 406,1426, detect.: 406,1424.

Example 110

3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic

The mixture 16,34 g (250 mmol) of zinc dust (Aldrich company with a particle size of -325 mesh) and 6 ml of dry tetrahydrofuran in an argon atmosphere was treated 0,94 g (5 mmol) of 1,2-dibromethane. Next, a suspension of zinc was heated by the apparatus for drying a stream of warm air to a rapid boil, let it cool down and re-heated. This process was repeated three times to ensure activation of the zinc dust. Then the suspension of activated zinc dust was treated with 0.54 g (5 mmol) of tributyltinchloride and the suspension was stirred for 15 min at 25°C. After the reaction mixture was treated by adding dropwise over 15 min a solution of 21 g (100 mmol) of cyclohexylamine in 30 ml of dry tetrahydrofuran. During this addition the temperature was increased to 60°C. Then diluted with 60 ml of dry tetrahydrofuran. The stirring was stopped to give the possibility to precipitate the excess zinc dust (~3 h). In a separate reaction flask, the mixture 8,48 g (200 mmol) of lithium chloride (previously dried at 130°C under high vacuum for 3 h) and of 8.95 g (100 mmol) of copper cyanide(I) in 110 ml of dry tetrahydrofuran was stirred at 25°C for 10 min to obtain a transparent solution. The reaction mixture was cooled to -70°C and then slowly treated with a freshly prepared solution of zinc its introduction with a syringe. After the addition the reaction mixture was allowed to warm to 0°C, after which it was stirred for 5 minutes, the Reaction mixture was again cooled to -70°C and then slowly worked 7,56 g (90 mmol) methylpropionate. The resulting reaction mixture was stirred for 15 h at a temperature of from -70 to -50°C, and then slowly treated with a solution 34,26 g (135 mmol) of iodine in 30 ml of dry tetrahydrofuran, maintaining the temperature from -70°C to -60°C. After adding a solution of iodine cooling bath was removed and the reaction mixture was heated to 25°C, after which it was stirred for 2 h Then the reaction mixture was poured into a solution, containing 400 ml of a saturated aqueous solution of ammonium chloride and 100 ml hydraecia extracts are successively washed with 1 portion in 500 ml of a saturated aqueous solution of sodium thiosulfate and 1 portion in 500 ml of a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/diethyl ether) as a light pink oil received 26,3 g (yield: 99%) of methyl ester of (E)-3-cyclohexyl-2-iodically acid: EI-HRMS m/e Rasch. for C10H15IO2(M+): 294,0117, detect.: 294,0114.

A mixture of 2.6 g (40 mmol) of zinc dust (Aldrich company, with a particle size of -325 mesh) and 3 ml of dry tetrahydrofuran in an argon atmosphere was treated and 0.37 g (2 mmol) of 1,2-dibromethane. Next, a suspension of zinc was heated by the apparatus for drying a stream of warm air to a rapid boil, let it cool down and re-heated. This process was repeated three times to ensure activation of the zinc dust. Then the suspension of activated zinc dust was treated with 217 mg (2 mmol) of tributyltinchloride and the suspension was stirred for 15 min at 25°C. After the reaction mixture was treated by adding dropwise over 5 min a solution 5,88 g (20 mmol) of methyl ester of (E)-3-cyclohexyl-2-iodically acid in 5 ml of dry tetrahydrofuran. During this addition the temperature was increased up to 50°C. Then the reaction mixture was stirred at 40 to 45°With those who l of dry tetrahydrofuran and stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask 270 mg (0.5 mmol) of bis (dibenzylideneacetone) palladium (0) and 520 mg (2 mmol) of triphenylphosphine in 25 ml of dry tetrahydrofuran was stirred in an argon atmosphere at 25°C for 10 min, and then were treated to 4.23 g (18 mmol) of 4-bromophenylacetate and their connection zinc in tetrahydrofuran. Received a brick-red solution was kept at 50°C for 24 hours after this time the data thin-layer chromatographic analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25°C, and then poured into 150 ml of a saturated aqueous solution of ammonium chloride and the organic compound was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic extracts were washed 1 portion 200 ml of a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/2 hexane/ethyl acetate) as a low melting white solid substance was obtained 5,79 g (yield: 99%) of methyl ester of (E)-3-cyclohexyl-2-(4-methanesulfonyl)acrylic acid: EI-HRMS m/e Rasch. for C17H22O4S (M+17H24O4S (M+): 324,1395, detect.: 324,1395.

A solution of 1.00 g (is 3.08 mmol) of methyl ester of 3-cyclohexyl-2-(4-methanesulfonyl)propionic acid in 15 ml of ethanol was treated with 6 ml of 1 N. aqueous sodium hydroxide solution. The solution was kept at 45 to 50°C for 15 h, after this time the data tonkoslojnuju the mixture was concentrated under vacuum to remove ethanol, the residue was diluted with 20 ml water and was extracted with 1 portion in 40 ml of diethyl ether to remove neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed 1 portion 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid substance 570 mg (yield: 60%) 3-cyclohexyl-2-(4-methanesulfonyl)propionic acid: EI-HRMS m/e Rasch. for C16H22O4S (M+): 310,1239, detect.: 310,1241.

A solution of 416 mg (1,58 mmol) of triphenylphosphine in 8 ml of methylene chloride was cooled to 0°C and then processed 281 mg (1,58 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of 290 mg (0,93 mmol) of 3-cyclohexyl-2-(4-methanesulfonyl)propionic acid in 5 ml of methylene chloride. A clear solution was stirred at 0°C for 15 min and then was heated to 25°C, after which it was stirred for 1.5 hours Then the reaction mixture was treated with 233 mg (2.32 mmol) of 2-aminothiazole and the resulting suspension was stirred at 25 what does 50 ml of ethyl acetate and 50 ml of 1 N. an aqueous solution of hydrochloric acid. Both layer was isolated and the aqueous layer was extracted with 1 portion in 30 ml of ethyl acetate. The combined organic extracts are then washed 1 portion 50 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica, hexane/acetate in a ratio of from 4/1 to 1/1) as amorphous solids received 337 mg (yield: 92%) of 3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic: EI-HRMS m/e Rasch. for C19H24N2O3S2(M+): 392,1228, detect.: 392,1230.

Example 111

3-cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-ylpropionic

A solution of 5.0 g (27.6 mmol) of (3-nitrophenyl) acetic acid in 50 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 48 hours and Then the reaction mixture was concentrated under vacuum. The residue was dissolved in 50 ml of methylene chloride and washed with 2 portions of 25 ml of a saturated aqueous solution bicarbonates layers were dried over sodium sulfate, was filtered and concentrated under vacuum obtaining in the form of a pale yellow solid at 5.27 g (yield: 97,9%) methyl ester (4-nitrophenyl) acetic acid: tPL: 29-30°C; EI-HRMS m/e Rasch. for C9H9NO4(M+): 195,0531, detect.: 195,0532.

43,3 ml solution of their diisopropylamide lithium (0.3 M source solution, 12,99 mmol), cooled to -78°C, treated of 2.45 g (12,56 mmol) methyl ether (3-nitrophenyl) acetic acid in 32 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution 2,78 g (13,23 mmol) iodomethylpropane in 2,78 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and the mixture was stirred at -78°C for 3 hours, the Reaction mixture was heated to 25°C and was stirred at 25°C for 16 h Then the reaction in the reaction mixture was suppressed by adding dropwise 25 ml of a saturated aqueous solution of ammonium chloride and concentrated under vacuum. The residue was diluted with 50 ml water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed with 2 portions of 25 ml of a saturated aqueous solution of chloride liefie (Silica gel 60, firm Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow oil was obtained 1.63 g (yield: 46,8%) methyl ester 3-cyclopentyl-2-(3-nitrophenyl)propionic acid: EI-HRMS m/e Rasch. for C15H19NO4(M+): 277,1314, detect.: 277,1317.

A solution of 0.55 g (2.0 mmol) of methyl ester of 3-cyclopentyl-2-(3-nitrophenyl)propionic acid in 12 ml of tetrahydrofuran/water (in the ratio 3:1) was treated with 185 mg (4.40 mmol) of lithium hydroxide. The reaction mixture was stirred at 25°C for 48 hours and Then under vacuum, remove the tetrahydrofuran. The residue was diluted with 25 ml water and was extracted with 1 portion in 20 ml of diethyl ether. 3 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 2. The product was extracted with 3 portions of 25 ml of methylene chloride. The organic fraction was washed with 2 portions of 25 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellowish-brown solid of 0.48 g (yield: 91,9%) 3-cyclopentyl-2-(3-nitrophenyl)propionic acid: tPL: 95-99°C; EI-HRMS m/e Rasch. for C14H17NO4(M+): 263,1157, detect.: 263,1156.

A solution of 432 mg (1,64 mmol) 3-cyclopentyl-2-(3-nitrophenyl)propionic kitty in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 1,2 hours Then the reaction mixture was treated with a solution 361,4 mg (3.61 mmol) of 2-aminothiazole and 0.70 ml (3.93 mmol) of N,N-diisopropylethylamine in 16 ml of tetrahydrofuran. The reaction mixture was stirred at 25°C for 6 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a yellowish brown solid was obtained 409,3 mg (yield: 72.2 per cent) 3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-ylpropionic: tPL: 171-174°C; EI-HRMS m/e Rasch. for C17H19N3O3S (M+): 345,1147, detect.: 345,1153.

Example 112

3-cyclopentyl-2-(3-methoxyphenyl)-N-thiazol-2-ylpropionic

23 ml of a solution of their diisopropylamide lithium (0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.07 g (5,94 mmol) methyl ether (3-methoxyphenyl) acetic acid in 14.8 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated to 1.37 g (6,53 mmol) idmec is within 3 hours Next, the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours after this time the reaction was suppressed by adding dropwise a saturated aqueous solution of ammonium chloride. The resulting solution was diluted with 100 ml water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed for 1 portion 75 ml saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 95/5 hexane/ethyl acetate) in the form of a clear oil was obtained 1.39 g (yield: 89,1%) methyl ester 3-cyclopentyl-2-(3-methoxyphenyl)propionic acid: EI-HRMS m/e Rasch. for C16H22O3(M+): 262,1568, detect.: 262,1561.

A solution of 1.39 g (from 5.29 mmol) of methyl ester of 3-cyclopentyl-2-(3-methoxyphenyl)propionic acid in 13.2 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) at 25°With the handle of 3.97 ml (7,94 mmol) 2 N. aqueous sodium hydroxide solution. The reaction mixture was stirred at 25°C for 48 hours, after this time the reaction mixture was poured into 50 ml of water and was extracted with 3 portions of 25 ml of chloroform. 1 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified with a length of over sodium sulfate, was filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate with glacial acetic acid) in the form of transparent wax received of 1.05 g (yield: 79.8 per cent) 3-cyclopentyl-2-(3-methoxyphenyl)propionic acid: EI-HRMS m/e Rasch. for C15H20O3(M+): 248,1412, detect.: 248,1409.

A solution of 500 mg (2.0 mmol) of 3-cyclopentyl-2-(3-methoxyphenyl)propionic acid in 20 ml of methylene chloride, cooled to 0°C, was treated with 1.1 ml (2,20 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and then at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 444 mg (4,42 mmol) of 2-aminothiazole and 0.84 ml (a 4.83 mmol) of N,N-diisopropylethylamine in 10.1 ml of tetrahydrofuran. The resulting solution was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 549 mg (yield: 82.6% of) 3-cyclopentyl-2-(methoxyphenyl)-N-thiazol-2-ylpropionic: tPL: 44-45°C; EI-HRMS m/e Rasch. for C18H22N2O2S (ionamin

of 3.53 ml (of 3.53 mmol) of 1.0 M solution tribromide boron in methylene chloride at 25°C was treated with a solution of 0.11 g (0.35 mmol) of 3-cyclopentyl-2-(3-methoxyphenyl)-N-thiazol-2-ylpropionic (obtained in example 112) in 3.5 ml of methylene chloride. The resulting solution was stirred at 25°C for 1 h, after this time the reaction mixture was cooled to 0°C and was treated with a dilute aqueous solution of ammonium hydroxide. The resulting mixture was stirred at 0°C for 15 minutes after this time the aqueous layer was separated from the organic layer. The aqueous layer was extracted with 3 portions of 50 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 50 mg (yield: 44,7%) 3-cyclopentyl-2-(3-hydroxyphenyl)-N-thiazol-2-ylpropionic: tPL: 177-179°C; EI-HRMS m/e Rasch. for C17H20N2O2S (M+): 316,1245 the detection.: 316,1244.

Example 114

3-cyclopentyl-N-thiazol-2-yl-2-(4-trifloromethyl)propionamide

23 ml of a solution of their diisopropylamide lithium (0,31 M source solution, 7,13 of maryjofoley/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated 0,78 g (3.73 mmol) of iodomethylpropane in 1 ml of 1,3-dimethyl-3,4,5,6-Tetra-hydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 18 h Then the reaction in the reaction mixture was suppressed by adding dropwise 10 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was concentrated under vacuum, removing the excess solvent. The residue was diluted with 100 ml of water and acidified 1 N. aqueous solution of hydrochloric acid to pH 1. The resulting solution was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed for 1 portion 100 ml saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a yellowish brown solid was obtained 0.31 g (yield: 30,6%) 3-cyclopentyl-2-(4-trifloromethyl)propionic acid: tPL: 62-64°C; EI-HRMS m/e Rasch. for C15H17F3O3(M+): 302,1129 the detection.: 302,1131.

A solution of 0.16 g (0,52 mmabatho of 0.29 ml of 0.58 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 0.11 g (1,16 mmol) of 2-aminothiazole and 0.22 ml (1,27 mmol) of N,N-diisopropylethylamine 2.65 ml of tetrahydrofuran. The reaction mixture was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 203,8 mg (yield: 100%) 3-cyclopentyl-T-thiazol-2-yl-2-(4-trifloromethyl)propionamide: tPL: 168-170°C; EI-HRMS m/e Rasch. for C18H19F3N2O2S (M+): 384,1119, detect.: 384,1118.

Example 115

3-cyclopentyl-2-(3,4-acid)-N-thiazol-2-ylpropionic

58,5 ml solution of their diisopropylamide lithium (0,91 M source solution, 53.2 mmol), cooled to -78°C, treated equal to 4.97 g (to 25.3 mmol) (3,4-acid) acetic acid to 25.3 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 min and at 25°C for 15 minutes after this time the reaction mixture was cooled to 0&#none. The reaction mixture was stirred at 0°C for 30 minutes the Reaction mixture was heated to 25°C and was stirred at 25°C for 18 h Then the reaction in the reaction mixture was suppressed by adding dropwise 10 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was concentrated under vacuum. The residue was diluted with 100 ml of water and acidified 1 N. aqueous solution of hydrochloric acid to pH 1. The resulting solution was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed for 1 portion 100 ml saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) in the form of a yellow solid was obtained 4.5 g (yield: 63.8 per cent) 3-cyclopentyl-2-(3,4-acid)propionic acid: tPL: 111-112°C; EI-HRMS m/e Rasch. for C16H22O4(M+): 278,1518 the detection.: 278,1517.

A solution of 0.50 g (1,79 mmol) 3-cyclopentyl-2-(3,4-acid)propionic acid 17.9 ml of methylene chloride, cooled to 0°C, was treated with 1.0 ml (1.97 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C in Tectona and from 0.76 ml (4.3 mmol) of N,N-diisopropylethylamine in 8,98 ml of tetrahydrofuran. The reaction mixture was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow solid was obtained 665 mg (yield: 100%) 3-cyclopentyl-2-(3,4-acid)-N-thiazol-2-ylpropionic: tPL: 50-52°C; EI-HRMS m/e Rasch. for C19H24N2O3S (M+): 360,1507, detect.: 360,1516.

Example 116

3-cyclopentyl-2-(3,4-dihydroxyphenyl)-N-thiazol-2-ylpropionic

7,43 ml (7,43 mmol) of 1.0 M solution tribromide boron in methylene chloride at 25°C was treated with a solution of 0.27 g (0,74 mmol) 3-cyclopentyl-2-(3,4-acid)-N-thiazol-2-ylpropionic (obtained in example 115) in the 7.43 ml of methylene chloride. The resulting solution was stirred at 25°C for 1 h, after this time the reaction mixture was cooled to 0°C and was treated with a dilute aqueous solution of ammonium hydroxide. The resulting mixture was stirred at 0°C for 20 minutes after this time the reaction mixture was poured into water and was extracted with 3 portions of 50 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated the de white solid substance was obtained to 38.8 mg (yield: 15.7 percent) 3-cyclopentyl-2-(3,4-dihydroxyphenyl)-N-thiazol-2-ylpropionic: tPL: 170-173°C; EI-HRMS m/e Rasch. for C17H20N2O3S (M+): 332,1194 the detection.: 332,1192.

Example 117

3-cyclopentyl-2-(4-methoxyphenyl)-N-thiazol-2-ylpropionic

58,5 ml solution of their diisopropylamide lithium (0.93 M source solution, 53.2 mmol), cooled to -78°C, cultivated 4,21 g (25,35 mmol) (4-methoxyphenyl)acetic acid to 25.3 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 5.85 g (27.8 mmol) of iodomethylpropane in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 45 min and at 0°C for 1 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours then the reaction in the reaction mixture was suppressed by adding dropwise 10 ml of a saturated aqueous solution of ammonium chloride. Under vacuum, remove the excess solvent. The residue was acidified using 1 N. aqueous solution of hydrochloric acid to pH 1. The resulting mixture was poured into 50 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed what was interaval under vacuum. Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) in the form of a yellow solid was obtained 2.76 g (yield: 43,8%) 3-cyclopentyl-2-(4-methoxyphenyl)propionic acid: tPL: 119-121°C; EI-HRMS m/e Rasch. for C15H20O3(M+): 248,1412 the detection.: 248,1415.

A solution of 500 mg (2.0 mmol) of 3-cyclopentyl-2-(4-methoxyphenyl)propionic acid of 20.1 ml of methylene chloride, cooled to 0°C, was treated with 1.1 ml (2.21 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and then at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 444 mg (4,42 mmol) of 2-aminothiazole and 0.84 ml (a 4.83 mmol) of N,N-diisopropylethylamine in 10.1 ml of tetrahydrofuran. The solution was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a pale yellow solid was obtained 638 mg (yield: 95,8%) 3-cyclopentyl-2-(4-methoxyphenyl)-N-thiazol-2-yl-propionamide: tPL: 166-167°C; EI-HRMS m/e Rasch. for C18H22N2O2S (M+): 330,1402 the detection.: 330,1398.

PL: 198-200°C; EI-HRMS m/e Rasch. for C17H20N2O2S (M+): 316,1245 the detection.: 316,1256.

Example 119

Methyl ester 4-[2-cyclopentyl-1-(thiazol-2-ylcarbonyl)ethyl]benzoic acid

A solution of 10 g (73.4 mmol) of 4-methylbenzoic acid in 133 ml of benzene was treated with 72 mg (0.29 mmol) of benzoyl peroxide. The resulting mixture was boiled under reflux until then, until it became homogeneous. After this time the reaction mixture was treated with 13 g (73.4 mmol) of N-bromosuccinimide and DOP for 2.5 hours After this time the reaction mixture was cooled to 25°C. the precipitate was collected by filtration and washed with 50 ml of hot water. This solid substance was collected in 150 ml of water. The resulting suspension was heated to 80°C, and then hot filtered. Solids, which were collected, dried under vacuum obtaining in the form of a white solid substance 12.3 g (yield: 77,9%) 4-bromomethylphenyl acid: tPL: 224-226°C; EI-HRMS m/e Rasch. for C8H7BrO2(M+): 213,9629, detect.: 213,9628.

A solution of 4.0 g (to 18.6 mmol) 4-bromomethylphenyl acid in 186 ml of acetonitrile was treated with a solution of 1.0 g (to 20.4 mmol) of sodium cyanide and 0.74 g (to 18.6 mmol) of sodium hydroxide in 24 ml of water. The reaction mixture is boiled under reflux for 2 hours after this time the reaction mixture was cooled to 25°C and concentrated under vacuum. The resulting solution was washed for 1 portion 50 ml of chloroform. 1H. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 3. This aqueous layer was extracted with 3 portions of 100 ml of chloroform/methanol (ratio 9:1). The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of the aircraft is>H7NO2(M+): 161,0476, detect.: 161,0483.

A solution of 0.53 g (of 3.31 mmol) 4-cyanomethylene acid in 42.8 ml of 50% aqueous hydrochloric acid solution kept at 80°C for 16 hours after this time the reaction mixture was cooled to 25°C and added dropwise a 50% aqueous sodium hydroxide solution the pH was brought to 3. The resulting mixture was diluted with water and was extracted with 2 portions of 50 ml of butanol. Next, the organic fraction was extracted with 5 portions of 50 ml of water (pH 6-7). The pH value of aqueous extracts of 3 M aqueous hydrochloric acid solution was brought to 3 and the mixture was concentrated under vacuum obtaining in the form of a white solid 70 mg (yield: 11.7 per cent) 4-carboxymethylamino acid: tPL: 235-237°C; EI-HRMS m/e Rasch. for C9H8O4(M+): 180,0422, detect.: 180.

A mixture of 0.20 g (1.11 mmol) of 4-carboxymethylamino acid and 27 mg (0.1 mmol) of uranyl chloride Nickel(II) 1,11 ml of methanol kept at 120°C for 24 hours after this time the reaction mixture was cooled to 25°C and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) in the form of a clear oil was obtained from 66.7 mg (M+): 208,0735, detect.: 208,0733.

The solution of their diisopropylamide lithium (2.3 ml, 0,31 M source solution, 0.71 mmol), cooled to -78°C, treated with a solution of 66 mg (0.31 mmol) of 4-methoxycarbonylmethylene acid of 0.85 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 86 mg (0.40 mmol) of iodomethylpropane in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 18 hours after this time the reaction in the reaction mixture was marked by the gradual addition of 10 ml saturated aqueous solution of ammonium chloride. Then the reaction mixture was poured into 50 ml of water. The resulting solution was extracted with 3 portions of 25 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) in the form of a clear oil was obtained of 60.5 mg (yield: 65.7 per cent) methyl ester of 4-(2-cyclopentyl-1 metuximab the tx2">A solution of 0.40 g (1.37 mmol) of methyl ester of 4-(2-cyclopentyl-1-methoxycarbonylethyl)benzoic acid of 13.7 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) was treated with 1 N. aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 1 h, after this time the reaction mixture was poured into water. 1H. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 1 and extracted with 4 portions of 25 ml of chloroform/methanol (ratio 9:1). The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a clear oil was obtained 161,8 mg (yield: 42,5%) of a mixture of methyl ester of 4-(1-carboxy-2-cyclopentylmethyl)benzoic acid and methyl ester of 4-(1-carboxy-2-cyclopentylmethyl)benzoic acid: EI-HRMS m/e Rasch. for C16H20O4(M+): 276,1361, detect.: 276,1364.

The solution to 24.2 mg (0.08 mmol) of a mixture of methyl ester of 4-(1-carboxy-2-cyclopentylmethyl)benzoic acid and methyl ester of 4-(1-carboxy-2-cyclopentylmethyl)benzoic acid of 0.87 ml of methylene chloride, cooled to 0°C, and treated with 0.05 ml (0.10 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and natezenie 30 minutes Next, the reaction mixture was treated with a solution of 19.3 mg (0,19 mmol) of 2-aminothiazole and 0.04 ml (0.21 mmol) of N,N-diisopropylethylamine in of 0.44 ml of tetrahydrofuran. The solution was stirred at 25°C for 4 h, after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of not quite white solid substance was obtained to 18.1 mg (yield: 57.6%) of methyl ester 4-[2-cyclopentyl-1-(thiazol-2-ylcarbonyl)ethyl] benzoic acid: tPL: 54-56°C; EI-HRMS m/e Rasch. for C19H22N2O3S (M+): 358,1351, detect.: 358,1346.

Example 120

3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)-N-thiazol-2-ylpropionic

A solution of 1.0 g (by 5.87 mmol) (3-fluoro-4-hydroxyphenyl)acetic acid in 20 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture was stirred at 120°C for 6 hours after this time the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained of 1.05 g (yield: 97,6%) methyl ether (3-fluoro-4-hydroxyphenyl)acetic acid: tPL: the l) methyl ester 3-fluoro-4-hydroxyphenyl)acetic acid, of 1.87 g (13,57 mmol) of potassium carbonate and 1.12 g (8,14 mmol) under the conditions in 27,1 ml of acetone was kept at 90°C for 4 h after which time the potassium carbonate was removed by filtration. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) in the form of a clear oil was obtained 1.01 g (yield: 94,3%) methyl ether (3-fluoro-4-methoxyphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H11FO3(M+): 198,0692, detect.:198,0693.

to 21.6 ml solution of their diisopropylamide lithium (0,31 M source solution, 6,69 mmol), cooled to -78°C, treated with a solution of 1.26 g (6.38 mmol) of methyl ether (3-fluoro-4-methoxyphenyl)acetic acid in 16 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.47 g (7,02 mmol) iodomethylpropane in 2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h, the Reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours Then the reaction in the reaction mixture extinguished gradual EXT who had strayaway 3 portions of 50 ml of ethyl acetate. The organic fraction was washed for 1 portion 50 ml saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60, Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) in the form of a clear oil was obtained 1,50 mg (yield: 83.8 per cent) methyl ester 3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)propionic acid: EI-HRMS m/e Rasch. for C16H21FO3(M+): 280,1477, detect.: 280,1474.

A solution of 1.04 g (3.73 mmol) of methyl ester of 3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)propionic acid 9.3 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) was treated to 3.73 ml (3.73 mmol) of 1 N. aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 18 hours, after this time, 1 N. aqueous solution of hydrochloric acid, the reaction mixture was acidified to pH 1 and extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 707,8 mg (yield: 71.3 per cent) 3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)propionic acid: tPL: 149-151°C; EI-HRMS m/e Rasch. the-2-(3-fluoro-4-methoxyphenyl)propionic acid in 5.0 ml of methylene chloride, cooled to 0°C, treated of 0.82 ml of 1.65 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 10 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 331 mg (3,30 mmol) of 2-aminothiazole and 0.62 ml (of 3.60 mmol) of N,N-diisopropylethylamine in 7.5 ml of tetrahydrofuran. This solution was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 538,4 mg (yield: 100%) 3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)-N-thiazol-2-ylpropyl-amide: tPL: 51-53°C: EI-HRMS m/e Rasch. for C18H21FN2O2S (M+): 348,1307 the detection.: 348,1312.

Example 121

3-cyclopentyl-2-(3-fluoro-4-hydroxyphenyl)-N-thiazol-2-ylpropionic

The solution 305,4 mg (0.87 mmol) of 3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)-N-thiazol-2-ylpropionic (obtained in example 120) in 8.7 ml of methylene chloride at 25°With the handle of 8.75 ml (8,75 mmol) of 1.0 M solution tribromide boron in methylene chloride. The resulting solution was stirred at 25°C for 5 h protesting solution of ammonium hydroxide. The resulting solution was stirred at 0°C for 15 minutes Then the mixture was poured into 50 ml of water and was extracted with 3 portions of 30 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 212,7 mg (yield: 72,5%) 3-cyclopentyl-2-(3-fluoro-4-hydroxyphenyl)-N-thiazol-2-ylpropyl-amide: tPL: 199-201°C: EI-HRMS m/e Rasch. for C17H19FN3O2S (M+): 334,1151 the detection.: 334,1152.

Example 122

6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid

141,3 ml solution of their diisopropylamide lithium (0,32 M source solution of 45.0 mmol), cooled to -78°C, were treated to 3.41 g (20.0 mmol) of (3-chlorophenyl)acetic acid in 49,7 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 1 h, after this time the reaction mixture was treated with 4.64 g (22,08 mmol) iodomethylpropane in with 4.64 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then implement eponym by adding the reaction mixture into 50 ml of 2 N. an aqueous solution of hydrochloric acid. The product was extracted with 1 portion 150 ml of ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) in the form of a yellow solid was obtained (3,68 g 72,9%) of 2-(3-chlorophenyl)-3-cyclopentylpropionic acid: tPL: 70-72°C; EI-HRMS m/e Rasch. for C14H17ClO2(M+): 252,0917, detect.: 252,0915.

A solution of 504 mg (2.0 mmol) of 2-(3-chlorophenyl)-3-cyclopentylpropionic acid in 20 ml of methylene chloride, cooled to 0°C, was treated with 1.1 ml (2.2 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 2 h Then the reaction mixture was treated with 532 mg (3.5 mmol) of methyl ester of 6-aminonicotinic acid and 0.84 ml (4.8 mmol) of N,N-diisopropylethylamine. The resulting solution was stirred at 25°C for 18 hours after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a colourless oil was obtained 151,9 mg (yield: 19,7%) of methyl ester of 6-[2-(3-harfe the+): 386,1397, detect.: 386,1398.

The solution 146,9 mg (0.38 mmol) of the methyl ester of 6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl] nicotinic acid in 10 ml of tetrahydrofuran/water/methanol (ratio 3:1:1) was treated with 0.4 ml (0.80 mmol) of 2n. an aqueous solution of sodium hydroxide. The reaction mixture was stirred at 25°C for 4 days. After this time the reaction mixture was concentrated under vacuum. The residue was diluted 50 water and was extracted with 1 portion 50 ml of diethyl ether. The aqueous layer was acidified to pH 1 by adding dropwise 3 N. aqueous solution of hydrochloric acid. This solution was extracted with 3 portions of 75 ml of methylene chloride/methanol (ratio 3:1). The organic fraction was dried over magnesium sulfate, filtered and concentrated under vacuum. The obtained solid was ground into powder in diethyl ether/hexano (2:1) to obtain a white solid of 63.6 mg (yield: 44,4%) 6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid: tPL: 251-255°C; EI-RMS m/e Rasch. for C20H21ClN2O3(M+): 372,1240, detect.: 372,1250.

Example 123

Methyl ester of 6-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]nicotinic acid

A solution of 14.1 g (48,06 mmol) of ethyl ester of 3-CEC is 103,67 mmol) of lithium hydroxide. The reaction mixture was stirred at 25°C for 21 hours Then under vacuum, remove the tetrahydrofuran. The residue was diluted with 75 ml of water and was extracted with 3 portions of 75 ml of diethyl ether. 3 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 1 and extracted with 3 portions of 75 ml of methylene chloride. The organic fraction was washed with 2 portions of 100 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum to obtain a yellow solid of $ 11.97 g (yield: 93,6%) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: tPL: 119-125°C; EI-HRMS m/e Rasch. for C14H17NO4(M+): 263,1157, detect.: 263,1162.

A solution of 526 mg (2.0 mmol) of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid in 20 ml of methylene chloride was cooled to 0°C and was treated with 1.2 ml (2.4 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 30 minutes Then the reaction mixture was treated with a solution of 532 mg (3.5 mmol) of methyl ester of 6-aminonicotinic acid in 10 ml of tetrahydrofuran and 0.84 ml (4.8 mmol) of N,N-diisopropylethylamine. The resulting solution VT. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale orange glassy material was obtained 353,9 mg (yield: 44.6 per cent) methyl ester of 6-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]nicotinic acid: EI-HRMS m/e Rasch. for C21H23N3O5(M+): 397,1637, detect.: 397,1631.

Example 124

2-(4-AMINOPHENYL)-3-cyclopentyl-N-pyridine-2-ylpropionic

A solution of 263 mg (1.0 mmol) 3-cyclopentyl-2-(4-nitrophenyl)propionic acid (obtained in example 22) in 10 ml of methylene chloride, cooled to 0°C, and treated with 0.6 ml (1.2 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and then at 25°C for 30 minutes Then the reaction mixture was treated with a solution 200,6 mg (2.14 mmol) of 2-aminopyridine in 5 ml of tetrahydrofuran and 0.42 ml (2.4 mmol) of N,N-diisopropylethylamine. The resulting solution was stirred at 25°C for 48 hours, after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale yellow glassy material was obtained 138,6 mg (yield: 40 (M+): 339,1581, detect.: 339,1582.

A mixture of 130 mg (0.38 mmol) of 3-cyclopentyl-2-(4-nitrophenyl)-N-pyridin-2-ylpropionic in 50 ml of ethyl acetate and 5 ml of methanol was treated with a catalytically effective amount (50 mg), 10% palladium on charcoal. The resulting mixture was shaken at 25°C under the pressure of the hydrogen gas 60 psi in a Parr apparatus for 24 hours after this time the catalyst was removed by filtration through a layer of brownmillerite. The filtrate was concentrated under vacuum obtaining in the form of a yellowish-brown oil to 99.9 mg (yield: 84.3 percent) of 2-(4-AMINOPHENYL)-3-cyclopentyl-N-pyridine-2-ylpropionic: EI-HRMS m/e Rasch. for C19H23N3O (M+): 309,1834, detect.: 309,1849.

Example 125

Methyl ester of 6-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]nicotinic acid

A solution of 526 mg (2.0 mmol) of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid (obtained in example 22) in 20 ml of methylene chloride, cooled to 0°C, was treated with 1.2 ml (2.4 mmol) of a 2.0 M solution of oxalicacid in methylene chloride and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0°C for 15 min and at 25°C for 30 min. Then the reaction mixtures is and 0.84 ml (4.8 mmol) of N,N-diisopropylethylamine. The resulting solution was stirred at 25°C for 48 hours, after this time the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a pale orange glassy material was obtained 353,9 mg (yield: 44.6 per cent) methyl ester of 6-[3-cyclopentyl-2-(4-nitrophenyl)propionamide] nicotinic acid: EI-HRMS m/e Rasch. for C21H23N3O5(M+): 397,1637, detect.: 397,1631.

A mixture of 300 mg (0.75 mmol) of the methyl ester of 6-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]nicotinic acid in 30 ml of ethyl acetate was treated with a catalytically effective amount (30 mg), 10% palladium on charcoal. The resulting mixture was shaken at 25°C under the pressure of the hydrogen gas 60 psi in a Parr apparatus for 24 hours after this time the catalyst was removed by filtration through a layer of brownmillerite. The filtrate was concentrated under vacuum obtaining in the form of a pale yellow glassy material 262,8 mg (yield: 94.7 percent) of the methyl ester of 6-[2-(4-AMINOPHENYL)-3-cyclopentyl-pinellino]nicotinic acid: EI-HRMS m/e Rasch. for C21H25N3O3(M+): 367,1895, detect.: 367,1899.

The solution was 4.02 ml (30 mmol) of isoamylamine in 19.8 ml (220 mmol) of dimethyl disulfide at 25°C was slowly treated with 4.8 g (20 mmol) 4-bromo-2-(trifluoromethyl) aniline. Proceeded exothermic reaction with evolution of gas. The resulting brown reaction mixture is kept at 80 to 90°C for 2 h, after this time the data thin-layer chromatographic analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25°C and then concentrated under vacuum. The obtained residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed successively 1 portion 200 ml of 1 N. aqueous solution of hydrochloric acid and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40S, silica, 8/1 hexane/ethyl acetate) as a brown oil was obtained to 4.73 g (yield: 87%) of 4-bromo-1-methylsulfanyl-2-cryptomelane: EI-HRMS m/e Rasch. for C8H6BrF3S (M+): 269,9326, detect.: 269,9327.

A solution of 4.71 g a (17.4 mmol) of 4-bromo-1-methylsulfanyl-2-cryptomelane in 100 ml of methylene chloride was cooled to-beshevli at -10°C for 10 min, and then was heated to 25°C, and then stirred over night. After this time the data thin-layer chromatographic analysis of the reaction mixture indicated the absence of starting material. Next, the reaction mixture was filtered, the solids washed with 1 portion 50 ml of methylene chloride. The filtrate was concentrated under vacuum. The obtained residue was dissolved in 100 ml of ethyl acetate. The organic layer was washed sequentially with 2 portions of 100 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain a yellow solid. By recrystallization from 20 ml of methylene chloride, 10 ml of diethyl ether and hexanol in the form of a white solid substance was obtained of 3.46 g (yield: 57%) of 4-bromo-1-methanesulfonyl-2-cryptomelane: tPL: 110-112°C; EI-HRMS m/e Rasch. for C8H6BrF3O2S (M+): 301,9224, detect.: 301,9223.

A mixture of 1.3 g (20 mmol) of zinc dust (Aldrich company, with a particle size of -325 mesh) and 2 ml of dry tetrahydrofuran in an argon atmosphere was treated with 187 mg (1 mmol) of 1,2-dibromethane. Next, a suspension of zinc was heated with the help of the SS was repeated three times to ensure activation of the zinc dust. Then the suspension of activated zinc dust was treated with 110 mg (1 mmol) trimethylsilylpropyne and the suspension was stirred for 15 min at 25°C. After the reaction mixture was treated by adding dropwise over 5 min a solution of 2.5 g (8.5 mmol) of the methyl ester (E)-3-cyclohexyl-2-iodically acid (obtained in example 110) in 3 ml dry tetrahydrofuran. After this addition the reaction mixture was stirred at 40 to 45°C for 1 h, followed by stirring overnight at 25°C. further, the reaction mixture was diluted in 4 ml of dry tetrahydrofuran and stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask 108 mg (0.2 mmol) of bis(dibenzylideneacetone) palladium (0) and 209 mg (0.8 mmol) of triphenylphosphine in 10 ml of dry tetrahydrofuran was stirred in an argon atmosphere at 25°C for 10 min, and then treated 2,12 g (7 mmol) of 4-bromo-1-methanesulfonyl-2-cryptomelane and their connection zinc in tetrahydrofuran. Received a brick-red solution was kept at 40 to 45°C for 2 days. The reaction mixture was cooled to 25°C, and then poured into 100 ml saturated aqueous solution of ammonium chloride and organicly 1 portion of 100 ml of a saturated aqueous solution of ammonium chloride, was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 40M, silica, hexane/acetate in a ratio of from 9/1 to 3/1) in the form of a viscous oil was obtained 2.7 g (yield: 99%) of methyl ester of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid: EI-HRMS m/e Rasch. for C18H21F3O4S (M+): 391,1191, detect.: 391,1200.

A solution of 36.6 mg (0,154 mmol) of uranyl chloride Nickel(II) and 302 mg (0.77 mmol) of methyl ester of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid in 8 ml of methanol was cooled to 0°C, and then processed into four portions 87 mg (to 2.29 mmol) of sodium borohydride. After adding the black reaction mixture was stirred for 15 min at 0°C, and then it was heated to 25°C, after which it was stirred for 15 hours using filter paper black solid was filtered and washed with methanol. The combined solution was concentrated under vacuum and the residue was diluted with 50 ml ethyl acetate. The organic layer is successively washed with 1 portion of 50 ml of 3 N. aqueous solution of hydrochloric acid, 1 portion of 50 ml of a saturated aqueous solution of bicarbona what I was filtered and concentrated under vacuum obtaining in the form of a viscous oil 280 mg (yield: 93%) of racemic methyl ester of 3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C18H23F3O4S (M+): 392,1269, detect.: 392,1276.

A solution of 265 mg (0.67 mmol) of methyl ester of 3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid in 5 ml of ethanol was treated with 1.5 ml 1 N. aqueous sodium hydroxide solution. The solution was kept at 45 to 50°C for 5 h, after this time the data thin-layer chromatographic analysis of the mixture indicated the absence of starting material. Next, the reaction mixture was concentrated under vacuum, removing the ethanol, the residue was diluted with 20 ml water and was extracted with 1 portion in 40 ml of diethyl ether to remove neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed 1 portion 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a viscous oil 249 mV>H21F3O4S (M+): 378,1113, detect.: 378,1121.

A solution of 279 mg (1.06 mmol) of triphenylphosphine in 5 ml of methylene chloride was cooled to 0°C and then was treated amounts to 188.7 mg (1.06 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of 237 mg (0,626 mmol) of 3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid in 4 ml of methylene chloride. A clear solution was stirred at 0°C for 15 min and then was heated to 25°C, after which it was stirred for 2 h Then the reaction mixture was treated with 188 mg (1.88 mmol) of 2-aminothiazole and the resulting suspension was stirred at 25°C for 15 hours, the Reaction mixture was concentrated under vacuum removal of methylene chloride and the residue was diluted with 50 ml ethyl acetate and 50 ml of 1 N. aqueous solution of hydrochloric acid. Both layer was isolated and the aqueous layer was extracted with 1 portion in 30 ml of ethyl acetate. The combined organic extracts are then washed 1 portion 50 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Chromatography (column etvertogo substances received 83 mg (yield: 29%) of 3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic: EI-HRMS m/e Rasch. for C20H23F3N2O3S2(M+): 460,1102, detect.: 460,1100.

Example 127

(A) 3-cyclohexyl-2-(3,4-dichlorophenyl)propionyl]urea

A solution of 14.0 g (0,068 mol) of (3,4-dichlorophenyl) acetic acid in 71 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 12 hours the Reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 15.0 g (quantitative yield) of methyl ether (3,4-dichlorophenyl) acetic acid: tPL: 30-32°C; EI-HRMS m/e Rasch. for C9H8CL2O2(M+): 217,9901, detect.: 217,9907.

of 16.3 ml (0,31 M source solution 5,04 mmol) of their diisopropylamide lithium cooled to -78°C, and treated with 1.0 g (4,58 mmol) methyl ether (3,4-dichlorophenyl) acetic acid 8.6 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with 1.92 ml (13,76 mmol) bromeilles in 1 ml hexamethylphosphoramide at 25°C for 16 hours Then the reaction in the reaction mixture was suppressed by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) in the form of a clear oil was obtained 1.5 g (quantitative yield) of methyl ester of 3-cyclohexyl-2-(3,4-dichlorophenyl)propionic acid: EI-HRMS m/e Rasch. for C16H20Cl2O2(M+): 314,0840, detect.: 314,0836.

The mixture 582 mg (of 1.84 mmol) of methyl ester of 3-cyclohexyl-2-(3,4-dichlorophenyl)propionic acid and 222 mg (3,69 mmol) of urea in 3,96 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, was 2.76 mmol) was boiled under reflux at 120°C for 12 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 52,9 mg (yield: 8.3%) of 3-cyclohexyl-2-(3,4-dichlorophen-yl)PROPYNYL]urea: tPL: 76-79°C; EI-HRMS m/e Rasch. for C16H20Cl2N2O2(M+): 342,0902, detect.: 342,0904.

(B) the Number of urea: [3-cyclopropyl-2-(3,4-dichlorophenyl)propionyl]urea as a white solid: tPL: 117-119°C; EI-HRMS m/e Rasch. for C13H14Cl2N2O2(M+): 300,0432, detect.: 300,0431;

(b) of the methyl ester 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid and urea: [3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl] urea as a white solid: tPL: 103-105°C; EI-HRMS m/e Rasch. for C15H18Cl2N2O2(M+): 328,0745, detect.: 328,0750;

(C) of the methyl ester 3-cyclobutyl-2-(3,4-dichlorophenyl)propionic acid and urea: [3-cyclobutyl-2-(3,4-dichlorophenyl)propionyl] urea as a white solid: tPL: 65-67°C; EI-HRMS m/e Rasch. for C14H16Cl2N2O2(M+): 314,0589, detect.: 314,0597;

(g) of the methyl ester 3-cycloheptyl-2-(3,4-dichlorophenyl)propionic acid and urea: [3-cycloheptyl-2-(3,4-dichlorophenyl)propionyl] urea as a white solid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C17H22Cl2N2O2(M+): 356,1058, detect.: 356,1054;

(d) from 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-methyl ether and metalmachine: 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine in the form of a white solid: tPL: 120-125°C; EI-HRMS m/e Rasch. DL 3-cyclohexyl-2-(3,4-dichlorophenyl)propionic acid and metalmachine: [3-cyclohexyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine in the form of a white solid: tPL: 69-73°C; EI-HRMS m/e Rasch. for C17H22Cl2N2O2(M+): 356,1058, detect.: 356,1046;

(g) from 1-[2-(3,4-dichlorophenyl)-4-methylpentanoic]-3-methyl ether and metalmachine: 1-[2-(3,4-dichlorophenyl)-4-methylpentanoic]-3-metalmachine in the form of a white solid: tPL: 123-125°C; EI-HRMS m/e Rasch. for C14H18Cl2N2O2(M+): 316,0745, detect.: 316,0740;

(C) of the methyl ester of 2-(3,4-dichlorophenyl)hexanoic acid and metalmachine: 1-[2-(3,4-dichlorophenyl)hexanoyl]-3-metalmachine in the form of a clear oil: EI-HRMS m/e Rasch. for C14H18Cl2N2O2(M+): 316,0743, detect.: 316,0745.

Example 128

1-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine

6,03 g (0.03 mol) of (3-chlorophenyl) acetic acid was dissolved in 37,7 ml of ethanol and was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 12 hours the Reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a clear oil was obtained 6,10 g (yield: 86.8% of) ethyl ester (3-chlorophenyl) acetic acid: EI-HRMS m/e Rasch. for C16H21ClO2(M+): 280,1230, detect.: 280,1238.

A mixture of 1.70 g (6.05 mmol) of the ethyl ester of 2-(3-chlorophenyl)-3-cyclopen-dipropionate acid and 673 mg (remaining 9.08 mmol) netilmicin for 6 hours Next, the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained 149,1 mg (yield: 8%) 1-[2-(3-chlorophenyl)-3-cyclopentyl-propionyl]-3-metalmachine: tPL: 52-55°C; EI-HRMS m/e Rasch. for C16H21ClN2O2(M+): 308,1292, detect.: 308,1287.

Example 129

1-[3-cyclopentyl-2-(3,4-differenl)propionyl] -3-metalmachine

5.0 g (0,029 mol) of (3,4-differenl) acetic acid and 30.0 ml of methanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 4 hours the Reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a clear oil was obtained of 5.15 g (yield: 95.2 per cent) methyl ether (3,4-differenl)acetic acid: EI-HRMS m/e Rasch. for C9H8F2O2(M+): 186,0493, detect.: 186,0492.

23,0 ml solution of their diisopropylamide lithium (0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.20 g (6,48 mmol) methyl ether (3,4-differenl) acetic acid 16,1 ml of tetrahydrofuran/hexathia this time the reaction mixture was treated with a solution of 1.50 g (7,13 mmol) iodomethylpropane in 1 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) in the form of a clear oil was obtained 1,79 g (quantitative yield) of methyl ester of 3-cyclopentyl-2-(3,4-differenl)propionic acid: EI-HRMS m/e Rasch. for C15H18F2O2(M+): 268,1275, detect.: 268,1278.

A mixture of 1.65 g (6,14 mmol ) methyl ester 3-cyclopentyl-2-(3,4-differenl)propionic acid and 683 mg (which 9.22 mmol) of metallocene 16.6 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 12.3 mmol) was boiled under reflux at 100°C for 8 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained 180 mg (yield: 9.4%) of 1-[3-cyclopentyl-2-(3,4-debtor(M+): 310,1493, detect.: 310,1499.

Example 130

1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine

A solution of 6.29 g (0.03 mol) (4-chlorophenyl) acetic acid of 38.4 ml of ethanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 12 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a pale yellow solid was obtained 6,45 g (yield: 88%) of ethyl ester (4-chlorophenyl) acetic acid: tPL: 39-41°C; EI-HRMS m/e Rasch. for C10H11ClO2(M+): 198,0448, detect.: 198,0452.

23,0 ml solution of their diisopropylamide lithium (0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.28 g (6,48 mmol) ethyl ester (4-chlorophenyl)acetic acid 16,1 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.50 mg (7,13 mmol) iodomethylpropane in 1 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 thou hast extinguished by adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a yellow oil was obtained of 1.65 g (yield: 90.9 per cent) ethyl ester 2-(4-chlorophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21Cl2O2(M+): 280,1230, detect.: 280,1227.

A mixture of 1.65 g (of 5.89 mmol) ethyl ester 2-(4-chlorophenyl)-3-cyclopentylpropionic acid and 654 mg (8,83 mmol) of metallocene 16.9 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 11,78 mmol) was boiled under reflux at 100°C for 6 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a white solid substance was obtained to 105.3 mg (yield: 5,8%) 1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl] -3-metalmachine: tPL: 145-147°C; EI-HRMS m/e Rasch. for C16H21CN2O2(M+): 308,1292, detect.: 308,1291.

Example 131

1-[3-cyclopentyl-2-(4-nitrophenyl)propionyl]-3-metalmachine

430,55 ml their disaprove ether (4-nitrophenyl) acetic acid in 312,5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution 27,75 g (132,1 mmol) iodomethylpropane 27.8 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise to 250 ml of a saturated aqueous solution of ammonium chloride. The reaction mixture was concentrated under vacuum. The residue was diluted with 250 ml of water and was extracted with 3 portions of 300 ml of ethyl acetate. The organic fraction was washed with 2 portions of 250 ml of saturated aqueous lithium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 95/5 hexane/ethyl acetate) as a yellow oil was obtained 28,30 g (yield: 77.2 percent) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: EI-HRMS m/e Rasch. for C16H21NO4(M+): 291,1470, detect.: 291,1470.

A mixture of 1.27 g (4,36 mmol) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid and 647 mg (8,73 mmol) of metallocene in 9,36 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 6,54 maguuma. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 183,6 mg (yield: 13,2%) 1-[3-cyclopentyl-2-(4-nitrophenyl)propionyl]-3-metalmachine: tPL: 179-183°C; EI-HRMS m/e Rasch. for C16H21N3O4(M+): 319,1532, detect.: 319,1527.

Example 132

1-(3-cyclopentyl-2-phenylpropionyl)-3-metalmachine

23 ml of a solution of their diisopropylamide lithium (0,31 M source solution, 7,13 mmol), cooled to -78°C, was treated with 1.06 g (6,48 mmol) ethyl ester of phenylacetic acid in 16,1 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.50 mg (7,14 mmol) iodomethylpropane 1.5 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise 5 ml of a saturated aqueous solution of ammonium chloride. The reaction mixture was poured into 100 ml of water and was extracted with 2 portions of 100 ml of ethyl acetate. Organic, what was intervali and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 95/5 hexane/ethyl acetate) as a pale yellow oil was obtained 1.70 g (quantitative yield) of ethyl ester of 3-cyclopentyl-2-phenylpropionic acid: EI-HRMS m/e Rasch. for C16H22O2(M+): 247,1698, detection. 247,1704.

A mixture of 1.70 g (7,06 mmol) of ethyl ester of 3-cyclopentyl-2-phenylpropionic acid and 1.04 mg (14,13 mmol) of metallocene in 130,3 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 21,18 mmol) was boiled under reflux at 100°C for 24 h Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained to 1.21 mg (yield: 62.4 per cent) of 1-(3-cyclopentyl-2-phenylpropionyl)-3-metalmachine: tPL: 145-147°C; EI-HRMS m/e Rasch. for C16H22N2O2(M+): 274,1681, detect.: 274,1682.

Example 133

1-[2-(4-bromophenyl)-3-cyclopentylpropionyl]-3-metalmachine

A solution of 7.7 ml (54,88 mmol) Diisopropylamine in 23 ml of dry tetrahydrofuran and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated to 22.0 ml (em was treated by the addition dropwise of a solution 5,62 g (26,13 mmol) 4-bromoferrocene acid in 23 ml of dry tetrahydrofuran and 10 ml of 1,3-dimethyl-3,4,5,6-Tetra-hydro-2(1H)-pyrimidinone. The reaction mixture was bought dark colored, after which it was left mixed at -78°C for 1 h, after which was added dropwise a solution 5,76 g (27,44 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 24 h the Reaction in the reaction mixture extinguished with water, and then the mixture was concentrated under vacuum removal of tetrahydrofuran. The aqueous residue was acidified with 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with 2 portions of 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a pale yellow solid was obtained 3.88 g (yield: 50%) of 2-(4-bromophenyl)-3-cyclopentylpropionic acid: tPL: 91-93°C; EI-HRMS m/e Rasch. for C14H17BrO2(M+): 296,0412, detect.: 296,0417.

A solution of 1.37 g (4.61 mmol) of 2-(4-bromophenyl)-3-cyclopentylpropionic acid in 23 ml of methanol was slowly treated with 5 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled od vacuum removal of methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.40 g (yield: 97%) of methyl ester of 2-(4-bromophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H19BrO2(M+): 310,0568, detection. 310,0569.

420,0 mg (1.35 mmol) of the methyl ester of 2-(4-bromophenyl)-3-cyclopen-dipropionate acid and 299,9 mg (of 4.05 mmol) of metallocene processed and 7.7 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 5.40 mmol). Next, the resulting reaction mixture is boiled under reflux for 48 hours the Reaction mixture was allowed to cool to 25°C, and then it was filtered through brownmillerite. Brownmillerite thoroughly washed with ethyl acetate and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a white solid substance was obtained of 58.7 mg (yield: 12%) 1-[2-(4-bromophenyl)-3-cyclopentyl-propionyl]-3-methyl urea: tPL the example 134

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in a nitrogen atmosphere, and then was treated with 6,7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 1.89 g (8,00 mmol) 4-(triptoreline)phenylacetic acid in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after that time, it was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water, and then it was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion 100 ml saturated aqueous cromatografia (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3O2S (M+): 318,0901, detect.: 318,0912.

A solution of 1.33 g (4,18 mmol) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 10 ml of methanol was slowly treated by adding 4 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 36 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to remove methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 3)propionic acid and to 140.5 mg (1,90 mmol) of metallocene was treated with 3.6 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, of 2.53 mmol). Next, the resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered through brownmillerite. Brownmillerite thoroughly washed with ethyl acetate until then, until the solvent passing through brownmillerite, not shown according to thin-layer chromatography absence of the target product. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a white solid was obtained and 42.7 mg (yield: 18%) of 1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine: tPL: 144-145°C; EI-HRMS m/e Rasch. for C17H21F3N2O2S (M+): 374,1276, detect.: 374,1270.

Example 135

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine

A solution of 2.4 ml (Ls 16.80 mmol) Diisopropylamine in 7.5 ml of dry tetrahydrofuran and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in a nitrogen atmosphere, and then was treated with 6,7 ml (Ls 16.80 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated add the Ana and 2.5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 55 min, after that time, it was added dropwise a solution of 1.85 g (8,80 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 41 hours the Reaction in the reaction mixture extinguished with water, and then it was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase of 10% aqueous solution of hydrochloric acid acidified to pH 2 and then extracted with 1 portion 300 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.47 g (yield: 58%) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: tPL: 69-71°C; EI-HRMS m/e Rasch. for C15H17F3O2S (M+): 318,0901, detect.: 318,0912.

A solution of 1.33 g (4,18 mmol) 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid in 10 ml of methanol was slowly treated by adding 4 drops of concentrated sulfuric acid. The resulting p then it was concentrated under vacuum to remove methanol. The residue was diluted with 200 ml of ethyl acetate. The organic phase is washed with 1 portion of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 97/3 hexane/ethyl acetate) as a pale yellow oil was obtained of 1.37 g (yield: 99%) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1052.

A solution of 1.14 g (3,43 mmol) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid 8.6 ml of methylene chloride was treated with 2.00 g of 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 9,26 mmol). The reaction mixture was stirred at 25°C for 17 h, after this time the data thin-layer chromatographic analysis indicated the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added optional 2.00 g of 3-chloroperoxybenzoic acid and obrazovanim remove methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 3 portions of 100 ml of saturated aqueous sodium bicarbonate solution, washed with 1 portion of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained 1.19 g (yield: 95%) methyl ester 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0965.

383,8 mg (1.05 mmol) of methyl ester of 3-cyclopentyl-2-(4-triftormetilfullerenov)propionic acid and 234,1 ml (3,16 mmol) of metallocene was treated with 6.0 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, is 4.21 mmol). Next, the resulting reaction mixture is boiled under reflux for 2 days. The reaction mixture was allowed to cool to 25°C, and then it was filtered through brownmillerite. Brownmillerite thoroughly washed with ethyl acetate until then, until the solvent passing through brownmillerite, not shown according to thin-layer chromatography absence of the target product. The filtrate was concentrated under was vacuumable 119,3 mg (yield: 28%) of 1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine: tPL: 191-192°C; FAB-HRMS m/e Rasch. for C17H21F3N2O4S (M+N)+: 407,1252, detect.: 407,1247.

Example 136

1-[3-cyclopentyl-2-(4-methylsulfinylphenyl)propionyl]-3-metalmachine

A solution of 3.2 ml (23,16 mmol) Diisopropylamine in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in nitrogen atmosphere and then was treated with 2.3 ml (23,16 mmol) of a 10 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 2,01 g (11,03 mmol) of 4-(methylthio)phenylacetic acid in 10.3 ml of dry tetrahydrofuran and 3.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 1 h, after this time was treated by the addition dropwise of a solution of 2.55 g (12,13 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at -78°C for 30 min and then was heated to 25°C, after which it was stirred for 24 h the Reaction in the reaction mixture extinguished with water and then the mixture was concentrated under vacuum removal of tetrahydrofuran. The remaining womanifesto layer was washed for 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) in the form of a cream solid was obtained 1.01 g (yield: 35%) 3-cyclopentyl-2-(4-methylsulfinylphenyl)propionic acid: tPL: 91-93°C; EI-HRMS m/e Rasch. for C15H20O2S (M+): 264,1184, detect.: 264,1177.

A solution of 500 mg (1,89 mmol) 3-cyclopentyl-2-(4-methylsulfinylphenyl)-propionic acid in 8 ml of methanol was slowly treated with 2 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. The orange residue was separated between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow-orange oil 481 mg (yield: 91%) of pure methyl ester 3-cyclopentyl-2-(4-methylsulfinylphenyl)propionic acid which was used without further purification: EI-HRMS m/e Rasch. for C16H22O2S (M+): 278,1341, detect.: 278,1347.

400 mg (1.44 mmol) of methyl ester of 3-cyclopentyl-2-(4-methylsulfonate (7.4 wt.%, the 3.89 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, it was filtered through brownmillerite and this brownmillerite thoroughly washed with ethyl acetate. An ethyl acetate filtrate was washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) as a white solid substance was obtained 141 mg (yield: 31%) of 1-[3-cyclopentyl-2-(4-methylsulfinylphenyl)propionyl]-3-metalmachine: tPL: 185-186°C; EI-HRMS m/e Rasch. for C17H24N2O2S (M+): 320,1559, detect.: 320,1559.

Example 137

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine

A solution of 3.3 ml (23.5 mmol) of Diisopropylamine in 50 ml of dry tetrahydrofuran and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in nitrogen atmosphere was cooled to -78°C and then was treated with 2.35 ml (23.5 mmol) of a 10 M solution of n-utility in hexano. The yellow reaction mixture was stirred at -78°C for 30 min, and Isom the amount of dry tetrahydrofuran. After about half an hour was added 4-methylsulfonylmethane acid in dry tetrahydrofuran, was formed precipitate. When you next add the remaining 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture had become a thick consistency. After adding 4-methylsulfonylmethane acid in dry tetrahydrofuran, the reaction mixture became very thick and barely resisted mixing. This thick reaction mixture was added an additional amount of dry tetrahydrofuran (20 ml) and the reaction mixture was stirred at -78°C for 45 min, after which was added dropwise a solution of 2.35 g (of 11.2 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 100 ml of water and the resulting yellow reaction mixture was concentrated under vacuum removal of tetrahydrofuran. Using conc. hydrochloric acid aqueous residue was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated on the matter was received of 1.80 g (yield: 52%) of 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 152-154°C; EI-HRMS m/e Rasch. for C15H20O4S (M+): 296,1082, detect.: 296,1080.

A solution of 500 mg (1,89 mmol) 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid in 15 ml of methanol was slowly treated with concentrated sulfuric acid (3 drops). The resulting reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white solid substance was obtained 377 mg (yield: 72%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid: tPL: 63-66°C; EI-HRMS m/e Rasch. for C16H22O4S (M+): 310,1239, detect.: 310,1230.

350 mg (1.13 mmol) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl)propionic acid and 184 mg (2.48 mmol) of metallocene was treated with 6.0 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 4,18 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, it was filtered through br Organic layer was dried over magnesium sulfate, was filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white solid substance was obtained 124 mg (yield: 31%) of 1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine: tPL: 205-206°C; EI-HRMS m/e Rasch. for C17H24N2O4S (M+): 352,1457, detect.: 352,1445.

Example 138

(A) 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-atilmotin

The solution 28,80 g (109,8 mmol) of triphenylphosphine and 14.9 g (219,6 mmol) of imidazole in 160 ml of methylene chloride was cooled to 0°C and then was treated by slow addition of 27,87 g (109,8 mmol) of iodine. Next, the reaction mixture was treated by the addition dropwise of a solution of 10.0 g (99,8 mmol) cyclopentylmethyl in 10 ml of methylene chloride. The resulting reaction mixture was heated to 25°C, after which it was stirred for 4 h Then the reaction mixture was diluted with 50 ml water and the reaction mixture was additionally extracted with 3 portions of 20 ml of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum at 25°C. the Obtained solid was washed with 4 portions of 50 ml of pentane and filtered by passing h is Noah fluid 18,48 g (yield: 88%) of iodomethylpropane: EI-HRMS m/e Rasch. for C6H11I (M+): 209,9906, detect.: 209,9911.

The solution is made 13.36 ml (101,89 mmol) Diisopropylamine in 250 ml of tetrahydrofuran was cooled to -78°C in nitrogen atmosphere and then was treated with 51 ml (101,89 mmol) of a 2.0 M solution of n-utility in hexano. The reaction mixture was stirred at -78°C for 15 min, after this time using a hollow needle was slowly added to the solution remaining 9.08 g (44,3 mmol) of 3,4-dichlorophenylamino acid in 60 ml of tetrahydrofuran and 20 ml hexamethylphosphoramide. The bright yellow solution was stirred at -78°C for 1 h, after this time using a hollow needle solution was added 11,17 g (53.2 mmol) of iodomethylpropane in 10 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 1 h Then the reaction mixture was heated to 25°C, after which it was stirred for 14 h Then the reaction mixture was acidified to pH 2 by adding dropwise 1 N. aqueous solution of hydrochloric acid and was extracted with 3 portions of 50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, chloroform, then 99/1 chloroform/methanol) as a white solid substance was obtained which 14H16Cl2O2(M+): 286,0527, detect.: 286,0534.

A solution of 366 mg (1,27 mmol) 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid in 10 ml of methylene chloride and 1 drop of N,N-dimethylformamide was cooled to 0°C, and then processed 0,76 ml (1.53 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. The reaction mixture was stirred at 0°C for 30 min, after this time the reaction mixture was added 0,81 ml (3,81 mmol) of 1,1,1,3,3,3-hexamethyldisilazane. The reaction mixture was slowly heated to 25°C, and then stirred at 25°C for 16 hours Then the reaction mixture was treated with 5 ml of methanol. The resulting reaction mixture was washed with 2 portions of 10 ml of 5% aqueous solution of sulfuric acid. The combined organic layers were extracted with 3 portions of 10 ml of methylene chloride. Then the combined organic layers were washed 1 portion 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a white solid substance was obtained 229 mg (yield: 63%) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide: tPL: 98,6-100,1°C; EI-HRMS m/e Rasch. for C14H1717H22Cl2N2O2(M+): 356,1058, detect.: 356,1066.

(B) Similarly received:

(a) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide and isopropylmalate: 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-isopropylamino in the form of a white solid: tPL: 134,6-138,3°C; EI-HRMS m/e Rasch. for C18H24Cl2N2O2(M+): 370,1215, detect.: 370,1232;

(b) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide and propositionthe: 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-propylacetic in the form of a white solid: tPL: 117,8-120°C; EI-HRMS m/e Rasch. for C18H24Cl2N2O2(M+): 370,1215, detect.: 370,1209;

(C) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide and ethyl-3-isocyanatopropyl: ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}propion the ): 428,1270, the detection.: 428,1265;

(g) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide and utilizationfocused: ethyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}acetic acid as a light yellow oil: EI-HRMS m/e Rasch. for C19H24Cl2N2O4(M+): 414,1113, detect.: 414,1108;

(d) from 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide and arylisocyanate: 1-allyl-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl] urea in the form of a clear colorless oil: EI-HRMS m/e Rasch. for C18H22Cl2N2O2(M+): 368,1058, detect.: 368,1064.

Example 139

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine

A solution of 5.00 g a (17.4 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionic acid (obtained in example 12) in 150 ml of tetrahydrofuran, cooled to -78°C, cultivated 2,77 ml (to 19.9 mmol) of triethylamine, and then of 2.24 ml (18.2 mmol) of trimethylacetylchloride. The resulting white suspension was stirred at -78°C for 15 min and then at 0°C for 45 minutes In a separate flask a solution of 2.14 g (16,57 mmol) of (S)-4-isopropyl-2-oxazolidinone in 80 ml of tetrahydrofuran, cooled to -78°C, was treated with 8.7 ml of a (17.4 mmol) of a 2.0 M solution of n-utility in GE for another 10 minutes After this time, the first reaction mixture was again cooled to -78°C. over a 5 minute period using a hollow needle, the second reaction mixture is introduced into the first reaction mixture. Then combined the resulting mixture was stirred at -78°C for 15 minutes and Then it was heated to 25°C and was stirred for another 1.5 hours after this time the reaction was suppressed by the additional amount of saturated aqueous solution of sodium bisulfite (50 ml) and was extracted with 3 portions of 40 ml of ethyl acetate. The organic layers were combined, washed with 1 portion 20 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) received (1) in the form of a clear oil of 2.15 g (yield: 33%) of 3-[3-cyclopentyl-2(S)-(3,4-dichlorophenyl)propionyl]-4(S)-isopropylacetanilide-2-it: []23589=+87,5° (C=0,160, chloroform); EI-HRMS m/e Rasch. for C20H25Cl2NO3(M+): 397,1211, detect.: 397,1215 and (2) in the form of a white solid 1.88 g (yield: 28%) of 3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-4(S)-isopropylacetanilide-2-it: t3(M+): 397,1211, detect.: 397,1212.

A solution of 1.88 g (4,72 mmol) 3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionyl]-4(S)-isopropylacetanilide-2-it in 73 ml of tetrahydrofuran and 22 ml of water, cooled to 0°C, and treated with 2.1 ml of 30% aqueous hydrogen peroxide solution and 394 mg (9.4 mmol) of lithium hydroxide. The reaction mixture was stirred at 0°C for 1 h, after this time the reaction was suppressed by adding 16 ml of a saturated aqueous solution of sodium sulfite followed by adding 50 ml of 0.5 N. aqueous sodium bicarbonate solution. Next, under vacuum, remove the tetrahydrofuran. The residue was diluted with 40 ml water and was extracted with 3 portions of 20 ml of methylene chloride. Then the aqueous layer was 5 N. aqueous hydrochloric acid solution was acidified to pH 2 and extracted with 4 portions of 25 ml of ethyl acetate. Then an ethyl acetate layers were dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid 928 mg (yield: 70%) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionic acid: tPL: 75,1-78,3°C; []23589=-50,3° (C=0,100, chloroform); EI-HRMS m/e Rasch. for C14H16Cl2O2(M+): 286,0527, detect.: 286,0535.

A solution of 105 mg (from 0.37 mmol) 3-cyclopentyl-2(R)-(3,4-dichlor atively of 0.18 ml (from 0.37 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. The reaction mixture was stirred at 0°C for 30 min, after this time the reaction mixture was added 0.25 ml (1,17 mmol) of 1,1,1,3,3,3-hexamethyldisilazane. Then the reaction mixture was slowly heated to 25°C and was stirred at 25°C for 16 hours Then the reaction mixture was washed with 2 portions of 10 ml of 5% aqueous solution of sulfuric acid. The combined organic layers were extracted with 3 portions of 10 ml of methylene chloride. Then the combined organic layers were washed 1 portion 10 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 60/40 hexane/ethyl acetate) as a white solid substance was obtained 60 mg (yield: 58%) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide: []23589=-67,6° (C=0,106, chloroform); EI-HRMS m/e Rasch. for C14H17Cl2N1O1(M+): 285,0687, detect.: 285,0685.

A solution of 54 mg (0,19 mmol) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide in 5 ml of toluene was treated 0,03 ml (0.47 mmol) of methyl isocyanate. The resulting solution was boiled under reflux for 24 hours after this time the reaction mixture was concentrated under substances received 40 mg (yield: 63%) of 1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine: tPL: OF 124.8-127,5°C; []23589=-21,2° (C=0,099, chloroform); EI-HRMS m/e Rasch. for C16H20Cl2N2O2(M+): 342,0902, detect.: 342,0902.

Example 140

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionyl]-3-metalmachine

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C, and then treated by adding dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -(to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time was added dropwise a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml dimethylate which formed a brown sticky substance. Then the mixture was diluted with 50 ml ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

The solution 865 mg (2,43 mmol) methyl ester 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid in 6 ml of tetrahydrofuran was treated with 4.6 ml (3.65 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The resulting aqueous residue was diluted with 25 ml of water, and then was treated with 10 ml of 1N. an aqueous solution of hydrochloric acid. Next, the resulting aqueous layer was extracted with 2 portions of 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and conely foam received 723 mg (yield: 87%) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid. Analytical data indicated the presence of small amounts of impurities, but this 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid was used in the subsequent reactions without further purification.

A mixture of 300 mg (0.88 mmol) of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid and 1 drop of N,N-dimethylformamide in 2 ml of methylene chloride was cooled to 0°C, and then slowly worked 84 μl (0.97 mmol) of oxalicacid. The reaction mixture was stirred at 0°C for 10 min, and then stirred at 25°C for 1 h Then the resulting reaction mixture was treated by adding dropwise 560 μl (2,64 mmol) of 1,1,1,3,3,3-hexamethyldisilazane, followed by stirring at 25°C for 15 hours the Resulting reaction mixture was diluted with 20 ml of methylene chloride and 15 ml of methanol, then washed with 20 ml of 5% aqueous solution of sulfuric acid. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a yellow foam was obtained 140 mg (yield: 47%) 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionamide: tPL: 72-76°C (foam ultinationals); FAB-HRMS m/e Rasch. C is entil-2-(4-methanesulfonyl-3-nitrophenyl) propionamide and 211 mg (3,70 mmol) of methyl isocyanate in 2 ml of toluene was boiled under reflux (120°C) within 15 PM The reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. The resulting product in the form of a yellow oil was treated with a small amount of the mixture of hexane/acetate in a ratio of 1/1, and then began to precipitate. Then, in order to further deposition of material kept in the freezer for 2 hours, the Solid was collected by filtration and then dried under vacuum obtaining in the form of a pale yellow solid 50 mg (yield: 35%) of 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionyl]-3-metalmachine: tPL: 241-242°C; FAB-HRMS m/e Rasch. for C17H23N3O6S (M+N)+: 398,1386, detect.: 398,1399.

Example 141

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-atilmotin

A solution of 103 mg (0.36 mmol) of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl-propionamide (obtained in example 139) in 10 ml of toluene was treated with 40 μl (0.54 mmol) utilizationof. The resulting solution was boiled under reflux for 24 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a white foam was obtained 54 mg (yield: 42%) of 1-[3-cyclopentyl-(2R)-(3,4-dichlor the l2N2O2(M+N)+: 357,1136, detect.: 357,1137.

Example 142

[2-(4-chlorophenyl)-4-methylpentanoic]urea

A solution of 6.29 g (0.03 mol) (4-chlorophenyl) acetic acid of 38.4 ml of ethanol was treated with a catalytically effective amount of sulfuric acid. The reaction mixture is boiled under reflux for 12 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a pale yellow solid was obtained 6,45 g (yield: 88%) of ethyl ester (4-chlorophenyl) acetic acid: tPL: 39-41°C; EI-HRMS m/e Rasch. for C10H11ClO2(M+): 198,0448, detect.: 198,0452.

of 21.2 ml of a solution of their diisopropylamide lithium (0,31 M source solution, 6,14 mmol), cooled to -78°C, cultivated 1,11 g (5,58 mmol) ethyl ester (4-chlorophenyl)acetic acid, 13.9 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.81 ml (16,7 mmol) 1-bromo-2-methylpropane in 1 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 3 hours Deasily adding dropwise 20 ml of a saturated aqueous solution of ammonium chloride. The reaction mixture was poured into 100 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained 1.24 g (yield: 87.1 per cent) ethyl ester 2-(4-chlorophenyl)-4-methylpentanoic acid: tPL: 34-35°C; EI-HRMS m/e Rasch. for C14H19ClO2(M+): 254,1074, detect.: 254,1069.

A mixture of 508 mg (1,99 mmol) ethyl ester 2-(4-chlorophenyl)-4-methyl-pentanol acid and 239 mg (3,99 mmol) of urea in 4,28 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, to 2.99 mmol) was boiled under reflux for 24 hours Then the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained to 28.1 mg (yield: 5,2%) [2-(4-chlorophenyl)-4-methylpentanoic] urea: tPL: 164-165°C; EI-HRMS m/e Rasch. for C13H17ClN2O2(M+): 268,0979, detect.: 268,0972.

Example 143

R-[2-(3,4-dichlorophenyl)-4-methylpentanoic]urea

A solution of 10.0 g (0,048 mol) of (3,4-dichlorophenyl)acetic acid in 50 ml ATiM fridge for 7 hours The reaction mixture was concentrated under vacuum, diluted with diethyl ether and poured into water. The ether layer was washed with saturated aqueous sodium bicarbonate solution and water. Next, the organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. By distillation under vacuum (bath temperature: 175°C; the temperature in the head part: 125°C) in the form of a clear oil was obtained 9,38 g (yield: 82.5 percent ethyl ether (3,4-dichlorophenyl)acetic acid: EI-HRMS m/e Rasch. for C10H10CL2ABOUT2(M+): 232,0058, detect.: 232,0066.

4,88 ml solution of their diisopropylamide lithium (0,29 M source solution of 1.41 mmol), cooled to -78°C, was treated with 300 mg (1.28 mmol) of ethyl ether (3,4-dichlorophenyl) acetic acid in 3.2 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution of 1.53 mg (1,41 mmol) 1-bromo-2-methylpropane in 1 ml hexamethylphosphoramide. The reaction mixture was stirred at -78°C for 6 hours Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours then the reaction in the reaction mixture Guiliani in 50 ml of water and was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) in the form of a clear oil was obtained 356,4 mg (yield: 95,8%) ethyl ester of 2-(3,4-dichlorophenyl)-4-methylpentanoic acid: EI-HRMS m/e Rasch. for C14H18CL2ABOUT2(M+): 288,0683, detect.: 288,0677.

A mixture of 197 mg (of 0.68 mmol) of ethyl ester of 2-(3,4-dichlorophenyl)-4-methylpentanoic acid and 82 mg (1,36 mmol) of urea in a 1.46 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, of 1.02 mmol) was boiled under reflux for 3 h Then the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) and subsequent liquid chromatography under high pressure (product Chirobiotic T, 5 M, 25 cm×4,6 cm (inner diameter), buffer (0.1% triethylamine in water, titrated to pH 5 glacial acetic acid/ethanol in a ratio of 40/60) in the form of a white solid substance was obtained to 120.0 mg (yield: 58.1 per cent) R-[2-(3,4-dichlorophenyl)-4-methylpentanoic] urea: tPL: 138-140°C; EI-HRMS m/e Rasch. for C13H16CL2N2ABOUT2(M+): 302,0589, detect.: 302,0595.

PR is">A solution of 75 mg (0.20 mmol) of 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)propionyl]urea (obtained in example 12B-e) in 10 ml dry methylene chloride and methanol (2 drops required to solubilize the compound) was cooled to -78°C and the reaction mixture was methoxyindole by bubbling argon through it. To further benefit the ozone and it was barbotirovany through the reaction mixture until the blue color, after which the reaction mixture was stirred for five minutes.

After this time the bubbling argon through the solution was resumed until the disappearance of the blue color. Next was added 54 mg (0.20 mmol) of triphenylphosphine, the reaction mixture was heated to 25°C and was stirred for 16 hours after this time the reaction mixture was concentrated under vacuum and then dissolved in 10 ml dry methanol. The reaction mixture was cooled to 0°C, and then it was slowly treated with added 31 mg (0.81 mmol) of sodium borohydride. Then the reaction mixture was heated to 25°C and was stirred for 1 h then the reaction was suppressed with 10 ml water and the mixture was extracted with 3 portions of 15 ml of ethyl acetate. The organic fractions were combined and washed with 1 portion 15 ml of water and 1 portion 15 ml saturated aqueous rautaharju (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a hygroscopic white solid substance was obtained 48 mg (yield: 64%) of 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxyethyl) urea: EI-HRMS m/e Rasch. for C17H22CL2N2ABOUT3(M+): 370,1215, detect.: 370,1209.

Example 145

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl) urea

A solution of 132 mg (0.36 mmol) of 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)propionyl]urea (obtained in example 138-d) in 10 ml of tetrahydrofuran, cooled to 0°C, was treated with 0.7 ml (to 0.72 mmol) of 1M solution of balancetransfer. The reaction mixture for 1 h was heated from 0°C to 25°C. after this time the solution was again cooled to 0°C and treated with 2 ml of ethanol with subsequent slow addition of a mixture of 6 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of 30% hydrogen peroxide. The resulting mixture slowly over 1 h was heated to 25°C. after this time the reaction mixture was again cooled to 0°C and the reaction slowly extinguished 20 ml of a saturated aqueous solution of sodium sulfite. The resulting mixture was extracted with 3 portions of 20 ml of ethyl acetate. The organic fraction was washed 1 then is the cosmology vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) was carried out by the selection in column two zones and were treated by elution first of these two product areas to produce in the form of a white solid substance 36 mg (yield: 26%) of 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)-urea: tPL: of 116.7-119,9°C; EI-HRMS m/e Rasch. for C18H24CL2N2ABOUT3(M+): 386,1164, detect.: 386,1173.

Example 146

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea

A solution of 132 mg (0.36 mmol) of 1-allyl-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea (obtained in example 138-d) in 10 ml of tetrahydrofuran, cooled to 0°C, was treated with 0.7 ml (to 0.72 mmol) of 1M solution of balancetransfer. The reaction mixture slowly over 1 h was heated from 0 to 25°C. after this time the solution was again cooled to 0°C and treated with 2 ml of ethanol with subsequent slow addition of a mixture of 6 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of 30% hydrogen peroxide. The mixture slowly over 1 h while stirring, they were heated to 25°C. after this time the reaction mixture was again cooled to 0&#Ali 3 portions of 20 ml of ethyl acetate. The organic fraction was washed for 1 portion 15 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) was carried out by the selection in column two zones and processed by a second elution of these two product areas to produce in the form of a white hygroscopic solid substance 73 mg (yield: 53%) of 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)-urea: EI-HRMS m/e Rasch. for C18H24CL2N2ABOUT3(M+): 386,1164, detect.: 386,1172.

Example 147

Methyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}acetic acid

A solution of 77 mg (0,19 mmol) ethyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}acetic acid (obtained in example 138-g) in 5 ml of ethanol at 25°C was treated with a solution of 36 mg (of 0.65 mmol) of potassium hydroxide in 1 ml of water. The reaction mixture was stirred at 25°C for 2 hours after this time the reaction mixture was diluted with 5 ml of water and under vacuum, remove the ethanol. Next, 1 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 2 and was extracted with 3 portions of 15 ml meowma. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 88/12 chloroform/methanol plus 1% acetic acid) in the form of a white solid substance was obtained 43 mg (yield: 60%) {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}acetic acid: tPL: 204,2-206,8°C; EI-HRMS m/e Rasch. for C17H20CL2N2ABOUT4(M+): 386,0800, detect.: 386,0795.

A solution of 30 mg (0.08 mmol) of {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionyl]ureido}acetic acid in 5 ml of methanol was treated with concentrated sulfuric acid (4 drops). The reaction mixture was stirred at 80°C for 8 hours after this time the reaction mixture was cooled to 25°C and diluted with 10 ml of water. The resulting solution was extracted with 3 portions of 20 ml of ethyl acetate. The organic fraction was washed for 1 portion 20 ml saturated aqueous sodium bicarbonate solution, 1 portion 20 ml of a saturated aqueous solution of sodium chloride and 1 portion in 10 ml of water, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 21 mg (yield: 68%) of methyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} acetic sour the easiest.: 400,0970.

Example 148

Methyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}propionic acid

A solution of 94 mg (0.22 mmol) of ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido]propionic acid (obtained in example 138) in 5 ml of ethanol at 25°C was treated with a solution of 43 mg (0.77 mmol) of potassium hydroxide in 1 ml of water. The solution was stirred at 25°C for 2 hours after this time the reaction mixture was diluted with 5 ml of water and under vacuum, remove the ethanol. 1 N. aqueous solution of hydrochloric acid, the aqueous layer was acidified to pH 2 and was extracted with 3 portions of 15 ml of methylene chloride. Then the organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate plus 1% acetic acid) as a white foam was obtained 30 mg (yield: 35%) 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido]propionic acid: FAB-HRMS m/e Rasch. for C18H22CL2N2ABOUT4(M+H)+: 401,1035, detect.: 401,1022.

A solution of 20 mg (0.05 mmol) of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionyl]ureido]propionic acid in 5 ml of methanol was treated with concentrated sulfuric sour the Ali to 25°C and diluted with 10 ml of water. The resulting solution was extracted with 3 portions of 20 ml of ethyl acetate. The organic fraction was washed for 1 portion 20 ml saturated aqueous sodium bicarbonate solution, 1 portion 20 ml of a saturated aqueous solution of sodium chloride and 1 portion in 10 ml of water, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white solid substance was obtained 18 mg (yield: 86%) of methyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}propionic acid: tPL: 93,6-95,8°C; EI-HRMS m/e Rasch. for C19H24CL2N2ABOUT4(M+): 414,1113, detect.: 414,1114.

Example 149

Ethyl ester {3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]ureido}acetic acid

A solution of 600 mg (2.10 mmol) of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionamide (obtained in example 139) in 15 ml of toluene was treated with 0.35 ml (3.14 mmol) of utilizationfocused. The resulting solution was boiled under reflux for 16 hours after this time the reaction mixture was cooled to 25°C and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane is Il)propionyl]ureido}acetic acid: []23589=-27,4° (C=0,113, chloroform); EI-HRMS m/e Rasch. for C19H24CL2N2ABOUT4(M+): 414,1113, detect.: 414,1123.

Example 150

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea

A solution of 1.02 g (3,55 mmol) 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide (obtained in example 139) in 30 ml of toluene was treated to 0.47 ml (5.33 mmol) arylisocyanate. The resulting solution was boiled under reflux for 16 hours after this time the reaction mixture was cooled to 25°C and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a colourless oil was obtained 1.06 g (yield: 81%) of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea: []23589=-25,2° (C=0,151, chloroform); EI-HRMS m/e Rasch. for C18H22Cl2N2O2(M+): 368,1058, detect.: 368,1054.

Example 151

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)urea

The solution 765 mg (2,07 mmol) of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea (obtained in example 24) in 50 ml of tetrahydrofuran, cooled to 0°C, were treated to 4.14 ml (4.14 mmol)tvii this time the reaction mixture was again cooled to 0°C and was treated with 15 ml of ethanol, and then with a mixture of 45 ml of a saturated aqueous solution of sodium bicarbonate and 15 ml of hydrogen peroxide. The resulting mixture for 1 h was heated from 0 to 25°C. the reaction slowly extinguished saturated aqueous solution of sodium sulfite and then was extracted with 3 portions of 30 ml of ethyl acetate. The organic fraction was washed for 1 portion 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white foam was obtained 103 mg (yield: 11%) of 1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxypropyl)urea: []23589=-33,0° (C=0,094, chloroform); EI-HRMS m/e Rasch. for C18H24Cl2N2O3(M+): 386,1164, detect.: 386,1151.

Example 152

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea

The solution 765 mg (2,07 mmol) of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea (obtained in example 24) in 50 ml of tetrahydrofuran, cooled to 0°C, were treated to 4.14 ml (4.14 mmol) of 1.0 M solution of borane in tetrahydrofuran. The reaction mixture for 1 h was heated from 0 to 25°C. after this vyvodnogo solution of sodium bicarbonate and 15 ml of hydrogen peroxide. The resulting mixture for 1 h was heated from 0 to 25°C. the reaction slowly extinguished saturated aqueous solution of sodium sulfite and then was extracted with 3 portions of 30 ml of ethyl acetate. The organic fraction was washed for 1 portion 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a white foam was obtained 173 mg (yield: 22%) of 1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxypropyl)urea: []23589=-37,3° (C=0,075, chloroform); EI-HRMS m/e Rasch. for C18H24Cl2N2O3(M+): 386,1164, detect.: 386,1154.

Example 153

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine

A solution of 34.8 g (261,4 mmol) trichloride aluminum in 120 ml of chloroform, cooled to 0°C, was treated with 18.7 ml (167,5 mmol) of a solution of ethylchloroformiate in 120 ml of chloroform. The mixture was stirred at 0°C for 30 minutes after this time the reaction mixture was added dropwise a solution of 25.0 g (156,5 mmol) of 2-chloroanisole in 120 ml of chloroform. Next, the mixture was heated to 25°C and was stirred at 25°C in techician 50 ml of chloroform. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a yellow oil was obtained 31,37 g (yield: 77%) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)octoxynol acid: EI-HRMS m/e Rasch. for C18H24Cl2N2O3(M+): 386,1164, detect.: 386,1154.

A solution of 725 mg (1.53 mmol) of cyclopentanetetracarboxylic (obtained in example 33) in 10 ml of tetrahydrofuran, cooled to 0°C, cultivated and 2.14 ml (2.14 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran. The reaction mixture was stirred at 0°C for 45 minutes after this time the reaction mixture was treated with a solution of 355 mg (1.37 mmol) of ethyl ester of (3-chloro-4-methylsulfinylphenyl)octoxynol acid in 5 ml of tetrahydrofuran. Next, the reaction mixture was heated to 25°C and was stirred at 25°C for 20 hours and Then the reaction mixture was diluted with 50 ml water and was extracted with 3 portions of 25 ml of diethyl ether. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 12M, silica is phenyl)-3-cyclopentylacetic acid (mixture of E - and Z-isomers in the ratio 2:1), which was used without characterization.

A solution of 100 mg (0.31 mmol) of isomers E and Z ethyl ester 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylacetic acid in 5 ml of methylene chloride, cooled to 0°C, cultivated 157 mg 3-chloroperoxybenzoic acid (80%, 0.73 mmol) and stirred for 3.5 hours the Reaction mixture was diluted with 25 ml of methylene chloride. The resulting solution was washed with 2 portions of 10 ml of a saturated aqueous solution of sodium carbonate and 2 portions of 10 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Chromatography (column for rapid chromatography, Biotage 12M, silica, 80/20 hexane/ethyl acetate) as a colourless oil was obtained 95 mg (yield: 86%) of the ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid (mixture of E - and Z-isomers in the ratio 2:1), which was used without characterization.

A solution of 1.04 g (only 2.91 mmol) of E - and Z-isomers of ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid and 69 mg (0.29 mmol) of uranyl chloride Nickel in 25 ml of methanol, cooled to 0°C, cultivated 221 mg (5.83 mmol) of sodium borohydride, to be placed sodium borohydride, the reaction mixture was stirred at 25°C for 1.5 hours After this time the reaction mixture was filtered by passing through brownmillerite and washed with methanol. The filtrate was concentrated under vacuum. The residue was diluted with 15 ml water and was extracted with 3 portions of 15 ml of ethyl acetate. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate) as a clear colorless oil (under reaction conditions proceeded interesterification reaction) received 937 mg of a mixture of methyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (as in the reaction conditions proceeded interesterification reaction, the mixture of esters was further used without characterization).

A solution of 268 mg of methyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and 110 mg (1.5 mmol) of metallocene 1.6 ml of magnesium methoxide in methanol (7.4 wt.%, 1.1 mmol) kept at 100°C for 8 hours after this time the reaction mixture kontsentrirovanii ethyl acetate. The filtrate was concentrated under vacuum. Express chromatography (Merck Silica gel 60, 230-400 mesh mesh, 60/40 hexane/ethyl acetate) as a white foam was obtained 55 mg (yield: 19%) 1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine: FAB-HRMS m/e Rasch. for C17H23ClN2O4S (M+H)+: 387,1145, detect.: 387,1156.

Example 154

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-atilmotin

A solution of 937 mg of methyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid and ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid (obtained in example 27) in 30 ml of ethanol at 25°C was treated with a solution of 733 mg (13,1 mmol) of potassium hydroxide in 7 ml of water. The resulting solution was stirred for 3 h at 25°C. after this time the reaction mixture was concentrated under vacuum. The processing of 1 N. hydrochloric acid, the residue was acidified to pH 2. In the future, this solution was extracted with 3 portions of 15 ml of methylene chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate plus 1% oxydhaltigen)-3-cyclopentylpropionic acid: tPL: 123,9-126,2°C; FAB-HRMS m/e Rasch. for C15H19ClO4S (M+N)+: 331,0771, detect.: 331,0776.

A solution of 147 mg (0.44 mmol) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid in 5 ml of toluene and 2 drops of N,N-dimethylformamide at 25°C was treated with 0.05 ml (about 0.53 mmol) oxalicacid. The reaction mixture was stirred at 25°C for 30 minutes after this time the reaction mixture was cooled to -60°C and were processed and 0.50 ml (3.8 mmol) of ammonium hydroxide. The resulting suspension was heated to 25°C and was stirred at 25°C for 1 h, after this time the reaction was suppressed by the addition of 1 ml of 2n. an aqueous solution of hydrochloric acid, and then the mixture was extracted with 3 portions of 25 ml of diethyl ether. The organic fraction was dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 65/35 hexane/ethyl acetate) as a white foam was obtained 130 mg (yield: 89%) of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate: EI-HRMS m/e Rasch. for C15H20ClNO3S (M+): 329,0852, detect.: 329,0852.

Example 155

1-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine

PL: 106,1-108,8°C; []23589=-43,0° (C=0,172, chloroform); EI-HRMS m/e Rasch. for C15H19ClO4S (M+): 330,0692, detect.: 330,0690.

A solution of 200 mg (0.61 mmol) of 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionic acid in 4.8 ml of toluene and 12 μl of N,N was stirred at 25°C for 30 minutes After this time the reaction mixture was cooled to -60°C and was treated by the addition dropwise of 0.59 ml (5,24 mmol) of 30% aqueous ammonium hydroxide solution. The resulting suspension was heated to 25°C and was stirred at 25°C for 1 h Then the reaction mixture was extracted with 3 portions of 25 ml of ethyl acetate. The organic fraction was dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (column for rapid chromatography, Biotage 40S, ethyl acetate) as a colourless oil received 175 mg (yield: 88%) 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate: []23589=-45,8° (C=0,096, chloroform); EI-HRMS m/e Rasch. for C15H20ClNO3S (M+): 329,0852, detect.: 329,0851.

A solution of 160 mg (0.49 mmol) of 2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate in 5 ml of toluene was treated to 0.12 ml (1.94 mmol) of methyl isocyanate. Next, the reaction mixture was stirred at 100°C for 16 hours after this time the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (column for rapid chromatography, Biotage 40S, silica, 60/40 hexane/ethyl acetate) as a white foam was obtained 79 mg (yield: 42%) of 1-[2(R)-(3-chloro-4-/e Rasch. for C17H23ClN2O4S (M+H)+: 387,1145, detection. 387,1142.

Example 156

1-(2-chloroethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea

A solution of 182 mg (0.64 mmol) of 3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide (obtained in example 12) in 10 ml of toluene was treated to 0.08 ml (0.95 mmol) of 2-chlorotriazine. The reaction mixture is boiled under reflux for 16 hours after this time the reaction mixture was cooled to 25°C and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) as a colourless oil was obtained 189 mg (yield: 76%) of 1-(2-chloroethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea: EI-HRMS m/e Rasch. for C17H21Cl3N2O2(M+): 390,0669, detect.: 390,0659.

Example 157

1-[3-cyclopentyl-2-(3-triftormetilfullerenov)propionyl]-3-metalmachine

A solution of 5.00 g (21,17 mmol) 3-(triptoreline)phenyl acetic acid in 50 ml of methanol was treated by slow addition of 10 drops of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 18 hours the Reaction mixture gave othervoices phase was washed for 1 portion 100 ml saturated aqueous sodium bicarbonate solution, was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum obtaining in the form of a pale yellow oil which was used without additional purification, 5,28 g (yield: 99%) of crude methyl ester (3-triftormetilfullerenov) acetic acid: EI-HRMS m/e Rasch. for C10H9F3O2S (M+): 250,0275, detect.: 250,0274.

A solution of 1.5 ml (10.5 mmol) of Diisopropylamine in 27 ml of dry tetrahydrofuran and 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, were treated to 4.2 ml (10.5 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min and then treated by the addition dropwise of a solution of 2.50 g (10.0 mmol) of methyl ether (3-triftormetilfullerenov)acetic acid in a small amount of tetrahydrofuran. The reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution of 2.10 g (10.0 mmol) of iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 50 ml of water, and then it was divided between 75 ml of water and 75 ml ethylacetoacetate (Silica gel 60 Merck, 230-400 mesh mesh, 8/1 hexane/ethyl acetate) as a colourless oil was obtained 2,95 g (yield: 89%) of methyl ester of 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O2S (M+): 332,1058, detect.: 332,1047.

A solution of 2.75 g (of 8.27 mmol) of methyl ester of 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid in 30 ml of methylene chloride was treated 4,28 g 3-chloroperoxybenzoic acid (80-85% grade, in terms of 80% of the basic substance, 20,67 mmol). The reaction mixture was stirred at 25°C for 6 hours after this time the data thin-layer chromatography showed the presence of two new products with reduced values of Rf. In order to initiate the conversion of the sulfoxide in sulfon in the reaction mixture was added addition of 4.00 g of 3-chloroperoxybenzoic acid and the resulting reaction mixture was stirred at 40°C for 3 days. The reaction mixture was allowed to cool to 25°C and then it was divided between 100 ml of water and 100 ml of methylene chloride. The layers were shaken and separated. The organic phase is twice washed with saturated aqueous sodium bicarbonate, washed with water, dried over magnesium sulfate, filtered and koncentrirane oil received 2,07 g (yield: 69%) of methyl ester of 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid: EI-HRMS m/e Rasch. for C16H19F3O4S (M+): 364,0956, detect.: 364,0947.

A solution of 500 mg (1.37 mmol) of methyl ester of 3-cyclopentyl-2-(3-triftormetilfullerenov)propionic acid and 305 mg (4,12 mmol) of metallocene were treated to 5.9 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, of 4.12 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, it is diluted with 10 ml of ethyl acetate, and then filtered through brownmillerite. This brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a white foam was obtained 253 mg (yield: 45%) of 1-[3-cyclopentyl-2-(3-triftormetilfullerenov)propionyl]-3-metalmachine: tPL: 59-62°C (foam ultinationals); EI-HRMS m/e Rasch. for C17H21F3N2O4S (M+): 406,1174, detect.: 406,1178.

Example 158

1-[3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionyl]-3-metalmachine

A solution of 2.50 g (of $ 11.25 mmol) 3-fluoro-4-(trifluoromethyl)phenylacetic KIS is camping boiled under reflux for 15 hours The reaction mixture was allowed to cool to 25°C and then it was concentrated under vacuum to remove methanol. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a colourless oil was obtained 2.58 g (yield: 97%) of methyl ester of (3-fluoro-4-triptoreline)acetic acid: EI-HRMS m/e Rasch. for C10H8F4O4(M+): 236,0460, detect.: 236,0457.

A solution of 1.5 ml (10,67 mmol) Diisopropylamine in 24 ml of dry tetrahydrofuran and 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, was treated with 4.3 ml (10,67 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 45 min and then treated by the addition dropwise of a solution of 2.40 g (10,16 mmol) methyl ether (3-fluoro-4-triptoreline) acetic acid in a small amount of tetrahydrofuran. The reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution of 2.24 g (10,67 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 10 ml of a saturated aqueous solution x is Oh additionally was extracted with 75 ml of ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 5/1 hexane/ethyl acetate) as a colourless oil was obtained 2,69 g (yield: 83%) of methyl ester of 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C16H18F4O2(M+): 318,1243, detect.: 318,1250.

A solution of 750 mg (2.36 mmol) of methyl ester of 3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionic acid and 437 mg (5,90 mmol) of metallocene were treated with 14.5 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, was 7.08 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, and then it was divided between 75 ml of water and 75 ml of ethyl acetate. Formed emulsion, for the destruction of which used a saturated aqueous solution of sodium chloride. Next, the aqueous layer was extracted with 2 portions of 75 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and the concentration of the thief of hexanol/ethyl acetate in a ratio of 2/1 to obtain white solids. This solid was filtered, thoroughly washed with hexane and dried to produce in the form of a white solid substance 322 mg (yield: 38%) of 1-[3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionyl]-3-metalmachine: tPL: 187-189°C; FAB-HRMS m/e Rasch. for C17H20F4N2O2(M+N)+: 361,1539, detect.: 361,1549.

Example 159

1-[3-cyclopentyl-2-(4-ethanolgasoline)propionyl]-3-metalmachine

The mixture 72,35 g (0.54 mol) of aluminium chloride in 181 ml of chloroform, cooled to 0°C, was stirred to its homogenization. Next, the reaction mixture was treated by slow addition of 61 ml (0.54 mol) of acrocallosal. The resulting reaction mixture was stirred at 0°C for 30 minutes Then it was treated by slow addition of 25.0 g (0.18 mol) of ethylvinylacetate. The solution has gained a deep red color and gradually become a retinoid. Then the resulting reaction mixture was stirred at 0°C for 2 h, the Reaction mixture was slowly poured into a large amount of ice/water. The resulting aqueous layer was extracted with 3 portions of 200 ml of chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated under was vacuumable 23,64 g (yield: 55%) of ethyl ester (4-ethylsulfanyl)octoxynol acid. This material was used in subsequent reactions without further purification and characterization.

The solution 4,60 g (21,89 mmol) iodomethylpropane and grade of 5.74 g (21,89 mmol) of triphenylphosphine in 22 ml of acetonitrile was heated under reflux for 2 weeks. The reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to obtain an orange solid. This orange solid was ground into powder in diethyl ether, and then filtered. The solid material is thoroughly washed with diethyl ether until then, until thin layer chromatographic analysis of wash fluids showed no iodomethylpropane and triphenylphosphine. The solid was left to dry in air to produce in the form of a light orange solid substance of 8.92 g (yield: 86%) of cyclopentadienylsodium: tPL: 195-198°C; FAB-HRMS m/e Rasch.: for C24H26P (M+N)+345,1772, detect.: 345,1784.

Suspension 24,48 g (51,82 mmol) cyclopentadienylsodium in 100 ml of tetrahydrofuran, cooled to 0°C, was treated by adding dropwise 52 ml (51,82 mmol) of 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran. Bright orangle) ethyl ester (4-ethylsulfanyl)octoxynol acid. The resulting reaction mixture was heated to 25°C, after which it was stirred for 20 hours the Reaction mixture was concentrated under vacuum, removing the tetrahydrofuran and then diluted with 300 ml of water. The aqueous layer was extracted with 3 portions of 200 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexane/ethyl acetate) as a yellow oil was obtained between 6.08 g (yield: 50%) of ethyl ester of 3-cyclopentyl-2-(4-ethylsulfanyl)acrylic acid, comprising a mixture of isomers (E) and (Z) in the ratio is 1.82:1; FAB-LRMS m/e Rasch. for C18H24O2S (M+N)+the mass in the form of an integer number: 304, detect.: 305.

The solution 5,76 g (18,92 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethylsulfanyl)acrylic acid (isomers (E) and (Z) in the ratio is 1.82:1) in 47 ml of methylene chloride was slowly processed the addition of 11.45 g of 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 37,83 mmol). The reaction mixture was stirred at 25°C for 1 h, the Reaction mixture was concentrated under vacuum, removing IU is about 200 ml of a saturated aqueous solution of sodium bicarbonate, washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 4,89 g (yield: 77%) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)acrylic acid. The product was a mixture of isomers (E) and (Z) in the ratio 3:1, which was used without further purification and characterization.

The solution 4,89 g (14,53 mmol) of ethyl ester of 3-cyclopentyl-2-(4-(ethane-sulfanilyl)acrylic acid (isomers (E) and (Z) in the ratio 3:1) in 36 ml of ethanol was slowly treated 244,5 mg of 10% palladium on charcoal. The reaction mixture was stirred under an elevated pressure of hydrogen gas (balloon) at 25°C and under atmospheric pressure for 44 hours Later, the catalyst was filtered by passing through a layer of brownmillerite and this layer brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless viscous oil was obtained 3.50 g (yield: 71%) of ethyl ester of 3-cyclopentyl-2-the de-integer: 338, the detection.: 339.

500 mg (1.48 mmol) of ethyl ester of 3-cyclopentyl-2-(4-ethanolgasoline)propionic acid and 274 mg (3,70 mmol) of metallocene was treated with 6.5 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 4,43 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 2 days. The reaction mixture was allowed to cool to 25°C, and then it was diluted with 25 ml ethyl acetate. The mixture was filtered through a layer of brownmillerite and this layer brownmillerite washed with 50 ml of ethyl acetate. The obtained filtrate was washed with 40 ml of water and then the aqueous layer was additionally extracted with 40 ml ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain the product as a colourless oil. The product oil was treated with 10 ml of hexanol/ethyl acetate in a ratio of 2/1, and began the precipitation of white solids. In order to promote crystallization, the suspension was kept in the freezer. The solid material was filtered to obtain a white solid of 178 mg (yield: 33%) of 1-[3-cyclopentyl-2-(4-ethanolgasoline)propionyl] the external.: 367,1697.

Example 160

1-[2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionyl]-3-metalmachine

A solution of 2.00 g (to 9.32 mmol) 4-chloro-3-nitrophenylacetate in 40 ml of methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, cultivated added dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 minutes after this time the reaction mixture was treated by adding within a 15-minute period a solution of 5.00 g (to 21.8 mmol) of methyl ester 4-holdem what about the purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution 4,58 g (21,8 mol) of iodomethylpropane in a small amount of dry tetrahydrofuran. Further the reaction mixture was stirred at -78°C, and then it was heated to 25°C, after which it was stirred for 48 hours Then the reaction was suppressed to 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 260 mg (0,834 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid in 3 ml of tetrahydrofuran was treated with 1.25 ml (1.00 mmol) of 0.8 M aqueous solution of lithium hydroxide. The reaction mixture was stirred who was treated with 10 ml of 1 N. an aqueous solution of hydrochloric acid. The layers were shaken and separated. Next, the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain a yellow solid which was used without further purification, 243 mg (yield: 98%) of 2-(4-chloro-3-nitrophenyl)-cyclopentylpropionic acid: tPL: 112-115°C; FAB-HRMS m/e Rasch. for C14H16ClNO4(M+H)+: 298,0847, detect.: 298,0851.

A mixture of 450 mg (1,51 mmol) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid in 4 ml of methylene chloride was treated with 1 drop of N,N-dimethylformamide, and then was cooled to 0°C. Next, the reaction mixture was slowly treated with 145 μl (of 1.66 mmol) oxalicacid. The reaction mixture was stirred at 0°C for 10 min, and then stirred at 25°C for 1 h Then the reaction mixture was treated by adding dropwise 960 ál (a 4.53 mmol) of 1,1,1,3,3,3-hexamethyldisilazane, followed by stirring at 25°C for 15 h Formed the reaction mixture was diluted with 10 ml of methylene chloride and 10 ml of methanol. The organic layer is washed with 5% aqueous sulfuric acid solution and a saturated aqueous solution of chloride is in the form of a yellow oil, which was hard as a yellow solid, 295 mg (yield: 67%) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionate. This yellow solid was used without further purification: tPL: 112-114°C; EI-HRMS m/e Rasch. for C14H18ClN2O3(M+): 296,0927, detect.: 296,0931.

A solution of 200 mg (0.67 mmol) of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionate and 382 mg (6,70 mmol) of methyl isocyanate in 3 ml of toluene was boiled under reflux (120°C) for 15 h the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) as a white foam was obtained 139 g (yield: 60%) 1-[2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionyl]-3-metalmachine: tPL: 61-64°C (foam was ultinationals); FAB-HRMS m/e Rasch. for C16H20ClN3O4(M+H)+: 354,1220, detect.: 354,1232.

Example 161

1-[2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine

The solution 21,21 g (116,38 mmol) of 4-(methylthio)phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. The resulting reaction mixture was heated with reverse holo is the pressure of methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H12O2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic acid in 130 ml of carbon tetrachloride was slowly processed the addition of 1.74 ml (33,84 mmol) of bromine. The reaction mixture was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. Next, the reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C, and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum removal of tetrol the Kie layers were dried over sodium sulfate, was filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H11BrO2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, was treated with 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution 6,10 g (22,17 mmol) methyl ether (3-bromo-4-methylsulfanyl-phenyl) acetic acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution 5,59 g (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The resulting reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then it contml ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21BrO2S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, of 5.99 mmol). The reaction mixture was stirred at 25°C for 3 hours the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 geki)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19BrO4S (M+): 388,0344, detect.: 388,0343.

A solution of 1.62 g (4,16 mol) methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid in 10 ml of methanol was treated with 8.7 ml (a total of 8.74 mol) 1 N. aqueous sodium hydroxide solution. The reaction mixture was stirred at 25°C for 27 hours, the Reaction mixture was concentrated under vacuum to remove methanol. The resulting aqueous residue 10% aqueous solution of hydrochloric acid acidified to pH 2, and then was extracted with 1 portion 400 ml of ethyl acetate. The organic layer was washed 1 portion 300 ml of water and washed 1 portion 300 ml of a saturated aqueous solution of sodium chloride. Next, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a white solid, which was used without additional purification, 1.39 g (yield: 89%): 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: tPL: 149-150°C; FAB-HRMS m/e Rasch. for C15H19BrO4S (M+N)+: 375,0266, detect.: 375,0274.

A mixture of 400 mg (1.07 mmol) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid in 4 ml of methylene chloride, cooled to 0°C, and treated with 2 drops of N,N-dimethylformamide, Merivale at 25°C for 1 h Next, the resulting reaction mixture was treated by adding dropwise 680 ál (3,21 mmol) of 1,1,1,3,3,3-hexamethyldisilazane, followed by stirring at 25°C for 15 hours later, the reaction mixture was diluted with 20 ml of methylene chloride and 20 ml of methanol. The organic layer was washed 1 portion in 44 ml of 5% aqueous solution of sulfuric acid and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a white foam 271 mg (yield: 68%) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionate. This product is in the form of a white foam were used without additional purification: tPL: 60-63°C; EI-HRMS m/e Rasch. for C15H20rN3S (M+): 373,0347, detect.: 373,0348.

A solution of 200 mg (of 0.53 mmol) of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionate and 61 mg (1.07 mmol) of methyl isocyanate in 1 ml of toluene was boiled under reflux for 24 hours, the Reaction mixture became very muddy and formed a white precipitate. The reaction mixture was allowed to cool to 25°C, and then it was treated with hexane. The reaction mixture was placed for 1 hour in the freezer, and then filtered. White solid was washed with cold hexaprotodon]-3-metalmachine: tPL: 259-260°C; FAB-HRMS m/e Rasch. for C17H23rN2ABOUT4S (M+H)+: 431,0641, detect.: 431,0646.

Example 162

1-[2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine

The solution 21,21 g (116,38 mmol) of 4-(methylthio)phenylacetic acid 291 ml of methanol was slowly treated by adding 3 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 3 days. The reaction mixture was allowed to cool to 25°C and then it was concentrated under vacuum to remove methanol. The obtained residue was diluted with 600 ml of diethyl ether. The organic layer was washed with 3 portions of 300 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow liquid which was used without additional purification, 20,95 g (yield: 92%) of methyl ester of (4-methylsulfinylphenyl) acetic acid: EI-HRMS m/e Rasch. for C10H12ABOUT2S (M+): 196,0558, detect.: 196,0559.

A solution of 5.11 g (26,03 mmol) methyl ether (4-methylsulfinylphenyl) acetic CES was stirred at 25°C for 4 h, after this time the data thin-layer chromatography still indicated the presence of significant amount of starting material. Next, the reaction mixture was treated with an additional portion of bromine (1,74 ml, 33,84 mmol). The reaction mixture was stirred for another 4 h at 25°C, and then the reaction was suppressed 150 ml of 10% aqueous solution of sodium bisulfite. The reaction mixture was concentrated under vacuum removal of carbon tetrachloride. The resulting aqueous layer was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 9/1 hexane/ethyl acetate) as a pale yellow oil was obtained 6,10 g (yield: 85%) of methyl ester of (3-bromo-4-methylsulfinylphenyl)acetic acid: EI-HRMS m/e Rasch. for C10H11Ged2S (M+): 273,9663, detect.: 273,9661.

A solution of 3.4 ml (24,38 mmol) Diisopropylamine in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, was treated with 9.8 ml (24,38 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then Oberoi acid in 21 ml of dry tetrahydrofuran and 7 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution 5,59 g (26,60 mmol) iodomethylpropane in a small amount of dry tetrahydrofuran. The resulting reaction mixture was heated to 25°C, after which it was stirred for 15 h the Reaction in the reaction mixture extinguished 300 ml of water and then the mixture was concentrated under vacuum removal of tetrahydrofuran. The remaining aqueous phase was extracted with 3 portions of 150 ml of ethyl acetate. The combined organic layers were washed 1 portion 200 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) as a pale yellow oil was obtained to 4.52 g (yield: 57%) of methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H21Ged4S (M+): 356,0446, detect.: 356,0435.

A solution of 1.07 g (2,99 mmol) methyl ester of 2-(3-bromo-4-methylsulfinylphenyl)-3-cyclopentylpropionic acid in 15 ml of methylene chloride was treated 1,81 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% osnovnoi under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml diethyl ether. The organic phase is washed with 3 portions of 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a colourless oil was obtained 1,09 g (yield: 94%) of methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H19Ged4S (M+): 388,0344, detect.: 388,0343.

The mixture 990,0 mg (2.54 mmol) of the methyl ester of 2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionic acid and 273,3 mg (3,05 mmol) of copper cyanide(I) in 2.5 ml of dry N,N-dimethylformamide was heated under reflux for 4 hours the Reaction mixture was allowed to cool to 25°C and the crude reaction mixture was purified directly without additional chemical treatment. As a result, the Express chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanol, then 3/1 hexane/ethyl acetate) as a pale yellow oil was obtained 646,5 mg (yield: 76%) of methyl ester of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. forPL: 180-181°C; EI-HRMS m/e Rasch. for C16H19NO4S (M+): 321,1034, detect.: 321,1039.

A solution of 200 mg (of 0.62 mmol) of 2-(3-cyano-4-methanesulfonyl)-3-, cyclopentylpropionic acid in 2 ml of methylene chloride, cooled to 0°C, and treated with 2 drops of N,N-dimethylformamide. Then the reaction mixture was treated by slow addition of 60 μl (0.69 mmol) of oxalicacid. The reaction mixture was stirred at 0°C for 10 min, and then stirred PR 1,1,1,3,3,3-hexamethyldisilazane, followed by stirring at 25°C for 15 hours Further, the reaction mixture was divided between 20 ml of methylene chloride, 15 ml of methanol and 25 ml of 5% aqueous solution of sulfuric acid. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/3 hexane/ethyl acetate) as a white foam was obtained 141 mg (yield: 70%) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionate: tPL: 67-70°C (foam ultinationals); EI-HRMS m/e Rasch. for C16H20rN2ABOUT3S (M+): 320,1195, detect.: 320,1195.

A solution of 135 mg (0.42 mmol) of 2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionate and 72 mg (1,26 mmol) of methyl isocyanate in 1 ml of toluene was boiled under reflux for 15 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum to obtain a yellow semi-solid product. Semi-solid product was treated with 3 ml of hexanol/ethyl acetate in a ratio of 2/1, formed a white precipitate. The suspension was placed for 1 hour in the freezer, and then filtered to obtain a white solid, 55 mg (yield: 35%) 1-[2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metallocen.

Example 163

1-[2-(3,4-bistanbulholiday)-3-cyclopentylpropionyl]-3-metalmachine

A solution of 5.00 g (29,05 mmol) of 3,4-dipertanyakan acid in 73 ml of methanol was treated by slow addition of 4 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 65 hours, the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was slowly diluted with 300 ml saturated aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 5,38 g (yield: 99%) of methyl ether (3,4-differenl) acetic acid as a yellow oil which was used without further purification.

The solution to 6.39 g (86,69 mmol) timelocked sodium in 72 ml of dimethylsulfoxide was treated 5,38 g (28,89 mmol) methyl ether (3,4-differenl) acetic acid. The reaction mixture was stirred at 25°C for 2 h, then at 70°C for 15 minutes after this time the data thin-layer chromatography indicated the absence of starting material and n is also to acid. The resulting reaction mixture was allowed to cool to 25°C. Next, the reaction mixture was treated with 200 ml of 10% aqueous hydrochloric acid solution and then was extracted with 3 portions of 200 ml of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain the substance in the form of a yellow oil. This substance is in the form of a yellow oil was dissolved in 100 ml of methanol and then slowly treated with 5 ml of concentrated sulfuric acid. The reaction mixture is boiled under reflux for 3 hours the Reaction mixture was allowed to cool to 25°C and then concentrated under vacuum to remove methanol. The obtained residue was slowly diluted with 300 ml saturated aqueous sodium bicarbonate solution and then was extracted with 1 portion 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil with 4.65 g (yield: 75%) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methylsulfinylphenyl)acetic acid methyl ester (4-fluoro-3-methylsulfinylphenyl)acetic acid which was used without further purification and characterization.

A solution of 4.44 the methyl ester (4-fluoro-3-methylsulfinylphenyl)acetic acid in 103 ml of methylene chloride was treated by slow addition of 13,80 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 45,59 mmol). The reaction mixture was stirred at 25°C for 4 h the Reaction mixture was concentrated under vacuum removal of methylene chloride. The obtained residue was diluted with 300 ml of ethyl acetate. The organic phase is washed with 1 portion 200 ml of a saturated aqueous solution of sodium bicarbonate and 1 serving of 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 20/1 methylene chloride/ethyl acetate) was obtained and 3.31 g (yield: 65%) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl)acetic acid methyl ester (4-fluoro-3-methanesulfonyl) acetic acid as colorless liquid, which was used without further purification and characterization.

The solution of (2.28 g 9,26 mmol) pratdesaba isomeric mixture of methyl ether (3-fluoro-4-methanesulfonyl)acetic acid methyl ester (4-fluoro-3-methanesulfonyl) acetic acid, 23 ml of dimethylsulfoxide was treated to 1.37 g (holds 18.52 mmol) timelocked sodium. The reaction mixture was stirred at 25°C for 4 h and then the reaction was suppressed 10% aqueous concrete is ovale and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 70-230 mesh, 3/2 hexane/ethyl acetate) received 2,19 g (yield: 86%) of pratdesaba isomeric mixture of methyl ether (3-methanesulfonyl-4-methylsulfinylphenyl) acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl)acetic acid as a yellow liquid which was used without further purification and characterization.

The solution 2,19 g (7,98 mmol) pratdesaba isomeric mixture of methyl ether (3-methanesulfonyl-4-methylsulfinylphenyl)acetic acid methyl ester (4-methanesulfonyl-3-methylsulfinylphenyl) acetic acid in 20 ml of methylene chloride was treated by slow addition 6,41 g 3-chloroperoxybenzoic acid (57-86% grade, in terms of 57% of the basic substance, 31,93 mmol). The reaction mixture was stirred at 25°C for 5 h and then the reaction it slowly extinguished 1,5 N. aqueous solution of sodium sulfite. The resulting reaction mixture was extracted with 300 ml of methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 70-230 mesh, 10/1 methylene chloride/ethyl acetate) as a white solid substance was obtained 1.89 g (yield: 77%) >The14ABOUT6S2(M+): 306,0232, detect.: 306,0234.

The solution 951 ál (6,79 mmol) Diisopropylamine in 6 ml of dry tetrahydrofuran and 2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was cooled to -78°C in a nitrogen atmosphere, and then was treated with 2.5 ml (6,79 mmol) of a 2.5 M solution of n-utility in hexano. The resulting reaction mixture was stirred at -78°C for 30 min, and then treated by the addition dropwise of a solution of 1.89 g (6,17 mmol) methyl ether (3,4-bistanbulholiday) acetic acid in 12 ml of dry tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The resulting reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution of 1.56 g (7.40 mmol) of iodomethylpropane in a small amount of dry tetrahydrofuran. The reaction mixture was heated to 25°C, after which it was stirred for 64 hours, the Reaction in the reaction mixture extinguished 150 ml of water and then concentrated under vacuum removal of tetrahydrofuran. Further, the obtained residue was diluted with 100 ml of water and then was extracted with 1 serving of 250 ml of ethyl acetate. The organic layer was washed 1 portion of 100 ml of a saturated aqueous solution chlorides gel 60 Merck, 70-230 mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained of 1.61 g (yield: 67%) of methyl ester of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C17H24ABOUT6S2(M+): 388,1014, detect.: 388,1014.

375 mg (0.97 mmol) of the methyl ester of 2-(3,4-bistanbulholiday)-3-cyclopentylpropionic acid and 214 mg (2,90 mmol) of metallocene were treated to 4.2 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 2,90 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 48 hours the Reaction mixture was allowed to cool to 25°C, diluted with 5 ml of ethyl acetate, and then filtered through a layer of brownmillerite. This brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/2 hexane/ethyl acetate) as a white solid substance was obtained 65 mg (yield: 16%) 1-[2-(3,4-bistanbulholiday)-3-cyclopentylpropionyl]-3-metalmachine: tPL: 220-222°C; EI-HRMS m/e Rasch. for C18H26N2ABOUT6S2(M+): 430,1232, detect.: 430,1231.

Example 164

PL: 66-68°C; EI-HRMS m/e Rasch. for C15H16F4ABOUT2(M+) 305,1165, detect.: 305,1174.

The solution dimethyl-formamide was cooled to 0°C and then was treated with 1.5 ml (3.0 mmol) of a 2.0 M solution of oxalicacid in methylene chloride. The reaction mixture was stirred at 0°C for 30 minutes after this time the reaction mixture was added 2.0 ml (9.5 mmol) of 1,1,1,3,3,3-hexamethyldisilazane. The reaction mixture was slowly heated to 25°C, and then stirred at 25°C for 16 hours Then the reaction mixture was treated with 3 ml of methanol and diluted with 35 ml of methylene chloride. The resulting mixture was washed with 2 portions of 10 ml of 5% aqueous solution of sulfuric acid, 1 portion of 25 ml of water and 3 portions of 25 ml of a saturated aqueous solution of sodium chloride. The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a pale yellow oil 333 mg (yield: 92,5%) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionamide: EI-HRMS m/e Rasch. for C15H17F4NO (M+): 303,1246, detect.: 303,1252.

A solution of 303 mg (1.0 mmol) 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)propionamide in 5 ml of toluene was treated with a 0.59 ml (10 mmol) of methyl isocyanate. The resulting reaction mixture is boiled under reflux for 24 hours after this time the reaction mixture was concentrated under vacuum. In ax mg (yield: 49,2%) 1-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionyl]-3-metalmachine: FAB-HRMS m/e Rasch. for C17H20F4N2ABOUT2(M+N)+: 361,1539, detect.: 361,1534.

Example 165

1-[2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionyl}-3-metalmachine

430,55 ml solution (0.3 M source solution, 129,16 mmol) of their diisopropylamide lithium cooled to -78°C, cultivated 26,32 g (125,83 mmol) ethyl ester (4-nitrophenyl)acetic acid in 312,5 ml of tetrahydrofuran/hexamethylphosphoramide (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated 27,75 g (132,1 mmol) iodomethylpropane in 27,75 ml hexamethylphosphoramide. The mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 16 hours and Then the reaction in the reaction mixture was suppressed by adding dropwise to 250 ml of a saturated aqueous solution of ammonium chloride. The resulting mixture was concentrated under vacuum, diluted with 250 ml of water and was extracted with 3 portions of 300 ml of ethyl acetate. The organic phase was washed with 2 portions of 250 ml of saturated aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. Express chromatogra ester 3-cyclopentyl-2-(4-nitrophenyl)propionic acid: EI-HRMS m/e Rasch. for C16H21NO4(M+): 291,1470, detect.: 291,1470.

The solution 7,37 mg (to 25.3 mmol) of ethyl ester of 3-cyclopentyl-2-(4-nitrophenyl)propionic acid 316 ml of ethyl acetate was treated with 500 mg of 10% palladium on charcoal. The reaction mixture was stirred in an atmosphere of hydrogen gas under a pressure of 60 pounds per square inch at 25°C for 18 hours Then the catalyst was filtered by passing through a layer of brownmillerite (ethyl acetate). The filtrate was concentrated under vacuum obtaining in the form of a yellow oil 3,52 mg (yield: 53.3 per cent) ethyl ester of 2-(4-AMINOPHENYL)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C16H23NO2(M+): 261,1727 the detection.: 261,1727.

A mixture of 0.38 ml of concentrated hydrochloric acid and 380 mg of ice, cooled to 0°C, cultivated 497 mg (1,90 mmol) ethyl ester of 2-(4-AMINOPHENYL)-3-cyclopentylpropionic acid. After 5 min the reaction mixture was added a solution of 139 mg (2.0 mmol) of sodium nitrite in 0,31 ml of water. The resulting solution was stirred at 0°C for 5 minutes, after this time the solution was added to a solution of 0.23 ml (2,20 mmol) n-butylmercaptan in 0.4 ml of water heated to 45°C. the Reaction mixture was stirred at 45°C in the Techa is of methylene chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product as a brown oil (588 mg) in 16.5 ml of methylene chloride was cooled to 0°C and was treated with 1.5 g of 3-chloroperoxybenzoic acid (80-85% grade, 8,78 mmol). The reaction mixture was stirred at 25°C for 48 hours, after this time the reaction mixture was diluted with 100 ml of methylene chloride. The resulting solution was washed with 1 portion of 100 ml of a saturated aqueous solution of sodium bisulfite, 1 portion of 100 ml of a saturated aqueous solution of sodium chloride, 1 portion of 100 ml of a saturated aqueous solution of sodium bicarbonate and 1 portion of 100 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) as a yellow oil was obtained 144,3 mg (yield: 20.7 per cent) ethyl ester 2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C20H30ABOUT4S (M+): 366,1865 the detection.: 366,1858.

The solution to 125.3 mg (0.34 mmol) of the ethyl ester of 2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionic acid and 0.98 ml of a solution of magnesium methoxide in m the under reflux at 110°C for 12 hours Next, the reaction mixture was concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate) as a white solid substance was obtained to 61.8 mg (yield: 45,8%) 1-{2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentylpropionyl}-3-metalmachine: tPL: 189-191°C; EI-HRMS m/e Rasch. for C20H30N2ABOUT4S (M+): 395,2005, detect.: 395,2008.

Example 166

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionyl]-3-metalmachine

35,3 ml solution of their diisopropylamide lithium (0,31 M source solution, 10.9 mmol), cooled to -78°C, cultivated 1,11 g (5.0 mmol) of (4-fluoro-3-triptoreline)acetic acid in 12.4 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 1 h, after this time the reaction mixture was treated with a solution of 1.16 g (5,52 mmol) iodomethylpropane in 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h Then the reaction mixture was heated to 25°C and was stirred at 25°C for 48 hours In the further reaction of this solution extinguished gradual DOB ml of ethyl acetate and 1 portion of 50 ml of diethyl ether. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 50/50 hexane/ethyl acetate with acetic acid) in the form of a white solid substance was obtained 1.28 g (yield: 84.3 percent) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid: tPL: 66-68°C; EI-HRMS m/e Rasch. for C15H16F4ABOUT2(M+) 305,1165, detect.: 305,1174.

The solution to 7.77 g (to 25.3 mmol) 3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionic acid in 50 ml of methanol was slowly treated with 0.01 ml of concentrated sulfuric acid. The resulting reaction mixture is boiled under reflux for 24 hours the Reaction mixture was allowed to cool to 25°C, and then it was concentrated under vacuum. The residue was dissolved in 75 ml ethyl acetate and washed with 1 portion 50 ml saturated aqueous sodium bicarbonate solution, 1 portion of 50 ml of water and 4 portions of 50 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil 8,48 g (yield: 87,5%) of methyl ester of 3-cyclopentyl-2-(4-fluoro-3-triptoreline)tx2">A solution of 7.0 g (21.9 mmol) of methyl ester of 3-cyclopentyl-2-(4-for-triptoreline)propionic acid in 50 ml of N,N-dimethylformamide was treated 2,61 g (33.0 mmol) methanolate sodium. Next, the reaction mixture was stirred at 100-110°C for 24 hours after this time the reaction mixture was poured into 100 ml of a mixture of ice and 2n. an aqueous solution of hydrochloric acid. The resulting mixture was extracted with 3 portions of 75 ml of ethyl acetate and 1 portion of 50 ml of diethyl ether. Then the organic fraction was washed for 1 portion in 75 ml of water and 3 portions of 100 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 85/15 hexane/ethyl acetate) as a pale yellow oil was obtained 2,48 g (yield: 35.5 per cent) methyl ester 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C17H21F3ABOUT2S (M+): 346,1214, detection. 346,1212.

A solution of 2.36 g (for 6.81 mmol) of methyl ester of 3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)propionic acid in 75 ml of methylene chloride at 25°With the processed RS 9.69 g of 3-chloroperoxybenzoic acid (80-actionnow the mixture was diluted with 75 ml of methylene chloride. The resulting solution was washed with 2 portions of 50 ml of a saturated aqueous solution of sodium bisulfite, 1 portion of 50 ml of water, 3 portions of 75 ml of a saturated aqueous solution of sodium chloride, 1 portion 75 ml saturated aqueous sodium bicarbonate solution and 3 portions of 75 ml of a saturated aqueous solution of sodium chloride. The organic fraction was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a clear oil 2,88 g of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionic acid: EI-HRMS m/e Rasch. for C17H21F3ABOUT2S (M+): 378,1112 the detection.: 378,1116.

A solution of 378 mg (1.0 mmol) of the methyl ester 3-cyclopentyl-2-(4 - methanesulfonyl-3-triptoreline)propionic acid in 2.0 ml of a solution of magnesium methoxide in methanol (concentration of 7.4 wt.%, of 1.40 mmol) was treated with 148 mg (2.0 mmol) of metallocene. The resulting mixture was boiled under reflux at 110°C for 12 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, the 40/60 hexane/ethyl acetate) as a white solid substance was obtained to 61.8 mg (yield: 45.8%) of 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifloromethyl the S (M+): 420,1331, detect.: 420,1345.

Example 167

Ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}-3-oxopropanoic acid

A solution of 402 mg (1,22 mmol) [3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl] urea (obtained in example 1B-g) and 0.15 ml (1,83 mmol) of pyridine in 15 ml of toluene was treated to 0.19 ml (1.5 mmol) of ethylmaleimide. The resulting reaction mixture is boiled under reflux for 2 hours after this additional time was added 0.15 ml (1,83 mmol) of pyridine and to 0.19 ml (1.5 mmol) of ethylmaleimide. Next, the reaction mixture is boiled under reflux for 90 minutes and Then the reaction mixture was cooled to 25°C, diluted with 50 ml ethyl acetate, washed with 2 portions of 25 ml of water and dried over magnesium sulfate. The solution was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a colourless resin was obtained 172 mg (yield: 32%) of ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)propionyl] ureido}-3-oxopropanoic acid: EI-HRMS m/e Rasch. for C20H24Cl2N2O5(M+): 443,1140, detect.: 443,1128.

Example 168

1-[3-cyclopentyl-2-(3-fluoro-4-methansulfonate the methanol was treated 15,00 g of ion-exchange resin Amberlyst® 15. The resulting reaction mixture is boiled under reflux for 64 hours, the Reaction mixture was allowed to cool to 25°C, and then it was filtered, removing the ion-exchange resin Amberlyst® 15. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) as a yellow oil was obtained at 1.91 g (yield: 89%) of methyl ester 4-chloro-3-nitrophenylarsonic acid: EI-HRMS m/e Rasch. for C9H8ClNO4(M+): 229,0142, detect.: 229,0146.

The solution to 3.35 ml (23,9 mmol) Diisopropylamine in 45 ml of dry tetrahydrofuran and 15 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -78°C, cultivated added dropwise over a 10 minute period of 9.56 ml (23,9 mmol) of a 2.5 M solution of n-utility in hexano. The pale yellow reaction mixture was stirred at -78°C for 20 min and then was treated by slow addition over a 15 minute period a solution of 5.00 g (to 21.8 mmol) of methyl ether 4-chloro-3-nitrophenylarsonic acid in a small amount of tetrahydrofuran. The reaction mixture was bought dark purple (almost black) color. Next, the reaction mixture was stirred at -78°C for 1 h, after this time the reaction mixture abraksascan the reaction mixture was stirred at -78°C and then it was heated to 25°C, after which it was stirred for 48 hours the Reaction in the reaction mixture extinguished 50 ml of a saturated aqueous solution of ammonium chloride and the resulting reaction mixture was concentrated under vacuum removal of tetrahydrofuran. The residue was diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) as a yellow oil was obtained 2.17 g (yield: 32%) of methyl ester of 2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H18ClNO4(M+): 311,0924, detect.: 311,0927.

A solution of 1.00 g (3,21 mmol) methyl ester of 2-(4-chloro-3-nitrophenyl)~ 3-cyclopentylpropionic acid and 0.36 g (of 3.53 mmol) of methanesulfonate of sodium in 3 ml of DMSO was kept at 130°C for 5 hours Then the black reaction mixture was poured into 20 g of ice, which formed the brown sticky substance. Then the mixture was treated with 50 ml of ethyl acetate and 50 ml of water and the layers were separated. The aqueous layer was further extracted with 2 portions of 50 ml of ethyl acetate. On the fester, was filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a yellow gel was obtained 0.95 g (yield: 84%) of methyl ester of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid: FAB-HRMS m/e Rasch. for C16H21NO6S (M+H)+356,1169, detect.: 356,1175.

A solution of 1.50 g (4,22 mmol) methyl ester 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionic acid in 30 ml of methanol was treated with a solution of 474 mg (8,86 mmol) of ammonium chloride in 3 ml of water. The reaction mixture was stirred at 25°C for 5 min and then it was treated with 2.70 g (41,36 mmol) of zinc dust. The reaction mixture is boiled under reflux for 2 hours the Reaction mixture was allowed to cool to 25°C, and then it was filtered by passing through a layer of brownmillerite. The filtrate was concentrated under vacuum. The resulting substance in the form of an orange oil was dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 2/1 hexane/ethyl acetate) as a white solid substance was obtained for 1.49 g (yield: 98%) of methyl ester of 2-(3-amino-4-methanesulfonyl)-3-cyclopentylpropionic the P>

The suspension 215 mg (of 1.84 mmol) nitrosodiethanolamine in 6 ml of methylene chloride, cooled to 0°C, was treated by the addition dropwise of a solution of 500 mg (1.54 mmol) of the methyl ester of 2-(3-amino-4-methanesulfonyl)-3-cyclopentylpropionic acid in a small amount of methylene chloride. The resulting reaction mixture was stirred at 0°C for 1 h Then the reaction mixture was heated to 25°C and then was treated with 6 ml of 1,2-dichlorobenzene. The resulting reaction mixture was stirred at 100°C for 1 h, and during this time drove methylene chloride. After 1 h of exposure at 100°C the reaction mixture was allowed to cool to 25°C. the Crude reaction mixture was purified directly Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate for the elution of 1,2-dichlorobenzene, then 2/1 hexane/ethyl acetate) to obtain as a yellow oil crude methyl ester 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionic acid. The re-cleaning Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 3/1 hexane/ethyl acetate) received 214 mg (yield: 42%) of pure methyl ester 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionic acid as a pale yellow oil, to whom S/m / e Rasch. for C16H21FO4S (M+): 328,1144, detect.: 328,1148.

90 mg (0,274 mmol) methyl ester 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionic acid and 61 mg (0,822 mmol) of metallocene was treated with 1.0 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, 0,685 mmol). Next, the reaction mixture was concentrated under vacuum to approximately half volume of methanol. Then the reaction mixture is boiled under reflux for 24 hours the Resulting cloudy white reaction mixture was allowed to cool to 25°C, and then it was filtered through brownmillerite. This brownmillerite thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 1/1 hexane/ethyl acetate) as a white solid substance was obtained with 23.3 mg (yield: 23%) of 1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl)propionyl]-3-metalmachine: tPL: 199-200°C; EI-HRMS m/e Rasch. for C17H23FN2O4S (M+): 370,1362, detect.: 370,1370.

Example 169

1-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]-3-metalmachine

The solution 6,77 g (31,48 mol) (4-bromophenyl) acetic acid in 32 ml of ethanol was treated with a catalytically effective to the after this time the reaction mixture was concentrated under vacuum. The residue was treated with 100 ml of an aqueous solution of sodium bicarbonate. The resulting solution was extracted with 3 portions of 100 ml of ethyl acetate. The organic layers were washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum obtaining in the form of a yellow oil of 6.75 g (yield: 94%) of the methyl ester (4-bromophenyl) acetic acid. This product was used without further purification.

50.5 ml of a solution of their diisopropylamide lithium (0.3 M, br15.15 mmol), cooled to -78°C, were treated to 3.36 g (14,67 mmol) methyl ether (4-bromophenyl) acetic acid in 37 ml of tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (in the ratio 3:1). The resulting solution was stirred at -78°C for 45 minutes after this time the reaction mixture was treated with a solution 3,24 g (15,45 mmol) iodomethylpropane in 3,24 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction mixture was stirred at -78°C for 4 h, the Reaction mixture was heated to 25°C and was stirred at 25°C for 20 hours then the reaction in the reaction mixture was suppressed by slow addition of 40 ml of saturated solution of ammonium chloride. Next, the reaction mixture is poured into the 100 ml of a saturated aqueous solution of sodium chloride and 3 portions of 100 ml of a saturated aqueous solution of lithium chloride, was dried over sodium sulfate and magnesium sulfate, filtered and concentrated under vacuum. As a result, the Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) in the form of a clear oil was obtained 3,86 g (yield: 84.6 per cent) methyl ester of 2-(4-bromophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. for C15H19BrO2(M+): 310,0568 the detection.: 310,0564.

A solution of 1.55 g (5.0 mmol) of the methyl ester of 2-(4-bromophenyl)-3-cyclopentylpropionic acid in 12.5 ml of N,N-dimethylformamide was treated with 672 mg (7.5 mmol) of copper cyanide. The resulting mixture was boiled under reflux for 21 hours, the Reaction mixture was cooled to 25°C and was poured into 25 ml of an aqueous solution of ammonium hydroxide. The resulting solution was diluted with 25 ml water. The resulting solution was extracted with 3 portions of 50 ml of ethyl acetate. The organic fraction was washed with 3 portions of 75 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and magnesium sulfate, filtered and concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 90/10 hexane/ethyl acetate) in the form of a clear oil was obtained of 1.17 g (yield: 91.3 percent) methyl ester of 2-(4-cyanophenyl)-3-cyclopentylpropionic acid: EI-HRMS m/e Rasch. and 2-(4-cyanophenyl)-3-cyclopentylpropionic acid and 148 mg (2.0 mmol) of metallocene in 2.0 ml of a solution of magnesium methoxide in methanol (7.4 wt.%, of 1.40 mmol) was boiled under reflux for 48 hours Then the reaction mixture was concentrated under vacuum. Express chromatography (Silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) as a white solid substance was obtained to 48.8 mg (yield: 16,3%) 1-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]-3-metalmachine: tPL: 61-65°C; FAB-HRMS m/e Rasch. for C17H21N3O2(M+H)+: 300,1712 the detection.: 300,1722.

Examples of biological activity

Example: the activity of glucokinase in vitro

The definition of glucokinase activity of glucokinase (GK) was determined by the paired reactions of formation of glucose-6-phosphate with the generation ABOVE.N using glucose-6-phosphatedehydrogenase (GFDG, 0,75-1 K units/mg, firm Boehringer Mannheim, Indianapolis, PCs Indiana), the enzyme involved in the reaction mates and extracted from Leuconostoc mesenteroides (scheme 2).

Recombinant GK-1 from the liver of a person expressed in E-coli in the form of a fused protein with glutathione-S-transferase (ST-GK) (Liang and others, 1995) and affinity purified by chromatography on a column of glutathione-separate 4B according to the method of the manufacturer. Preliminary studies have shown that the enzymatic properties of native ha and S-G the s tablet for fabrics with a flat bottom firm Costar (Cambridge, PCs Minnesota), end incubated amount equal to 120 μl. The incubation mixture contained: 25 mm HEPES-buffer (with pH of 7.1), 25 mm KCl, 5 mm D-glucose, 1 mm ATP, 1.8 mm NAD, 2 mm MgCl2, 1 μm sorbitol-6-phosphate, 1 mm dithiothreitol, test medication or 10% DMSO, and 1.8 u/ml GFDG and GK (see below). In all cases used organic reagents purity >98% of the company Boehringer Mannheim, with the exception of D-glucose and HEPES-buffer firm Sigma Chemical Co, St. Louis, PCs Missouri. Test compounds were dissolved in DMSO and added to inkubiruemykh mixture not containing S-Ledger, in a volume of 12 μl to achieve the final concentration of DMSO 10%. This mixture is pre-incubated in a thermostatted chamber microplate spectrophotometer SPECTRAmax 250, Molecular Devices Corporation, Sunnyvale, PCs California) for 10 minutes to achieve thermal equilibrium, and then the reaction was started by the introduction of 20 ál of the peso-Ledger.

For measure activity Ledger took the increase of optical density (OD) at 340 nm for 10 min inkubirovanija after adding the enzyme. In wells containing 10% DMSO without test compounds were added ST-Ledger in an amount sufficient to make a 10 min incubation to increase OP340from 0.08 to 0.1 units will Precede the tvii activator, which causes a 5-fold increase in the activity of the Ledger. The activity of the SC in the control wells was compared with the activity in the wells containing the test GK activators. Then calculates the concentration of the activator, which caused a 50% increase in ck activity, i.e, SC1,5. The value of SC1,55 for all of the compounds of formula I described in examples of the synthesis, was less than or equal to 30 microns.

Liang, Y., Kesavan, P., Wang, L., Niswender, K., Tanizawa, Y., Permut, M. A., Magnuson, M., and Matschinsky, F. M. Variable effects of maturity-onset-diabetes-of-youth (MODY)-associated glucokinase mutations on the substrate interactions and stability of the enzyme. Biochem. J. 309: 167-173, 1995.

Neet, K., Keenan, R. P., and Tippett, P. S. Observation of a kinetic slow transition in monomeric glucokinase. Biochemistry 29; 770-777, 1990.

Example B: the activity of glucokinase in vivo

Activators of glucokinase in vivo according to screening

Mice C57BL/6J after a two-hour period of fasting orally via a stomach tube was introduced activator of glucokinase (GK) in an amount of 50 mg/kg of body weight. Determination of glucose in blood was performed five times within six hours after a dose.

Mice (6 animals) were weighed and processed before pills were forced to starve for a two-hour period. Activators Ledger was introduced in the media Gelucire (ethanol:gelucire 44/14:PEG 400 in quantities is but 7.5 μl of composition per gram of body weight to dose, equal to 50 mg/kg Immediately prior to the first dose recorded the level of glucose in the blood (zero time), cutting off a small part of the tail of animals (~1 mm) and collecting 15 ml of blood in a heparinized capillary tube for analysis. After the introduction of the activator Ledger additional data on concentrations of blood glucose were obtained by taking blood from the same wounds in the tail after 1, 2, 4 and 6 h after dose. The results are interpreted by comparing the mean values of glucose concentration in the blood of six mice treated with medium containing activator, with data from six mice treated with GK activator within 6 h of testing. Compounds were considered active if they showed a statistically significant decrease (P0,05) of glucose in the blood compared to the control for two consecutive tests.

The pharmaceutical composition

Example

Tablets containing the following ingredients can be obtained in the usual way:

Ingredients per tablet mg

3-Cyclopentyl-2-(4-

methanesulfonyl)-N-

the thiazole-2 - ylpropionic 10-100

Lactose 125,0

Corn starch 75,0

Talc 4,0

Ingredients per capsule, mg.

3-Cyclopentyl-2-(4-methanesulfonyl)-N-thiazol - 2-ylpropionic 25,0

Lactose 150,0

Corn starch 20,0

Talc 5,0

The Example

The solution for injection may be presented in the following composition, mg:

3-Cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic 3,0

Gelatin 150,0

Phenol 4,7

Water for injection To 1.0

Example D

500 mg of 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic suspended in 3.5 ml of Miglyol 812 and 0.08 g of benzyl alcohol. This suspension is placed in a container with a metering valve. Through this metering valve in the container is injected 5.0 g of Freon 12 under pressure. Freon is dissolved in a mixture of Miglyol-benzyl alcohol with shaking. This spray container contains approximately 100 single doses, which can be used for individual use.

In the examples A-D may also be used and other ingredients, other than 3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic, such as, for example, obtained as the target products in examples 11, 12, 97, 98 or 99.

1. Deadrody atom;

R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl;

R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms;

R4denotes-C(O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on a ring carbon atom other than adjacent to the connecting carbon atom, and Deputy selected from a range including (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)ORwho achet hydrogen atom, (ness.)alkyl, (ness.)alkenyl, hydroxy(ness.)alkyl, halo(ness.)alkyl, -(CH2)n-C(O)OR SIG5or-C(O)-(CH2)n-C(O)OR6;

R5denotes a hydrogen atom, (ness.)alkyl or PERFLUORO(ness.)alkyl;

R6, R7and R8independently from each other represent a hydrogen atom or (ness.)alkyl; and

n denotes 0, 1, 2, 3 or 4;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where R1and R2independently from each other represent a hydrogen atom, halogen, amino, hydroxyamino-, cyano-, nitro-group, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO-(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl, (ness.)alkylsulfonyl or sulfamidihappo; R3denotes cycloalkyl containing from 3 to 7 carbon atoms; R4denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen or nitrogen, with one heteroatom is attygalle monogamist on a ring carbon atom, other than connecting with the connecting carbon atom, and Deputy selected from a range including (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6; n denotes 0, 1, 2, 3 or 4; R5denotes a hydrogen atom, (ness.)alkyl or PERFLUORO(ness.)alkyl; and R6, R7and R8independently from each other represent a hydrogen atom or (ness.)alkyl; or its pharmaceutically acceptable salt.

3. Connection on p. 2, in which R1and R2independently from each other represent a hydrogen atom, halogen, amino, nitro-group, (ness.)alkyl, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl, R4denotes unsubstituted or monosubstituted five-membered heteroaromatic ring connected by a ring carbon atom to the said amino group, where it is five-membered heteroaromatic ring contains a first heteroatom connected with the adjacent carbon atom of the ring, and the second heteroatom is connected with the adjacent carbon atom of the ring or the first heteroatom, despite the fact that the first gateroad the n six-membered heteroaromatic ring, linked via a ring carbon with the specified amino group, where the six-membered heteroaromatic ring contains one nitrogen heteroatom, associated with the adjacent ring carbon atom or two nitrogen heteroatoms, and one or two of which are connected to adjacent ring carbon atoms, with the specified substituted heteroaromatic ring monogamist the carbon atom of the ring, not related with the specified neighboring carbon atom, Deputy selected from the group comprising lower alkyl, halo, nitro, -(CH2)n-OR6, -(CH2)n-C(O)-OR7or-C(O)-C(O)-OR8; n=0, 1, 2, 3 or 4; and R6, R7and R8independently represent hydrogen or lower alkyl; or their pharmaceutically acceptable salts.

4. Connection on p. 3, in which R4denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring selected from the group comprising thiazolyl, pyridinyl, imidazolyl, isoxazolyl, pyridazinyl and pyrimidinyl.

5. Connection on p. 2, in which R4denotes unsubstituted or monosubstituted five - or six-membered heteroaromatic ring selected from the group comprising oxazolyl and TIA is original or pyridinyl, substituted with halogen, lower alkyl, hydroxy(ness.)the alkyl, or-C(O)OR5where R5means lower alkyl.

7. Connection on p. 1, where R1and R2independently from each other represent hydrogen, halo, amino, nitro, cyano, sulfamidihappo, lower alkyl, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.) alkyl containing from 2 to 4 carbon atoms; R4denotes-C(O)other40; R40denotes hydrogen, lower alkyl, lower alkenyl, hydroxy (ness.) alkyl, halo (ness.) alkyl, -(CH2)n-C(O)OR SIG5or-C(O)-(CH2)n-C(O)OR6; R5and R6represent hydrogen or lower alkyl, and n denotes 0, 1, 2, 3 or 4;

or its pharmaceutically acceptable salt.

8. Connection on p. 7, in which R1and R2independently from each other represent hydrogen, halo, amino, nitro, lower alkyl, PERFLUORO (ness.) alkyl, (ness.)alkylthio, PERFLUORO (NISS. )alkylthio, (ness.)alkylsulfonyl or PERFLUORO (ness.) alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms; R40means or lower alkyl; or their pharmaceutically acceptable salts.

9. The compound according to any one of paragraphs.1 and 8, in which R40denotes lower alkyl.

10. The compound according to any one of paragraphs.1 and 7, in which R40indicates the lowest alkenyl.

11. The compound according to any one of paragraphs.1-9, in which R1denotes hydrogen, halo, or nitro.

12. The compound according to any one of paragraphs.1-10, in which R1denotes cyano.

13. The compound according to any one of paragraphs.1-11, in which R1denotes hydrogen or halo.

14. The compound according to any one of paragraphs.1-13, in which R2denotes hydrogen, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, PERFLUORO(ness.)alkylsulfonyl or halo.

15. The compound according to any one of paragraphs.1-13, in which R2means-OR5where R5means PERFLUORO(ness.)alkyl.

16. The compound according to any one of paragraphs.1-14, in which R2denotes a halogen atom or (ness.)alkylsulfonyl.

17. The compound according to any one of paragraphs.1-16, in which the amide is a marked asymmetric carbon atom has the R-configuration.

18. The compound according to any one of paragraphs.1-17, in which R3denotes cyclopentyl or cyclohexyl.

19. The compound according to any one of paragraphs.1-17, in which the t cyclopentyl.

21. Connection on p. 3 in which R1and R2independently of one another denote hydrogen or (ness.)alkylsulfonyl, and R4means thiazolyl.

22. 3-Cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic.

23. (2R)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic.

24. The compound according to any one of paragraphs.2-6 and 11-20 selected from the group including

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triptoreline)propionamide,

2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-cyanophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methylsulfanyl-3-triptoreline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic,

2-(3-amino-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl)-N-thiazol-2-ylpropionic,

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-the-2-ylpropionic,

3-cyclopentyl-2-(4-sulfamoyl)-N-thiazol-2-ylpropionic,

2-[4-(butane-1-sulfonyl)phenyl]-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-[4-(propane-1-sulfonyl)phenyl]-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic,

2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide,

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triftormetilfullerenov)propionamide,

3-cyclopentyl-N-thiazol-2-yl-2-(4-trifloromethyl)propionamide,

3-cyclopentyl-2-(3-methoxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3-hydroxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-acid)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dihydroxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methoxyphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-hydroxyphenyl)-N-thiazol-2-ylpropionic,

methyl ester 4-[2-cyclopentyl-1-(thiazol-2-ylcarbonyl)ethyl]benzoic acid,

3-cyclopentyl-2-(3-fluoro-4-methoxyphenyl)-N-thiazol-2-ylpropionic,

methyl ester 2-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionamido]thiazole-4-carboxylic acid,

ethyl ether {2-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionamido]thiazol-4-yl}-octoxynol acid,

ethyl ether {2-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]thiazol-4-yl}-octoxynol acid,

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-yl-propionamide,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triptoreline)-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(3-triptoreline)-propionamide,

2-(4-AMINOPHENYL)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-cyanophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

3-cyclopentyl-2-(4-ethanolgasoline)-N-pyridin-2-ylpropionic,

2-(3,4-bis-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

methyl ester of 6-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]-nicotinic acid,

6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid,

6-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]nicotinic acid,

6-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionamido]-nicotinic acid,

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-triptorelin-2-yl)propionamide,

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionamide,

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(4-trifloromethyl-phenyl)propionamide,

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-triftorbyenzola-ylphenyl) propionamide,

N-(5-bromopyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl) propionamide,

2-(3-bromo-4-methanesulfonyl)-N-(5-bromopyridin-2-yl)-3-cyclopentylpropionate,

N-(5-bromopyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate,

2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-(5-triptorelin-2-yl)propionamide,

N-(5-chloropyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate,

3-cyclopentyl-2-(4-fluoro-3-triptoreline)-N-(5-LASS="ptx2">3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazole-2-ylpropionic,

2-[4-methanesulfonyl]-3-cyclohexyl-N-thiazol-2-ylpropionic, and

2-[4-methanesulfonyl]-3-cycloheptyl-N-thiazol-2-ylpropionic.

25. The compound according to any one of paragraphs.2-6 and 11-20 selected from the group including

2-(3-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-bromophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-chlorophenyl)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-(4-triptoreline)propionamide,

3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-ylpropionic,

2-(4-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(3-AMINOPHENYL)-3-cyclopentyl-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-(4-triftormetilfullerenov)propionamide,

3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylpropionic,

2-[3-chloro-4-methanesulfonyl]-3-cyclopentyl-N-thiazol-2-ylpropionic,

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethylimidazole-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethylimidazole-2-yl)-propionamide,

3-cyclopentyl-N-(4-hydroxymethylimidazole-2-yl)-2-(4-methanesulfonyl)propionamide,

3-cyclopentyl-N-[4-(2-hydroxyethyl)thiazol-2-yl]-2-(4-methanesulfonyl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethylimidazole-2-yl)-propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylthiazole-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylthiazole-2-yl)propionamide,

ethyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-thiazol-4-yl}acetic acid,

methyl ether {2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-thiazol-4-yl}acetic acid,

methyl ester 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-thiazole-4-carboxylic acid,

ethyl ester of 2-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,

ethyl ether {2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-thiazol-4-yl} acetic acid,

methyl ester 2-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-thiazole-4-carboxylic acid,

ethyl ester enyl)-3-cyclopentylpropionyl]-thiazol-4-yl}acetic acid,

{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl}-acetic acid,

ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamido]-thiazol-4-yl}acetic acid,

2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid,

2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid,

methyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-4-yl}acetic acid,

methyl ester of (2R)-2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-4-carboxylic acid,

methyl ester 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazole-5-carboxylic acid,

ethyl ester of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamido]-thiazole-5-carboxylic acid,

ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazol-4-yl}acetic acid,

methyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazol-4-yl}acetic acid,

methyl ester 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazole-4-carboxylic acid,

ethyl ester of 2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]-thiazole-4-carboxylic acid,

metalair 2-[2-(4-AMINOPHENYL)-3-cyclopentylpropionyl]-thiazole-4-carboxylic acid,

ethyl ester of 2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazole-4-carboxylic acid,

methyl ether {2-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]thiazol-4-yl}-4-acetic acid,

ethyl ether {2-[3-cyclopentyl-2-(4-nitrophenyl)propionamide]thiazol-4-yl}-octoxynol acid,

ethyl ether {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide]thiazol-5-yl}-octoxynol acid,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitrothiazol-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic,

2-(3-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

2-(4-chlorophenyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

3-cyclopentyl-2-(4-nitrophenyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-2-(4-methylsulfinylphenyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)-propionamide,

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide,

3-cyclopentyl-2-(4-methanesulfonyl)-N-pyridin-2-ylpropionic,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)-propionamide,

3-cyclopentyl-2-(3,4-dinyl)propionamido]nicotinic acid,

6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]nicotinic acid,

methyl ester of 6-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-nicotinic acid,

methyl ester of 6-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-nicotinic acid,

methyl ester of 6-[3-cyclopentyl-2-(4-triftormetilfullerenov)-propionamido]nicotinic acid,

methyl ester of 6-[3-cyclopentyl-2-(4-methanesulfonyl)propionamido]nicotinic acid,

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-(5-hydroxymethyluracil-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxypyridine-2-yl)prop-ionamin,

2-(4-chlorophenyl)-3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)-propionamide,

3-cyclopentyl-N-(5-hydroxymethyluracil-2-yl)-2-(4-meanswhen-ylphenyl)propionamide,

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-bromopyridin)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitropyridine)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylpyridin)-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methylpyridin)-2-ylpropionic,

3-is(4-trifloromethyl-phenyl) propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methylisoxazol-3-yl) propionamide,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-2-ylpropionic,

3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidine-6-ylpropionic,

3-cyclopentyl-2-(4-nitrophenyl)-N-pyrimidine-4-ylpropionic.

26. The compound according to any one of paragraphs.7-20 selected from the group including

1-[2-(4-cyanophenyl)-3-cyclopentylpropionyl]-3-metalmachine

1-allyl-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea,

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea,

1-[3-cyclopentyl-2-(3-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[2-(4-chloro-3-nitrophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-(butane-1-sulfonyl)phenyl-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-ethanolgasoline)propionyl]-3-metalmachine,

1-[2-(3,4-bistanbulholiday)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(3-bromo-4-m is ylphenyl)propionyl]-3-metalmachine,

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-stor-Ilocano,

1-[2-(3-cyano-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-fluoro-3-triptoreline)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3-fluoro-4-triptoreline)propionyl]-3-metalmachine,

[2-(4-chlorophenyl)-4-methylpentanoic]urea,

R-[2-(3,4-dichlorophenyl)-4-methylpentanoic]urea,

1-[2-(3,4-dichlorophenyl)-4-methylpentanoic]-3-metalmachine,

1-[2-(3,4-dichlorophenyl)hexanoyl]-3-metalmachine,

methyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} acetic acid

methyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido}propionic acid,

ethyl ester {3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-ureido}acetic acid,

ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}-3-oxopropyl the-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxyprop-yl)urea,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxyprop-yl)urea,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(2-hydroxy-propyl)urea,

1-(2-chloroethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea and

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-(3-hydroxy-propyl)urea. (P2)

27. The compound according to any one of paragraphs.7-20 selected from the group including

1-(3-cyclopentyl-2-phenylpropionyl)-3-metalmachine,

1-[2-(3-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-chlorophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2-(4-bromophenyl)-3-cyclopentylpropionyl]-3-metalmachine,

[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]urea,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-utilmately,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-utilmately,

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-isopropylamino,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-propylbetaine,

1-[3-cyclopentyl-2-(3,4-differeni the[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methylsulfinylphenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-triftormetilfullerenov)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)propionyl]-3-metalmachine,

[3-cyclopropyl-2-(3,4-dichlorophenyl)propionyl]urea,

[3-cyclobutyl-2-(3,4-dichlorophenyl)propionyl]urea,

[3-cyclohexyl-2-(3,4-dichlorophenyl)propionyl]urea,

1-[3-cyclohexyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

[3-cycloheptyl-2-(3,4-dichlorophenyl)propionyl]urea,

ethyl ester of 3-{3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-ureido}propionic acid,

ethyl ester {3-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]ureido} acetic acid.

28. The compound according to any one of paragraphs.2-6 and 11-20 selected from the group including

3-cyclopentyl-N-thiazol-2-yl-2-(4-trifloromethyl)propionamide,

3-cyclopentyl-2-(3-fluoro-4-triptoreline)-N-pyridin-2-ylpropionic,

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide,

2-(3-cyano-4-methanesulfonyl)-3-ASS="ptx2">2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylpropionic,

N-(5-bromopyridin-2-yl)-2-(3-chloro-4-methanesulfonyl)-3-CEC-opentempfile,

2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-rprop-ionamin,

2-(3-cyano-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide,

3-cyclopentyl-2-(4-ethanolgasoline)-N-thiazol-2-ylpropionic,

3-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylpropionic and

N-(5-bromopyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionate.

29. The compound according to any one of paragraphs.2-6 and 11-20 selected from the group including

3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylpropionic,

3-cyclopentyl-N-thiazol-2-yl-2-(4-triftormetilfullerenov)propionamide,

3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-N-pyridin-2-ylpropionic,

methyl ester of 6-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl amino] nicotinic acid,

N-(5-chloropyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)prop-ionamin,

3-cyclopentyl-N-pyridin-2-yl-2-(4-triftormetilfullerenov)-propionamide,

3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-(4-triptorelin,

methyl ester of 6-[3-cyclopentyl-2-(4-triftormetilfullerenov)-propionamido]nicotinic acid,

3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide,

2-[3-chloro-4-(methanesulfonyl)]-3-cyclopentyl-N-thiazol-2-ylpropionic,

(2R)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-rprop-ionamin. (P1)

30. The compound according to any one of paragraphs.7-20 selected from the group including

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-utilmately,

1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]urea,

1-[2-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine,

1-[2(R)-(3-chloro-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine and

1-[2-(3-bromo-4-methanesulfonyl)-3-cyclopentylpropionyl]-3-metalmachine.

31. The compound according to any one of paragraphs.7-20 selected from the group including

1-[3-cyclopentyl-2(R)-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(3,4-dichlorophenyl)propionyl]-3-metalmachine,

1-[3-cyclopentyl-2-(4-methanesulfonyl)propionyl]-3-metalmachine.

32. Pharmaceutical composition having activity in otnosheniya fact, as active compounds, the composition contains a compound according to any one of paragraphs.1-31.

Priority items:

29.03.1999 on PP.3, 4, 6, 8, 9, 11, 13, 14, 16-18, 20-23, 25, 27, 29 and 31;

17.11.1999 on PP.7, 10, 12, and 26;

17.11.1999 on PP.2, 5, 15, 28, 24 and 30.



 

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