Trans-olefinic activators of glucokinase

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

 

Glucokinase (GK) is one of four hexokinase found in mammals [Colowick, S.P., in the collection "The Enzymes", Vol.9 (P.Boyer, as amended). Academic Press, new York, NY, pages 1-48, 1973]. Hexokinase catalyzes the first stage of glucose metabolism, the conversion of glucose into glucose-6-phosphate. Glucokinase has a limited distribution in the cell, being mainly in pancreatic beta-cells and cells of the liver parenchyma. In addition, GK is the enzyme that controls the rate of glucose metabolism in these two types of cells, which are known to play a crucial role in glucose homeostasis of the whole organism [Chipkin, S.R., Kelly, K.L., and Ruderman, N.B. in Joslin′s Diabetes (C.R.Khan and G.C.Wier, ed), Lea and Febiger, Philadelphia, PA, pp. 97-115, 1994]. The glucose concentration at which GK takes half maximal activity, is about 8 mm. Three other hexokinase saturated with glucose at much lower concentrations (<1 mm). Therefore, the intake of glucose by metabolic pathways of GK increases, while the concentration of glucose in the blood increases the level of concentration when hunger (5 mm) to the level of concentration that occurs after a meal (≈10-15 mm), it was after food containing carbohydrates [Printz, R.G., Magnuson, M.A., and Granner, D.. in Ann. Rev. Nutrition, Vol. 13 (R.E. Olson, D.M. Bier, and D.B. McCormick, editor). Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993]. This data more than ten years ago has contributed to the hypothesis that GK options is anirul as a glucose sensor in beta-cells and hepatocytes (Meglasson, M.D. and Matschinsky, F.M., Amer. J.Physiol., 246, E1-E13, 1984). Recently, studies using transgenic animals have confirmed that GK does play a crucial role in glucose homeostasis of the whole organism. Animals that do not Express GK, die within days of birth from severe diabetes, while animals sverkhekspressiya GK, have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell, 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F., and others, FASEB J., 10, 1213-1218, 1996). The increased excretion of glucose linked via GK in beta-cells with increased secretion of insulin in hepatocytes with increased deposition of glycogen and possibly with reduced production of glucose.

There is evidence that diabetes type II reached maturity young people (MODY-2) is caused by loss of function mutations in the gene GK, assume that GK also operates in humans as a glucose sensor (Liang, Y., Kesavan, P., Wang, L., and others, Biochem. J., 309, 167-173, 1995). Additional evidence supporting the important role of GK in the regulation of glucose metabolism in humans was presented by identifying patients expressing the mutant form of the GK with increased enzymatic activity. These patients detected sustainable 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). is the GK gene mutation is not detected in most patients with type II diabetes, compounds that activate GK and thereby increase the sensitivity of the sensory system, the GK will be also useful in the treatment of hyperglycemic symptoms of all types of diabetes type II. Activators of glucokinase will increase during the process of glucose metabolism in beta-cells and hepatocytes, which will be combined with increased secretion of insulin. Such tools will be useful for the treatment of type II diabetes.

The present invention provides a compound comprising amide of the formula

where R1and R2mean independently from each other hydrogen, halogen, an amino group, a nitrogroup, PERFLUORO(ness.)alkyl, (ness.)allylthiourea, PERFLUORO(ness.)allylthiourea, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl, (ness.)alkylsulfonyl or (ness.)alkylsulfonyl;

R is -(CH2)m-R3or lower alkyl containing from 2 to 4 carbon atoms;

R3means cycloalkyl containing from 3 to 8 carbon atoms;

R4means

or unsubstituted or one-deputizing five - or six-membered heteroaromatic ring linked via a carbon atom of the ring with the specified amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms, selected from the group consisting whom she sulfur or nitrogen, where one heteroatom being nitrogen, is located next to the connecting carbon atom rings, and asanee one-deputizing heteroaromatic ring substituted with another carbon atom of the ring, non-contiguous with said connecting carbon atom rings, Deputy, which is selected from the group consisting of halogen or

m denotes 0 or 1;

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

R7means hydrogen or lower alkyl and

Δ means the TRANS-configuration relative to the double bond,

or its pharmaceutically acceptable salt.

The compounds of formula I are activators of glucokinase and useful for increasing insulin secretion in the treatment of type II diabetes.

This invention provides a compound comprising amide of the formula

where R1and R2mean independently from each other hydrogen, halogen, an amino group, a nitrogroup, PERFLUORO(ness.)alkyl, (ness.)allylthiourea, PERFLUORO(ness.)allylthiourea, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl;

R is -(CH2)m-R3or lower alkyl containing from 2 to 4 carbon atoms;

R3means cycloalkyl containing from 3 to 8 carbon atoms;

R4means

or unsubstituted or one-deputizing five - or six-membered heteroaromatic ring linked via a carbon atom of the ring with the specified amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom being nitrogen, is located next to the connecting carbon atom of the ring, and the specified one-deputizing heteroaromatic ring substituted with another carbon atom of the ring, non-contiguous with said connecting carbon atom rings, Deputy, which is selected from the group consisting of halogen or

m denotes 0 or 1;

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

R7means hydrogen or lower alkyl and

Δ means the TRANS-configuration relative to the double bond,

or its pharmaceutically acceptable salt, of which are suitable as activators for increasing insulin secretion in the treatment of type II diabetes. According to this invention it has been found that the compounds of formula I, having the TRANS configuration relative to the double bonds are of such glucokinase activity. On the other hand, the compounds of formula I with CIS-configuration relative to the double bonds do not have glucokinase activity.

When you use the term "CIS" d who authorized the application, this means that the two largest substituent attached to the double bond are on the same side relative to the double bond. The term "TRANS"as used in this application, means that the highest substituents attached to the double bond are on opposite sides of the double bond and have the E-configuration.

The present invention also relates to pharmaceutical compositions comprising the compounds of formula I and a pharmaceutically acceptable carrier and/or adjuvant. In addition, the present invention relates to the use of such compounds to obtain drugs for the treatment of type II diabetes. The present invention also relates to methods of preparing compounds of formula I. in Addition, this invention relates to a method of therapeutic treatment of type II diabetes, the method comprising introducing the compound of formula I to a human or animal.

Used in this application, the term "lower alkyl" includes alkyl groups and straight and branched chain, containing from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl, most preferably methyl.

Used herein, the term "halogen or halogen, unless specified otherwise, means all four Halogens, i.e. fluorine, chlorine, bromine and iodine.

As mentioned here, "PERFLUORO(ness.)and the keel" means any of the lower alkyl group, where all the hydrogen atoms of the lower alkyl group substituted or replaced by fluorine. Among the preferred PERFLUORO(ness.)alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl etc. preferred trifluoromethyl.

Used herein, the term "aryl" signifies mononuclear aromatic hydrocarbon groups, such as phenyl, tolyl, etc. which may be unsubstituted or substituted by one or more positions by halogen, a nitro-group, a lower alkyl or (ness.)CNS deputies, and polynuclear aryl groups such as naphthyl, antril and tenantry, which can be unsubstituted or can be substituted by one or more of the aforementioned groups. Preferred aryl groups are substituted or unsubstituted mononuclear aryl group, in particular phenyl. Used herein, the term "(ness.)alkoxygroup" includes alkoxygroup and straight and branched chain, containing from 1 to 7 carbon atoms, such as methoxy group, ethoxypropan, propoxylate, isopropoxide, preferably methoxy and ethoxypropan.

The term "aralkyl" means alkyl group, preferably lower alkyl, in which one of the hydrogen atoms may be substituted by an aryl group. Examples Uralkalij groups are benzyl, 2-phenylethyl, 3-f is ylpropyl, 4-Chlorobenzyl, 4-methoxybenzyl and similar groups.

Used herein, the term "lower albanova acid" means the lowest alcamovia acid containing from 2 to 7 carbon atoms, such as propionic acid, acetic acid and the like. The term "lower alkanoyl" means a monovalent alcoholnye group containing from 2 to 7 carbon atoms, such as, for example, propionyl, acetyl and the like.

The term "areeve acid" means arylalkylamine acid, where aryl is as above, and almanova acid contains from 1 to 6 carbon atoms. The term "aroyl" means the remains of arousal acid, where aryl is as stated here previously, remote from the carboxyl part of the hydroxyl group. Among the preferred rolnych groups called benzoyl.

During the reaction of various functional groups, such as free carboxyl or hydroxyl groups, protected using conventional liable to undergo hydrolysis of the ester or ether protective groups. Used herein, the term "liable to undergo hydrolysis of the ester or ether protective group" means any ester or ether, usually used to protect carboxylic acids or alcohols, which can be subjected to hydrolysis with the formation of the ACC is respectively hydroxyl or carboxyl group. Examples of ester groups used for these purposes are those in which the acyl residues are derived lower alanovoy acid, aryl(ness.)alanovoy acid or (ness.)alkalicarbonate acid. Among the activated acids that can be used for the formation of such groups are the anhydrides of the acids, galodamadruga acid, preferably the acid chlorides of the acids or bromohydrin acids derived from aryl or lower alkanovykh acids. Examples of anhydrides are anhydrides, derivatives of monocarboxylic acids, such as acetic anhydride, the anhydride of benzoic acid and anhydrides of lower alkalicarbonate acids, for example succinic anhydride, and esters of Harborview acid, for example, the preferred trichloronat, ethylchloride. Suitable ether protective groups for alcohols are, for example, a simple tetrahydropyranyloxy esters, as, for example, a simple 4-methoxy-5,6-dihydroxy-2H-pornlove esters. Others are simple roulettelive esters, such as benzyl, benzhydryl or triphenylmethyl ethers, or simple α-(ness.)alkoxy(ness.)alkalemia esters, for example methoxymethyl or allyl ethers, or simple alkylsilane esters, as, for example, a simple trimethylsilyloxy ether.

The term "protective group for the amino group" means any conventional protective group for an amino group which can be cleaved with the formation of free amino groups. Preferred protective groups are the conventional protective group for the amino group used in peptide synthesis. Particularly preferred protective groups for amino groups, which are in slightly acidic conditions at a pH from 2.0 to 3. Particularly preferred protective groups for amino group, such as tert-butoxycarbonylamino, benzyloxycarbonylamino, 9-fluorenylmethoxycarbonyl.

Heteroaromatic ring, denoted by R4may be unsubstituted or one-deputizing five - or six-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, or sulfur, linked through a carbon atom of the ring with the specified amine residue amide group. Heteroaromatic ring contains the first nitrogen heteroatom next to the connecting carbon atom of the ring, and if there are other heteroatoms, they can be sulfur or nitrogen. Preferred heteroaromatic rings are pyridinyl, pyrimidinyl and thiazolyl preferred pyridinyl and thiazolyl. These heteroaromatic rings that are not only at the Ute R 4, linked through a carbon atom of the ring with the amide group to form the amide of formula I. the Ring carbon atom of the heteroaromatic ring, which is connected by an amide bond to form compounds of formula I, may not contain any Deputy. When R4is unsubstituted or one-deputizing five - or six-membered heteroaromatic ring, the preferred rings are those which contain nitrogen heteroatom next to the linking carbon atom ring and a second heteroatom next to the linking carbon atom of the ring or adjacent to the first-mentioned a heteroatom.

The term "pharmaceutically acceptable salt", as used here, includes any salt with inorganic 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, p-toluensulfonate and the like acids. The term "pharmaceutically acceptable salt" also includes any pharmaceutically acceptable salt with a base, such as, for example, salts with amines, salts with trialkylamine and the like. Salt can be quite easily obtained by specialists in this field is t using standard techniques.

The compound of formula I according to this invention represents two preferred form, the compound of the formula

where Δ, R, R1, R2and R7are as described above;

and the compound of the formula

where R, R1, R2and Δ are as described above;

R11is unsubstituted or one-deputizing five - or six-membered heteroaromatic ring linked via a carbon atom of the ring with the specified amino group is five - or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom is nitrogen, beside the connecting carbon atom of the ring; the one-deputizing heteroaromatic ring has a Deputy at the carbon atom of the ring, other, and non-contiguous with said connecting carbon atom, Deputy selected from the group consisting of halogen or

n means 0, 1, 2, 3 or 4 and

R7means hydrogen or lower alkyl.

In accordance with one preferred example embodiment of the compounds of formula I, R may be lower alkyl, containing from 2 to 4 carbon atoms. In another preferred example, the domestic is R can be -(CH 2)m-R3where R3and m are as described above. Preferred heterocyclic residues R3are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, more preferred cyclopentyl, cyclohexyl and cycloheptyl. In one preferred embodiment of the invention R3means cyclopentyl, in another preferred embodiment, R3means cyclohexyl. In a preferred embodiment of the invention m is 1, in another preferred embodiment, m is 0. Preferred heteroaromatic rings R11according to the invention are unsubstituted or one-deputizing a pyridinyl or thiazolyl. In one preferred variant of the invention, the heteroaromatic ring R11is unsubstituted or one-deputizing a pyridinyl, in another preferred variant of the invention, the heteroaromatic ring R11means unsubstituted or one-deputizing thiazolyl. In accordance with a further preferred variants of the invention, the heteroaromatic ring R11is either unsubstituted or has one substituent in the form of halogen or -(CH2)n-C(O)-OR7where n and R7are as indicated the ANO above. Preferred substituents R1and R2are selected independently from the group comprising hydrogen, halogen, a nitro-group, PERFLUORO(ness.)alkyl, (ness.)alkylsulfonyl and (ness.)alkylsulfonamides. In a preferred embodiment of the invention one of R1and R2means halogen, (ness.)alkylsulfonyl or (ness.)alkylsulfonates and the other denotes hydrogen, halogen, the nitro-group or PERFLUORO(ness.)alkyl. In a more preferred embodiment of the invention one of R1and R2means (ness.)alkylsulfonyl and other means hydrogen, halogen, the nitro-group or PERFLUORO(ness.)alkyl. The preferred residue R7is lower alkyl.

In accordance with one example embodiment of the compounds of formula I-A R can be cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclohexyl (compound I-A1). In various examples of embodiments of cyclohexylamino of compound I-A1 included those compounds where one of R1and R2means hydrogen, halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of the mentioned R1and R2means halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl, and particularly those compounds where one of R1and R2means hydrogen or (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl and other oznacza the t (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl. Another example embodiment of the compounds of formula I-A are those compounds where R is a lower alkyl group containing from 2 to 4 carbon atoms (compounds of formula I-A2). Examples of embodiments of compounds of formula I-A2 are those compounds where one of R1and R2means hydrogen, halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl and the other of the mentioned R1and R2means halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl.

An example embodiment of the compounds of formula I-B are those compounds where R11is unsubstituted or one-deputizing thiazole ring. When R11means unsubstituted thiazole ring, R can be lower alkyl group containing from 2 to 4 carbon atoms (compound I-B1). Examples of embodiments of compounds of formula I-B1 are such compounds where one of R1or R2means hydrogen, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen, the nitro-group and the other of the mentioned R1or R2means (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen or nitro-group, and preferably those compounds of formula IB-1, where one of R1and R2means hydrogen, (ness.)alkylsulfonyl and another mentioned R1and R2means (ness.)alkylsulfonyl.

An example embodiment of the compounds of formula I-B are those compounds where R is cycloalkyl containing from 3 to 8 carbon atoms (compound IB-2).

Examples of embodiments of compounds of formula I-B2 are such compounds where cycloalkyl group is cyclopentyl (IB-2(a)). An example embodiment of the compounds I-B2(a) are compounds of formula IB-2(a), where R11is unsubstituted thiazole ring (compounds IB-2A(1)). Among the examples of embodiment of the compounds IB-2A(1) are such compounds where one of the mentioned R1and R2means hydrogen, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen or nitro-group and the other of the mentioned R1and R2means (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen or nitro-group, and particularly preferred examples of embodiments of compounds IB-2(a)(1) are compounds where

a) one of R1or R2means (ness.)alkylsulfonyl and the other denotes hydrogen, a nitro-group, (ness.)alkylsulfonyl, halogen or PERFLUORO(ness.)alkyl;

b) one of R1and R2means halogen, hydrogen or PERFLUORO(ness.)alkyl and the other means PERFLUORO(ness.)alkyl or halogen, and

C) one of R1and R2means (ness.)alkylsulfonates and the other denotes hydrogen, (ness.)alcalali arylmethyl or halogen.

Among the examples of embodiment of the compounds of formula IB-2A are such compounds where R11is one-deputizing thiazolidine ring that includes compounds where R11is galoidzamyescyennykh thiazole ring (compounds of formula IB-2(a)(2)). Examples of embodiments of compounds of formula IB-2(a)(2) are such compounds where one of R1and R2is (ness.)alkylsulfonyl, hydrogen or halogen and the other is (ness.)alkylsulfonyl or halogen.

Another example embodiment of the compounds IB-2 are those compounds where R is cyclohexyl (compound IB-2(b)). Examples of embodiments of compounds IB-2(b) are such compounds where R11is unsubstituted thiazolidine ring (compound 1B-2(b)(1)). Among the preferred compounds IB-2(b) are such compounds where one of R1or R2means hydrogen, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen, the nitro-group and other means (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl, halogen or nitro-group, in particular

(a) where one of R1or R2means (ness.)alkylsulfonyl and the other denotes hydrogen, a nitro-group, (ness.)alkylsulfonyl, halogen or PERFLUORO(ness.)alkyl;

(b) where one of R1and R2means halogen, hydrogen or n is htor(ness.)alkyl and the other means PERFLUORO(ness.)alkyl or halogen, and

(C) where one of R1and R2means (ness.)alkylsulfonates and the other denotes hydrogen, (ness.)alkylsulfonyl or halogen.

Another example embodiment of compound IB-2(b) are such compounds where R11is one-deputizing diazolidinyl cycle and, in particular, galoidzamyescyennykh cycle (compound IB-2(b)(2)). Examples of embodiments of compounds IB-2(b)(2) are such compounds where one of R1and R2means (ness.)alkylsulfonyl and other means halogen, PERFLUORO(ness.)alkyl or hydrogen.

Another example embodiment of the compounds IB-2 are those compounds where R is cycloheptyl (compound IB-2(d)) or cyclooctyl (compound IB-2(e)). An example embodiment of the compounds (compound IB-2(d) and compound IB-2(e)) are those compounds where R11means unsubstituted thiazolyl (compound IB-2(d)(1) and IB-2(e)(1)), respectively. In this case, compounds IB-2(d)(1) and IB-2(e)(1), which are preferred are such compounds where one of R1and R2means (ness.)alkylsulfonyl, hydrogen, halogen or PERFLUORO(ness.)alkyl and the other means (ness.)alkylsulfonyl, halogen or PERFLUORO(ness.)alkyl.

Another example embodiment of compound IB-2(d) and compound IB-2(e) are such compounds where R11means one-deputizing thiazolidine ring and the Deputy is halogen. Inthese cases, one of R 1and R2can be hydrogen, (ness.)alkylsulfonyl, PERFLUORO(ness.)by alkyl or halogen, and the second may be a halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)the alkyl. In the compounds IB-2(d) and (IB-2(e) R11is monosubstituted by thiazolium, the Deputy may be

where n and R7are as described above.

In the case of such compounds one of R1and R2in these compounds may be (ness.)alkylsulfonyl and the second of the aforementioned R1and R2is (ness.)alkylsulfonyl or hydrogen.

Another class of compounds of formula IB are those compounds where R is-CH2-R3and R3is the same as described above. Among the compounds included in the scope of this variant of the invention, there are compounds where R is a group-CH2-cyclohexyl (compound IB-3). Compounds IB-3 include those where R11is substituted or unsubstituted thiazolidine ring and, in particular, those compounds where R11is unsubstituted thiazolidine ring and where the substituent in thiazolidine ring is

where n and R7are as described above.

In this case, the preferred compounds where one of R1and R2means (ness.)alcalali the Nile and other means (ness.)alkylsulfonyl or hydrogen. In accordance with an example embodiment of the compounds of formula IB R can be cyclopentyl. Example embodiments of this class include compounds where R11is unsubstituted or one-deputizing pyridinium ring. The preferred example embodiment of this class are those compounds where one of R1and R2means hydrogen, (ness.)alkylsulfonyl or halogen and the other of the mentioned R1and R2means (ness.)alkylsulfonyl or halogen.

In accordance with the present invention the compounds of formula IA and IB can be obtained from the following compounds of the formulas:

where R1and R2are as described above.

According to this invention the compounds of formula IA and IB are obtained from compounds of the formula V according to the following reaction scheme:

Scheme 1

where R, R1, R2, R7and R11are as described above;

R5together with the associated oxygen atom forms can be subjected to hydrolysis, the protective group for acids and

X means a halogen.

The compound of formula V or XIX where one of R1and R2means the nitrogroup, tigroup, amino group, halogen and the other denotes hydrogen, are known substances. Substituted amine compounds of the formula V or XX can be converted into compounds with other substituents, either before or after conversion into the compounds of formula IA or IB. This amino group can be progesterone with the formation of the corresponding diazonium compounds which in situ may be subjected to reaction with the desired (ness.)alkylthio, PERFLUORO(ness.)alkylthiols (see, for example, Baleja, J.D., Synth. Somme. 1984, 14, 215; Giam, C.S., Kikukawa, K.,J. Chem.Soc, Chem. Comm. 1980, 756; Kau, D., Krushniski, J.H., Robertson, D.W., J.Labelled Compd Rad. 1985, 22, 1045; Oade, S., Shinhama, K., Kim, Y.H., Bull Chem Soc Jpn. 1980, 53, 2023; Baker, B.R., and others, J.Org. Chem. 1952, 17, 164) to obtain the corresponding compounds of formulas V and XIX, where one of the substituents is (ness.)alkylthiol, PERFLUORO(ness.)alkylthiophene and the other is hydrogen. If desirable, (ness.)alkylthiophene or PERFLUORO(ness.)alkylthiophene can be converted by oxidation into the corresponding (ness.)alkylsulfonyl - or PERFLUORO(ness.)alkylsulfonamides the compounds of formula V or XIX. To perform such a transformation can be used by any accepted method of oxidation of alkyldiethanolamine in sulfones. If it is desired to obtain compounds with PERFLUORO(ness.)the alkyl groups of the formula V or XIX, as starting substances can be taken golozhabernyi the compounds of formula V or XIX. Any accepted way of turning haloesters aromatic group to the corresponding PERFLUORO(ness.)the alkyl group can is to be applied for the implementation of this transformation (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.C.. 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., Bishop, D., Blade, R.J., Tetrahedron Lett.1989, 2133; Powell, R.L., Heaton, S., US patent No. 5113013).

The compounds of formula V or XIX where both Deputy R1and R2are amino groups, can be obtained from the corresponding dinitrosobenzene formula V or XIX. To perform such transformations can be used by any accepted method of recovery of the nitro group to the amino group. The compound of formula V or XIX where both R1and R2mean amino groups, can be applied to obtain the corresponding compound of formula V or XIX where both R1and R2mean iodine or bromine, using the reaction of diazotization. To perform such a transformation can be applied to any accepted method of conversion of the amino group in the form of iodine or bromine (see, for example, Lucas, H.J., Kennedy, E.R., Org. Synth. Coll., Vol, II, 1943, 351). If it is desired to obtain compounds of formula V or XIX where both R1and R2mean (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea, the compound of formula V or XIX where R1and R2are amino groups, can be used as the starting material. Any conventional method of turning killingray in arieti the alkyl group can be applied to perform such a transformation. If it is desired to obtain a compound of formula V or XIX where R1and R2mean (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl, corresponding compounds of formula V or XIX where R1and R2mean (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea, can be used as starting substances. To perform such a transformation can be used any traditional method of oxidation of alkyldiethanolamine in sulfones. If it is desired to obtain compounds of formula V or XIX where both R1and R2substituted PERFLUORO(ness.)alkyl groups, corresponding golozhabernyi the compounds of formula V or XIX may be used as starting substances. To perform such a transformation may be used any conventional method of transformation of aromatic haloesters group in the corresponding PERFLUORO(ness.)alkyl group.

The compounds of formula V or XIX where one of R1and R2means the nitrogroup, and other means halogen, known from the literature (see for 4-chloro-3-nitrophenylarsonic acid, Tadayuki, S., Hiroki, M., Shinji, U., Mitsuhiro, S., patent JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenylalanine acid, 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). So, if it is desired to obtain a compound of the formula or XIX, where one of R1and R2means nitrogroup and other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea, as a starting compound may be used the corresponding compound where one of R1and R2is the nitro-group and the other is chlorine. In this reaction may be used any conventional method of nucleophilic substitution of aromatic chlorinated group (ness.)alkylthiols (see, for example, Singh, P.; Batra, M.S.; Singh, H., J. Chem. Res.-S 1985 (6), S 204; 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., patent US 5169951). When the compounds of formula V or XIX where one of R1and R2means nitrogroup and other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea, they can be converted into the corresponding compounds of formula V or XIX where one of R1and R2means nitrogroup and other means (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl, using standard methods of oxidation. If it is desired to obtain compounds of formula V or XIX where one of R1and R2means the amino group and the other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea, as the starting material can be applied to the corresponding compound where one of R1and R2means the nitro-group and the other is th mean (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea. To perform such a transformation can be used any traditional method of recovery associated with the aromatic nucleus of the nitro group to the amino group. If it is desired to obtain compounds of formula V or XIX where one of R1and R2means (ness.)allylthiourea and other means PERFLUORO(ness.)allylthiourea, as the starting material may be used the corresponding compound where one of R1and R2means the amino group and the other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea. To perform such a transformation can be applied to any generally accepted method comprising the diazotization of the amino group in the aromatic ring and the interaction obtained with this compound in situ with the desired (ness.)alkylthiols. If it is desired to obtain compounds of formula V or XIX where one of R1and R2means (ness.)alkylsulfonyl and other means PERFLUORO(ness.)alkylsulfonyl, as starting substances can be used, the corresponding compound where one of R1and R2means (ness.)allylthiourea and other means PERFLUORO(ness.)allylthiourea. To perform such a transformation can be applied to any standard way of oxidation of simple aromatic thioester group in the corresponding sulfon. If you want the LNO to obtain the compounds of formula V or XIX, where one of R1and R2means halogen and other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea as starting substances can be used, the corresponding compound where one of R1and R2means the amino group and the other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea. To perform such a transformation may be used any conventional method of diazotization of the aromatic amine and transformation in situ in the aromatic halide compound. If it is desired to obtain compounds of formula V or XIX where one of R1and R2means halogen and other means (ness.)alkylsulfonyl or PERFLUORO(ness.)alkylsulfonyl, as starting substances can be used, the corresponding compound where one of R1and R2means halogen and other means (ness.)allylthiourea or PERFLUORO(ness.)allylthiourea. To perform such a transformation can be used with any standard method of oxidation of simple aromatic tiefer in the appropriate sulfon. If it is desired to obtain a compound of formula V or XIX where one of R1and R2means the nitro-group and the other denotes the amino group, as the initial substance can be used a compound of formula V or XIX where one of R1and R2means nits is Gruppo and other means chlorine. Chlorine Deputy at the phenyl ring can be converted into iodine Deputy (see, for example, Bunnett, J.F.; Conner, R.; Org. Synth. Coll Vol V, 1973, 478; Clark, J.H.; Jones, C.W., J.Chem. Soc. Chem. Commun. 1987, 1409), which in turn can react with carrying azide agent with formation of the corresponding azide (see, for example, Suzuki, N.; Miyoshi, K.; Shinoda, M., Bull. Chem. Soc. Jpn, 1980, 53, 1765). This azide can be recovered in the usual way in Amin when restoring commonly used regenerating means for the conversion of azides to amines (see, for example, Soai, K.; Yokoyama, S.; Ookawa, A., Synthesis, 1987, 48).

To obtain compounds where R1and/or R2mean (ness.)alkylsulfonamides in the compound of formula I, can proceed from the known compounds of formula V where one or both of R1and R2means methyl. The methyl group in these compounds can be bromirovanii using any standard means for the synthesized methyl groups at the phenyl ring. This is a brominated compound is then treated with sodium salt (ness.)alkylthiol (as, for example, diameterat sodium) to obtain (ness.)alkyltrimethylenedi derived. To obtain (ness.)alkylsulfonyl Deputy can be used to implement this transformation any accepted method of oxidation of substituents in the form (ness.)alkylthio in sulfones, such as, for example, you described what that is

The deputies, who represent R1and R2can be attached to the ring after the formation of the compounds of formulas IA and IB. Therefore, all of the described reactions for various substituents R1and R2in the compound of the formula I can be carried out on the compounds of formulas IA and IB after their formation.

The compounds of formula IA and IB are obtained from the compounds of formula V or XIX, as shown in schemes 1 or 2. In the first stage of this reaction in scheme 1, the compound of formula V is subjected to reaction with oxalylamino where free, capable of either hydrolyzed organic acid group oxanilide protected using any conventional protective groups for the acid. To the preferred protective groups for acids are able to undergo hydrolysis of esters of oxalicacid. The protective group formed by R5. The interaction of protected oxalicacid with the compound of the formula V to obtain the compounds of formula VI is carried out by the reaction of the Friedel -. When carrying out this reaction can be used any of the conditions adopted for the implementation of the reaction Friedel -. In this reaction, R1and R2may not be the nitrogroup. On the other hand, R1and R2can be an amino group. However, prior to the reaction of this amino group must be is protected using a conventional, liable to undergo hydrolysis of the protective group for amino group. At some later stage of the reaction, these protective groups for the amino group can be removed and converted into an amino group of the nitro group as described herein previously.

The compound of formula VI may react with halide salt triphenylphosphine formula IX according to the Wittig reaction with the formation of the compounds of formula VII. When carrying out this reaction, any of the conditions conventional for carrying out the Wittig reaction, can be used for successful implementation of such synthesis of the compounds of formula VI and a compound of formula IX to obtain the compounds of formula VII. Compound of formula VII is obtained in the form formed by Wittig reaction of a mixture of CIS - and TRANS-isomers with respect to the double bond. The mixture of CIS - and TRANS-isomers of compounds of formula VII directly hydrolyzed to the compound of formula VIII. When this hydrolysis reaction of the compound of formula VIII is obtained predominantly in the form of the TRANS isomer in the mixture. In addition, formed by the hydrolysis of TRANS-isomer is obtained in the form of solids, while the CIS-isomer is obtained as an oily substance. Taking this into account, it is very easy to separate the TRANS-isomer, using conventional methods of crystallization from the mixture to obtain the compounds of formula VIII in the form of pure Proc. of the na-isomer, essentially free of the corresponding CIS-isomer. Such crystallization can be performed at this stage or the next stage of reaction in the formation of compounds of formula IA or IB. Therefore, by using such methods, the compound of formula IA and IB can be obtained in pure TRANS-form, substantially free from the corresponding CIS-isomer.

In the designation of the TRANS-isomer cleaning should be performed by hydrolysis of the protective group OR5to the corresponding compounds of formula VIII in the form of the free acid and the allocation of the free acid with crystallization in the form of TRANS-isomer free of the corresponding CIS-isomer. Upon receipt of the compounds of formula IB in the form of its TRANS-form is preferable to carry out the procedure of crystallization with the compound of the formula VIII. On the other hand, purification by crystallization can be carried out using the compounds of formula IB and IA. Because TRANS-isomers of these compounds are solids and CIS-isomers are oily substances, any conventional method of crystallization can be applied for a successful treatment.

In the next stage of this method, the compound of formula VIII is attached to the compound of the formula

where R11so, as stated above,

DL is obtaining the compounds of formula IB. This reaction mix can be carried out using any of the conventional methods by reacting the acid with the primary amine to obtain the amide. On the other hand, the compound of formula VII can be directly connected with the compound of the formula XIV to obtain the compounds of formula IB, without any intermediate stages of hydrolysis.

Upon receipt of the compounds of formula IA, the compound of formula VII is subjected to reaction with

This reaction can be carried out by transformation of compounds of formula VII to the corresponding free acid by removal of the protective group R5with the formation of carboxylic acids. Carboxylic acid of formula VIII can be converted into the corresponding amide when turning the acid into the acid chloride and then reaction of the carboxylic acid with ammonia. When this procedure can be used the conditions conventional for the conversion of the acid to its acid chloride. This acid chloride acid then undergoes reaction with alkylsulfonates formula XV to obtain the adduct with urea of the formula IA. Any conventional method of interaction alkylsulfonate with Amida for the formation of ties with urea uses compound of formula IA.

The compound of formula IA may be formed as a mixture of CIS - and TRANS-isomers, if the compound of formula VII is e has been cleared. If desired, the treatment can be carried out in the case of the compounds of formula IA to obtain the compounds of formula IA in the form of a fully TRANS-isomer, are exempt from the CIS isomer. In the same way can be purified compound of formula IB or a compound of formula VIII, may be purified compound of formula IA to obtain a fully TRANS-isomer.

In accordance with another embodiment of this invention the compound of formula VII can also be obtained by the following reaction scheme 2. This reaction scheme is applicable for producing compounds of formula IA and IB, where one or both of R1and R2mean the nitrogroup. The reaction mix can be easily carried out with any of these groups of R1and R2in particular, when R1and R2are nitro groups.

Scheme 2

where R5together with the associated oxygen atom forms can be subjected to hydrolysis, the protective group of carboxylic acid, R, R1, R2and Δ are as described above.

According to scheme 2, the compound of formula XI can be generated in situ or from the corresponding magyarkanizsa reagent, or from tsinkorganicheskih reagent and soluble copper reagent (and CuCN 2LiCl) (see, for example, Knochel, P.; Singer, R.D., Chem. Rev. 1993, 93, 2117). Then the compound of formula XI to ablaut to the compound of formula XVII with the aim of obtaining by 1,4-conjugated join a highly Regio - and stereoselective manner vinylmania intermediate compounds, which when idolize using iodine formed compound of the formula XVIII, in which R and iodine are in the SYN-with respect to each other. The compound of formula XVIII is then reacts with active metal zinc (see, for example, Knochel, P.; Janakiram Rao. C., Tetrahedron, 1993, 49, 29) for receiving Vinichenko intermediate compounds, which are then subjected to interaction with bromide or iodide compound of formula XIX in the presence of a source of Pd(0) to obtain the compounds of formula VII. When conducting this reaction, aromatic Deputy is attached so that the compound of formula VII was TRANS-configuration relative to the double bond.

All the compounds of formula I, which include the following examples compounds, activated glucokinase in vitro using the methods of example A. Thus, they reinforce the process of glucose metabolism, which causes increased insulin secretion. Therefore, the compounds of formula I are activators of glucokinase, useful for increasing insulin secretion.

Were studied the following are given as examples of compounds and have shown that they are excellent activators of glucokinase in the study of activity in vivo when introduced in accordance with the analysis described in example B:

(E)-3-cyclopentyl-2-(4-methanesulfonyl)-N-TIA the ol-2-ylacrylic;

(E)-3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic;

(E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic;

(E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylacrylic;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylacrylic;

(E)-N-(5-bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl)acrylamide;

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

(E)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide;

the thiazole-2-alamid (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid;

methyl ester (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-anolamine]thiazole-4-carboxylic acid and

the thiazole-2-alamid (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid.

On the basis of their ability to activate glucokinase compounds of the above formula I can be used as medicines for the treatment of type II diabetes. Therefore, as previously mentioned, the drug containing the compound of formula I, are also the object of the present invention, as the method of preparation of drugs such method, which provides for the inclusion of the aqueous or more compounds of the formula I and, if desirable, one or more other therapeutically valuable substances in herbal form for injection.

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. The administration can also be carried out via the rectum using, for example, suppositories, topical or percutaneous, for example, using ointments, creams, gels or solutions, or parenterally, for example intravenously, intramuscularly, subcutaneously, vnutriobolochechnoe or percutaneous, using, for example, injectable solutions. In addition, the introduction can be conducted sublingual or in aerosol form, for example in the form of a sprayable solution. For the preparation of tablets, coated tablets, coated tablets or hard gelatin capsules of the compounds of the present invention can be mixed with pharmaceutically inert, inorganic or organic fillers. Examples of suitable excipients for tablets, coated tablets or hard gelatin capsules include lactose, corn starch or derivatives thereof, talc or stearic acid or its salts. Suitable fillers for use with soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols etc; according the nature of the active ingredients may, however, be such that for soft gelatin capsules don't need filler. For the preparation of solutions and syrups fillers that may be used include, for example, water, polyols, saccharose, invert sugar and glucose. For injectable solutions fillers that may be used include, for example, water, alcohols, polyols, glycerine and vegetable oils. For suppositories and for local or percutaneous application of fillers that may be used include, for example, natural or hardening of oils, waxes, fats and semi-solid or liquid polyols. Pharmaceutical compositions may also contain preservatives, solubilizing means, stabilizing means, the wetting means, emulsifiers, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, means for coating or antioxidants. As mentioned earlier, they can also contain other therapeutically valuable tools. A necessary condition is that all materials used in preparation of drugs adjuvants were non-toxic.

The preferred forms of use are intravenous, intramuscular or oral administration, most preferably oral administration. The dosages in which are compounds of formula (I) in ffektiwnyj quantities depend on the specific nature of the active ingredients, the age and needs of the patient and the route of administration. Usually considered dose comprising about 1-100 mg/kg of body weight per day.

The invention will be better understood from the following examples, which are given to illustrate and not limit the invention defined by the claims below.

EXAMPLES

Examples of biological activity

Example a: in vitro glucokinase activity

Analysis of glucokinase: glucokinase (GK) was tested by linking the production of glucose-6-phosphate to generate the recovered adenine dinucleotide (NADH) using glucose-6-phosphate dehydrogenase (G6PDH, 0.75 to 1 units/mg; firm Boehringer Mannheim, Indianapolis, IN) from Leuconostoc mesenteroides as the binding of the enzyme (scheme 3).

Scheme 3

Recombinant GK1 from human liver was expressed in E. coli in the form of an integral protein glutathione-S-transferase (GST-GK) [Liang and others, 1995] and purified by affinity chromatography on a column of glutathione-separate 4B, using the methodology provided by the manufacturer (Amersham Pharmacia Biotech, Piscataway, NJ). Previous research has demonstrated that the enzymatic properties of native GK and GST-GK are essentially identical (Liang and others, 1995); Neet and others, 1990).

<> The test was carried out at 25°in flat-bottomed 96-cell tablet for cell culture tissue from Costar (Cambridge, MA) at finite volume during incubation in 120 µl. The incubation mixture contained 25 mm buffer with N-2-hydroxyethylpiperazine-N′-2-econsultancy acid (Hepes) (pH of 7.1), 25 mm KCl, 5 mm D-glucose, 1 mm adenosine triphosphate (ATP), 1.8mm nicotinamide dinucleotide (NAD), 2 mm magnesium chloride, 1 μm sorbitol-6-phosphate, 1 mm dithiothreitol studied the connection or 10% dimethyl sulfoxide (DMSO), 1.8 units/ml G6-PDH and GK (see below). All organic reagents were of purity >98% and were provided by the company Boehringer Mannheim, with the exception of D-glucose and Hepes, which were obtained from the company Sigma Chemical Co, St Louis, MO. The compounds were dissolved in DMSO and were added to the incubation mixture without GST-GK in a volume of 12 ál, to obtain a final concentration of DMSO in 10%. This mixture is pre-incubated in a chamber with temperature-controlled spectrophotometer with a microtiter plate reader SPECTRAmax 250 (Molecular Devices Corporation, Sunnyvale, CA) for 10 minutes prior to the establishment of thermal equilibrium and then started the reaction with the addition of 20 μl of GST-GK.

After addition of enzyme, the increase of optical density (OD) at 340 nm was recorded for 10-minute incubation period as a criterion of activity of GK. Added GST-GK enough to get Uwe is icene OP 340from 0.08 to 0.1 units over a 10-minute incubation period the cells containing 10% DMSO, but without the compounds. Preliminary experiments established that the reaction rate GK was linear over this period of time even in the presence of activators, which led to 5-fold increase in the activity of GK. The GK activity in control cells was compared with the activity in cells containing the analyzed GK activators, and calculates the concentration of the activator, leading to a 50% increase in activity GK-SC1,5. All the compounds of formula I described in examples synthesis, had SC1,5less than or equal to 30 microns.

Example B: in vivo activity

Protocol for in vivo screening of glucokinase activator

Mice C57BL/6J oral forcibly injected activator of glucokinase (GK) in a dose of 50 mg/kg body weight after a two-hour period of fasting. Determination of glucose in blood is carried out five times in a six-hour study period after injection.

Mice (n=6) are weighed and subjected to starvation for a two-hour period before oral treatment. GK activators are prepared at a concentration of 6,76 mg/ml in media Gelucire (ethanol : Gelucire 44/14 : polyethylene glycol (PEG) 400 a sufficient amount of, 4 : 66 : 30./wt./vol.). Mice orally administered 7.5 ál dosage forms per gram of body weight up to a dose of 50 mg/is. Immediately prior to dosing for reference readings blood glucose pre-selected sample (time zero) by cutting a small piece of the tail of the animal (~1 mm) and selection of 15 µl of blood in heparinised capillary tube for analysis. After the introduction of GK activator from the same wounds tail taken after 1, 2, 4 and 6 hours after dosing additional blood samples for determination of glucose in blood. The results are interpreted by comparison of mean values of glucose in the blood six-treated filler mice with values in the six-treated GK activator mice in the six-hour study period. Compounds are considered active if they show a statistically significant (p≤0.05) reduction in blood glucose compared with a filler for two consecutive time points of analysis.

Example 1

The thiazole-2-alamid (E)-2-(4-methanesulfonyl)Penta-2-ene acid

A mixture of lithium chloride (1.7 g, 40 mmol, previously dried at 130°C in high vacuum for 2 h) and copper cyanide (1.78 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) was stirred at 25°C in argon atmosphere for 10 minutes to obtain a transparent solution. The reaction mixture was cooled to -70°and then slowly treated with 1 M solution of Atil is glibamide in tetrahydrofuran (20 ml, 20 mmol). After addition, the reaction mixture was allowed to warm to -30°C and stirred at this temperature for 5 minutes. The resulting reaction mixture was again cooled to -70°and then slowly treated with methyl ether propionovoi acid (1.52 g, 18 mmol). The reaction mixture was stirred 4 hours at a temperature of from -40 to -30°and then cooled to a temperature of -70 - -60°Since, at this time, the reaction mixture was slowly treated with a solution of iodine (6,86 g, 27 mmol) in anhydrous tetrahydrofuran (20 ml). After addition of a solution of iodine bath for cooling was removed and the reaction mixture was allowed to warm to 25aboutSince, at this temperature, it was stirred 1 h the Reaction mixture was then poured into a solution consisting of a saturated aqueous solution of ammonium chloride (90 ml) and ammonium hydroxide (10 ml)and the organic compound was extracted with diethyl ether (3×50 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 19/1 hexane/diethyl ether) resulted methyl ether (E)-2-japantravel acid (2, g, 67%) as a colorless oil: mass spectrometry high-resolution ionization by electron impact (EI-msvr) m/e calculated for C6H9IO2(M+) 239,9647 found 239,9646.

A mixture of zinc dust (2,36 g, 36 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) in an argon atmosphere was treated with 1,2-dibromethane (0.28 g, 1.5 mmole). The zinc suspension was then heated using a jet air dryer to a rapid boil, allowed to cool and again heated. This operation was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (163 mg, 1.5 mmole) and the suspension was stirred 15 min at 25aboutC. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-2-japantravel acid (2.9 g, 12 mmol) in anhydrous tetrahydrofuran (3 ml) for 3 min, the Reaction mixture was then stirred at 40-45°C for 1 hour and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (10 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction vessel was stirred bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmole) and triphenylphosphine (260 mg, 1 mmol) in anhydrous tetrahydrofuran (16 ml) at 25° With under argon for 10 min and then was treated with 4-bromophenylacetate (2,11 g, 9 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 50°within 24 hours the Reaction mixture was then cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (100 ml)and the organic compound was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 3/2 hexane/ethyl acetate) led to methyl ether (E)-2-(4-methanesulfonyl)partenopei acid (1.88 g, 78%) as a viscous yellow oil: EI-SVR m/e calculated for C13H16O4S (M+) 268,0769 found 268,0772.

A solution of methyl ester (E)-2-(4-methanesulfonyl)partenopei acid (1,83 g, PC 6.82 mmole) in ethanol (30 ml) was treated with 1 N. solution of sodium hydroxide (15 ml). The solution was heated at 45-50°C for 15 h, by which time analysis of the reaction mixture using thin layer chromatography indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. OST is OK was diluted with water (50 ml) and was extracted with diethyl ether (1× 50 ml) to remove any neutral impurities. The aqueous layer was then acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-2-(4-methanesulfonyl)pontenova acid (1,43 g, 82%) as a solid black color: EI-SVR m/e calculated for C12H14O4S (M+H)+254,0621 found 254,0623.

A solution of triphenylphosphine (1.23 g, 4.7 mmole) in methylene chloride (15 ml) was cooled to 0°and then was treated with N-bromosuccinimide (836 mg, 4.7 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-2-(4-methanesulfonyl)partenopei acid (703 mg, was 2.76 mmole) in methylene chloride (5 ml). A clear solution was stirred 10 min at 0°and then left to warm to 25°Since, at this temperature it was stirred for 1.5 hours. The reaction mixture was then treated with 2-aminothiazole (829 mg, of 8.28 mmole) and the resulting suspension was stirred 15 h at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (100 ml) and 1 N. aqueous solution of hydrochloric acid (100 ml Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1-1/1 hexane/ethyl acetate) led to the thiazole-2-ylamide (E)-2-(4-methanesulfonyl)Penta-2-ene acid (150 mg, 16%) as a crystalline solid substance: tPL155-158°C; EI-SVR m/e calculated for C15H16N2O3S2(M+) 336,0602 found 336, 0601.

Example 2

The thiazole-2-alamid (E)-2-(4-methanesulfonyl)-4-methylpent-2-ene acid

A mixture of lithium chloride (1,69 g, 40 mmol, previously dried at 130°C in high vacuum for 2 h) and copper cyanide (1,79 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) was stirred at 25°C under argon for 10 min to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with a 2 M solution of isopropylacrylamide in tetrahydrofuran (10 ml, 20 mmol). After addition, the reaction mixture was allowed to warm to -30°C and at this temperature it was stirred 5 min. P is obtained as a result of the reaction mixture was again cooled to -70° With and then slowly treated with methyl ether propionovoi acid (1.52 g, 18 mmol). The reaction mixture was stirred 4 h at a temperature of from -40 to -30°and then was cooled to -70 - -60°Since, at this time, the reaction mixture was slowly treated with a solution of iodine (6,86 g, 27 mmol) in anhydrous tetrahydrofuran (20 ml). After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, it was stirred 1 h Then the reaction mixture was poured into a solution containing a saturated aqueous solution of ammonium chloride (90 ml) and ammonium hydroxide (10 ml)and the organic compound was extracted with diethyl ether (3×50 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 20/1 hexane/diethyl ether) resulted methyl ether (E)-2-iodine-4-methylpentanoic acid (2,23 g, 49%) as a colorless oil: EI-SVR m/e calculated for C7H11IO2(M+) 253,9804 found 253,9805.

A mixture of zinc dust (1,71 g, 26 mmol, Aldrich company, - 325 mesh) and anhydrous tetrahydrofuran (2 ml) about amityvale under argon 1,2-dibromethane (0.28 g, 1.5 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (163 mg, 1.5 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-2-iodine-4-methylpentanoic acid (2,22 g, 8.7 mmole) in anhydrous tetrahydrofuran (3 ml) for 2 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (8 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone)palladium(0) (81 mg, 0.15 mmole) and triphenylphosphine (156 mg, 0.6 mmole) in anhydrous tetrahydrofuran (15 ml) at 25°C under argon for 10 min and then was treated with 4-bromophenylacetate (1.64 g, 7 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 50°within 24 hours the Reaction mixture was then cooled to 25°and then was poured into saturated the aqueous solution of ammonium chloride (100 ml), and the organic compound was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 3/2 hexane/ethyl acetate) led to methyl ether (E)-2-(4-methanesulfonyl)-4-methylpentanoic acid (1,876 g, 95%) as a viscous yellow oil: EI-SVR m/e calculated for C14H18O4S (M+) 282,0926 found 282,0933.

A solution of methyl ester (E)-2-(4-methanesulfonyl)-4-methylpentanoic acid (1,83 g, 6,48 mmole) in ethanol (35 ml) was treated with 1 N. aqueous solution of sodium hydroxide (15 ml). The solution was heated at 45-50°C for 15 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (50 ml) and was extracted with diethyl ether (1×50 ml) to remove any neutral impurities. The aqueous layer was then acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (× 100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-2-(4-methanesulfonyl)-4-methylpentanol acid (1.6 g, 92%) as a solid white color: tPL179-182°C; EI-SVR m/e calculated for C13H16O4S (M+H)+269,0847 found 269,0858.

A solution of triphenylphosphine (1,11 g, 4,24 mmole) in methylene chloride (15 ml) was cooled to 0°and then was treated with N-bromosuccinimide (755 mg, 4,24 mmole). The reaction mixture was stirred at 0°C for 30 minutes and then treated with a solution of (E)-2-(4-methanesulfonyl)-4-methylpentanoic acid (655 mg, 2.12 mmole) in methylene chloride (4 ml). A clear solution was stirred 10 min at 0°and then he was allowed to warm to 25°Since, at this temperature it was stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (636 mg, 6,36 mmole) and the resulting suspension was stirred 15 h at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (100 ml) and 1 N. aqueous solution of hydrochloric acid (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous chloride is about sodium (1× 100 ml), dried over anhydrous magnesium sulfate,filtered and evaporated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1-1/1 hexane/ethyl acetate) led to the crude mixture of compound (365 mg). This mixture was dissolved in ethyl acetate (5 ml) and diethyl ether (5 ml) and then treated with hexane (10 ml). The solid precipitate was filtered and washed with hexane, got thiazol-2-alamid (E)-2-(4-methanesulfonyl)-4-methylpent-2-ene acid (219 mg, 29%) as an amorphous solid: EI-SVR m/e calculated for C16H18N2O3S2(M+) 350,0759 found 350,0754.

Example 3

(E)-3-Cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic

A mixture of aluminum chloride (412,65 g, to 3.09 mol) in methylene chloride (1,11 l) was cooled to 0°and was stirred to dissolve the solids. The reaction mixture was then slowly treated with heterocalixarenes (300 ml, 2,69 mol) and the resulting reaction mixture changed color from yellow to orange. The reaction mixture was then slowly treated with a solution of thioanisole (300 ml, of 2.56 mol) in methylene chloride (244 ml) in small portions during 1 h With the addition of thioanisole the temperature of the reaction mixture was maintained below 10°C. the resulting reaction mixture was allowed to warm to 25°when this is th temperature was stirred 1 h The reaction mixture was then again cooled to 0°and then slowly treated with ice/water (800 ml) for 1 h, the Reaction mixture was then transferred into a separating funnel portions in 1 L. one litre portions continuously was extracted with methylene chloride prior to the absence in the water layer of the product according to thin-layer chromatography. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum, received ethyl ester (4-methylsulfinylphenyl)octoxynol acid (481,67 g, 84%)as a yellow liquid which was used without further purification: EI-SVR m/e calculated for C11H12About3S (M+) 224,0507 found 224,0500.

The solution iodomethylpropane (129,38 g, 0,616 mol) and triphenylphosphine (161,54 g, 0,616 mol) in acetonitrile (308 ml) was boiled under reflux for 9 days. The reaction mixture was left to cool to 25°and then was concentrated in vacuum to obtain a solid substance. The solid is triturated with diethyl ether and then filtered. The solid residue is well washed with diethyl ether to lack in the wash liquid iodomethylpropane and triphenylphosphine according to thin-layer chromatography. The resulting solid was dried in the air and got modesty cyclopentanoperhydrophenanthrene (266,92 g, 92%) in view of the solid light yellow: t PL195-198°C; SVR with fast atom bombardment (FAB) m/e calculated for C24H26R (M+N)+345,1772 found 345,1784.

Suspension iodotope cyclopentanoperhydrophenanthrene (151,73 g, 0,321 mol) in anhydrous tetrahydrofuran (494 ml) was cooled to 0°and then slowly treated with a 1.0 m solution of bis(trimethylsilyl)amide lithium (309 ml, 0,309 mol). The reaction mixture is bright orange color was stirred 1 h at 0°C. the Reaction mixture then was treated with small portions of the solution of the ethyl ester (4-methylsulfinylphenyl)octoxynol acid (to 55.42 g, 0,247 mol) in anhydrous tetrahydrofuran (100 ml). The resulting reaction mixture was stirred at 0°C for 30 min and then allowed it to warm to 25°Since, at this temperature, was stirred for 6 hours. Then the reaction mixture was diluted with water (500 ml), at this time the reaction mixture had a pH=11. In the reaction mixture has set pH=6 with 10% aqueous hydrochloric acid solution and then the reaction mixture was left overnight at 25°C. the Reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then diluted with diethyl ether (1 l). Began to precipitate the precipitate and the reaction mixture was left for 1 h at 25°C. the Solid precipitate was filtered and well washed with diethyl ether. The resulting filtrate of two layers of re is osili into a separating funnel and the layers were separated. The aqueous layer was further extracted with diethyl ether (1×500 ml).

The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×500 ml), dried over sodium sulfate, filtered and concentrated in vacuum. Purification using a layer of silica gel (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) led to ethyl ether, 3-cyclopentyl-2-(4-methylsulfinylphenyl)acrylic acid (58,93 g, 82%) as a yellow oil consisting of a mixture of isomers (E):(Z)=1,44:1. The substance was used without further separation and identification.

Solution mixture of isomers of ethyl ester of 3-cyclopentyl-2-(4-methylsulfinylphenyl)acrylic acid [58,93 g, 0,203 mole, (E):(Z)=1,44:1] formic acid (203 ml) was cooled to 0°and then slowly treated with 30%aqueous hydrogen peroxide solution (62,2 ml, 0,609 mol). The reaction mixture was stirred at 0°C for 30 min, then the mixture was allowed to warm to 25°Since, at this temperature, stirred 2 hours, the Reaction mixture was again cooled to 0°and then slowly treated with a saturated aqueous solution of sodium bisulfite (1 liter). The reaction mixture was then extracted with ethyl acetate (2×700 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×700 ml), dried over magnesium sulfate, filtered and concentri is ovale in vacuum, received ethyl ester 3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid (65,02 g, 99%) as a yellow oil consisting of a mixture of isomers (E):(Z)=1,63:1. The product was used without further purification and identification.

Solution mixture of isomers of ethyl ester of 3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid [65,02 g, 0,202 mole, (E):(Z)=1,63:1] in methanol (504 ml) was treated with 1 N. aqueous solution of sodium hydroxide (423 ml, 0,423 mol). The reaction mixture was stirred 20 h at 25°With, by this time thin layer chromatography indicated the presence of the original substance. The reaction mixture was then concentrated in vacuo to remove a certain amount of methanol (300 ml). The resulting reaction mixture is boiled under reflux for 1 h, by which time thin layer chromatography indicated the absence of starting material. Then the reaction mixture was concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then was extracted with ethyl acetate (2×1 l). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum, received a 3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid (62,58 g) as a cream solid color, consisting of a mixture of isomers (E):(Z)=16,2:1. Solid prophetic the STV cream color was treated with ethyl acetate (200 ml) and the resulting suspension was heated to boiling. The resulting solid white liquid light yellow color, representing the ethyl acetate was left to cool to 25°C. the Solid was filtered and obtained pure (E)-3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid (41,18 g, 69%) as a solid white color, tPL200-202°C; EI-SVR m/e calculated for C15H18O4S (M+) 294,0926 found 294,0921.

A solution of N,N-dimethylformamide (17.5 ml, 226,61 mmole) in anhydrous tetrahydrofuran (420 ml) was cooled to -25°C in an atmosphere of nitrogen and then treated with oxalylamino (18.8 ml, 215,42 mmole). The solution became turbid shortly after the addition of oxalicacid. The reaction mixture was allowed to warm to 25°C. When heated to 25°With gas evolution began about -20°and deposited solids white with increasing temperature. The reaction mixture was stirred at 25°C for 15 min, the result has been a heavy suspension of solid particles in white. The reaction mixture was then cooled again to -25°and treated with a solution of (E)-3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid (41,18 g, 139,88 mmole) in anhydrous tetrahydrofuran (300 ml) for 10 minutes After completion of addition, the solution of (E)-3-cyclopentyl-2-(4-methanesulfonyl)acrylic acid reaction sosiaali to warm to 0° Since, at this temperature, it was stirred 1 h During the time spent at 0°With dense solid particles were partially dissolved and formed a fine suspension of solid particles in white. After 1 h of exposure at 25°the reaction mixture was cooled to -45°C. the Reaction mixture is then treated by insertion through the tube for 10 min pre-cooled (-45° (C) solution of 2-aminothiazole (44,97 g, 449,02 mmole) and triethylamine (62,6 ml, 449,02 mmole) in tetrahydrofuran (280 ml). Reactionaries changed color from suspension white to light brown after addition of a solution of 2-aminothiazole/triethylamine. The reaction mixture gave then heated to 0°C for 15 min using a bath of ice/water. Then the reaction mixture was allowed to warm to 25°C for 30 min and then stirred 1 h at 25°C. After the reaction mixture was cooled to -25°and then were treated with 1 M aqueous citric acid solution (250 ml)and the resulting reaction mixture was allowed to warm to 25°C. the Reaction mixture was filtered through a layer of celite to remove settled solids. Celite was washed with ethyl acetate until no product in the washing liquid according to thin-layer chromatography. The filtrate in the form of two layers was transferred into a separating funnel and the layer was separated. Water was kolektyviniai with ethyl acetate (1× 500 ml). The organic layer was concentrated in vacuo to remove tetrahydrofuran and the resulting residue was diluted with ethyl acetate (700 ml). The combined organic layers are successively washed with 2 M aqueous solution of sodium bisulfate (3×200 ml), saturated aqueous sodium chloride (1×200 ml), 10%aqueous solution of potassium carbonate (4×200 ml) and saturated aqueous sodium chloride (1×300 ml). The organic layer then was dried over magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 70-230 mesh, 3/2 hexane/ethyl acetate) led to (E)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic (27,93 g, 53%) as a solid white color: tPL172-173°C; FAB-MCBP m/e calculated for C18H20N2O3S2(M+H)+377,0993 found 377,0986.

Example 4

(E)-3-Cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic

A mixture of zinc dust (16,34 g, 250 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (6 ml) was treated in an argon atmosphere 1,2-dibromethane (0,94 g, 5 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust is reaktywowana. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (0.54 g, 5 mmol) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of iodine cyclohexyl (21 g, 100 mmol) in anhydrous tetrahydrofuran (30 ml) for 15 minutes. During the addition the temperature rose to 60°C. the Reaction mixture was then stirred 3 h at 40-45°C. the Reaction mixture then was cooled to 25°and diluted With anhydrous tetrahydrofuran (60 ml). The stirring was stopped to give the possibility to precipitate the excess zinc dust (~3 h). In a separate reaction flask was stirred mixture of lithium chloride (8,48 g, 200 mmol, previously dried at 130°C in high vacuum for 3 h) and copper cyanide (of 8.95 g, 100 mmol) in anhydrous tetrahydrofuran (110 ml) for 10 min at 25°C to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with freshly prepared zinc solution using a syringe. After addition, the reaction mixture was allowed to warm to 0°Since, at this temperature, stirred 5 minutes, the Reaction mixture was again cooled to -70°and then slowly treated with methyl ether propionovoi acid (7,56 g, 90 mmol). The resulting reaction mixture was stirred 15 h at a temperature of from -70 to -50° With and then slowly treated with a solution of iodine (34,26 g, 135 mmol) in anhydrous tetrahydrofuran (30 ml)maintaining the temperature from 70 to -60°C. After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, stirred 2 hours, the Reaction mixture was then poured into a solution consisting of a saturated solution of sodium chloride (400 ml) and ammonium hydroxide (100 ml)and the organic compound was extracted with ethyl acetate (3×250 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×500 ml) and saturated aqueous sodium chloride (1×500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-iodically acid (26,3 g, 99%) as a oil light pink color: EI-SVR m/e calculated for C10H15IO2(M+) 294,0117 found 294,0114.

A mixture of zinc dust (2.6 g, 40 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0,37 g, 2 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This is procedure was repeated three times, to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (217 mg, 2 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (5,88 g, 20 mmol) in anhydrous tetrahydrofuran (5 ml) for 5 minutes. During the addition the temperature rose to 50°C. the Reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (10 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred under argon for 10 min at 25°bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmole) and triphenylphosphine (520 mg, 2 mmole) in anhydrous tetrahydrofuran (25 ml) and then was treated with 4-bromophenylacetate (to 4.23 g, 18 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 50°within 24 hours, by this time in the analysis using thin-layer chromatography of the reaction mixture did not detect the source of the substance. The reaction mixture was cooled to 25°C and then poured into saturated water is the first solution of ammonium chloride (150 ml), and the organic compound was extracted with ethyl acetate (CH ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 3/2 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-(4-methanesulfonyl)acrylic acid (5,79 g, 99%) as a low melting solid white color: EI-SVR m/e calculated for C17H22O4S (M+) 322,1238 found 322,1236.

A solution of methyl ester (E)-3-cyclohexyl-2-(4-methanesulfonyl)acrylic acid (5.7 g, 17,95 mmole) in ethanol (65 ml) was treated with 1 N. aqueous sodium hydroxide solution (54 ml). The solution was heated at 45-50°C for 15 h, by which time analysis by thin-layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove the ethanol, the residue was diluted with water (100 ml) and was extracted with diethyl ether (1×150 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×250 ml), dried over anhydrous magnesium sulfate, was filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(4-methanesulfonyl)acrylic acid (5,18 g, 94%) as a solid white color: tPL195-197°C; EI-SVR m/e calculated for C16H20O4S (M+N)+309,1160 found 309,1165.

A solution of triphenylphosphine (8,79 g, 33,52 mmole) in methylene chloride (100 ml) was cooled to 0°and then was treated with N-bromosuccinimide (5,97 g, 33,52 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl)acrylic acid (5,17 g, 16,76 mmole) in methylene chloride (20 ml). A clear solution was stirred 15 min at 0°and then gave him to warm up to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (5,04 g, 50,3 mmole) and the resulting suspension was stirred 2 days at 25°C. the Reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (250 ml) and 1 N. aqueous solution of hydrochloric acid (150 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×100 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×150 ml) and saturated aqueous sodium chloride (1×250 ml), dried over betwedn the m magnesium sulfate, was filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 8,5/1,5-3/2 hexane/ethyl acetate) led to (E)-3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic (2.8 g, 42%) as amorphous solids: tPL167-169°C.; EI-SVR m/e calculated for C19H22N2O3S2(M+) 390,1072 found 390,1073.

Example 5

(E)-3-Cycloheptyl-2-(4-methansulfonate)-N-thiazol-2-ylacrylic

A mixture of magnesium metal (to 4.81 g, 200 mmol) and anhydrous tetrahydrofuran (10 ml) was treated in an argon atmosphere a solution of 1,2-dibromethane (0,94 g, 5 mmol) in anhydrous tetrahydrofuran (5 ml). The resulting reaction mixture was stirred 10 min to activate the metal magnesium. The reaction mixture was then treated dropwise with a solution of cycloheptylamine (17,7 g, 100 mmol) in anhydrous tetrahydrofuran (30 ml), one-fifth part within 5 minutes the resulting reaction mixture was stirred for 5-10 min to initiate the exothermic reaction. The remaining part of cycloheptylamine was then added dropwise, maintaining the internal temperature below 50°C. After complete addition the solution was stirred 1 h and then was diluted with anhydrous tetrahydrofuran (80 ml). In a separate reaction flask was stirred at 25°in atmosphere is argon for 10 min, the mixture of lithium chloride (8,48 g, 200 mmol, previously dried at 130°C in high vacuum for 3 h) and copper cyanide (8,96 g, 100 mmol) in anhydrous tetrahydrofuran (110 ml) to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with freshly prepared cycloheptylamine. After addition, the reaction mixture was allowed to warm to -10°Since, at this temperature, stirred 5 minutes the resulting reaction mixture was again cooled to -70°and then was treated with methyl ether propionovoi acid (EUR 7.57 g, 90 mmol). The reaction mixture was stirred 15 h at a temperature of from -70 to -50°and then slowly treated with a solution of iodine (34.3 g, 135 mmol) in anhydrous tetrahydrofuran (30 ml)maintaining the temperature from -70 to -60°C. After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, stirred 2 hours, the Reaction mixture was then poured into a solution consisting of a saturated aqueous solution of ammonium chloride (400 ml) and ammonium hydroxide (100 ml), and the organic compound was extracted with ethyl acetate (3×200 ml). The combined extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×400 ml) and saturated aqueous sodium chloride (1×400 ml). The organic layer is ZAT what m was dried over anhydrous magnesium sulfate, was filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 20/1-10/1 hexane/ethyl acetate) led to methyl ether (E)-3-cycloheptyl-2-iodically acid (17,86 g, 64%) as a colorless oil: EI-SVR m/e calculated for C11H17IO2(M+) 308,0273 found 308,0273.

A mixture of zinc dust (2.6 g, 40 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0,38 g, 2 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (220 mg, 2 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cycloheptyl-2-iodically acid (6,16 g, 20 mmol) in anhydrous tetrahydrofuran (5 ml) for 10 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (10 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask displaced ivali bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmole) and triphenylphosphine (520 mg, 2 mmole) in anhydrous tetrahydrofuran (25 ml) at 25°C in an atmosphere of argon for 10 min and then was treated with 4-bromophenylacetate (to 4.23 g, 18 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 50°C for 24 h, the Reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (150 ml)and the organic compound was extracted with ethyl acetate (3×150 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 4/1-1/1 hexane/ethyl acetate) led to methyl ether (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid (6,01 g, 99%) as a viscous oil lead color: EI-SVR m/e calculated for C18H24O4S (M+) 336,1395 found 336,1395.

A solution of methyl ester (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid (6,01 g, 17.8 mmole) in ethanol (65 ml) was treated with 1 N. aqueous sodium hydroxide solution (55 ml). The solution was heated at 45-50°C for 15 h, by which time analysis by thin-layer chromatography indicated the absence of starting in the society. The reaction mixture was then concentrated in vacuo to remove ethanol. The residue was diluted with water (100 ml) and was extracted with diethyl ether (1×150 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×150 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid (4,99 g, 86%) as a solid white color: tPL164-166°C; EI-SVR m/e calculated for C17H22O4S (M+N)+322,1239 found 322,1237.

A solution of triphenylphosphine (8,08 g, 30.8 mmole) in methylene chloride (100 ml) was cooled to 0°and then was treated with N-bromosuccinimide (5,48 g, 30.8 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cycloheptyl-2-(4-methanesulfonyl)acrylic acid (equal to 4.97 g, 15,41 mmole) in methylene chloride (20 ml). A clear solution was stirred 15 min at 0°and then gave him to warm up to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (4,63 g, 46,23 mmole) and the resulting suspension re exively 2 days at 25° C. the Reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (250 ml) and 1 N. aqueous solution of hydrochloric acid (150 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×150 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×250 ml) and saturated aqueous sodium chloride (1×200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 5/1-3/2 hexane/ethyl acetate) led to (E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic (2.7 g, 43%) as amorphous solids. This compound was dissolved in acetonitrile (~55 ml) and kept overnight at 25°C. the Solid was filtered and washed with acetonitrile (5 ml), was obtained (E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic (2.1 g, 33%) as a crystalline solid: tPL163-165°C; EI-SVR m/e calculated for C20H24N2O3S2(M+) 404,1253 found 404,1251.

Example 6

(E)-3-Cyclooctyl-2-(4-methanesulfonyl)-N-thiazol-2-ylacrylic

A mixture of magnesium metal (1,94 g, 80 mmol) and anhydrous tetrahydrofuran (3 ml) was treated according to the argon with a solution of 1,2-dibromethane (0.56 g, 3 mmole) in anhydrous tetrahydrofuran (2 ml). The resulting reaction mixture was stirred for 10 minutes to activate the metal magnesium. The reaction mixture was then treated dropwise with a solution of cyclooctylamine (of 7.64 g, 40 mmol) in anhydrous tetrahydrofuran (15 ml), one-fifth part within 5 minutes the resulting reaction mixture was stirred for 5-10 min to initiate the exothermic reaction. The remaining part of the solution cyclooctylamine was then added dropwise, maintaining the internal temperature below 50°C. After complete addition the solution was stirred 1 h and then was diluted with anhydrous tetrahydrofuran (30 ml). In a separate reaction flask a mixture of lithium chloride (3,39 g, 80 mmol, previously dried at 130°C in high vacuum for 3 h) and copper cyanide (3.58 g, 40 mmol) in anhydrous tetrahydrofuran (40 ml) was stirred at 25°C in argon atmosphere for 10 min to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with freshly prepared cyclooctylamine. After addition, the reaction mixture was allowed to warm to -10°Since, at this temperature, stirred 5 minutes the resulting reaction mixture was again cooled to -70°and then was treated with methyl ether propionovoi acid (3,02 g, 36 mmol). The reaction to the offer was stirred 15 h at a temperature of from -70 to -50° With and then slowly treated with a solution of iodine (15,22 g, 60 mmol) in anhydrous tetrahydrofuran (15 ml), keeping the temperature from -70 to -60°C. After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, stirred 2 hours, the Reaction mixture was then poured into a solution consisting of a saturated aqueous solution of ammonium chloride (200 ml) and ammonium hydroxide (50 ml)and the organic compound was extracted with ethyl acetate (3×100 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×200 ml) and saturated aqueous sodium chloride (1×200 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 20/1-10/1 hexane/diethyl ether) resulted methyl ether (E)-3-cyclooctyl-2-iodically acid (5,04 g, 43%) as a colorless oil: EI-SVR m/e calculated for C12H19IO2(M+) 322,0430 found 322,0432.

A mixture of zinc dust (1.3 g, 20 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0,38 g, 2 mmole). The zinc suspension was then heated to a rapid boil with jet air Sushil is, was allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (220 mg, 2 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclooctyl-2-iodically acid (3,22 g, 10 mmol) in anhydrous tetrahydrofuran (4 ml) for 10 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (8 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred under argon for 10 min at 25°bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmole) and triphenylphosphine (260 mg, 1 mmol) in anhydrous tetrahydrofuran (10 ml) and then was treated with 4-bromophenylacetate (2,12 g, 9 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 50°C for 24 h, the Reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (100 ml) and the organic compound was extracted with ethyl acetate (3×75 ml). Volume is yennie organic extracts were washed with saturated aqueous solution of sodium chloride (1× 200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 4/1-1/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclooctyl-2-(4-methanesulfonyl)acrylic acid (2.85 g, 90%) as a semi-solid substance light yellow color: EI-SVR m/e calculated for C19H26O4S (M+) 350,1552 found 350,1554.

A solution of methyl ester (E)-3-cyclooctyl-2-(4-methanesulfonyl)acrylic acid (2,82 g, 8,05 mmole) in ethanol (30 ml) was treated with 1 N. aqueous sodium hydroxide solution (20 ml). The solution was heated at 45-50°C for 15 h, by which time analysis by thin-layer chromatography indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (100 ml) and was extracted with diethyl ether (1×75 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×150 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclooctyl-2-(4-methanesulfonyl)acrylic acid (2.64 g, 97%) as a solid which substances pale yellow: EI-SVR m/e calculated for C 18H24O4S (M+) 336,1395 found 336,1390.

A solution of triphenylphosphine (2,09 g, 8 mmol) in methylene chloride (25 ml) was cooled to 0°and then was treated with N-bromosuccinimide (1.42 g, 8 mmol). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclooctyl-2-(4-methanesulfonyl)acrylic acid (1,345 g, 4 mmole) in methylene chloride (10 ml). A clear solution was stirred 15 min at 0°and then gave him to warm up to 25°Since, at this temperature it was stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (1.2 g, 12 mmol) and the resulting suspension was stirred 2 days at 25°C.

The reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (100 ml) and 1 N. aqueous solution of hydrochloric acid (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×150 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 5/1-3/2 hexane/ethyl acetate) led to (E)-3-cyclooctyl-2-(4-methanesulfonyl)-N-thiazol-2-and is the acrylamide (1.22 g, 73%) as an amorphous solid: EI-SVR m/e calculated for C21H26N2O3S2(M+) 418,1385 found 418,1385.

Example 7

(E)-N-(5-Bromothiazole-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl)acrylamide

A suspension of (E)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia (obtained in example 3 3,044 g at 1.17 mmole) and N-bromosuccinimide (0.20 g, of 1.17 mmole) in carbon tetrachloride (4 ml) at 25°was treated with benzoyl peroxide (14,17 mg, 0,058 mmole). The resulting mixture was heated to 90°Since, at this temperature, was stirred over night. The reaction mixture was allowed to cool to 25°and then concentrated in vacuum. The residue was dissolved in ethyl acetate (50 ml). The organic phase is then washed with water (1×50 ml) and saturated aqueous sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1-1/1 hexane/ethyl acetate) led to (E)-N-(5-bromothiazole-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl)acrylamide (115 mg, 22%) as a solid white color: tPL202-205 are°C.

Example 8

(E)-3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylacrylic

A mixture of aluminum chloride (value of 16,81 g, 126,05 mmol who) in methylene chloride (105 ml) was cooled to 5° C and was stirred to dissolve the solids. The reaction mixture was then slowly treated with methylacetylene (8.1 ml, 88,24 mmole) and the resulting reaction mixture was stirred at 5°C for 30 minutes. The reaction mixture was then slowly treated with 1,2-dichlorobenzene (12,35 g, 84,04 mmole). The resulting reaction mixture was allowed to warm to 25°Since, at this temperature it was stirred for 6 hours the Reaction mixture is then kept at 0°C for 15 hours, the Reaction mixture was slowly poured into ice/water (400 ml). The layers were shaken and separated. The aqueous layer was further extracted with methylene chloride (1×200 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (1×200 ml) and water (1×100 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) led to methyl ether (3,4-dichlorophenyl)octoxynol acid (0,78 g, 4%) as a solid yellow: tPL58,2-63°C; EI-SVR m/e calculated for C9H6CL2O3(M+) 231,9694 found 231,9699.

A suspension of iodine cyclopentanoperhydrophenanthrene (obtained in example 3 of 3.95 g of 8.37 mmole) in anhydrous tetrahydrofuran (10 ml) was cooled to 0°and then was treated dropwise a 1.0 m solution of bis(t is Immission)sodium amide (8,4 ml, of 8.37 mmole). The reaction mixture is bright orange color was stirred at 0°C for 45 minutes the Reaction mixture is then treated with a solution of methyl ester (3,4-dichlorophenyl)octoxynol acid (1.30 grams, to 5.58 mmole) in tetrahydrofuran (4 ml). The resulting reaction mixture was allowed to warm to 25°Since, at this temperature, was stirred for 64 hours. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The residue was diluted with water (150 ml) and then was extracted with diethyl ether (1×200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 70-230 mesh, 19/1 hexane/ethyl acetate) led to methyl ether 3-cyclopentyl-2-(3,4-dichlorophenyl)acrylic acid (821,1 mg, 49%) as a yellow oil consisting of a mixture of (E):(Z)-isomers in the ratio of 4.5:1. The mixture of isomers was used without further separation and identification.

A solution of the isomeric mixture of methyl ester of 3-cyclopentyl-2-(3,4-dichlorophenyl)acrylic acid [821,1 mg, is 2.74 mmole, (E):(Z)=4,5:1] in tetrahydrofuran (3.4 ml) was treated with 0.8 M aqueous solution of lithium hydroxide (3.4 ml, is 2.74 mmole). The reaction mixture was stirred at 25°C for 17 h and then boiled under reflux 4 h the Reaction mixture was allowed to cool to 25°and then it was concentrated vacuume to remove tetrahydrofuran. The remaining aqueous layer was acidified to pH=2 with 10%aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 70-230 mesh, 1/1 hexane/ethyl acetate) led to pure (E)-3-cyclopentyl-2-(3,4-dichlorophenyl)acrylic acid (205,4 mg, 26%) as a solid white color: tPL119-120°C; EI-SVR m/e calculated for C14H14CL2About2(M+) 284,0371 found 284,0370.

A solution of (E)-3-cyclopentyl-2-(3,4-dichlorophenyl)acrylic acid (73,9 mg of 0.26 mmole), hexaflurophosphate O-benzotriazol-1-yl-N,N,N′,N′-tetramethylurea (108,1 mg of 0.29 mmole) and N,N-diisopropylethylamine (136 μl, 0,78 mmole) in anhydrous N,N-dimethylformamide (1.3 ml) was stirred at 25°C for 15 min and then was treated with 2-aminothiazole (51.9 mg, of 0.52 mmole). The resulting reaction mixture was stirred at 25°C for 21 hours, the Reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The residue was then diluted with ethyl acetate (100 ml). The organic layer is washed with 10%aqueous solution of hydrochloric acid (1×100 ml), saturated aqueous sodium bicarbonate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The body is ical layer was dried over sodium sulfate, was filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 70-230 mesh, 4/1 hexane/ethyl acetate) led to two isomeric products. A product with a higher value of Rfconsistent with the desired (E)-3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-ylacrylic (15.3 mg, 16%), allocated in the form of a solid waxy substance white: tPL57-59°C; EI-SVR m/e calculated for C17H16CL2N2OS (M+) 366,0360 found 366,0360.

Example 9

(E)-2-(3-Chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic

A solution of aluminum chloride (34.8 g, 261,4 mmole) in chloroform (120 ml) in an argon atmosphere was cooled to 0°and then was added dropwise a solution of ETHYLACETYLENE (18.7 ml, 167,5 mmol) in chloroform (120 ml). The reaction mixture was stirred at 0°C for 30 min and then treated dropwise with a solution of 2-chloroanisole (25,0 g, 156,5 mmole) in chloroform (120 ml). The resulting reaction mixture has acquired a red color. The reaction mixture was allowed to warm to 25°Since, at this temperature, stirred for an additional 3.5 hours, the Reaction mixture was then slowly mixed with water (500 ml) and after addition of water the reaction mixture was bought yellow color. The resulting solution then was extracted with chloroform (3×50 ml). the content of inorganic fillers phase was dried over sodium sulfate, was filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 80/20 hexane/ethyl acetate) led to ethyl ether (3-chloro-4-methylsulfinylphenyl)octoxynol acid (31,37 g, 77%) as a yellow oil.

A suspension of iodine cyclopentanoperhydrophenanthrene (obtained in example 3, 725 mg, 1,53 mmole) in tetrahydrofuran (10 ml) was cooled to 0°and then was treated with 1.0 M solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran (2,14 ml, and 2.14 mmole). The resulting reaction mixture red was stirred 45 min at 0°and then slowly treated with a solution of ethyl ester (3-chloro-4-methylsulfinylphenyl)octoxynol acid (355 mg, of 1.37 mmole) in tetrahydrofuran (5 ml). The reaction mixture was heated to 25°Since, at this temperature, was stirred for 20 hours the Reaction mixture was then diluted with water (50 ml) and was extracted with diethyl ether (3×25 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (Flash 12M, silica, 80/20 hexane/ethyl acetate) led to ethyl ether, 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylacetic acid (267 mg, 60%) as a yellow oil consisting of a mixture of 2:1 (E):(Z)-isomers. The isomer mixture is used without further separation and Ident is the codification.

Solution mixture of isomers of ethyl ester of 2-(3-chloro-4-methylsulfinylphenyl)-3-cyclopentylacetic acid [100 mg, 0.31 in mmole, (E):(Z)=2:1] in methylene chloride (5 ml) was cooled to 0°and then was treated with 3-chlormadinone acid (content of 80%, 157 mg, advanced 0.729 mmole). The reaction mixture was stirred at 0°C for 3.5 h and then diluted with methylene chloride (25 ml). The organic phase is washed with saturated aqueous sodium carbonate (2×10 ml) and saturated aqueous sodium chloride (2×10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (Flash 12M, silica, 80/20 hexane/ethyl acetate) led to ethyl ether, 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid (95 mg, 86%) as a colorless oil consisting of a mixture of 2:1 (E):(Z)-isomers. The mixture of isomers was used without further separation and identification.

Solution mixture of isomers of ethyl ester of 2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid [500 mg, of 1.40 mmole, (E):(Z)=2:1] in ethanol (16 ml) was treated with a solution of potassium hydroxide (393,6 mg, 7,00 mmol) in water (3,7 ml). The yellow solution was stirred 3 hours at 25°and then concentrated in vacuo to remove ethanol. The remaining aqueous layer was acidified using 1 N. aqueous solution of hydrochloric sour the s to pH=2 and then was extracted with methylene chloride (3× 15 ml). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 75/25 hexane/ethyl acetate plus 1% acetic acid) gave (E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid (458 mg, 99%, 95% of E-isomer) as a foamy substance white: FAB-MCBP m/e calculated for C15H17ClO4S (M+N)+329,0614 found 329,0628.

A solution of triphenylphosphine (120 mg, and 0.46 mmole) in methylene chloride (5 ml) was cooled to 0°and then slowly treated with N-bromosuccinimide (92 mg, 0.52 in mmole). The reaction mixture was stirred at 0°as long as the reaction mixture became homogeneous. The resulting reaction mixture is light purple color then was treated with (E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentylacetic acid (100 mg, 0.30 mmole) and the reaction mixture was stirred at 0°C for 20 minutes the Reaction mixture was then allowed to warm to 25°Since, at this temperature, stirred 30 minutes then the reaction mixture was treated with 2-aminothiazole (46 mg, and 0.46 mmole) and pyridine (0,044 ml, 0.55 mmole) and the resulting the reaction mixture was stirred at 25°C for 16 hours the Reaction mixture was then diluted with water (10 ml) and was extracted with methylene chloride (3×15 ml)Obyedinenie organic layers were dried over sodium sulfate, was filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 70/30 hexane/ethyl acetate) led to (E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic (63 mg, 50%) as a yellow oil: EI-SVR m/e calculated for C18H19ClN2O3S2(M+) 410,0526 found 410,0529.

Example 10

(E)-2-(3-Bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic

The solution isoamylamine (of 8.06 ml, 60 mmol) in dimethyl disulfide (36,02 ml, 400 mmol) at 25°was slowly treated with 2,4-dibromoanisole (4.8 g, 20 mmol). The reaction proceeded exothermically with evolution of gas. The resulting reaction mixture brown was heated to 80-90°C for 2 h, by which time analysis of the reaction mixture using thin-layer chromatography indicated the absence of starting material. The reaction mixture was cooled to 25°and then concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (200 ml). The organic layer was washed successively 1 N. aqueous solution of hydrochloric acid (1×200 ml) and saturated aqueous sodium chloride (1×200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Cleaning with the use of a layer of silica gel (silica gel 60 is Irma Merck, 230-400 mesh mesh, 4/1 hexane/ethyl acetate) led to 2,4-dibromoanisole (11,04 g, 99%) as a brown oil: EI-SVR m/e calculated for C7H6VG2S (M+) 279,8623 found 279,8619.

A solution of 2,4-dibromoanisole (11,04 g, 39,15 mmole) in methylene chloride (280 ml) was cooled to -10°and then was treated with 3-chlormadinone acid (the content of 86%, 20,26 g, 117,4 mmole). The reaction mixture was stirred at -10°C for 10 min and then gave her to warm up to 25°Since, at this temperature, was stirred over night. By this time, the analysis of the reaction mixture using thin layer chromatography indicated the absence of starting material. The reaction mixture is then filtered and the solid residue washed with methylene chloride (1×100 ml). The filtrate was then diluted 1 N. solution of sodium hydroxide (100 ml) and the two layers were separated. The organic layer was concentrated in vacuum, received a solid brown color. Solid brown was dissolved in ethyl acetate (200 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain a syrup. This syrup was treated with diethyl ether and hexane to receive the Oia solid white. The resulting solid was collected by filtration, received 2,4-dibromoindigotin (10.3 g, 84%) as a solid white color: tPL124-126°C; EI-SVR m/e calculated for C7H6VG2O2S (M+) 311,8455 found 311,8455.

A mixture of lithium chloride (8,48 g, 200 mmol, previously dried at 130°C in high vacuum for 2 h) and copper cyanide (8,96 g, 100 mmol) in anhydrous tetrahydrofuran (100 ml) was stirred at 25°C under argon for 10 min to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with a 2 M solution of cyclopentylamine in diethyl ether (55 ml, 110 mmol). After addition, the reaction mixture was allowed to warm to -30°and at this temperature, stirred 5 minutes the resulting reaction mixture was again cooled to -70°and then slowly treated with methyl ether propionovoi acid (7,99 g, 95 mmol). The reaction mixture was stirred at a temperature of from -60 to -50°C overnight and then was cooled to -70 - -60°C, at this time, the reaction mixture was slowly treated with a solution of iodine (34.3 g, 135 mmol) in anhydrous tetrahydrofuran (30 ml). After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, stirred 2 h Then d is Klenow mixture was poured into a solution, containing a saturated aqueous solution of ammonium chloride (200 ml) and ammonium hydroxide (50 ml)and the organic compound was extracted with diethyl ether (3×100 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×300 ml) and saturated aqueous sodium chloride (1×300 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 20/1 hexane/diethyl ether) resulted methyl ether (E)-3-cyclopentyl-2-iodically acid (25,8 g, 97%) as a yellow oil: EI-SVR m/e calculated for C9H13IO2(M+) 279,9960 found 279,9961.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (1 ml) was treated in an argon atmosphere 1,2-dibromethane (187 mg, 1.5 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (108 mg, 1 mmol) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-C is clopotel-2-iodically acid (660 mg, 2.25 mmole) in anhydrous tetrahydrofuran (2 ml) for 3 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (4 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone)palladium (0) (37 mg, 0.07 mmole) and triphenylphosphine (72 mg, 0.3 mmole) in anhydrous tetrahydrofuran (6 ml) at 25°C in an atmosphere of argon for 10 min and then was treated with 2,4-dibromopropylsulfonyl (of 1.05 g, 3.5 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated at 40-45°With over the weekend at the end of the week. The reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (50 ml)and the organic compound was extracted with ethyl acetate (3×35 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 5/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclopentyl-2-(3-bromo-4-metasolv ylphenyl)acrylic acid (1,03 g, 77,6%) in the form of oil is light yellow in color.

A solution of methyl ester (E)-3-cyclopentyl-2-(3-bromo-4-methanesulfonyl)acrylic acid (357 mg, of 0.92 mmole) in ethanol (6 ml) was treated with 1 N. aqueous solution of sodium hydroxide (2 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 ml) and was extracted with diethyl ether (1×30 ml) to remove any neutral impurities. The aqueous layer was then acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclopentyl-2-(3-bromo-4-methanesulfonyl)acrylic acid (339 g, 98%) as an amorphous solid: EI-SVR m/e calculated for C15H17BrO4S (M+) 372,0031 found 372,0028.

A solution of triphenylphosphine (467 mg, of 1.78 mmole) in methylene chloride (8 ml) was cooled to 0°and then was treated with N-bromosuccinimide (317 mg, of 1.78 mmole). The reaction mixture was stirred at 0°C for 30 min is then treated with a solution of (E)-3-cyclopentyl-2-(3-bromo-4-methanesulfonyl)acrylic acid (334 mg, to 0.89 mmole) in methylene chloride (4 ml). The reaction mixture was stirred 15 min at 0°and then was allowed to warm to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (713 mg, 7,12 mmol) and the resulting suspension was stirred 2 days at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (40 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×25 ml). The combined organic extracts are successively washed with 1 N. aqueous solution of hydrochloric acid (1×50 ml), saturated aqueous sodium bicarbonate (1×50 ml) and saturated aqueous sodium chloride (1×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 3,1 hexane/ethyl acetate) led to pure (E)-2-(3-bromo-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic (71 mg; 17,5%) as amorphous solid white color: EI-SVR m/e calculated for C18H19BrN2O3S2(M+) 454,0020 found 454,0025.

Example 11

(E)-3-Cyclohexyl-2-(3,4-differenl)-N-thiazol-2-ylacrylic

A mixture of zinc dust (980 mg, 15 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0,37 g, 2 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (82 mg, 0.75 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (obtained in example 4, 1.47 g, 5 mmol) in anhydrous tetrahydrofuran (1.5 ml) for 3 minutes. During the addition the temperature rose to 45°C. the Reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (5 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in anhydrous tetrahydrofuran (10 ml) at 25°C under argon for 10 min and then was treated with 3,4-dipterigena (960 mg, 4 mmole) and freshly prigotovlennym zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 15 h at 25°With, by this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride (50 ml) and the organic compound was extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 5/1 hexane/diethyl ether) resulted methyl ether (E)-3-cyclohexyl-2-(3,4-differenl)acrylic acid (1.06 g, 95%) as an oil: EI-SVR m/e calculated for C16H18F2O2(M+) 280,1275 found 280,1275.

A solution of methyl ester (E)-3-cyclohexyl-2-(3,4-differenl)acrylic acid (0.55 g, 1.97 mmole) in ethanol (10 ml) was treated with 1 N. aqueous solution of sodium hydroxide (4 ml). The solution was heated at 40°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove the ethanol, the residue was diluted with water (30 ml) and then acidified 1 N. water R is the target of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(3,4-differenl)acrylic acid (0.51 g, 97%) as a solid white color: tPL119-121°C; EI-SVR m/e calculated for C15H16F2O2(M+H)+267,1196 found 267,1200.

A solution of triphenylphosphine (847 mg, 3.2 mmole) in methylene chloride (10 ml) was cooled to 0°and then was treated with N-bromosuccinimide (575 mg, 3.2 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(3,4-differenl)acrylic acid (507 mg, 1.9 mmole) in methylene chloride (4 ml). A clear solution was stirred 10 min at 0°and then was allowed to warm to 25°Since, at this temperature it was stirred 1 h, the Reaction mixture was then treated with 2-aminothiazole (476 mg, 4.75 mmole) and the resulting suspension was stirred 15 h at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (75 ml). The organic layer is successively washed with 1 N. aqueous solution of hydrochloric acid (2×30 ml), saturated aqueous rest the rum sodium bicarbonate (2× 30 ml) and saturated aqueous sodium chloride (1×50 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 8/1-4/1 hexane/ethyl acetate) led to (E)-3-cyclohexyl-2-(3,4-differenl)-N-thiazol-2-ylacrylic (520 mg; 78%) as amorphous solid substances: EI-SVR m/e calculated for C18H18F2N2OS (M+) 348,1108 found 348,1104.

Example 12

(E)-3-Cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylacrylic

The solution isoamylamine (as 4.02 ml, 30 mmol) in dimethyl disulfide (19,8 ml, 220 mmol) at 25°was slowly treated with 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction proceeded exothermically with evolution of gas. The resulting reaction mixture brown was heated to 80-90°C for 2 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was cooled to 25°and then concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (200 ml). The organic layer was washed successively 1 N. aqueous solution of hydrochloric acid (1×200 ml) and saturated aqueous sodium chloride (1#x000D7; 200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40, silicon dioxide, 8/1 hexane/ethyl acetate) led to 4-bromo-1-methylsulfanyl-2-triptoreline (4,73 g, 87%) as a brown oil: EI-SVR m/e calculated for C8H6rF3S (M+) 269,9326 found 269,9327.

A solution of 4-bromo-1-methylsulfanyl-2-triptoreline (4.71 g, to 17.4 mmole) in methylene chloride (100 ml) was cooled to -10°and then was treated with 3-chlormadinone acid (the content of 86%, 9.0 g, 52,2 mmole). The reaction mixture was stirred at -10°C for 10 min and then was allowed to warm to 25°Since, at this temperature, was stirred over night. By this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture is then filtered and the solid residue washed with methylene chloride (1×50 ml). The filtrate was concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (100 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum, received a solid yellow color. P is recrystallization from methylene chloride (20 ml), diethyl ether (10 ml) and hexanol led to 4-bromo-1-methanesulfonyl-2-triptoreline (of 3.46 g, 57%) as a solid white color: tPL110-112°C; EI-SVR t/f calculated8H6rF3About2S (M+) 301,9224 found 301,9223.

A mixture of zinc dust (1.3 g, 20 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (2 ml) was treated in an argon atmosphere 1,2-dibromethane (187 mg, 1 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (110 mg, 1 mmol) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (obtained in example 4, 2.5 g, 8.5 mmol) in anhydrous tetrahydrofuran (3 ml) for 5 minutes. After addition, the reaction mixture was stirred at 40-45°C for 1 h and then stirred overnight at 25°C.

The reaction mixture was then diluted with anhydrous tetrahydrofuran (4 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred under argon 10min at 25° With bis(dibenzylideneacetone)palladium(0) (108 mg, 0.2 mmole) and triphenylphosphine (209 mg, 0.8 mmole) in anhydrous tetrahydrofuran (10 ml) and then was treated with 4-bromo-1-methanesulfonyl-2-triftorperasin (2,12 g, 7 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 2 days at 40-45°C. the Reaction mixture was cooled to 25°C, then poured into saturated aqueous solution of ammonium chloride (100 ml) and the organic compound was extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 9/1-3/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (2.7 g, 99%) as a viscous oil: EI-SVR m/e calculated for C18H21F3O4S (M+) 391,1191 found 391,1200.

A solution of methyl ester (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (1.8 g, 4.6 mmole) in ethanol (20 ml) was treated with 1 N. aqueous solution of sodium hydroxide (15 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture with what omashu thin-layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove the ethanol, the residue was diluted with water (40 ml) and then was extracted with diethyl ether (1×50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (1,74 g, 99%) as a solid white color: tPL62-64°C; EI-SVR m/e calculated for C17H19F3O4S (M+N)+377,1034 found 377,1041.

A solution of triphenylphosphine (1.39 g, 5.3 mmole) in methylene chloride (50 ml) was cooled to 0°and then was treated with N-bromosuccinimide (0,94 g, 5.3 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (1,00 g of 2.66 mmole) in methylene chloride (10 ml). A clear solution was stirred 15 min at 0°and then gave him to warm up to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (800 mg, 7,98 mmole) and p is obtained as a result of the suspension was stirred 2 days at 25° C. the Reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (100 ml) and 1 N. aqueous solution of hydrochloric acid (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are successively washed with 1 N. aqueous solution of hydrochloric acid (1×100 ml), saturated aqueous sodium bicarbonate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 5/1-3/2 hexane/ethyl acetate) led to (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylacrylic (367 mg, 30%) as an amorphous solid: EI-SVR m/e calculated for C20H21F3N2About3S2(M+) 458,0946 found 458,0947.

Example 13

(E)-N-(5-Bromothiazole-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide

A suspension of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-alacrimia (obtained in example 12, 150 mg of 3.27 mmole) and N-bromosuccinimide (69 mg, 0384 mmole) in carbon tetrachloride (2 ml) at 25°was treated with benzoyl peroxide (4,65 mg, 0.02 mmole). According to the scientists in the reaction mixture was heated to 90° Since, at this temperature, was stirred over night. The reaction mixture was allowed to cool to 25°and then concentrated in vacuum. The residue was dissolved in ethyl acetate (25 ml). The organic phase is then washed with water (1×30 ml) and saturated aqueous sodium chloride (1×30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 4/1 hexane/ethyl acetate) led to (E)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide (59 mg, 33%) as amorphous solid white color.

Example 14

(E)-3-Cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylacrylic

The solution isoamylamine (2,01 ml, 15 mmol) in dimethyl disulfide (9,9 ml, 110 mmol) at 25°was slowly treated with 4-bromo-2-nitroaniline (2.17 g, 10 mmol). The reaction proceeded exothermically with evolution of gas. The resulting reaction mixture brown was heated to 80-90°C for 2 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was cooled to 25°and then concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (100 ml). Organic is Loy was washed successively 1 N. aqueous solution of hydrochloric acid (1×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 6/1-5/1, hexane/ethyl acetate) led to 5-bromo-2-dimethoxybenzene (1.9 g, 76%) as a solid brown color: EI-SVR m/e calculated for C7H6BrNO2S (M+) 246,9372 found 246, 9368.

A solution of 5-bromo-2-dimethoxyethane (1,37 g, 5.5 mmole) in methylene chloride (40 ml) was cooled to -10°and then was treated with 3-chlormadinone acid (the content of 86%, 2,80 g, 16,56 mmole). The reaction mixture was stirred at -10°C for 10 min and then was allowed to warm to 25°Since, at this temperature, stirred 2 hours By this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (100 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40 M, TLD is CIS silicon, 3/1 hexane/ethyl acetate) led to the crude 4-bromo-2-nitrophenylacetylene (1.5 g) as a solid. This solid was dissolved in methylene chloride, treated with hexane and then filtered to obtain pure 4-bromo-2-nitrophenylacetylene (0,98 g, 63%) as a solid white color: tPL175-177°C; EI-SVR m/e calculated for C7H6rNO4S (M+) 278,9201 found 278,9210.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (1 ml) was treated in an argon atmosphere 1,2-dibromethane (187 mg, 1 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (110 mg, 1 mmol) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (obtained in example 4, 1.2 g, 4.2 mmole) in anhydrous tetrahydrofuran (2 ml) for 5 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (4 is l) and stirring was stopped, to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred under argon for 10 min at 25°bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in anhydrous tetrahydrofuran (4 ml) and then was treated with 4-bromo-2-nitrophenylacetylene (0,94 g, at 3.35 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 15 h at 50°C. the Reaction mixture then was cooled to 25°C, then poured into saturated aqueous ammonium chloride solution (70 ml) and the organic compound was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 9/1-3/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)acrylic acid (1 g, 82%) as amorphous solid white color: EI-SVR m/e calculated for C17H21NO6S (M+) 367,1090 found 367,1091.

A solution of methyl ester (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitro phenyl)acrylic acid (597 mg, of 1.62 mmole) in ethanol (10 ml) was treated with 1 n aq is m solution of sodium hydroxide (8 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol. The residue was diluted with water (20 ml) and then was extracted with diethyl ether (1×50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)acrylic acid (0,514 g, 90%) as a solid white color: tPL244-247°C; EI-SVR m/e calculated for C16H19NO6S (M+) 353,0933 found 353,0929.

A solution of triphenylphosphine (720 mg, of 2.75 mmole) in methylene chloride (25 ml) was cooled to 0°and then was treated with N-bromosuccinimide (490 mg, of 2.75 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)acrylic acid (485 mg, of 1.37 mmole) in methylene chloride (5 ml). The reaction mixture was stirred 15 min at 0&#HWS and then gave her to warm up to 25° Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (412 mg, 4,12 mmole) and the resulting suspension was stirred 2 days at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (70 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are successively washed with 1 N. aqueous solution of hydrochloric acid (1×100 ml), saturated aqueous sodium bicarbonate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 5/1-3/2 hexane/ethyl acetate) led to (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-ylacrylic (122 mg, 20%) as an amorphous solid: EI-SVR m/e calculated for C19H21N3O5S2(M+) 435,0923 found 435,0923.

Example 15

(E)-2-(3-Chloro-4-methysulfonylmethane)-3-cyclohexyl-N-thiazol-2-ylacrylic

A suspension of 2-chloro-4-iodotoluene (EUR 7.57 g, 30 mmol) and N-bromosuccinimide (5.34 g, 30 mmol) in carbon tetrachloride (40 m is) was treated with benzoyl peroxide (0.3 g, 1.2 mmole). The reaction mixture then was heated at 90°C for 15 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture then was cooled to 25°and concentrated in vacuum. The resulting residue pink was dissolved in ethyl acetate (200 ml). The organic layer was washed successively with water (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, hexane) led to methyl 2-chloro-4-iodobenzene (4.83 g, 48%) as a solid white color: tPL44-45,5°C; EI-SVR m/e calculated for C7H5rlI (M+) 329,8308 found 329,8319.

A solution of methyl 2-chloro-4-iodobenzyl (4,82 g, 14,54 mmole) in N,N-dimethylformamide (30 ml) was treated with timedelta sodium (2,04 g, 29,08 mmole). After addition the solution became turbid and was acquired by yellow color. The resulting reaction mixture was stirred 3 h at 25°C. the Reaction mixture then was diluted with ethyl acetate (100 ml). The organic layer was sequentially washed with water (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous sulfate MAGN what I was filtered and concentrated in vacuum was obtained 2-chloro-4-iodobenzylamine (4,24 g, 97%) as a colourless oil which was used without further purification: EI-SVR m/e calculated for C8H8ClIS (M+) 297,9080 found 297,9078.

A solution of 2-chloro-4-iodobenzaldehyde (4,24 g, 14.2 mmole) in methylene chloride (100 ml) was cooled to -5°and then was treated with 3-chlormadinone acid (the content of 86%, 7,35 g, 42,6 mmole). The reaction mixture was stirred at -5°C for 15 min and then was allowed to warm to 25°Since, at this temperature, the mixture was stirred 3 hours At this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The solid precipitate was filtered and then washed with methylene chloride (1×50 ml). The filtrate is then concentrated in vacuum and the resulting residue was dissolved in a mixture of ethyl acetate (20 ml) and diethyl ether (100 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (2×100 ml), saturated aqueous solution of sodium bisulfite (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 10/1/10 hexane/e is ylacetic/methylene chloride) gave 2-chloro-4-iodobenzenesulfonyl (3,67 g, 78%) as a solid white color: tPL125-127°C; EI-SVR m/e calculated for C8H8ClIO2S (M+) 329,8979 found 329,8969.

A mixture of zinc dust (650 mg, 10 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (2 ml) was treated in an argon atmosphere 1,2-dibromethane (187 mg, 1 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (110 mg, 1 mmol) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (obtained in example 4 of 1.17 g, 4 mmole) in anhydrous tetrahydrofuran (2 ml) for 5 minutes. The reaction mixture was then stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (4 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred under argon for 10 min at 25°bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in anhydrous tetrahydrofur the Ana (4 ml) and then was treated with 2-chloro-4-iodobenzenesulfonyl of 0.85 g, to 2.57 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 2 days at 50°C. the Reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (50 ml)and the organic compound was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 9/1-3/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-(3-chloro-4-(methylene)methylsulfinylphenyl)acrylic acid (0,94 g, 98%) as amorphous solid white color: EI-SVR m/e calculated for C18H23ClO4S (M+) 370,1005 found 370,1001.

A solution of methyl ester (E)-3-cyclohexyl-2-(3-chloro-4-(methylene)methylsulfinylphenyl)acrylic acid (887 mg, 2.4 mmole) in ethanol (10 ml) was treated with 1 N. aqueous solution of sodium hydroxide (8 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol. The remainder of resbala and water (20 ml) and was extracted with diethyl ether (1× 50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid and the resulting acid was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(3-chloro-4-(methylene)methylsulfinylphenyl)acrylic acid (0,847 g, 99%) as a solid white color: tPL105-108°C; EI-SVR m/e calculated for C17H21ClO4S (M+) 356,0849 found 356,0844.

A solution of triphenylphosphine (1.23 g, 4,69 mmole) in methylene chloride (15 ml) was cooled to 0°and then was treated with N-bromosuccinimide (830 mg, 4,69 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(3-chloro-4-(methylene)methylsulfinylphenyl)acrylic acid (837 mg, of 2.34 mmole) in methylene chloride (6 ml). The reaction mixture was stirred 15 min at 0°and then gave her to warm up to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (702 mg, 7,02 mmole) and the resulting suspension was stirred 2 days at 25°C. the Reaction mixture was then concentrated in vacuo to remove methylene chloride and the remainder is abbasli with ethyl acetate (70 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are successively washed with 1 N. aqueous solution of hydrochloric acid (1×100 ml), saturated aqueous sodium bicarbonate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 5/1 - 3/2 hexane/ethyl acetate) led to pure (E)-2-(3-chloro-4-methysulfonylmethane)-3-cyclohexyl-N-thiazol-2-ylacrylic (596 mg, 58%) as a solid white color: tPL218 to 221 C; EI-SVR m/e calculated for C20H23ClN2O3S2(M+) 438,0839 found 438,0834.

Example 16

(E)-N-(5-Bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl)acrylamide

A suspension of (E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia (obtained in example 5, 202 mg, 0.5 mmole) and N-bromosuccinimide (89 mg, 0.5 mmole) in carbon tetrachloride (2 ml) at 25°was treated with benzoyl peroxide (6 mg, of 0.025 mmole). The resulting reaction mixture was heated to 90°C and stirred at this temperature overnight.

The reaction mixture gave quench the change to 25° With and then concentrated in vacuum. The residue was dissolved in ethyl acetate (25 ml). The organic phase is then washed with water (1×30 ml) and saturated aqueous sodium chloride (1×30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1 hexane/ethyl acetate) led to (E)-N-(5-bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl)acrylamide (86 mg, 36%) as a solid white color: tPL159-163°C.

Example 17

(E)-3-Cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylacrylic

A mixture of zinc dust (390 mg, 6 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (1 ml) was treated in an argon atmosphere 1,2-dibromethane (94 mg, 0.5 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (55 mg, 0.5 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-3-cycloheptyl-2-iodically acid (obtained in example 5, 616 mg, 2 mmole) in anhydrous is tetrahydrofuran (2 ml). After addition, the reaction mixture was stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (2 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmole) and triphenylphosphine (52 mg, 0.2 mmole) in anhydrous tetrahydrofuran (4 ml) at 25°C in an atmosphere of argon for 10 min and then was treated with 4-bromo-1-methanesulfonyl-2-triftorperasin (obtained in example 12, 303 mg, 1 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 24 h at 40-45°C. the Reaction mixture then was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (30 ml)and the organic compound was extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1 hexane/ethyl acetate) led to methyl ether (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (387 mg, 9%) as a viscous oil.

A solution of methyl ester (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (387 mg, 0.96 mmole) in ethanol (6 ml) was treated with 1 N. aqueous solution of sodium hydroxide (2 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol and the residue was diluted with water (20 ml) and was extracted with diethyl ether (1×30 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×35 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (g ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (268 mg, 72%) as a solid brown color: tPL151-156°C.

A solution of triphenylphosphine (341 mg, 1.3 mmole) in methylene chloride (7 ml) was cooled to 0°and then was treated with N-bromosuccinimide (231 mg, 1.3 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl who enyl)acrylic acid (255 mg, 0.65 mmole). After stirring 15 min at 0°the reaction mixture became transparent. The transparent solution was allowed to warm to 25°Since, at this temperature it was stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (193 mg, 1,95 mmole) and the resulting suspension was stirred 2 days at 25°C. the Reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (50 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×30 ml). The combined organic extracts are successively washed with 1 N. aqueous solution of hydrochloric acid (1×50 ml), saturated aqueous sodium bicarbonate (1×50 ml) and saturated aqueous sodium chloride (1×50 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 4/1-2/1 hexane/ethyl acetate) led to pure (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-ylacrylic (133 mg, 43%) as amorphous solid substance.

Example 18

(E)-N-(5-Bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide

A suspension of (E)-3-cycloheptyl-2-(4-metasolv the Nile-3-triptoreline)-N-thiazol-2-alacrimia (obtained in example 17, 63 mg of 0.133 mmole) and N-bromosuccinimide (26 mg, 0,146 mmole) in carbon tetrachloride (2 ml) at 25°was treated with benzoyl peroxide (2 mg, 0,006 mmole). The resulting reaction mixture was heated to 90°C and stirred at this temperature overnight. The reaction mixture was allowed to cool to 25°and then concentrated in vacuum. The residue was dissolved in ethyl acetate (25 ml). The organic phase is then washed with water (1×30 ml) and saturated aqueous sodium chloride (1×30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 5/1 hexane/ethyl acetate) led to (E)-N-(5-bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide (of 35.5 mg, 48%) as amorphous solid substance of white color.

Example 19

(E)-2-(3-Chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylacrylic

A solution of triphenylphosphine (266 mg, 1,01 mmole) in methylene chloride (11 ml) was cooled to 0°and then was treated with N-bromosuccinimide (204 mg, 1.15 mmole). The reaction mixture was stirred at 0°until, when the reaction mixture became homogeneous. The resulting reaction mixture is light pink color then treated with a solution of (E)-2-(3-chloro-4-meanswhen fenil)-3-cyclopentylacetic acid (obtained in example 9, 222 mg, 0.68 mmole) and the reaction mixture was stirred 20 min at 0°C. the Reaction mixture was then allowed to warm to 25°Since, at this temperature, stirred 30 minutes, after this time the reaction mixture was treated with 2-aminopyridine (95 mg, 1,01 mmole) and pyridine (0,098 ml, 1,22 mmole) and the resulting reaction mixture was stirred 16 h at 25°C. the Reaction mixture then was diluted with water (10 ml) and was extracted with methylene chloride (3×15 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 75/25 hexane/ethyl acetate) led to (E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-pyridine-2-ylacrylic (70 mg, 25%) as a vitreous solid substances yellow: EI-SVR m/e calculated for C20H21ClN2O3S (M+) 404,0961 found 404,0962.

Example 20

(E)-N-(5-Bromopyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide

A solution of triphenylphosphine (525 mg, 2 mmole) in methylene chloride (12 ml) was cooled to 0°and then was treated with N-bromosuccinimide (356 mg, 2 mmole). The reaction mixture was stirred at 0°C for 30 min and then was treated with (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid is th (obtained in example 12, 376 mg, 1 mmol). The reaction mixture was stirred 15 min at 0°and then gave her to warm up to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-amino-5-bromopyridine (519 mg, 3 mmole) and the resulting suspension was stirred for 3 days at 25°C. the Reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (50 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×30 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×50 ml) and saturated aqueous sodium chloride (1×50 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40S, silica, 4/1-2/1 hexane/ethyl acetate) led to (E)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylamide (44 mg, 8.3 per cent) in the form of a solid amorphous substances: EI-SVR m/e calculated for C22H22rF3N2O3S (M+) 530,0487 found 530,0484.

Example 21

The thiazole-2-alamid (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid

A mixture of zinc dust (to 3.92 g, 60 mmol, the Irma Aldrich, -325 mesh) and anhydrous tetrahydrofuran (4 ml) was treated in an argon atmosphere 1,2-dibromethane (0.56 g, 3 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (0.32 g, 3 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of iodine cyclopentylmethyl (4,2 g, 20 mmol) in anhydrous tetrahydrofuran (7 ml) for 5 minutes During the addition the temperature rose to 50°C, the reaction mixture was stirred at 40-45°With during the night. The reaction mixture then was cooled to 25°and diluted With anhydrous tetrahydrofuran (5 ml). The stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask a mixture of lithium chloride (1.7 g, 40 mmol, previously dried at 130°C in high vacuum for 2 h) and copper cyanide (1,79 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) was stirred 10 min at 25°to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with a freshly prepared solution of zinc with a syringe. After PR is bauleni the reaction mixture was allowed to warm to -30° Since, at this temperature, stirred 5 minutes, the Reaction mixture was again cooled to -70°and then slowly treated with methyl ether propionovoi acid (1.52 g, 18 mmol). The reaction mixture was stirred 4 h at a temperature of from -40 to -30°and then slowly treated with a solution of iodine (6.85 g, 27 mmol) in anhydrous tetrahydrofuran (10 ml), keeping the temperature from -70 to -60°C. After addition of a solution of iodine cooling bath was removed and the reaction mixture was allowed to warm to 25°Since, at this temperature, stirred 1 h, the Reaction mixture was then poured into a solution consisting of a saturated aqueous solution of ammonium chloride (90 ml) and ammonium hydroxide (10 ml), and the organic compound was extracted with diethyl ether (3×50 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 9/1 hexane/diethyl ether) resulted methyl ether (E)-4-cyclopentyl-2-itbut-2-ene acid (4,56 g, 86%) as a colorless oil: EI-SVR m/e calculated for C10H15IO2(M+) 294,0116 found 294,0114.

A mixture of zinc dust (0,98 g, 1 mmol, the firm Aldrich, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0.14 g, 0.75 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (82 mg, 0.75 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-4-cyclopentyl-2-itbut-2-ene acid (1.47 g, 5 mmol) in anhydrous tetrahydrofuran (1.5 ml) for 3 min After the addition, the reaction mixture was stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture then was diluted with anhydrous tetrahydrofuran (5 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in anhydrous tetrahydrofuran (10 ml) for 10 min at 25°C in an atmosphere of argon and then treated with 4-bromophenylacetate (0,94 g, 4 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color red is on brick was heated for 24 h at 50° Since, by this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture then was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (75 ml)and the organic compound was extracted with diethyl ether (3×50 ml). The combined ether extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 3/7 hexane/diethyl ether) resulted methyl ether (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (1.10 g, 86%) as a colorless oil: EI-SVR m/e calculated for C17H22O4S (M+) 322,1235 found 322,1239.

A solution of methyl ester (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (1,00 g, 3.1 mmole) in ethanol (17 ml) was treated with 1 N. aqueous solution of sodium hydroxide (7 ml). The solution was heated at 45-50°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove the ethanol, the residue was diluted with water (30 ml) and was extracted with diethyl ether (1×50 ml) to remove l is any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-envoy acid (0.95 g, 99%) as a solid white color: tPL162 to 165°C; EI-SVR m/e calculated for C16H20O4S (M+H)+309,1160 found 308,1158.

A solution of triphenylphosphine (672 mg, of 2.56 mmole) in methylene chloride (7.5 ml) was cooled to 0°and then was treated with N-bromosuccinimide (456 mg, of 2.56 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (545,5 mg, about 1.47 mmole) in methylene chloride (4 ml). A clear solution was stirred 10 min at 0°and then gave him to warm up to 25°Since, at this temperature, stirred 1 h, the Reaction mixture was then treated with 2-aminothiazole (378 mg, 3,76 mmole) and the resulting suspension was stirred at 25°With over the weekend at the end of the week. The reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (75 ml) and 1 N. water RA is tworoom hydrochloric acid (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1-1/1 hexane/ethyl acetate) led to the thiazole-2-ylamide (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (200 mg, 35%) as a solid white color: tPL173-176°C; EI-SVR m/e calculated for C19H22N2O3S2(M+) 390,1071 found 390,1072.

Example 22

Methyl ester (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-anolamine]thiazole-4-carboxylic acid

A solution of triphenylphosphine (525 mg, 2 mmole) in methylene chloride (25 ml) was cooled to 0°and then was treated with N-bromosuccinimide (355 mg, 2 mmole). The reaction mixture was stirred at 0°C for 30 min and then was treated with (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (obtained in example 21, 308 mg, 1 mmol). A clear solution was stirred 10 min at 0°and then he was allowed to warm to 25°Since, at this temperature, stirred 1 h, the Reaction mixture then is probatively methyl ether 2-aminothiazol-4-carboxylic acid (400 mg, 2,52 mmole) and the resulting suspension was stirred at 25°With over the weekend at the end of the week. The reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (50 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×25 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 3/1-1/1 hexane/ethyl acetate) led to methyl ether (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-anolamine]thiazole-4-carboxylic acid (250 mg, 56%) as a solid white color: tPL85-90°C; EI-SVR m/e calculated for C21H24N2O5S2(M+) 448,1127 found 448, 1117.

Example 23

Ethyl ester of (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-anolamine]thiazole-5-carboxylic acid

A solution of triphenylphosphine (787 mg, 3 mmole) in methylene chloride (40 ml) was cooled to 0°and then was treated with N-bromosuccinimide (534 mg, 3 mmole). The reaction mixture was premesis is if 0° C for 30 min and then was treated with (E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid (obtained in example 21, 462 mg,1.5 mmole). A clear solution was stirred 10 min at 0°and then he was allowed to warm to 25°Since, at this temperature, stirred 1 h, the Reaction mixture was then treated with ethyl ether 2-aminothiazol-5-carboxylic acid (774 mg, 4.5 mmole) and the resulting suspension was stirred at 25°With over the weekend at the end of the week. The reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (70 ml) and 1 N. aqueous solution of hydrochloric acid (70 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 3/1-1/1 hexane/ethyl acetate) led to ethyl ether (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-anolamine]thiazole-5-carboxylic acid (250 mg, 36%) as amorphous solid white color: EI-SVR m/e calculated for C22H26N2O5S2(M+462,1283, found 462.1282.

Example 24

The thiazole-2-alamid (E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid

A mixture of zinc dust (0,98 g, 15 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (3 ml) was treated in an argon atmosphere 1,2-dibromethane (0.14 g, 0.75 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (82 mg, 0.75 mmole) and the suspension was stirred 15 min at 25°C. the Reaction mixture was then treated dropwise with a solution of methyl ester (E)-4-cyclopentyl-2-itbut-2-ene acid (obtained in example 21, 1.47 g, 5 mmol) in anhydrous tetrahydrofuran (1.5 ml) for 3 min After the addition, the reaction mixture was stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (5 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred at 25°C under argon for 10 min bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in betwo the nom tetrahydrofuran (10 ml) and then was treated with 3,4-dipterigena (0.96 g, 4 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 15 h at 25°With, by this time, the analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (50 ml)and the organic compound was extracted with diethyl ether (2×50 ml). The combined ether extracts were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1 hexane/diethyl ether) resulted methyl ether (E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid (0,82 g, 73%) as a viscous oil: EI-SVR m/e calculated for C16H18F2O2(M+) 280,1275 found 280,1275.

A solution of methyl ester (E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid (0,80 g, to 2.85 mmole) in ethanol (14 ml) was treated with 1 N. aqueous solution of sodium hydroxide (6 ml). The solution was heated at 40°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then conc is listed in vacuo to remove ethanol and the residue was diluted with water (30 ml) and then was extracted with diethyl ether (1× 50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×80 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-4-cyclopentyl-2-(3,4-differenl)but-2-envoy acid (0.65 g, 86%) as a colorless oil: EI-SVR m/e calculated for C15H16F2O2(M+N)+267,1196 found 267,1195.

A solution of triphenylphosphine (1,05 g, 4 mmole) in methylene chloride (15 ml) was cooled to 0°and then was treated with N-bromosuccinimide (712 mg, 4 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid (0,63 g, a 2.36 mmole) in methylene chloride (4 ml). A clear solution was stirred 15 min at 0°and then he was allowed to warm to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (0,59 g, 5.9 mmole) and the resulting suspension was stirred at 25°With over the weekend at the end of the week. The reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (100 ml) and 1 N. water R is the target hydrochloric acid (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×50 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 8/1 hexane/ethyl acetate) led to the thiazole-2-ylamide (E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid (435 mg, 53%) as an amorphous solid: EI-SVR m/e calculated for C18H18F2N2OS (M+) 348,1108 found 348,1103.

Example 25

The thiazole-2-alamid (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid

A mixture of zinc dust (0.65 g, 10 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (2 ml) was treated in an argon atmosphere 1,2-dibromethane (140 mg, 0.75 mmole). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (82 mg, 0.75 mmole) and the suspension was stirred 15 min at 25°C. the Reaction is th mixture was then treated dropwise with a solution of methyl ester (E)-4-cyclopentyl-2-itbut-2-ene acid (obtained in example 21, 1,03 g, 3.5 mmole) in anhydrous tetrahydrofuran (1.5 ml) for 3 min After the addition, the reaction mixture was stirred at 40-45°C for 1 h and then stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (3 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred at 25°C in argon atmosphere for 10 min bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmole) and triphenylphosphine (104 mg, 0.4 mmole) in anhydrous tetrahydrofuran (10 ml) and then was treated with 4-bromo-1-methanesulfonyl-2-triftorperasin (obtained in example 12, from 0.76 g, 2.5 mmole) and freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 15 h at 25°C. the Reaction mixture was then poured into a saturated aqueous solution of ammonium chloride (50 ml) and the organic compound was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 2/1 hexane/ethyl acetate) led to methyl ether (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triform terphenyl)but-2-ene acid (0.85 grams, 87%) as a viscous oil: EI-SVR m/e calculated for C18H21F3O4S (M+) 390,1113 found 390,1113.

A solution of methyl ester (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid (0,82 g, 2.1 mmole) in ethanol (10 ml) was treated with 1 N. aqueous solution of sodium hydroxide (5 ml). The solution was heated at 40°C for 15 hours, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol and the residue was diluted with water (30 ml) and was extracted with diethyl ether (1×50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×80 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-envoy acid (0.73 g, 92%) as a gummy solid: EI-SVR m/e calculated for C17H19F3O4S (M)+376,0243 found 376,0261.

A solution of triphenylphosphine (550 mg, 2.1 mmole) in methylene chloride (25 ml) was cooled to 0°and then clicks sativali N-bromosuccinimide (374 mg, 2.1 mmole). The reaction mixture was stirred at 0°C for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid (395 mg, 1.05 mmole) in methylene chloride (5 ml). A clear solution was stirred 15 min at 0°and then he was allowed to warm to 25°Since, at this temperature, stirred for 1.5 hours, the Reaction mixture was then treated with 2-aminothiazole (320 mg, 3.2 mmole) and the resulting suspension was stirred at 25°With over the weekend at the end of the week. The reaction mixture was concentrated in vacuo to remove methylene chloride and the residue was diluted with ethyl acetate (50 ml) and 1 N. aqueous solution of hydrochloric acid (50 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×30 ml). The combined organic extracts are then washed with saturated aqueous sodium bicarbonate solution (2×50 ml) and saturated aqueous sodium chloride (1×100 ml). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 1/1 hexane/ethyl acetate) led to the thiazole-2-ylamide (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid (77 mg, 16%) as an amorphous solid: EI-SVR m/e calculated for C20 H21F3N2About3S2(M+) 458,0946 found 458,0946.

Example 26

(E)-1-[2-(3,4-Dichlorophenyl)-4-methylpent-2-enoyl]-3-metalmachine

A mixture of aluminum chloride (value of 16,81 g, 126,05 mmole) in methylene chloride (105 ml) was cooled to 5°and was stirred to dissolve the solids. The reaction mixture was then slowly treated with methylacetylene (8.1 ml, 88,24 mmole) and the resulting reaction mixture was stirred at 5°C for 30 minutes. The reaction mixture was then slowly treated with 1,2-dichlorobenzene (12,35 g, 84,04 mmole). The resulting reaction mixture was allowed to warm to 25°Since, at this temperature it was stirred for 6 hours the Reaction mixture is then kept at 0°C for 15 hours, the Reaction mixture was slowly poured into ice/water (400 ml). Was shaken and the layers were separated. The aqueous layer was further extracted with methylene chloride (1×200 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (1×200 ml) and water (1×100 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) led to methyl ether (3,4-dichlorophenyl)octoxynol acid (0,78 g, 4%) as a solid yellow: tPL58,2-63°C; EI-SVR m/e calculated the C 9H6CL2O3(M+) 231,9694 found 231,9699.

A suspension of methyl isobutyrophenone (2,02 g, 4,96 mmole) in anhydrous tetrahydrofuran (5.4 ml) was cooled to 0°and then was treated dropwise a 1.0 m solution of bis(trimethylsilyl)amide, sodium (5 ml, 4,96 mmole). The reaction mixture is bright orange color was stirred at 0°C for 1 h, the Reaction mixture is then treated with a solution of methyl ester (3,4-dichlorophenyl)octoxynol acid (0,77 g, 3,30 mmole) in tetrahydrofuran (3 ml). The resulting reaction mixture was allowed to warm to 25°Since, at this temperature, it was stirred 15 h, the Reaction mixture was mixed with water (10 ml) and then concentrated in vacuo to remove tetrahydrofuran. The residue was then diluted with water (50 ml) and then extracted with ethyl acetate (2×75 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 97/3 hexane/ethyl acetate) led to the methyl ether of 2-(3,4-dichlorophenyl)-4-methylpent-2-ene acid (749 mg, 83%) as a viscous yellow oil containing a mixture of (E):(Z)-isomers in the ratio of 3.5:1. The mixture of isomers was used without further separation and identification.

The mixture of isomers of methyl ester of 2-(3,4-dichlorophenyl)-4-methylpent-2-ene acid [749,0 mg is 2.74 mmole, (E):(Z)=3,5:1] and metallocene (812,6 mg, 10,97 mmole) was treated with a solution of magnesium methylate in methanol (7.4 wt.%, 16 ml, 10,97 mmole). The resulting reaction mixture is boiled under reflux for 15 hours. The reaction mixture was allowed to cool to 25°and then filtered through celite. Celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/ethyl acetate) led to the crude 1-[2-(3,4-dichlorophenyl)-4-methylpent-2-enoyl]-3-metalmachine (280,2 mg) as a solid white color. Repeated flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 3/2 hexane/diethyl ether) was again led to the crude 1-[2-(3,4-dichlorophenyl)-4-methylpent-2-enoyl]-3-metalmachine (114,6 mg) as a solid white color. Recrystallization from hexanol/ethyl acetate resulted in pure (E)-1-[2-(3,4-dichlorophenyl)-4-methylpent-2-enoyl]-3-metalmachine (to 24.7 mg, 3%) as a solid white color: tPL177-178°C; FAB-MCBP m/e calculated for C14H16Cl2N2O2(M+H)+315,0667 found 315,0652.

Example 27

(E)-1-[3-Cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acryloyl]-3-metalmachine

The solution isoamylamine (as 4.02 ml, 30 mmol) in dimethyl disulfide (19,8 ml, 220 mmol) at 25°slowly processed and 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction proceeded exothermically with evolution of gas. The resulting reaction mixture brown was heated to 80-90°C for 2 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was cooled to 25°and then concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (200 ml). The organic layer is successively washed with 1 N. aqueous solution of hydrochloric acid (1×200 ml) and saturated aqueous sodium chloride (1×200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 8/1 hexane/ethyl acetate) led to 4-bromo-1-methylsulfanyl-2-triptoreline (4,73 g, 87%) as a brown oil: EI-SVR m/e calculated for C8H6rF3S (M+) 269,9326 found 269,9327.

A solution of 4-bromo-1-methylsulfanyl-2-triptoreline (4.71 g, to 17.4 mmole) in methylene chloride (100 ml) was cooled to -10°and then was treated with 3-chlormadinone acid (the content of 86%, 9.0 g, 52,2 mmole). The reaction mixture was stirred at -10°C for 10 min and then gave her to warm up to 25°Since, at this temperature, was stirred over night. By this time, the analysis of the reaction with the art by means of thin layer chromatography indicated the absence of starting material. The reaction mixture is then filtered and the solids washed with methylene chloride (1×50 ml). The filtrate was concentrated in vacuum. The resulting residue was dissolved in ethyl acetate (100 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum, received a solid yellow color. Recrystallization from methylene chloride (20 ml), diethyl ether (10 ml) and hexanol led to 4-bromo-1-methanesulfonyl-2-triptoreline (of 3.46 g, 57%) as a solid white color: tPL110-112°C; EI-SVR m/e calculated for C8H6rF3O2S (M+) 301,9224 found 301,9223.

A mixture of zinc dust (16,34 g, 250 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (6 ml) was treated in an argon atmosphere 1,2-dibromethane (0,94 g, 5 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (0.54 g, 5 mmol) and the suspension was stirred 15 min at 25°C. the Reactions is nnow the mixture was then treated dropwise with a solution of cyclohexylamine (21 g, 100 mmol) in anhydrous tetrahydrofuran (30 ml) for 15 minutes During the addition the temperature was increased to 60°C. the Reaction mixture was then stirred 3 h at 40-45°C. the Reaction mixture then was cooled to 25°and diluted With anhydrous tetrahydrofuran (60 ml). The stirring was stopped to give the possibility to precipitate the excess zinc dust (~3 h). In a separate reaction flask a mixture of lithium chloride (8,48 g, 200 mmol, previously dried at 130°C in high vacuum for 3 h) and copper cyanide (of 8.95 g, 100 mmol) in anhydrous tetrahydrofuran (110 ml) was stirred 10 min at 25°C to obtain a clear solution. The reaction mixture was cooled to -70°and then slowly treated with freshly prepared zinc solution using a syringe. After addition, the reaction mixture was allowed to warm to 0°Since, at this temperature, stirred for 5 minutes. The reaction mixture was again cooled to -70°and then slowly treated with methyl ether propionovoi acid (7,56 g, 90 mmol). The resulting reaction mixture was stirred 15 h at a temperature of from -70 to -50°and then slowly treated with a solution of iodine (34,26 g, 135 mmol) in anhydrous tetrahydrofuran (30 ml)maintaining the temperature from -70 to -60°C. After addition of a solution of iodine was removed the cooling bath and the reaction mixture gave regrets is up to 25° Since, at this temperature, stirred 2 hours, the Reaction mixture was then poured into a solution consisting of a saturated aqueous solution of ammonium chloride (400 ml) and ammonium hydroxide (100 ml)and the organic compound was extracted with ethyl acetate (3×250 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium thiosulfate (1×500 ml) and saturated aqueous sodium chloride (1×500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Flash chromatography (silica gel 60 Merck, 230-400 mesh mesh, 9/1 hexane/diethyl ether) resulted methyl ether (E)-3-cyclohexyl-2-iodically acid (26,3 g, 99%) as a oil light pink color: EI-SVR m/e calculated for C10H15IO2(M+) 294,0117 found 294,0114.

A mixture of zinc dust (1.3 g, 20 mmol, Aldrich company, -325 mesh) and anhydrous tetrahydrofuran (2 ml) was treated in an argon atmosphere 1,2-dibromethane (187 mg, 1 mmol). The zinc suspension was then heated to a rapid boil with jet air dryers, allowed to cool and again heated. This procedure was repeated three times to ensure that the zinc dust Proektirovanie. A suspension of activated zinc dust was then treated with trimethylsilylpropyne (110 mg, 1 mmol) and the suspension was stirred 15 min at 25°C. Reactio the ing the mixture was then treated dropwise with a solution of methyl ester (E)-3-cyclohexyl-2-iodically acid (2.5 g, 8.5 mmole) in anhydrous tetrahydrofuran (3 ml) for 5 minutes. After addition, the reaction mixture was stirred 1 h at 40-45°and then was stirred overnight at 25°C. the Reaction mixture was then diluted with anhydrous tetrahydrofuran (4 ml) and the stirring was stopped to give the possibility to precipitate the excess zinc dust (~2 h). In a separate reaction flask was stirred bis(dibenzylideneacetone)palladium(0) (108 mg, 0.2 mmole) and triphenylphosphine (209 mg, 0.8 mmole) in anhydrous tetrahydrofuran (10 ml) for 10 min at 25°C in an atmosphere of argon and then treated with 4-bromo-1-methanesulfonyl-2-triftorperasin (2,12 g, 7 mmol) and the freshly prepared zinc derivative in tetrahydrofuran. The resulting solution color from red brick was heated for 2 days at 40-45°C. the Reaction mixture was cooled to 25°and then was poured into a saturated aqueous solution of ammonium chloride (100 ml)and the organic compound was extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 9/1-3/1 hexane/ethyl acetate) led to methyl ether (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acre the gross acid (2.7 g, 99%) as a viscous oil: EI-SVR m/e calculated for C18H21F3O4S (M+) 391,1191 found 391,1200.

A solution of methyl ester (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (1.8 g, 4.6 mmole) in ethanol (20 ml) was treated with 1 N. aqueous solution of sodium hydroxide (15 ml). The solution was heated at 45-50°C for 15 h, by which time analysis of the reaction mixture by thin layer chromatography indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove the ethanol, the residue was diluted with water (40 ml) and was extracted with diethyl ether (1×50 ml) to remove any neutral impurities. The aqueous layer was acidified using 1 N. aqueous solution of hydrochloric acid. The resulting acid was extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with saturated aqueous solution of sodium chloride (1×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum was obtained (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid (1,74 g, 99%) as a solid white color: tPL62-64°C; EI-SVR m/e calculated for C17H19F3O4S (M+N)+377,1034 found 377,1041.

A solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acrylic acid(282 mg, 0.75 mmole) in fervently (1 ml) and N,N-dimethylformamide (3 ml) at 25°was treated dropwise with oxalylamino (81 μl, 0.9 mmole) in 2-3 minutes a Clear solution was stirred 1 h at 25°and then were treated with metalmachine (167 mg, 2.25 mmole). The resulting suspension was heated at 70°C (temperature in the bath) for 10 minutes and then treated with pyridine (121 μl, 1.5 mmole). The reaction mixture is then stirred for 20 h at 70°C. the Reaction mixture then was cooled to 25°C. and was diluted with ethyl acetate (50 ml) and 3 N. aqueous solution of hydrochloric acid (40 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (1×20 ml). The combined organic extracts are then washed with a saturated aqueous solution of sodium bicarbonate (1×50 ml) and saturated aqueous sodium chloride (1×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Chromatography using the Biotage system (FLASH 40M, silica, 4/1 hexane/ethyl acetate) led to (E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acryloyl]-3-metalmachine (104 mg, 32%) as a solid white color: tPL199-202°C, EI-SVR m/e calculated for C19H23F3H2O4S (M+) 432,1331 found 432,1332.

Example

Tablets containing the following ingredients can is to be obtained by the conventional method.

Ingredients mg / tablet:

The compound of formula (I)10,0-100,0
Lactose125,0
Corn starch75,0
Talc4,0
Magnesium stearate1,0

Example B

Capsules containing the following ingredients can be obtained in the conventional way.

Ingredients mg / capsule:

The compound of formula (I)25,0
Lactose150,0
Corn starch20,0
Talc5,0

1. TRANS-olefinic activator of glucokinase, representing a compound selected from the group consisting of olefinic amide of the formula

where R1and R2mean independently from each other hydrogen, halogen, a nitro-group, PERFLUORO(ness.)alkyl, (ness.)alkylsulfonyl or (ness.)alkylsulfonamides;

R is -(CH2)m-R3or lower alkyl containing from 2 to 4 carbon atoms;

R3means cycloalkyl containing from 3 to 8 carbon atoms;

R4means

or unsubstituted or one-deputizing five - or six-membered heteroaromatic ring linked via a carbon atom of the ring with the specified amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom being nitrogen, is located next to the connecting ring carbon atom; and the specified one-deputizing heteroaromatic ring substituted at the carbon atom of the ring, not contiguous with the said connecting carbon atom, Deputy selected from the group consisting of halogen and

m denotes 0 or 1;

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

R7means hydrogen or lower alkyl; and

Δ means the TRANS-configuration relative to the double bond;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1 where the above-mentioned amide has the formula

where Δ, R, R1and R2and R7are as indicated in claim 1.

3. The compound according to claim 1 where the above-mentioned amide has the formula

where R, R2, R1and Δ are such as defined in claim 1, and

R11is unsubstituted or one-deputizing five - and six-membered heteroaromatic ring, associated with the carbon atom of the ring with the specified amino group, and a five - or six-membered heteroaromatic ring contains 1-2 heteroatoms selected from the group consisting of sulfur or nitrogen, with one heteroatom being nitrogen, is located next to the connecting carbon atom of the ring; and the above-mentioned one-deputizing heteroaromatic ring substituted at the carbon atom of the ring, not contiguous with the said connecting carbon atom, Deputy selected from the group consisting of halogen or

n means 0, 1, 2, 3 or 4; and

R7means hydrogen or lower alkyl.

4. The compound according to any one of claims 1 to 3, where R7means lower alkyl.

5. The compound according to any one of claims 1 to 4, where R is lower alkyl containing from 2 to 4 carbon atoms.

6. The compound according to any one of claims 1 to 4, where R is -(CH2)m-R3and R3and m are as stated in claim 1.

7. The compound according to any one of claims 1 to 4 and 6, where R3means cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

8. The compound according to any one of claims 1 to 4 and 6-7, where m is 0.

9. The compound according to any one of claims 1 and 3-8, where the heteroaromatic ring R4or R11is selected from unsubstituted or one-deputizing pyridinyl and thiazolyl.

10. The connection according to claim 9, where heteroarm the political ring R 4or R11means unsubstituted or one-deputizing thiazolyl.

11. The connection according to claim 9, where the heteroaromatic ring R4or R11means unsubstituted or one-deputizing pyridinyl.

12. The compound according to any one of p-11, where the heteroaromatic ring R4or R11is unsubstituted.

13. The compound according to any one of p-11, where the heteroaromatic ring R4or R11has one Deputy in the form of halogen.

14. The compound according to any one of p-11, where the heteroaromatic ring R4or R11has one Deputy -(CH2)n-C(O)-OR7and n and R7are as in claim 1.

15. The compound according to any one of claims 1 to 14, where one of R1and R2means halogen, (ness.)alkylsulfonyl or (ness.)alkylsulfonates and the other denotes hydrogen, halogen, the nitro-group or PERFLUORO(ness.)alkyl.

16. The compound according to any one of claims 1 to 14, where one of R1and R2means (ness.)alkylsulfonyl and other means hydrogen, halogen, the nitro-group or PERFLUORO(ness.)alkyl.

17. The compound according to any one of claims 1 to 16, selected from the group consisting of

(E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)acryloyl)-3-methyl-urea;

(E)-1-[2-(3,4-dichlorophenyl)-4-methylpent-2-enoyl]-3-metallocene;

the thiazole-2-ylamide (E)-2-(4-methanesulfonyl)Penta-2-ene CIS is the notes;

the thiazole-2-ylamide (E)-2-(4-methanesulfonyl)-4-methylpent-2-ene acid;

(E)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-alacrimia;

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

(E)-3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-alacrimia;

(E)-N-(5-bromothiazole-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl)acrylamide;

(E)-3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-alacrimia;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-yl-acrylamide;

(E)-3-cyclohexyl-2-(3,4-differenl)-N-thiazol-2-alacrimia;

(E)-2-(3-chloro-4-methysulfonylmethane)-3-cyclohexyl-N-thiazol-2-alacrimia;

(E)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)acrylamide;

(E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-3-cyclooctyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-N-(5-bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl)acrylamide;

(E)-3-cycloheptyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-yl-acrylamide;

(E)-N-(5-bromothiazole-2-yl)-3-qi is lagati-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)acrylamide;

the thiazole-2-ylamide(E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid;

methyl ester (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-enoyl-amino]thiazole-4-carboxylic acid;

ethyl ester of (E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-enoyl-amino]thiazole-5-carboxylic acid;

(E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-ylacrylic;

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

(E)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)acrylamide;

the thiazole-2-ylamide(E)-4-cyclopentyl-2-(3,4-differenl)but-2-ene acid

and

the thiazole-2-ylamide (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid.

18. The compound according to any one of claims 1 to 16, selected from the group consisting of

(E)-3-cyclopentyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-3-cyclohexyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-3-cycloheptyl-2-(4-methanesulfonyl)-N-thiazol-2-alacrimia;

(E)-2-(3-chloro-4-methanesulfonyl)-3-cyclopentyl-N-thiazol-2-alacrimia;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-triptoreline)-N-thiazol-2-yl-acrylamide;

(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-alacrimia;

(E)-N-(5-bromothiazole-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl)acrylamide;

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

(E)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)acrylamide;

the thiazole-2-ylamide(E)-4-cyclopentyl-2-(4-methanesulfonyl)but-2-ene acid;

methyl ester(E)-2-[4-cyclopentyl-2-(4-methanesulfonyl)but-2-enoyl-amino]thiazole-4-carboxylic acid thiazol-2-ylamide(E)-4-cyclopentyl-2-(4-methanesulfonyl-3-triptoreline)but-2-ene acid.

19. The compound according to any one of claims 1 to 18, designed for use as a component in the composition of the medicinal product.

20. The compound according to any one of claims 1 to 18, designed for the treatment of type II diabetes.

21. Pharmaceutical composition having the ability to activate glucokinase and including a connection according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier and/or adjuvant.

22. The compound according to any one of claims 1 to 18, designed to produce drugs for the treatment or prophylaxis of diabetes type II.

23. A method of prophylactic or therapeutic treatment of type II diabetes, which consists in introducing the compound according to any one of claims 1 to 18 human or animal.

24. The method of obtaining the compounds of formula I according to claim 1, which is the first involves reacting the compounds of formula VIII

where R, R1and R2are as in claim 1, or compounds of formula VII

where R, R1and R2are such as defined in claim 1, and R5together with the associated oxygen atom forms can either hydrolyzed protective group for acid with the compound of the formula XIV

where R11so, as stated in claim 1, to obtain the compounds of formula I-B

where R, R1, R2, R11and Δ are such as defined in claim 3,

and then, in thecasenecessary, conversion of the remainder R1and/or R2in the remainder R1and/or R2as specified in claim 1.

25. The method of obtaining the compounds of formula I according to claim 1, which includes the interaction of the compounds of formula VII

where R, R1and R2are such as defined in claim 1, and R5together with the associated oxygen atom forms can either hydrolyzed protective group for acid with the compound of the formula XV

where R7so, as stated in claim 1,

to obtain the compounds of formula I-A

where R, R1, R2and Δ are such as defined in claim 3,

and then, if necessary, conversion of the remainder R1and/or R2in the remainder R1and/or R2as specified in claim 1.



 

Same patents:

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 found (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

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide

The invention relates to therapeutically active hydroxamic acids and derivatives of carboxylic acids, processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of such compounds in medicine

The invention relates to the basic organic synthesis and concerns a method for obtaining asymmetrically disubstituted ureas of General formula I

R-NH--Nwhere R is phenyl, unsubstituted or mono - or multiply substituted by halogen atom, lower alkyl, lower alkoxygroup, arroceros, trifluoromethyl, and unsubstituted or once substituted lower alkoxygroup benzothiazolyl, or benzoxazolyl, R1and R2means a hydrogen atom or lower alkyl, and R1and R2cannot simultaneously denote a hydrogen atom

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 found (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

The invention relates to new derivatives of benzene or pyridine of the formula (I)

where R denotes H, C1-C7alkyl and halogen; R1denotes H or halogen, provided that in the 4th position R1not denotes bromine or iodine; R2denotes H or CF3; R3denotes N or C1-C7alkyl; R4denotes H, halogen, C1-C7alkyl and others; R5denotes N or C1-C7alkyl; X represents-C(O)N(R5)-, -N(R5)-C(O)- or-C(O)O-; Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)- or N(R5’)-; R5’means (ness.)alkyl; Z represents =N-, -CH= or-C(C1)=; n denotes a number from 0 to 4; and their pharmaceutically acceptable salts

The invention relates to new derivatives of 3-phenylpyridine formula (I)

in which R denotes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen or CF3, R1means H or halogen, or R and R1may together form-CH=CH-CH=CH-; R2means H, halogen, CF3, R3means H or C1-C7alkyl, R4means H or piperazine-1-yl; R5means H or C1-C7alkyl, X is-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)- or N(R5)(CH2)m-; n is an integer from 0 to 4, m is 1 or 2, and their pharmaceutically acceptable acid additive salts

The invention relates to pharmaceutical compositions containing as active ingredient a compound of General formula (I)

in which: R1choose from one of the following groups: - H; - (C1-C20)alkyl, unsubstituted or substituted (C1-C5)alkyl; R2choose from: - (C3-C8)cycloalkyl - (C6-C14)aryl, unsubstituted or substituted with halogen, (C1-C5)alkyl, (C1-C5)alkylthiol, (C5-C6)heteroaryl containing a nitrogen atom which may be substituted by one or more (C1-C5) and alkyl (C1-C5)alkylthio groups, R3denotes hydrogen, and a is chosen from the groups: - CH2-, - CH2-CH2-, - CHR4-, R4choose from: - H; - (C1-C20)alkyl, unsubstituted or substituted (C1-C5)alkyl, and their solvate and a pharmaceutically acceptable salt, which can be used to treat pathologies associated with syndrome of insulin resistance, because it has anti-diabetic and hypoglycemic effect; the compounds of General formula I, 2-m methods for their preparation

The invention relates to the field of organic chemistry, class of amides of dicarboxylic acids, namely to a new biologically active 4-methyl-2-pyridylamino tetrachlorophthalic acid formula

The compound obtained by the interaction of 4-methyl-2-aminopyridine with anhydride tetrachlorophthalic acid

The invention relates to novel 1,3-disubstituted the ureas of General formula I, having the ability to inhibit the action of the enzyme acyl-COA: cholesterol-acyltransferase, which is responsible for the catalysis of intracellular esterification of cholesterol, and method of production thereof

The invention relates to new thiosemicarbazones formula I

< / BR>
where R4represents N or CH3, R5is CHR, benzyl or ortho - or para-substituted benzyl, R represents H, CH3CH2CH3CH2CH2-CH3or CH(CH3)2, R' represents the residue of phosphoric acid, salt of phosphoric acid or-S-S-R" group, R" is CH2CH2OTHER6CH2CH2HE, CH2COOR7, ortho - or para-substituted C1-C3alkylphenyl or ortho - or para-substituted nitrophenyl, R6represents H, C1-C4acyl group, trifluoracetyl, benzoyloxy or substituted benzoyloxy group, R7represents H, C1-C4alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl

The invention relates to an improved process for the preparation of compounds of formula (I), where R4represents N or CH3that includes the interaction of the compounds of formula 2 in which R1represents a group of NO2with thiosemicarbazide with getting thiosemicarbazone formula ТS1, and subsequent reduction of the obtained compound

The invention relates to new N1-[2,2-dimethyl-1S-(pyridin-2-ylcarbonyl)propyl] -N4-hydroxy-2R-isobutyl-3S-methoxybenzamido or its pharmaceutically acceptable salt, hydrate or solvate

The invention relates to new cyanoguanidine F.-ly (I)

< / BR>
where connection to the pyridine ring is in the 3rd or 4th position, R1indicates one or more substituents selected from the group consisting of hydrogen, C1-C4the alkyl or alkoxy, Q denotes a4-C20linear saturated divalent hydrocarbon radical, X denotes a carbonyl, carbylamine, aminocarbonyl, oxycarbonyl, oxycarbonyl, carbonyloxy, aminocarbonyl, iminodicarboxylate, oxycarbonyl or occationally, Y denotes a phenylene, R2denotes hydrogen, halogen

The invention relates to a new range of clinical compounds and method for their production, namely to poslednym N-benzhydryl-N'-(TRIFLUOROACETYL)ureas of General formula:

< / BR>
where R is ortho, meta, para-bromine

The invention relates to new chemical compound and method of its production, namely N-benzhydryl-N-(TRIFLUOROACETYL) urea of the formula

< / BR>
Chemical compound synthesized for the first time and assigned state registration number N 9973090
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