Isoindoline-1-on-glucokinase activators

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

 

Glucokinase (GK) is one of four hexokinase found in mammals (Colowick S.P., The Enzymes, v.9 (Ruoeg, ed.) Academic Press, New York, NY, c.1-48 (1973)). Hexokinase catalyzes the first stage of glucose metabolism, i.e. conversion of glucose into glucose-6-phosphate. Glucokinase is present not in all cell types and is found predominantly in pancreatic β-cells and parenchymal cells of the liver. In addition, SC is the rate-determining enzyme 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 N.B. Ruderman, Joslin''s Diabetes, C.R. Khan and G.C.Wier, eds., Lea and Febiger, Philadelphia, PA, c.97-115 (1994)). The glucose concentration at which the Ledger shows the half maximal activity, is 8 mm. The other three hexokinase saturated with glucose at much lower concentrations (<1 mm). Therefore, the flow of glucose through glucokinase (CC) path increases with increasing concentration of glucose in the blood from “hungry” (5 mm) to “afternoon” (~10-15 mm) levels after carbohydrate feeding (Printz R.G., M.A. Magnuson and Granner D.K., Ann. Rev. Nutrition, v.13, R.E.Olson, D.M.Bier and D.B.McCormick, eds., Annual Review, Inc., Palo Alto, CA, c.463-496 (1993)). Ten years ago these data stimulated the hypothesis that β-cells and hepatocytes Ledger functions as glucose the th sensor (Meglasson MD and F.M. Matschinsky, Amer. J. Physiol., 246, E1-E13 (1984)). Recent studies in transgenic animals have confirmed that the group really plays a crucial role in glucose homeostasis of the whole organism. Animals not expressing ha die in a few days after birth from severe diabetes, whereas animals with overexpression of GK tolerate glucose (Grupe, A., Hiltgren C., Ryan A. and others, Cell, 83, 69-78 (1995), Ferrie So, Riu, E., Bosch F., and others, FASEB J., 10, 1213-1218 (1996)). The increase in the resistance to glucose-connected thanks to the Ledger with increased secretion of insulin in β-cells and with increased deposition of glycogen in hepatocytes and probably low produced glucose.

Evidence that the emergence of adult diabetes type II in youth (MODY-2) is caused by loss of gene GK because of functional mutations, suggests that GK acts as a glucose sensor in humans (Liang Y., Kesavan, P., Wang L., etc., Biochem. J., 309, 167-173 (1995)). For more facts, confirming the participation of SC in the regulation of glucose metabolism in the human body, obtained by identifying patients that Express a mutant form of the Ledger with higher enzymatic activity. These patients have fasting hypoglycemia associated with unusually high levels of insulin in plasma (Glaser C., R. Kesavan, M. Heyman and others, New England J. Med., 338, 226-230 (1998)). Although mutations in the gene Ledger in most patients is diabetes type II is not detected, compounds that activate Ledger and thereby increase the sensitivity of GC-touch system, can find application in the treatment of hypoglycemia is common for all variants of type II diabetes. Activators of glucokinase increase glucose metabolism in β-cells and hepatocytes, which is associated with increased secretion of insulin. Such agents may find use in the treatment of type II diabetes.

In the present invention proposes a connection involving amide of the formula

where

And means unsubstituted phenyl or phenyl, one - or disubstituted by halogen or one-deputizing group (ness.)alkylsulfonyl, (ness.)alkylthio or nitro,

R1means cycloalkyl containing from 3 to 9 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms,

R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and five - or six-membered heteroaromatic cycle contains from 1 to 3 heteroatoms, selected from a number sulfur, oxygen or nitrogen, with one heteroatom is a nitrogen atom adjacent to the carbon atom linked with the amino group, and the cycle is monocyclic or condensed with the phenyl by two carbon atoms in the cycle, and indicated the one-deputizing p heteroaromatic cycle is one-deputizing for the carbon atom in the cycle, which is not adjacent with the specified carbon atom associated with the amino group, and Deputy selected from the group comprising halogen, (ness.)alkyl, nitro, cyano, PERFLUORO(ness.)alkyl; hydroxy, -(CH2)n-OR3, -(CH2)n-C(O)-OR3, -(CH2)n-C(O)-NH-R3, -C(O)C(O)-OR3and -(CH2)n-Other3where R3means hydrogen or (ness.)alkyl, and

n means 0, 1, 2, 3, or 4, or pharmaceutically acceptable salts or N-oxides.

Preferably R2means a five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the amino group shown in formula I, with the specified five - or six-membered heteroaromatic cycle contains from 1 to 3 heteroatoms, selected from a range of sulfur, oxygen and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the carbon atom linked with the amino group. This cycle may be monocyclic or condensed with the phenyl by two carbon atoms in the cycle. In one embodiment of the present invention adjacent the nitrogen atom in the nitrogen-containing heteroaromatic cycle may be present in the form of N-oxide, when the nitrogen atom adjacent to the carbon atom in the cycle, turn the N-oxide.

On the other hand, the compounds of formula I can exist in the form of pharmaceutically acceptable salts.

the setting, the compounds of formula I activate glucanase in vitro. Activators glucokinase used to increase insulin secretion in the treatment of type II diabetes.

In addition, the present invention relates to pharmaceutical compositions comprising a compound of formula I in a mixture with a pharmaceutically acceptable carrier and/or adjuvant. In addition, the present invention relates to the use of such compounds as therapeutically active compounds and to their use in obtaining medicines for the treatment or prophylaxis of diabetes type II. In addition, the present invention relates to a method of preparing compounds of formula I. the Present invention relates also to a method of prevention or teravpevtichesky treatment of type II diabetes, and the method includes the introduction of the compounds of formula I to a human or animal.

In more detail, the invention proposes a connection involving amide of formula I or N-oxide amide of formula I above and their pharmaceutically acceptable salts.

In the compound of formula I, the symbol "*" indicates asymmetric carbon atom in a particular connection. Due to the presence of asymmetric atom of the compound of formula I can exist in the form of a racemate. However, the preferred S-enantiomers, where asymmetric carbon atom in amide has the S-configuration. what if the phenyl cycle And monogamist groups (ness.)alkylsulfonyl, nitro or (ness.)alkylthio, it is preferable that he was substituted in the 5 or 6 position, as indicated for formula I. Thus, if a represents phenyl substituted by a nitro-group, it is preferable that the Deputy was in position 5 or 6, i.e. if And mean 5-nitrophenyl 6-nitrophenyl.

In one embodiment of formula I above cycle R2means one monocyclic (unfused) ring. Monocyclic ring R2preferably represents an unsubstituted pyridine. In another embodiment, formula I above cycle R2means bicyclic system, i.e. the cycle is condensed with phenyl.

The term “(ness.)alkyl”used in the text of the application, means an alkyl group with straight and branched chain, containing from 1 to 10, preferably from 3 to 9 carbon atoms, especially from 2 to 4 carbon atoms, such as propyl, isopropyl, heptyl, etc.

The term “cycloalkyl”used in the text of the application, means a 3-9-membered cycloalkyl ring, preferably 5-8-membered, for example cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term “PERFLUORO(ness.)alkyl”used in the text of the application, means any group (ness.)alkyl, where all the hydrogen atoms in the group (ness.)alkyl substituted or replaced by a fluorine atom. Preferred PERFLUORO(ness.)alkyl groups include the trifluoromethyl, pentaverate, heptafluoropropyl etc.

The term “(ness.)alkylthio”used in the text of the application means (ness.)alkyl having values mentioned above are associated with the remainder of the molecule via a sulfur atom of tigraphy.

The term “(ness.)alkylsulfonyl”as used in the text of the application means (ness.)alkyl having values mentioned above are associated with the remainder of the molecule via a sulfur atom sulfonyloxy group.

The term “halogen”used along with the term “halo”means, unless specified otherwise, all four Halogens, i.e. fluorine, chlorine, bromine and iodine.

The term “N-oxide”, as used in the text of the application, means a negatively charged oxygen atom covalently associated with a positively charged atom of nitrogen in the heteroaromatic cycle.

The term “heteroaromatic cycle”used in the text of the application, means a five - or six-membered unsaturated carbocyclic ring in which one or more carbon atoms replaced by a heteroatom, such as oxygen, nitrogen or sulfur. Heteroaromatic ring may indicate one cycle or it may be bicyclic, i.e. formed by the condensation of two cycles.

Heteroaromatic cycle R2can mean unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle containing 1 to 3 heteroatoms selected from the group, what with oxygen, the nitrogen and sulfur, and linked to the carbon atom in the cycle with the specified amine amide group. At least one heteroatom is a nitrogen atom, which is adjacent to the carbon atom linked with the amino group. If there are other heteroatoms, they can mean sulfur, oxygen or nitrogen. Cycle R2can mean one ring. Such heteroaromatic cycles include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolin, pyrazolyl, thiazolyl, oxazolyl and imidazolyl. Preferred heteroaromatic cycle is pyridinyl. Cycle R2may be bicyclic, i.e. condensed with a phenyl in two free atoms of carbon. Examples of such cycles are benzimidazolyl, benzothiazolyl, chinoline, benzoxazolyl etc. Cycle R2linked through a carbon atom in the cycle with the amide group to form the amide of formula I. the carbon Atom in the heteroaromatic cycle, participating in the amide bond with the formation of the compounds of formula I, may not contain any other zamestitel. If R2means unsubstituted or one-deputizing five-membered heteroaromatic cycle, preferred are such cycles, which contain a nitrogen atom adjacent to the carbon atom in the cycle-related amino group, and a second heteroatom adjacent to the carbon atom in C the glue, associated with the amino group.

Group-C(O)OR3used in the text of the application, means-C(=O)OR3etc.

The term “pharmaceutically acceptable salt”used in the text of the application, includes any salt of an inorganic or 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, a pair of toluensulfonate, etc. in Addition, the term “pharmaceutically acceptable salt” includes any pharmaceutically acceptable salt of a base such as an amine salt, salt trialkylamine etc. the person skilled in the art can easily obtain such salts by known methods.

In addition, the invention relates to prodrugs of compounds of formula I. the Prodrug is a metabolic precursor of a medicinal product, which when administered to a patient turns into a drug and acceptable by-products. Compounds of the present invention can be converted into any Prodrug. Specific prodrug of the present invention are N-oxides mentioned above. In the General case in the form of prodrugs can get any individual shall Obedinenie according to the invention.

When carrying out the reactions shown below in the Diagram and described in the comments of various functional groups such as free carboxyl group and a free hydroxyl group can be protected using hydrolyzable simple and complex esters. The term “protective group in the form of hydrolyzable complex and simple esters”as used in the text of this application, means any ester group, or a group of simple ether, which is usually used to protect carboxylic acids or alcohols and which is hydrolyzed with the formation of the corresponding carboxylic or hydroxyl groups. Typical ester groups, which are used for these purposes are those groups in which the acyl residues mean (ness.)alcamovia, aryl(ness.)alcamovia or (ness.)alkalicarbonate acid. Activated derivatives suitable for the production of such groups include acid anhydrides, acid halides, preferably acid chlorides or bromohydrin aryl or (ness.)alkanovykh acids. Examples of anhydrides are the anhydrides of monocarboxylic acids, such as acetic anhydride, the anhydride of benzoic acid, and anhydrides (ness.)alkalicarbonate acids, for example succinic anhydride, and chloroformiate, for example, preferred trichloro - and ethylchloride. Suitable simple group is on air for the protection of alcohols are, for example, tetrahydropyranyl ethers, such as 4-methoxy-5,6-dihydroxy-2H-perylene ethers. Another example ethers are roulettelive esters, such as benzyl, benzhydryl or triteleia ethers or α-(ness.)alkoxy(ness.)alkyl ethers, for example methoxymethyl or allyl simple ether or alkylsilane ethers, such as trimethylsilyl ether.

The term “aminosidine group” means any ordinary aminosidine group which can be split with the formation of free amino groups. Preferred protective groups are the usual aminosidine groups used in peptide synthesis. More preferred are such aminosidine groups, which are in the slightly acidic environment, at approximately pH 2-3. More preferred aminosidine groups are tert-BUTYLCARBAMATE (VOS), benzylcarbamoyl (CBZ) and 9-fluorenylmethoxycarbonyl (FMOC).

In preferred compounds of formula I R1means cycloalkyl containing from 5 to 8 carbon atoms, and R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and specified five - or six-membered heteroaromatic cycle-to-keep the it from 1 to 2 heteroatoms, chosen from a number of sulfur, oxygen and nitrogen, with one heteroatom means a nitrogen atom, which is adjacent to the carbon atom in the cycle-related amino group, and the cycle can contain one ring or may be condensed with the phenyl by two carbon atoms in the cycle, and the specified one-deputizing heteroaromatic cycle monogamist on the carbon atom that is not adjacent with the specified carbon atom associated with the amino group, and Deputy selected from the group comprising halogen or (ness.)alkyl (formula AB). As indicated in the formula AB, R2is a monocyclic ring (formula A) or bicyclic system by condensation with phenyl (formula). In the compounds of the formula And R2more preferably denotes a substituted or unsubstituted pyridine. In addition, R2preferably means cyclohexyl. Phenyl And preferably is unsubstituted.

In a preferred compound of formula I, R1means cyclohexyl, and R2means monocyclic ring (formula a-1). In the compound of formula a-1 phenyl And preferably is unsubstituted. More preferably the group R2means substituted or unsubstituted pyridine.

In one embodiment of formula A-1 group R2means unsubstituted pyridine, and in another embodiment the group R2oz achet one-deputizing pyridine. Preferably, the Deputy means halogen, such as bromine, fluorine or chlorine, or (ness.)alkyl, such as methyl.

In another embodiment of formula A-1 group R2means one-deputizing the pyrimidine. Preferably, the Deputy means (ness.)alkyl, such as methyl and phenyl And is unsubstituted. In addition, R2can mean unsubstituted pyrimidine of the formula a-1. Preferably phenyl And is unsubstituted or substituted in position 4 or 7 (ness.)alkylsulfonyl.

In another embodiment of formula A-1 group R2means the unsubstituted thiazole. In such preferred compounds, the group a represents phenyl, unsubstituted or substituted in positions 5 and 6 chlorine, or substituted in position 5 by a nitro group, or substituted in position 4 or 7 group halogen or (ness.)alkylsulfonyl.

In another embodiment of formula A-1 group R2means one-deputizing the thiazole. Preferably, the Deputy means halogen, and a group means phenyl, unsubstituted or substituted in positions 5 and 6 chlorine, or substituted in position 5 by a nitro group, or substituted in position 4 or 7 group halogen or (ness.)alkylsulfonyl.

In another embodiment of formula a-1 R2means the unsubstituted pyrazin. Group a represents phenyl, unsubstituted or substituted in position 4 or 7 group halogen or (ness.)alcalali is of IMT.

In yet another embodiment, a-1, where R1means cyclohexyl, and R2means monocyclic ring, R2means the unsubstituted imidazole, and means preferably unsubstituted phenyl.

In another embodiment, formula I or formula And phenyl And is unsubstituted, R2means monocyclic ring, preferably a substituted or an unsubstituted thiazole (formula a-2). In some compounds of formula a-2 group R1means cyclopentyl, in the other group, R1means cycloheptyl, in the third group, R1means cyclooctyl.

In a preferred compound of formula I, R2means bicyclic heteroaromatic ring formed by condensation with phenyl two carbon atoms in the cycle, and R1means cyclohexyl (formula 1). In compounds of formula B-1 phenyl And preferably is unsubstituted. In addition, R2preferably means benzthiazole, benzimidazole, benzoxazole or quinoline, each of which is preferably unsubstituted.

In yet another preferred embodiment of the present invention And means unsubstituted phenyl or phenyl which may be substituted by the group of fluorine, (ness.)alkylsulfonyl or (ness.)alkylthio in position 4 or 7, or chlorine in position 5 or 6 or 5 and 6, or a group of bromine or nitro in position 5 or 6. Drugom preferred embodiment, And means razmeshanny phenyl or phenyl, which is a one - or disubstituted by halogen or one-deputizing group (ness.)alkylsulfonyl or nitro. Most preferably, a represents unsubstituted phenyl or phenyl, one-deputizing halogen, preferably fluorine.

In yet another preferred embodiment of the present invention R1means cycloalkyl containing from 3 to 9, preferably from 5 to 8 carbon atoms. Most preferably the group R1mean cyclopentyl or cyclohexyl.

In yet another preferred embodiment of the present invention R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and specified five - or six-membered heteroaromatic cycle contains 1 or 2 heteroatoms, chosen from a number of sulfur, oxygen and nitrogen, with one heteroatom means a nitrogen atom, which is adjacent to the carbon atom linked with the amino group, and the cycle is monocyclic or condensed with the phenyl by two carbon atoms in the cycle, and the specified one-deputizing heteroaromatic cycle substituted on the carbon atom that is not adjacent with the specified carbon atom associated with the amino group, the Deputy selected from the group comprising halogen and (ness.)alkyl. In another, preferred is the preliminary version of R 2means heteroaromatic cycle, selected from a number thiazolyl, chinoline, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl or benzoxazolyl, and specified heteroaromatic cycle optional monogamist halogen, preferably chlorine or bromine, or (ness.)by alkyl, preferably by stands. More preferably heteroaromatic cyclic residues R2selected from a number thiazolyl, pyrimidyl, pyrazinyl or pyridyl, and specified heteroaromatic cycle optional monogamist halogen, preferably chlorine or bromine, or (ness.)by alkyl, preferably by stands. Most preferably the residue R2means unsubstituted heteroaromatic cycle, selected from a number thiazolyl, pyrimidyl, pyrazinyl or pyridyl, or one-deputizing heteroaromatic cycle, selected from a number thiazolyl substituted by chlorine, or pyridyl, substituted with chlorine, bromine or (ness.)by alkyl, preferably by the stands.

Preferred compounds of the present invention are compounds selected from the group including

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-Piri is in 2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic,

(R)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-

N-5-chloropyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-

N-4-methylpyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-

N-5-methylpyridin-2-ylpropionic,

3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-N-3-cyclohexyl-N-(2-methylpyrimidin-4-yl)-2-(1-oxo-

1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-3-CEC is hexil-2-(7-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide,

(S)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-chloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-chloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(5-nitro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(6-nitro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-fluoro-

1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-fluoro-

1-oxo-1,3-dihydroindol-yl)propionamide,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide,

3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

3-cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-N-benzothiazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(1H-benzimidazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-benzoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-quinoline-2-propionamide,

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-

N-(1-oxypyridine-2-yl)propionamide and

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic.

The most preferred compounds of the present invention selected from the group including

3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-

chloropyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-

yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-

yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-

N-5-methylpyridin-2-ylpropionic and

(R)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide.

Compounds of the present invention can be obtained according to the following schemes of reactions where a phenyl, R1, R2and R have the meanings specified for formula I.

Schema reactions

Scheme 1

Scheme 2

Scheme 2 Ra means halogen, Rb denotes H or halogen

Ra means nitro, Rb denotes H

Ra means (ness.)alkylthio, (ness.)alkylsulfonyl,

Rb denotes H

Scheme 3

Compounds of the present invention can be obtained by the interaction of substituted ortho-phenylenedimaleimide 1 or 1’ with the derived amino acids 2 or 2’ in an appropriate solvent, such as acetonitrile, with the formation of carboxylic acid derivative 3 or 3’. Then connect 3 or 3’ can condense with the corresponding heteroaromatic Amin H2N-R2under normal conditions the formation of amide bond to form compounds of formula I.

The compounds of formula I, where phenyl And substituted with halogen (obtained from gelegentlich acid) or nitrogroup, receive, as shown above in scheme 2, where the connection means 4 respectively substituted phthalic acid, which is a commercial product. Substituted ortho-phthalic dialdehyde 1 or 1’ can be obtained by recovering phthalic acid 4 with the formation of intermediate diodes and subsequent oxidation with the formation of compound 1 is.

The compounds of formula I, where phenyl And the substituted group (ness.)alkylsulfonyl, can be obtained from phthalic acid 4, where Ra denotes a fluorine, a Rb means a hydrogen according to the following sequence of reactions:

a) transformation into the corresponding dimethyl ether in methanol in the presence of sulfuric acid,

b) nucleophilic substitution of fluorine by thiomethoxam sodium in an appropriate solvent, such as dimethylsulfoxide, with the formation of compounds 4, where Ra means (ness.)alkylthio,

C) recovering the obtained phthalic acid 4 where Ra means (ness.)alkylthio, with the formation of the diol, followed by oxidation to the corresponding ortho-phenylendiamine 1, where Ra means (ness.)alkylthio,

g) interaction ortho-phenylenedimaleimide 1, where Ra means (ness.)alkylthio, with 2 amino acid by boiling under reflux in acetonitrile with formation of a mixture of isomers (ness.)alkylthiophenes acid 3, and

d) condensation with H2N-R2with the formation of compounds of formula I, where Ra means (ness.)alkylthio.

The compounds of formula I, where Ra means (ness.)alkylsulfonyl, a Rb means a hydrogen receive a first oxidation (ness.)alkylthio-isomers obtained in stage (g), and hydrogen peroxide with the formation of (ness.)alkylsulfonates acid of formula 3 (where Ra means (ness.)alkylsulfonyl, and Rb means a hydrogen),and then by condensation of the resulting carboxylic acid of formula 3 with H 2N-R2with the formation of the compounds of formula I, where Ra means (ness.)alkylsulfonyl.

The compounds of formula I, where R1means3-C9cycloalkyl or2-C4the alkyl (R, S, or racemic form) receive, as described above, with compound 2 or 2’ means the corresponding amino acid, which is a commercial product. Amino acid 2 or 2’ can be obtained according to scheme 3 from compounds 5. Connection 5 receive according to the method described in the literature (see O'donnell M.J., Polt R.L., J. Org. Chem., 47, 2663-2666 (1982)), and then injected into the reaction with the corresponding alkylhalogenide, substituted necessary R1in the presence of a base and after acid hydrolysis get any amino acid 2. Alkylhalogenide are commercial preparations, or can be obtained by the known methods.

The compounds of formula I, where R2matter specified in formula I, can be obtained by condensation necessary heteroaromatic amine (which is a commercial product, or can be obtained with known methods) derived from carboxylic acids of 3 or 3’ in the usual conditions interact amine with the acid. N-Oxide heteroaromatic amine (for example, 2-aminopyridine-N-oxide) can be condensing connection 3 or 3’, or the corresponding compound of formula I it is possible to oxidize the known methods for the AMI for unsubstituted cycle R 2obtaining N-oxide.

If you want to get the R or S isomer of compounds of formula I, isomers share common physical and chemical methods. Physical methods mean separation of enantiomeric pairs of compounds of formula I using chromatograph for liquid chromatography high resolution on a column filled with a chiral agent. Preferred chemical methods include vzaimodeistvie intermediate carboxylic acid 3 or 3’ with an optically active base. For division, you can use any conventional optically active base. Preferred optically active bases are optically active amines, such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha methylnaphthalene. When carrying out this reaction, apply the usual techniques used for separation of organic acids in the presence of optically active organic bases containing amino group.

When the separation of isomers of compound 3 or 3’ communicates with the optically active base in an inert organic solvent with the formation of salts of the optically active amine with R and S isomers of compound 3 or 3’. Upon receipt of such salts, temperature and pressure are not critical, salt is formed at room temperature and atmospheric pressure, the NII. Salt R and S isomers can be divided in the usual way, such as fractional crystallization. After crystallization of each of the salts are converted into the corresponding connection 3 or 3’, with R and S configuration, by acid hydrolysis. Preferred acids are dilute aqueous solutions of acids, for example, with concentrations of approximately 0,n. to 2n. solutions of acids, such as sulfuric or hydrochloric acid. The connection configuration 3 or 3’, which is obtained by this method of separation of isomers, is maintained during the entire sequence of reactions, and the result is the desired R or S isomer of formula I or II. The separation of R and S isomers can be performed by enzymatic hydrolysis of any hydroxy(ness.)alkyl esters of compounds 3 or 3’ (see, for example, Ahmar, M., Girard, S., Bloch R., Tetrahedron Lett., 7053 (1989)), which yields a mixture of the corresponding chiral acid and chiral complex ester. Ester and acid can be divided by any known method of separating acids from complex ester. Another preferred method of separation of racemates of compounds 3 or 3’ is receiving corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be obtained by condensation of carboxylic acids of 3 or 3’ with a chiral alcohol or chiral is an amine. The reaction is carried out in the usual method of condensation of carboxylic acids with alcohol or amine. The corresponding diastereomers derivatives of carboxylic acids of 3 or 3’ can be divided by any conventional separation method, for example, IHVR. Net diastereomeric esters or amides can then hydrolyze the corresponding pure R or S isomers. The hydrolysis is carried out by any conventional methods of hydrolysis of esters or amides, excluding racemization.

Due to its ability to activate glucokinase the compounds of formula I can be used as medicines for the treatment of type II diabetes. Therefore, as described above, an object of the present invention are also pharmaceutical preparations containing the compound of formula I, and the method of obtaining such drugs, and the method includes processing one or more compounds of the formula I and, optionally, one or more other therapeutically valuable compounds in finished herbal form, for example, mixing the compounds of formula I with a pharmaceutically acceptable carrier and/or adjuvant.

The pharmaceutical compositions can be administered orally by the way, for example, in the form of pills, tablets in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. BBB is Denia can also be carried out rectally way for example, using suppositories, local and percutaneous manner, for example, using ointments, creams, gels or solutions, or parenteral methods, such as intravenous, intramuscular, subcutaneous, intrathecal or percutaneous methods, using, for example, injection solutions. In addition, the introduction can be sublingual way or in aerosol form, for example, in the form of a spray. At reception of tablets, pills in the shell, coated tablets or hard gelatin capsules of the compounds of the present invention is mixed with pharmaceutically inert, inorganic or organic excipients. For example, suitable excipients for tablets, coated tablets or hard gelatin capsules include lactose, corn starch or its derivatives, talc or stearic Kishimoto or a salt thereof. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like, however, depending on the properties of the active ingredients in the case of soft gelatin capsules excipient may be unnecessary. Excipients to obtain solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Excipients for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Excipient the s for suppositories and local or percutaneous injection include, for example, vegetable and hardened oils, waxes, fats and semi-solid or liquid polyols. Pharmaceutical compositions may also contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, substances shell or antioxidants. As indicated above, the composition may also contain other therapeutically valuable substances. It is assumed that all used drugs adjuvants are non-toxic.

The preferred forms of use are intravenous, intramuscular or oral route of administration, the most preferred oral way. Dose, in which the compounds of formula I administered in effective amounts depend on the nature of the particular active ingredient, the age and condition of the patient, and the route of administration. In the General case we are talking about doses approximately 1-100 mg/kg of body weight per day.

The invention is illustrated by the following examples without limiting its scope specified in the claims.

Examples synthesis

Example 1

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

(S)-3-Cyclohexyl-2-(1-oxo-1,3-is hydroisotop-2-yl)-propionic acid

A mixture of hydrate of (S)-(+)-α-aminocyclohexanone acid (5,00 g, 29,2 mmole) and phthalic dicarboxaldehyde (4,21 g, 31,3 mmole) in acetonitrile (120 ml) was boiled under reflux in nitrogen atmosphere for 20 hours the Mixture was cooled to room temperature and then to 0°C. the Solid is separated by filtration and once washed with cold acetonitrile (50 ml), was received 6,54 g (yield 78%) of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid white color. MCBP(EI): m/e Rasch. for C17H21NO3(M+) 287,1521, neid. 287,1521.

Stage B

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

To a solution of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (286 mg, 1.0 mmole, obtained as described in stage a), hexaflurophosphate O-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (THIEF, 500 mg, 1.1 mmole) and 2-aminothiazole (125 mg, 1.2 mmole) in dry methylene chloride (10 ml) at 0°With the aqueous phase was added N,N-diisopropylethylamine (0,55 ml, 3.1 mmole). The mixture was heated to room temperature and was stirred overnight. Then added water, the organic layer was washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified Express chromatography (Biotage column 40S, eluent: 3% methanol/holdem is risty methylene), when this was received 325 mg (75%yield) of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic foam light brown color. MCBP(EI): m/e Rasch. for C20H23N3O2S (M+) 369,1511, neid. 369,1513.

Example 2

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide received in the form of a solid white color (yield 59%), MCBP(EI): m/e Rasch. for C20H22lN3O2S (M+) 403,1121, neid. 403,1124 during condensation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (120 mg, of 0.42 mmole, obtained as described in example 1, stage A) with the hydrochloride of 2-amino-5-chlorothiazole (90 mg, of 0.51 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic.

Example 3

(S)-N-(5-Bromothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide

To a suspension of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic (21 mg, 0.06 to mmole, obtained as described in example 1) and N-bromosuccinimide (11 mg, 0.06 to mmole) in anhydrous carbon tetrachloride (1.0 ml) was added b is serperated (1 mg, of 0.004 mmole). The mixture was stirred at 95 C in a sealed tube. After 1.5 h was added N-bromosuccinimide (2 mg) and benzoyl peroxide (1 mg) and the mixture was stirred for a further 30 minutes the mixture is Then cooled to room temperature and the solvent was removed in vacuum. The residue was transferred into ethyl acetate and washed with water. The organic extract was washed with saline, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified Express chromatography (Biotage 12S, eluent: 20% ethyl acetate/hexane), to receive 15 mg (yield 58%) of (S)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)propionamide foam gray. MCBP(EI): m/e Rasch. for C20H23BrN3O2S (M+) 447,0616, neid. 447,0623.

Example 4

(S)-3-Cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

Stage And

4,5-Dichloro-1,2-dihydroxyethylene

To a mixed solution of a complex of borane-tetrahydrofuran (45 ml of a 1.5 M solution in tetrahydrofuran/diethyl ether) at 0°C in nitrogen atmosphere is added dropwise within 20 min was added a solution of 4,5-dichlorphenol acid (USD 5,013 g, 21.1 mmole) in tetrahydrofuran (35 ml). After adding the reagent, and the mixture was stirred at 0°for 2.5 hours the Reaction was stopped by slow doba the population of methanol until gas evolution stops. The mixture was stirred at room temperature for 30 min and the solvent was removed in vacuum. The residue was transferred into ethyl acetate, washed with saturated sodium bicarbonate solution and saline. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuum, when it got to 4.41 g (yield 100%) of 4,5-dichloro-1,2-dihydroxyethylene in a solid white color. MCHP(ES): Rasch. for C8H7CL2O2(M+-1) 205, neid. 205.

Stage B

4,5-Dichloromaleic 1,2-dicarboxaldehyde

To a stirred solution of oxalicacid (2,6 ml, 29,2 mmole) in anhydrous methylene chloride (35 ml) in a nitrogen atmosphere at -78°C was added dropwise a solution of dimethylsulfoxide (4,2 ml, 59.1 mmole) in methylene chloride (10 ml). The solution was stirred for 10 min, then was added dropwise a solution of 4,5-dichloro-1,2-dihydroxyethylene (2.50 g, 12,1 mmole) in 16 ml of methylene chloride/DMSO, 1:1, and the resulting mixture was stirred at -78°C for 2 hours Then to the mixture slowly over 15 min was added triethylamine (30 ml, to 17.6 mmole) and the mixture was heated to room temperature within 2 hours the Mixture was diluted with cold water (150 ml) and was extracted with methylene chloride. The extracts were washed 1H. HCl, dried over sodium sulfate and concentrated, to receive 2.58 g of 4,5-dichlorphenol 1,2-di is carboxaldehyde in a solid yellow color. MCHP(ES): Rasch. for C8H3O2(M+-1) 201, neid. 201.

Stage

(S)-3-Cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid

A mixture of hydrate of (S)-(+)-α-aminocyclohexanone acid (1,05 g of 5.83 mmole) and 4,5-dichlorphenol of dicarboxaldehyde (1,25 g, 5,86 mmole, obtained in stage B) in acetonitrile (35 ml) was boiled under reflux in an argon atmosphere for 2 hours the Mixture was cooled and kept at room temperature for 2 hours, the Solid was separated by filtration and once washed with cold acetonitrile, were received of 1.33 g (yield 64%) of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid light brown color. Msvr(EI): m/e Rasch. for C17H19Cl2NO3(M+) 355,0742, neid. 355,0747.

Stage D

(S)-3-Cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

(S)-3-Cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic received in the form of a beige foam (yield 35%), MCBP(EI): m/e Rasch. for C20H21Cl2N3O2S (M+) 437,0731, neid. 437,0725 during condensation of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (248 mg, 0,70 mmole, obtained in stage b) with 2-aminothiazole (91 mg, from 0.88 mmole) in the presence the AI THIEF just as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic.

Example 5

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-

oxo-1,3-dihydroindol-2-yl)propionamide

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide received in the form of a solid beige color (yield 37%), MCBP(EI): m/e Rasch. for C20H20Cl3N3O2S (M+) 471,0342, neid. 471,0345 during condensation of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (250 mg, 0.70 to mmole, obtained as described in example 4, stage b) with the hydrochloride of 2-amino-5-chlorothiazole (154 mg, from 0.88 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic.

Example 6

(S)-N-(5-Bromothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-

1-oxo-1,3-dihydroindol-2-yl)propionamide

(S)-N-(5-Bromothiazole-2-yl)-3-cyclohexyl-2-(5,6-

dichloro-1-oxo-1,3-dihydroindol-2-yl)propionamide received in the form of a solid beige color (yield 40%), MCBP(EI): m/e Rasch. for C20H20BrCl2N3O2S (M+) 514,9837, neid. 514,9836 during condensation of (S)-3-cyclohexyl-2-(5,6-dichloro-1-the CSR-1,3-dihydroindol-2-yl)propionic acid (248 mg, 0,70 mmole, obtained as described in example 4, stage b) with the hydrochloride of 2-amino-5-bromothiazole (154 mg, of 0.89 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic.

Example 7

(S)-N-(1H-Benzimidazole-2-yl)-3-cyclohexyl-2-

(1-oxo-1,3-dihydroindol-2-yl)propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (287 mg, 1.0 mmole, obtained as described in example 1, stage A) are condensed with 2-aminobenzimidazole (119 mg, 1.0 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The crude product was purified by reversed-phase GHUR (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient of 10% acetonitrile/water/0.1% of triperoxonane acid to 100% acetonitrile). Combined fractions containing product were concentrated to remove the principal amount of acetonitrile and then was extracted with ethyl acetate. The extracts were dried (sodium sulfate) and concentrated in vacuum, it was received 240 mg (yield 60%) of (S)-N-(1H-benzimidazole-2-yl)-3-cyclohexyl-2-(1-oxo-

1,3-dihydroindol-2-yl)propionamide in a solid white color. MCBP(EI): m/e Rasch. for C24Hsub> 26N4O2(M+) 402,2056, neid. 402,2056.

Example 8

(S)-N-Benzothiazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (144 mg, 0.5 mmole, obtained as described in example 1, stage A) are condensed with 2-aminobenzothiazole (81 mg, 0.55 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The crude product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent: 35% ethyl acetate/hexane), was obtained 185 mg (yield 44%) of (S)-N-benzothiazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide in a solid white color. MCBP(EI): m/e Rasch. for C24H25N4O2S (M+) 419,1667, neid. 419,1661.

Example 9

(R)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

(R)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid

A mixture of the hydrochloride of (R)-(+)-α-aminocyclohexanone acid (2,69 g, 15.7 mmole) and phthalic dicarboxaldehyde (2.50 g, a 14.6 mmole) in acetonitrile (120 ml) was boiled under reflux in nitrogen atmosphere for 42 hours the Mixture is cooled is about room temperature, and then to 0°C. the Solid is separated by filtration and once washed with cold acetonitrile, obtained 2.65 g (yield 63%) of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid white color. MCBP(EI): m/e Rasch. for C17H21NO3(M+) 287,1521, neid. 287,1523.

Stage B

(R)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

To a solution of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (144 mg, 0.5 mmole, obtained as described in stage a), hexaflurophosphate O-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (THIEF, 268 mg, 0.55 mmole) and 2-aminothiazole (50 mg, 0.5 mmole) in dry methylene chloride (3 ml) at room temperature was added dropwise N.N-diisopropylethylamine (of 0.20 ml, 1.15 mmole) and the mixture was stirred for 1 h Then the mixture was diluted with methylene chloride and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuum. The crude product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent: 35% ethyl acetate/hexane), was obtained 150 mg (yield 81%) of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in the form of foam off-white color. MCBP(EI): m/e Rasch. for C20H23N3O2S (M+) 369,1511, neid. 369,1511.

Example 10

(S)-3-CEC is hexil-2-(1-oxo-1,3-dihydroindol-2-yl)-N-quinoline-2-yl-propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-quinoline-2-yl-propionamide received in the form of a solid white color (yield 99%), MCBP(EI): m/e Rasch. for C26H27N3O2(M+) 413,2103, neid. 413,2103 during condensation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid (288 mg, 1.0 mmole, obtained as described in example 1, stage A) with 2-aminoquinoline (180 mg, 1.2 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroiso-indol-2-yl)-N-thiazol-2-ylpropionic.

Example 11

11.1. (S)-3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic and

11.2. (S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

4-Nitro-1,2-dihydroxyethylene

To a mixed solution of a complex of borane-tetrahydrofuran (70 ml of 1.5 M solution in tetrahydrofuran/diethyl ether) at 0°C in nitrogen atmosphere is added dropwise within 20 min was added a solution of 4-nitrophthalic acid (7.01 g, a 33.2 mmole) in tetrahydrofuran (50 ml). After adding the reagent, and the mixture was stirred at 0°for 3.5 hours and Then the mixture was heated to room temperature and boiled under reflux for 18 hours the Mixture OHL who was waiting to room temperature, the reaction was stopped by adding methanol and the mixture was concentrated in vacuum. The residue was transferred into ethyl acetate, washed with saturated sodium bicarbonate solution and saline. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuum to receive 5,61 g (yield 92%) of 4-nitro-1,2-dihydroxyethylene in a solid white color. MCHP(ES): Rasch. for C8H8NO4(M+-1) 182, neid. 182.

Stage B

4-Nitro-ortho-phenylene-1,2-dicarboxaldehyde

To a stirred solution of oxalicacid (4,90 ml, 55,0 mmole) in anhydrous methylene chloride (60 ml) in a nitrogen atmosphere at -78°C was added dropwise a solution of dimethylsulfoxide (8,20 ml, 115 mmole) in methylene chloride (20 ml). The solution was stirred for 10 min and was added dropwise a solution of 4-nitro-1,2-dihydroxyethylene (3,99 g and 21.8 mmole) in 20 ml of methylene chloride/DMSO, 1:1. The resulting mixture was stirred at -78°C for 3 h, and then slowly over 15 min was added triethylamine (60 ml, 426 mmol) and the mixture was heated to room temperature within 2 hours the Mixture was diluted with cold water (300 ml) and was extracted with methylene chloride. The extracts were washed 1 .hcl, dried over sodium sulfate and concentrated, the crude 4-nitro-ortho-phenylene-1,2-dicarboxaldehyde was purified Express chromatography (iotage 40M eluent: 35% ethyl acetate/hexane), was obtained 2.5 g (yield 64%) of 4-nitro-1,2-dicarboxaldehyde. According to NMR the purity of the product was 40%. MCHP(ES): Rasch. for C8H4NO2(M+-1) 178, neid. 178.

Stage

(S)-3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)propionic acid

A mixture of hydrate of (S)-(+)-α-aminocyclohexanone acid (0,708 g, 3,93 mmole) and 4-nitrophthalimide of dicarboxaldehyde (2,02 g of 3.95 mmole, obtained in stage B) in acetonitrile (20 ml) was boiled under reflux in an argon atmosphere. Then portions over 2 h was added an additional amount of hydrate (S)-(+)-α-aminocyclohexanone acid (0,775 g, 4,30 mmole) and the mixture is boiled under reflux during the night. The mixture was cooled to room temperature, the solid was separated by filtration and once washed with cold acetonitrile, to receive solid beige color (0,511 g)containing (S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)propionic acid in a mixture with regioisomers (S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-

2-yl)propionic acid in a ratio of 1:2,7. The filtrate was concentrated in vacuo, the residue was recrystallized from acetonitrile, to receive the second portion of the product (1.01 g), enriched (S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroiso the ol-2-yl)propionic acid. MCHP(ES) of the mixture: Rasch. for C17H19N2O5(M+-1) 331, neid. 331.

Stage D

(S)-3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic and

(S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

(S)-3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (301 mg, of 0.91 mmole, mixture of regioisomers in a ratio of about 1:1, obtained in stage B) are condensed with 2-aminothiazole (116 mg, 1.12 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40M, eluent: 30% ethyl acetate/hexane) received 131 mg (S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-

yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C20H22N4O4S (M+) 414,1362, neid. 414,1362, and 121 mg of regioisomer(S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C20H22N4O4S (M+) 414,1362, neid. 414,1368.

Example 12

12.1. (S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(5-nitro-

1-oxo-1,3-dihydroindol-2-yl)propionamide and

12.2. (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(6-nitro-

1-oxo-1,3-dihydroindol-2-yl)propionamide

(S)-3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (307 mg, of 0.92 mmole, a mixture of 5,6-regioisomers in a ratio of about 1:1, obtained in stage B) are condensed with the hydrochloride of 2-amino-5-chlorothiazole (360 mg, 2,04 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40M, eluent: 25% ethyl acetate/hexane) received 134 mg (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(5-nitro-1-

oxo-1,3-dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21ClN4O4S (M+) 448,0972, neid. 448,0970, and 111 mg of regioisomer (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(6-nitro-1-

oxo-1,3-dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21ClN4O4S (M+) 448,0972, neid. 448,0972.

Example 13

13.1. (S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-

dihydroindol-2-yl)propionamide and

13.2. (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-

dihydroindol-2-yl)propionamide

Stage And

3-Fluoro-1,2-di(hydroxymethyl)benzene

To a mixed solution of a complex of borane-tetrahydrofuran (50 ml of 1.5 M solution in tetrahydrofuran/diethyl ether) at 0°C in an atmosphere of argon is added dropwise in the course is e 15 min was added a solution of 3-portaliou acid (4,51 g, 24,0 mmole) in tetrahydrofuran (40 ml). After adding the reagent, and the mixture was stirred at 0°C for 2 hours Then the mixture was heated to room temperature and boiled under reflux for 20 hours the Mixture was cooled to room temperature, the reaction was stopped by adding methanol (30 ml) and the mixture was concentrated in vacuum. The residue was transferred into ethyl acetate (150 ml) and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2×125 ml) and the combined extracts were washed with saline. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuum, when it got to 3.73 g (yield 99%) of 3-fluoro-1,2-di(hydroxymethyl)benzene in the form of a solid white color. MCHP(ES): Rasch. for C8H8FO2(M-1) 155, neid. 155.

Stage B

3-Portalify dicarboxaldehyde

To a stirred solution of oxalicacid (2,80 ml, 31.5 mmole) in anhydrous methylene chloride (35 ml) in a nitrogen atmosphere at -78°C was added dropwise a solution of dimethylsulfoxide (4.6 ml, 64.7 mmole) in methylene chloride (10 ml). The solution was stirred for 30 min and then was added dropwise a solution of 3-fluoro-1,2-dihydroxyethylene (2.00 g, 12.8 mmole) in 20 ml of methylene chloride/DMSO, 1:1. The resulting mixture was stirred at -78°C for 2.5 h, slowly than the s 15 min was added triethylamine (35 ml, 248,6 mmole), was stirred at -78°C for 30 min, and then heated to room temperature within 4 h the Mixture was poured into cold water (200 ml) and was extracted with methylene chloride. The extracts were washed 1.HCl, brine, dried (sodium sulfate) and concentrated, to receive the crude 3-portalify dicarboxaldehyde, which was used without further purification. MCHP(ES): Rasch. for C8H4FO2(M+-1) 151, neid. 151.

Stage

(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid

A mixture of hydrate of (S)-(+)-α-aminocyclohexanone acid (0.565 g, 3,14 mmole) and 3-porftolio of dicarboxaldehyde (1.60 g, and 3.16 mmole, obtained in stage B) in acetonitrile (20 ml) was boiled under reflux in an argon atmosphere. Then portions over 7 h was added an additional amount of hydrate (S)-(+)-α-aminocyclohexanone acid (0,437 g, 2,43 mmole) and the mixture is boiled under reflux for 72 hours the Mixture was cooled to room temperature over 3 h and kept in the refrigerator for 1 hour, the Solid was separated by filtration and once washed with cold acetonitrile, to receive solid white (1.39 g, yield 77%)containing (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid in a mixture of Regio what Zomer (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-

dihydroindol-2-yl)propionic acid in a ratio of about 1:1. MCHP(ES): Rasch. for C17H19FNO3(M+-1) 304, neid. 304.

Stage D

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(4-fluoro-

1-oxo-1,3-dihydroindol-2-yl)propionamide and

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-fluoro-

1-oxo-1,3-dihydroindol-2-yl)propionamide

(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (501 mg, of 1.64 mmole, mixture of regioisomers in a ratio of about 1:1, obtained in stage B) are condensed with the hydrochloride of 2-amino-5-chlorothiazole (643 mg, 3.64 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After GHUR product on normal phase chromatograph Waters Prep 500, when applying column equilibrated methylene chloride, eluent: 20% ethyl acetate/hexane) received 194 mg (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-fluoro-1-

oxo-1,3-dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21ClFN3O2S (M+) 421,1027, neid. 421,1024, and 173 mg of regioisomer (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-fluoro-1-

oxo-1,3-dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21ClFN3O2S (M+) 421,1027, neid. 421,1031.

Example 14

3-Cyclohexyl-2-(1-oxo-1,3-dihydro shall isoindol-2-yl)-N-pyrimidine-4-yl-propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-aminopyrimidine (108 mg, to 1.14 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent: 50% ethyl acetate/hexane), was obtained 271 mg (yield 74%) of 3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C21H24N4O2(M+) 364,1899, neid. 364,1893.

Example 15

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-aminopyrazine (95 mg, 1.00 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent 50% ethyl acetate/hexane), was obtained 350 mg (yield 96%) of (S)-3-cyclohexyl-2-(1-about the co-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C21H24N4O2(M+) 364,1899, neid. 364,1908.

Example 16

(S)-N-Benzoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (144 mg, of 0.50 mmole, obtained as described in example 1, stage A) are condensed with 2-aminobenzimidazole (67 mg, of 0.50 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent 50% ethyl acetate/hexane), was obtained 161 mg (yield 96%) of (S)-N-benzoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C24H25N3O3(M+) 403,1896, neid. 403,1895.

Example 17

3-Cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

3-Cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-propionic acid

A mixture of 2-amino-3-cyclopentylpropionic acid (0.800 to g 5,09 mmole) and phthalic dicarboxaldehyde (0,684 g, 5,10 mmole) in acetonitrile (30 ml) was boiled under reflux for 3 h under nitrogen atmosphere. A mixture of ohlord is whether to room temperature, the formed solid substance was separated by filtration, once washed with cold acetonitrile (5 ml), was received of 1.16 g (yield 83%) of 3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid white color. MCBP(EI): m/e Rasch. for C16H19NO3(M+) 273,1365, neid. 273,1374.

Stage B

3-Cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

3-Cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (273 mg, 1.00 mmol, obtained in stage A) are condensed with 2-aminothiazole (100 mg, 1.00 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent of 40% ethyl acetate/hexane), was obtained 132 mg (yield 37%) of 3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in a solid white color. MCBP(EI): m/e Rasch. for C19H21N3O2SNa (M++PA+) 378,1247. neid. 378,1250.

Example 18

N-(5-Chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide

3-Cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (277 mg, 1,01 mmole, obtained as described in example 1, stage A) what was undesirable hydrochloride 2-amino-5-chlorothiazole (397 mg, 2,30 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (Biotage 40M, eluent 20% ethyl acetate/hexane), was obtained 290 mg (yield 74%) of N-(5-chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide in the form of a solid of light yellow color. MCBP(EI): m/e Rasch. for C19H21N3About2S (M+) 389,0965, neid. 389,0966.

Example 19

3-Cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

Cycloheptadecane

To a mixed solution of a complex of borane-tetrahydrofuran (95 ml of 1.5 M solution in tetrahydrofuran/ether) at 0°C in an atmosphere of argon was added cycloheptanone acid (of 10.05 g, 69.3 mmole) in 30 ml of tetrahydrofuran. After 2 h the reaction was stopped by the careful addition of methanol and the mixture was concentrated in vacuum. The residue was transferred into ethyl acetate and sequentially washed with 1N. HCl saturated solution of sodium bicarbonate and saline. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuum to receive 9,19 g (yield 100%) of cycloheptanone in the form of a colorless oil.

Stage B

Cycloheptylmethyl

To paramashiva is the PTO to a solution of triphenylphosphine (24,59 g, 92,8 mmole) and imidazole (6,40 g, br93.1 mmole) in methylene chloride (100 ml) at 0°With portions over 10 min was added iodine (23,52 g of 92.7 mmole). Then within 5 min solution was added cyclopentanemethanol (9,14 g, 71.3 mmole) in methylene chloride (50 ml). The cooling bath was removed, the mixture was heated to room temperature and was stirred overnight. The mixture is then diluted with methylene chloride, washed with water, the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuum. The crude product was purified by chromatography (eluent: hexane), was obtained 15,35 g (yield 93%) of cycloheptylmethyl in the form of oil.

Stage

Tert-butyl ester 2-(benzhydrylidene)-3-cycloheptylamine acid

To a stirred solution of tert-butyl methyl ether (benzhydrylidene)acetic acid (2,56 g, 8,68 mmole) in 30 ml of tetrahydrofuran at -78°C in an atmosphere of argon was added dropwise a solution of diisopropylamide lithium (10.0 ml, 1.5 M solution in cyclohexane). After 30 min was added dropwise a solution of cycloheptylamine (3,48 g of 14.6 mmole, obtained in stage B) in 20 ml of tetrahydrofuran, the mixture was heated to room temperature and was stirred for 18 hours Then the reaction was stopped by adding a saturated solution of ammonium chloride (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. Obyedinenny the organic layers were dried (sodium sulfate), was filtered and concentrated in vacuum. The crude product was purified by chromatography (Biotage 40 M, eluent 5% ethyl acetate/hexane), was obtained of 2.56 g (yield 73%) of tert-butyl methyl ether 2-(benzhydrylidene)-3-cycloheptylamine acid in the form of oil is light yellow in color.

Stage D

2-Amino-3-cycloheptylamine acid

To a solution of tert-butyl methyl ether 2-(benzhydrylidene)-3-cycloheptylamine acid (1,34 g of 3.31 mmole) in methanol (5 ml) was added 10.l (15 ml) and the resulting mixture was boiled under reflux. After 15 h the mixture was cooled to room temperature, transferred into a separating funnel and washed with ethyl acetate. The aqueous layer was neutralized with concentrated ammonium hydroxide solution, the resulting solid white color was separated by filtration and dried in air, when it received 329 mg of 2-amino-3-cycloheptylamine acid.

Stage D

3-Cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid

A solution of phthalic dicarboxaldehyde (248 mg, of 1.80 mmole) and 2-amino-3-cycloheptylamine acid (318 mg, 1,72 mmole) in acetonitrile was heated under reflux for 18 hours Then the mixture was cooled to room temperature and kept in the refrigerator for 3 hours the Formed solid substance was separated by filtration, washed with cold and what lonitrile and dried in the air, when this was received 424 mg (yield 82%) of 3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid beige color. MCBP(EI): m/e Rasch. for C18H23NO3(M+) 301,1678, neid. 301,1668.

Stage E

3-Cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

3-Cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (173 mg, of 0.58 mmole, obtained in stage D) are condensed with 2-aminothiazole (97 mg, of 0.94 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when they arrive, (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (Biotage 40S, eluent: 35% ethyl acetate/hexane), was obtained 217 mg (yield 99%) 3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C21H25N3O2S (M+) 383,1667, neid. 383,1660.

Example 20

N-(5-Chlorothiazole-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide

3-Cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (177 mg, of 0.59 mmole, obtained as described in example 19, step D) are condensed with the hydrochloride of 2-amino-5-chlorothiazole (168 mg, 0.95 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclog the KSIL-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (Biotage 40M, eluent 20% ethyl acetate/hexane), was obtained 99 mg (yield 40%) of N-(5-chlorothiazole-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide in the form of foam off-white color. MCBP(EI): m/e Rasch. for C21H24ClN3O2S (M+) 417,1278, neid. 417,1289.

Example 21

3-Cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

Cyclooctylmethyl

To a stirred solution of cyclooctylmethyl (5,00 g of 35.2 mmole) and iodine (8,93 g of 35.2 mmole) in dry methylene chloride (100 ml) at room temperature portions over 10 min was added triphenylphosphine (9,23 g of 35.2 mmole). After 1 h the mixture was diluted with methylene chloride, washed with water and a saturated solution of sodium bisulfite, the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuum. The crude product was purified by chromatography (eluent: hexane), was obtained 5.35 g (yield 60%) of cyclooctylmethyl in the form of oil.

Stage B

Tert-butyl ester 2-(benzhydrylidene)-3-cyclooctylamino acid

To a stirred solution of tert-butyl methyl ether (benzhydrylidene)acetic acid (3.00 g, 10.1 mmole) in 60 ml of tetrahydrofuran at -78°C in an atmosphere of argon was added dropwise a solution of diisopropylamide lithium (11.5 ml,1.5 M solution in cyclohexane). After 30 min dropwise by syringe solution was added cycloheptylmethyl (3,83 g, 15.2 mmole, obtained in stage A), the mixture was heated to room temperature and was stirred for 18 hours Then the reaction was stopped by adding saturated sodium bicarbonate solution and most of the tetrahydrofuran was removed in vacuum. The mixture was diluted with water and was extracted with methylene chloride. The combined extracts were dried (sodium sulfate), filtered and concentrated in vacuum. The crude product was purified by chromatography (eluent: 4% ethyl acetate/hexane), was obtained 3,34 g (yield 79%) of tert-butyl methyl ether 2-(benzhydrylidene)-3-cyclooctylamino acid in the form of oil is light yellow in color.

Stage

2-Amino-3-cyclooctylamino acid

To a solution of tert-butyl methyl ether 2-(benzhydrylidene)-3-cyclooctylamino acid (2.00 g) in methanol (15 ml) was added 10h. HCl (30 ml) and the resulting mixture was boiled under reflux. After 20 h the mixture was cooled to room temperature, diluted with 20 ml water, transferred into a separating funnel and washed with ethyl acetate. The aqueous layer was neutralized 10h. sodium hydroxide and then cooled to 0°C. the Formed solid white color was separated by filtration and dried in air, when it received 590 mg of 2-amino-3-cyclooctylamino acid.

Stage D

3-Cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid

A solution of phthalic dicarboxaldehyde (349 mg, 2,60 mmole) and 2-amino-3-cyclooctylamino acid (500 mg, of 2.51 mmole) in acetonitrile (20 ml) was boiled under reflux for 3 hours the mixture is Then filytrovali hot to remove insoluble material was cooled to room temperature and then to 0°C. the Formed solid substance was separated by filtration, washed with cold acetonitrile and dried in air, were obtained 480 mg (yield 62%) of 3-cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid in the form of a solid white color. MCBP(EI): m/e Rasch. for C19H25NO3(M+) 315,1834, neid. 315,1840.

Stage D

3-Cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

3-Cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (200 mg, 0.65 mmole, obtained in stage G) are condensed with 2-aminothiazole (70 mg, 0,70 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (eluent: 30% ethyl acetate/hexane), was obtained 226 mg (yield 88%) of 3-cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in the form of a white foam CEE is and. MCBP(EI): m/e Rasch. for C22H27N3O2S (M+) 397,1824, neid. 397,1825.

Example 22

(R)-N-(5-Bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-amino-5-bromopyridine (173 mg, 1.00 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent 30% ethyl acetate/hexane), was obtained 243 mg (yield 55%) of (S)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)propionamide in the form of a white foam. MCBP(EI): m/e Rasch. for C22H24BrN3O2(M+) 441,1052, neid. 441,1036.

Example 23

23.1. (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic and

23.2. (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (499 mg, and 1.63 mmole, mixture of regioisomers in a ratio of 1:1 are condensed with 2-aminothiazole (376 mg, 3.64 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After rapid chromatography of the product (Biotage 40M, eluent: 30% ethyl acetate/hexane) was obtained (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic (221 mg), MCBP(EI): m/e Rasch. for C20H22FN3O2S (M+) 387,1417, neid. 387,1422, and the crude (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic, which was purified by radial chromatography (eluent: 35% ethyl acetate/hexane), was obtained 48 mg of pure (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C20H22FN3O2S (M+) 387,1417, neid. 387,1415.

Example 24

(S)-3-Cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydroindol-

2-yl)propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-aminoimidazole (241 mg, to 1.79 mmole) in the presence of a THIEF, in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express-chromatographie the (Biotage 40M, eluent: 4% methanol/methylene chloride), was 320 mg (S)-3-cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydroindol-

2-yl)propionamide, after recrystallization from ethyl acetate/hexane received 209 mg of the pure product. MCBP(EI): m/e Rasch. for C20H24N4O2(M+) 352,1899, neid. 352,1895.

Example 25

25.1. (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic and

25.2. (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (331 mg, 1,08 mmole, mixture of regioisomers in a ratio of 1:1) are condensed with 2-aminopyrazine (232 mg, 2,41 mmole) in the presence of a THIEF in the same way as described in example 9, step B when obtaining (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After rapid chromatography of the product (Biotage 40M, eluent: 30% ethyl acetate/hexane) was obtained (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic, which then was purified by reversed-phase GHUR (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient of 40% acetonitrile/water/0.1% t everysunday acid → 100% acetonitrile), was obtained 39 mg of pure (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic in the form of a white foam, MCBP(EI): m/e Rasch. for C21H23FN4O2(M+) 382,1805, neid. 382,1794, and 43 mg of regioisomer (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C21H23FN4O2(M+) 382,1805, neid. 382,1810.

Example 26

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-

2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-aminopyridine (94 mg, 1.00 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent: 45% ethyl acetate/hexane), was obtained 186 mg (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-elapinae in the form of a white foam. MCBP(EI): m/e Rasch. for C22H25N3O2(M+) 363,1947, neid. 363,1935.

Example 27

(S)-N-3-Cyclohexyl-N-(2-methylpyrimidin-4-yl)-2-(1-oxo-1,3-dihydroindol-

2-yl)propionamide

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (150 mg, of 0.52 mmole, obtained as described in example 1, stage A) are condensed with 2-amino-6-methylpyrimidine (57 mg, of 0.52 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving (R)-3-cyclohexyl-2-(1-oxo-1,3-

dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh, eluent: 65% ethyl acetate/hexane), was obtained 109 mg of (S)-3-cyclohexyl-N-(2-methylpyrimidin-4-yl)-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide in the form of a white foam. MCBP(EI): m/e Rasch. for C22H26N4O2(M+) 378,2056, neid. 378,2054.

Example 28

28.1. (S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic and

28.2. (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

Stage And

Dimethyl 3-portaliou acid

Through a solution of 3-portaliou acid (2.00 g, up 10.9 mmole) in dry methanol under stirring at room temperature for 2 min missed gaseous hydrogen chloride. The mixture was heated to the boiling point of the solvent, was heated under reflux for 1 h, was added 1 ml of concentrated sulfuric acid and boiled with about ATiM fridge for 22 PM Then the mixture was cooled to room temperature and neutralized with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered and concentrated in vacuum to receive 1.70 g of dimethyl ester of 3-portaliou acid in the form of oil.

Stage B

3-Dimethylphthalate acid

A mixture of dimethyl 3-portaliou acid (2,27 g, 10.7 mmole) and timelocked sodium (6,34 g, 85,9 mmole) in DMSO (20 ml) was heated to 50°C. After 24 h was added to crushed ice and the resulting mixture was acidified using 1N. HCl Solution was extracted with ethyl acetate, the extracts washed with brine, dried (sodium sulfate), filtered and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient from 0% acetonitrile/water/0.1% of triperoxonane acid →100% acetonitrile), was obtained 802 mg 3 dimethylphthalate acid.

Stage

3-Thiomethyl-1,2-di(hydroxymethyl)benzene

To a mixed solution of a complex of borane-tetrahydrofuran (14,0 ml of 1.5 M solution in tetrahydrofuran/diethyl ether) at 0°C in an atmosphere of argon was added a solution of 3-dimethylphthalate acid (0,739 g of 3.48 mmole) in 20 ml of tetrahydrofuran. After complete addition, the mixture was boiled under reflux during the 15h. The mixture was cooled to room temperature, the reaction was stopped by adding methanol (20 ml)was boiled under reflux for 2 h and concentrated in vacuum. The residue was distributed between 1 .HCl and ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined extracts were washed with saturated sodium bicarbonate solution, brine, dried (sodium sulfate), filtered and concentrated in vacuum to receive the crude 3-thiomethyl-1,2-di(hydroxymethyl)benzene, which was purified Express chromatography (column Biotage 40M, eluent: gradient of 25%-50% ethyl acetate/hexane), was obtained 454 mg of pure 3-thiomethyl-1,2-di(hydroxymethyl)benzene.

Stage D

3-Dimethylphthalate dicarboxaldehyde

To a stirred solution of oxalicacid (0,42 ml, 4,72 mmole) in anhydrous methylene chloride (5 ml) in an argon atmosphere at -78°C was added dropwise a solution of dimethylsulfoxide (0,70 ml, 9.67 mmole) in methylene chloride (2 ml). The solution was stirred for 10 min and then was added dropwise a solution of 3-thiomethyl-1,2-di(hydroxymethyl)benzene (0,415 g, 2.25 mmole) in 3 ml of methylene chloride/DMSO, 1:1. The resulting mixture was stirred at -78°C for 2 h, and then dropwise added triethylamine (5.5 ml, of 17.4 mmole)was gradually heated to room temperature and was stirred for 20 hours the Mixture was howling is Ali in ice water and the layers were separated. The extract was washed with saline, dried (sodium sulfate) and concentrated, to receive the crude 3-dimethylphthalate dicarboxaldehyde, which was used without further purification.

Stage D

(S)-3-Cyclohexyl-2-(4-methylthio-1-oxo-1,3-dihydroindol-2-yl)propionic acid

A mixture of hydrate of (S)-(+)-α-aminocyclohexanone acid (0.125 g, 0,70 mmole) and crude 3-dimethylphthalate of dicarboxaldehyde (0,250 g, 1.4 mmole, obtained in stage G) in acetonitrile (5 ml) was boiled under reflux in an argon atmosphere for 18 hours the Mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified Express chromatography (Biotage column 40S, eluent: 5% methanol/methylene chloride), received 260 mg (S)-3-cyclohexyl-2-(4-methylthio-1-oxo-1,3-dihydroindol-

2-yl)propionic acid in a mixture with regioisomers (S)-3-cyclohexyl-2-(7-methylthio-1-oxo-1,3-dihydroindol-

2-yl)propionic acid in a ratio of about 1:1.

Stage E

(S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)propionic acid

To a solution of (S)-3-cyclohexyl-2-(4-methylthio-1-oxo-1,3-dihydroindol-

2-yl)propionic acid and regioisomer (S)-3-cyclohexyl-2-(7-methylthio-1-oxo-1,3-dihydroindol-

2-yl)propionic acid (0,790 g, is 2.37 mmole, mix approx the tion 1:1) in formic acid (4 ml) at 0° With was added dropwise 30% hydrogen peroxide solution (1.3 ml, 12.7 mmole), was heated to room temperature and was stirred for 19 h the Mixture was concentrated in a stream of nitrogen to remove formic acid and was obtained of 0.901 g of a mixture of crude (S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)propionic acid and regioisomer (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)propionic acid.

Stage W

(S)-3-Cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)propionic acid and regioisomer (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-

2-yl)propionic acid (112 mg, 0.31 in mmole) are condensed with 2-aminothiazole (54 mg, of 0.52 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-hydroxy-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After rapid chromatography of the product (Biotage 40M, eluent: gradient of 15%-50% ethyl acetate/methylene chloride) was obtained 51 mg (S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C21H25N3O4S2(M+-2) 445,1130, neid. 445,1125, and 39 mg of (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

digit isoindol-2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C21H25N3O4S2(M+) 447,1286, neid. 447,1280.

Example 29

29.1. (S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroiso-indol-2-yl)-N-pyrazin-2-ylpropionic and

29.2. (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)propionic acid and regioisomer (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)propionic acid (200 mg, 0.55 mmole) are condensed with 2-aminopyrazine (88 mg, of 0.91 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After rapid chromatography of the product (Biotage 40S, eluent: gradient of 20%-60% ethyl acetate/methylene chloride) was obtained the crude mixture which was purified by reversed-phase GHUR (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient of 10% acetonitrile/water/0.1% of triperoxonane acid →100% acetonitrile), was obtained 21 mg (S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24N4O4SNa (M++Na+) 465,1567, neid. 465,1570, and 13 mg (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-,3-

dihydroindol-2-yl)-N-pyrazin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24N4O4SNa (M++Na+) 465,1567, neid. 465,1568.

Example 30

30.1. (S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic and

30.2. (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic

(S)-3-Cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)propionic acid and regioisomer (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)propionic acid (200 mg, 0.55 mmole) condensible 4-aminopyrimidine (89 mg, of 0.91 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After rapid chromatography of the product (Biotage 40S, eluent: gradient of 25%-70% ethyl acetate/methylene chloride) received 83 mg (S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic in the form of foam, MCBP(EI): m/e Rasch. for C22H24N4O4SNa (M++Na+) 465,1567, neid. 465,1568, and 77 mg (S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-

dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic in the form of foam, MCBP(EI): m/e Rasch. for C22H26N4O4SNa (M++Na +) 465,1567, neid. 465,1572.

Example 31

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-5-methylpyridin-2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-amino-5-methylpyridine (143 mg, 1,32 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (Biotage 40S, eluent: 30% ethyl acetate/hexane), was obtained 352 mg (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-5-methylpyridin-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C23H27N3O2(M+) 377,2103, neid. 377,2107.

Example 32

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-4-methylpyridin-2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-amino-4-methylpyridine (143 mg, 1,32 mmole) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic. The product was purified by expresscamera (Biotage 40S, eluent: 30% ethyl acetate/hexane), was obtained 344 mg (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-

yl)-N-4-methylpyridin-2-ylpropionic in the form of a white foam. MCBP(EI): m/e Rasch. for C23H27N3About2(M+) 377,2103, neid. 377,2106.

Example 33

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-5-chloropyridin-2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with 2-amino-5-chloropyridine (129 mg, 1.00 mmol) in the presence of a THIEF in the same way as described in example 1, stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (eluent: 25% ethyl acetate/hexane), was obtained 160 mg of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-chloropyridin-2-ylpropionic in the form of a white foam. Msvr(EI): m/e Rasch. for C23H24N3O2ClNa (M++Na+) 420,1449, neid. 420,1451.

Example 34

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-(1-oxypyridine-2-ylpropionic

(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionic acid (287 mg, 1.00 mmol, obtained as described in example 1, stage A) are condensed with N-oaks is the home of 2-aminopyridine (110 mg, 1.00 mmol) in the presence of a THIEF in the same way as described in example 9, step B), obtaining (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. The product was purified Express chromatography (silica gel 60 Merck, 230-400 mesh mesh, eluent: 2% methanol/ethyl acetate), was obtained 340 mg (yield 55%) of (S)-N-(pyridine-N-oxide-2-yl)-3-cyclohexyl-2-

(1-oxo-1,3-dihydroindol-2-yl)propionamide in the form of foam off-white color. According to NMR the product was inhomogeneous, and it was further purified by reversed-phase GHUR (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient of 10% acetonitrile/water/0.1% of triperoxonane acid →100% acetonitrile), was obtained 188 mg of pure (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-

2-yl)-N-(1-oxypyridine-2-yl)propionamide. ICSD(E, S): m/e Rasch. for C22H25N3O3(M++N+) 380, neid. 380.

Example 35

35.1. (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic and

35.2. (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (501 mg, of 1.64 mmole, mixture of regioisomers in a ratio of about 1:1, obtained as described in example 13, step B) are condensed with 2-aminopyridine (64 mg, 3.64 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After reverse-phase GHUR product (chromatograph Rainin Dynamax SD-1, column C18, eluent: gradient of 40% acetonitrile/water/0.1% of triperoxonane acid →70% acetonitrile) received 157 mg of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24FN3O2Na (M++Na+) 404,1745, neid. 404,1748, and 99 mg of regioisomer (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24FN3O2Na (M++Na+) 404,1745, neid. 404,1749.

Example 36

36.1. (S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic and

36.2. (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic

Stage And

3-Chloro-1,2-di(hydroxymethyl)benzene

3-Chloro-1,2-di(hydroxymethyl)benzene was obtained with the yield 97% when recovering 3-gliftalevoj acid with borane in the same way as described in example 13, step A, when receiving 3-fluoro-1,2-di(hydroxymethyl)benzene. 3-Gliftalevye acid was obtained according to the method described in the literature (see Fertel L.B. and other J. Org. Chem., 58(1), 261-263 (1993)).

Studyb

3-Hartley dicarboxaldehyde

3-Hartley dicarboxaldehyde was obtained by oxidation of 3-chloro-1,2-di(hydroxymethyl)benzene (obtained in stage A) in the same way as described in example 13, step B, when receiving a 3-porftolio of dicarboxaldehyde. The crude product was used in the next stage without further purification.

Stage

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid and

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid and (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (in a ratio of about 1:1) was obtained by condensation hydrate (S)-(+)-α-aminocyclohexanone acid with 3-chlorphenesin dicarboxaldehyde (obtained in stage B) same as described in example 13, step B, when receiving the (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionic acid and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-

dihydroindol-2-yl)propionic acid.

Stage D

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic and

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic sour is (326 mg, 1.0 mmol, mixture of regioisomers in a ratio of about 1:1, obtained in stage B) are condensed with 2-aminothiazole (231 mg, of 2.23 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40M, eluent: gradient of 5%-30% ethyl acetate/hexane) received 132 mg (S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C20H22lN3O2S (M++Na+) 426,1013, neid. 426,1016, and 91 mg of regioisomer (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-thiazol-2-ylpropionic, MCBP(EI): m/e Rasch. for C20H22ClN3O2SNa (M++Na+) 426,1013, neid. 426,1017.

Example 37

(S)-N-(5-Chlorothiazole-2-yl)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-

dihydroindol-2-yl)propionamide and

37.2. (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-

dihydroindol-2-yl)propionamide

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (151 mg, of 0.47 mmole, mixture of regioisomers in a ratio of about 1:1, obtained as described in example 36, step B) are condensed with the hydrochloride of 2-amino-5-chlorothiazole (186 mg, 1.05 mmole) in the presence of a THIEF in the same way as described in example stage B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40M, eluent: gradient of 5%-20% ethyl acetate/hexane) received 67 mg (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-

dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21Cl2N3O2S (M+) 437,0731, neid. 437,0727, and 46 mg of regioisomer (S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-

dihydroindol-2-yl)propionamide, MCBP(EI): m/e Rasch. for C20H21Cl2N3O2S (M++Na+) 437,0731, neid. 437,0726.

Example 38

38.1. (S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic and

38.2. (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (201 mg, of 0.62 mmole, mixture of regioisomers in a ratio of about 1:1, obtained as described in example 36, step B) are condensed with 2-aminopyridine (132 mg, of 1.39 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40S, eluent: 30% ethyl acetate/hexane) received 107 mg (S)-3-cyclohexyl-2-(4-chloro-1-the CSR-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24ClN3O2(M+) 397,1557, neid. 397,1563, and 46 mg of regioisomer (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyridin-2-ylpropionic, MCBP(EI): m/e Rasch. for C22H24ClN3O2(M+) 397,1557, neid. 397,1551.

Example 39

39.1. (S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic and

39.2. (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic

(S)-3-Cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionic acid (243 mg, from 0.76 mmole, mixture of regioisomers in a ratio of about 1:1, obtained as described in example 36, step B) are condensed with 2-aminopyrazine (170 mg, or 1.77 mmole) in the presence of a THIEF in the same way as described in example 9, step B, when receiving the (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic. After chromatography of the product (Biotage 40M, eluent: 20% ethyl acetate/hexane) received 53 mg of (S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-

2-yl)-N-pyrazin-2-ylpropionic, MCBP(EI): m/e Rasch. for C21H23ClN4O2(M+) 398,1510, neid. 398,1520, and 41 mg of regioisomer (S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic, MCBP(EI): m/e Rasch. for C21H23ClN 4O2(M+) 398,1510, neid. 398,1507.

Examples of biological tests

All compounds of the present invention, which include the compounds described in the examples, activate glucokinase in vitro according to the determination of biological activity (example A). These compounds increase the inflow of metabolic glucose, which causes increased insulin secretion. Therefore, the compounds of formula I are activators of glucokinase and are used to increase insulin secretion.

Example

Determination of biological activity of compounds in vitro

The definition of glucokinase:

The activity of glucokinase (GK) was determined by the formation of NADH glucose-6-phosphatedehydrogenase (GFDG, 0.75 to 1 ked/mg, firm Boehringer Mannheim, Indianapolis, IN) from Leuconostoc mesenteroides (scheme 2), paired with the synthesis of glucose-6-phosphate.

Scheme 2

Recombinant GK from human liver expressed in E. coli in the form of a chimeric protein with glutathione S-transferase (S-GK) (Liang and others, 1995) and was purified by affinity chromatography on a column of glutathione-separate 4B according to the method of the manufacturer (Amersham Pharmacia Biotech, Piscataway, NJ). Previously it was found that the enzymatic properties of native ha and S-Ledger almost identical (Liang and others, 1995, Neet and others, 1990).

The analysis was carried out at 25°in 96-well tablets with loscam bottom for tissue cultures (Gostar company, Cambridge, MA), the final volume of the reaction mixture was 120 μl. The reaction mixture had the following composition: 25 mm HEPES buffer solution (pH of 7.1), 25 mm KCl, 5 mm D-glucose, 1 mm ATP, 1.8 mm NAD, 2 mm MgCl2, 1 μm sorbitol-6-phosphate, 1 mm dithiotreitol, analyzed drug or 10% DMSO, and 1.8 u/ml GFDG and GK (see below). All organic reagents were of purification >98% (Boehringer Mannheim, D-glucose and HEPES company Sigma Chemical Co, St. Louis, MO). The analyzed compounds were dissolved in DMSO and added to the reaction mixture not containing S-Ledger, in the final volume of 12 ál, and the final concentration of DMSO was 10%. The resulting mixture was pre-incubated in a temperature-controlled chamber microplate spectrophotometer for SPECTRAmax 250, Molecular Devices Corporation, Sunnyvale, CA) for 10 min to achieve temperature equilibrium and then initiated the reaction by adding 20 ál S-Ledger.

After adding enzyme activity Ledger was determined by the increase in optical density (OD) at 340 nm after incubation for 10 min In the reaction mixture were added a number S-Ledger required to increase OD340from 0.08 to 0.1% after 10 min incubation in the wells containing 10%DMSO and not containing the analyzed compound. In preliminary experiments, it was found that the reaction of the Ledger is characterized by a linear dependence within the defined period of time even in the presence of activators, which lead to 5-fold increase in activity Ledger. The activity of the SC in the control wells was compared with the activity in the wells containing the analyzed GK activators, and calculates the concentration of the activator, in which there is increased activity of ha on 50%, i.e. SC1,5.

All compounds of the present invention, described in examples on the synthesis, characterized by the value of SC1,5less than 30 microns, with the exception of the compounds described in example 9, which is characterized by the value of SC1,536 μm. The results obtained show that the compounds possess activating activity against the Ledger.

Literature related to the example And

Liang Y., Kesavan, P., Wang L., Niswender, K., Tanizawa Y., Permut M.A., M. Magnuson and Matschinsky P.M., Variable effects of maturity-onset-diabetes-of-youth (MODY)-associated glucokinase mutations on the substrate interactions and stability of the enzyme, Biochem. J. 309,167-173 (1995).

Neet, K., Keenan R.P. and Tippett P.S., Observation of a kinetic slow transition in monomeric glucokinase. Biochemistry, 29, 770-777 (1990).

Example B

Determination of biological activity of compounds in vivo

The technique of the analysis of glucokinase activator in vivo:

After fasting for 2 h mice C57BL/6J orally via a stomach tube was introduced activator SC at a dose of 50 mg/kg of body weight. The glucose content in blood was determined five times within a 6-hour period after injection.

Mice were weighed (6 individuals) and before the introduction of compounds not feed and within 2 hours The GK activators were dissolved at a concentration of 6,76 mg/ml in media Gelucire (ethanol:Gluir 44/14:PEG q.s., 4:66:30./wt./about). Mice were administered orally with 7.5 μl of composition per 1 g of body weight, equivalent to a dose of 50 mg/kg just before the introduction to determine the level of glucose in the blood (time zero). In the selection of blood was cut off the tip of the tail (~1 mm) and selected 15 µl of blood in heparinised capillary tube for analysis. The level of glucose in blood was determined after 1, 2, 4 and 6 h after injection of the activator Ledger, and the blood was collected as described above. The results are interpreted by comparison of mean values of glucose in blood at 6 mice treated with media containing glucose at 6 mice treated with GK activator within 6 hours. The active compounds attributed such compounds, which caused a statistically significant decrease (p<0.05) of the glucose levels in the blood compared with the level of blood glucose in animals treated with media, when two consecutive measurements.

According to the results of the analysis of the compounds described in examples 1, 18, 22, 23.1, 25.1, 26, 14, 15, 31, 33, had extremely high trigger action against GC in vivo when administered orally according to the method described in example B.

Example

Tablets containing the following ingredients were obtained according to standard methods:

Ingredients mg/tabla is ka

The compound of formula I 10,0-100,0

Lactose 125,0

Corn starch 75,0

Talc 4,0

Magnesium stearate 1,0

Example B

Capsules containing the following ingredients were obtained according to standard methods:

Ingredients mg/capsule

The compound of formula I 25,0

Lactose 150,0

Corn starch 20,0

Talc 5,0

1. Amide of General formula

where a represents unsubstituted phenyl or phenyl, one - or disubstituted by halogen or one-deputizing group (ness.)alkylsulfonyl or nitro,

R1means cycloalkyl containing from 3 to 9 carbon atoms,

R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and five - or six-membered heteroaromatic cycle contains 1 or 2 heteroatoms, chosen from a number of sulfur, oxygen or nitrogen, one of which is a nitrogen atom adjacent to the carbon atom linked with the amino group, and the cycle is monocyclic or condensed with the phenyl by two carbon atoms in the cycle, the specified one-deputizing heteroaromatic cycle is one-deputizing for the carbon atom in the cycle, which is not adjacent with the specified carbon atom associated with the amino group, and Deputy select the n from halogen or group (ness.)alkyl,

* means an asymmetric carbon atom in a particular compound or its pharmaceutically acceptable salts or N-oxides.

2. The compound according to claim 1, with the connection specified means specified amide or its pharmaceutically acceptable salt.

3. The compound according to claim 2, where a represents unsubstituted phenyl or phenyl which is substituted by a group fluorine or (ness.)alkylsulfonyl in position 4 or 7, or chlorine in position 5 or 6 or 5 and 6, or bromine, or nitro-group in position 5 or 6.

4. The compound according to any one of claims 1 to 3, and amide specified asymmetric carbon atom is S-configuration.

5. The compound according to any one of claims 1, 2 or 4, where a represents unsubstituted phenyl or phenyl which is one - or disubstituted by halogen, or one-deputizing (ness.)alkylsulfonyl, or a nitro-group.

6. The compound according to any one of claims 1, 2 or 4, where a represents unsubstituted phenyl or phenyl, one-deputizing halogen.

7. The compound according to any one of claims 1 to 6, where R1means cycloalkyl containing from 3 to 9 carbon atoms.

8. The compound according to any one of claims 1 to 6, where R1means cyclopentyl or cyclohexyl.

9. The compound according to any one of claims 1 to 8, wherein R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and five-or six-membered heteroaromatic cycle contains 1 or 2 heteroatoms, selected from a number sulfur, oxygen or nitrogen, with one heteroatom is a nitrogen atom adjacent to the carbon atom linked with the amino group, and the cycle is monocyclic or condensed with the phenyl by two carbon atoms in the cycle, and the specified one-deputizing heteroaromatic cycle is one-deputizing for the carbon atom in the cycle, which is not adjacent to the carbon atom linked with the amino group, and Deputy selected from the group comprising halogen or (ness.)alkyl.

10. The compound according to any one of claims 1 to 8, wherein R2means heteroaromatic cycle, selected from a number thiazolyl, chinoline, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzothiazolyl or benzoxazolyl, and specified heteroaromatic cycle optional monogamist halogen or (ness.)the alkyl.

11. The compound according to any one of claims 1 to 8, wherein R2means heteroaromatic cycle, selected from a number thiazolyl, pyrimidyl, pyrazinyl or pyridyl, and specified heteroaromatic cycle optional monogamist halogen or (ness.)the alkyl.

12. The compound according to any one of claims 1 to 8, wherein R2means unsubstituted heteroaromatic cycle, selected from a number thiazolyl, pyrimidyl, pyrazinyl or pyridyl, or one-deputizing heteroaromatic cycle, selected from a number thiazolyl substituted by chlorine, Il is pyridyl, substituted by chlorine, bromine or (ness.)the alkyl.

13. The compound according to claim 1, where a represents unsubstituted phenyl or phenyl, one - or disubstituted by halogen or one-deputizing group (ness.)alkylsulfonyl or nitro; R1means cycloalkyl containing from 5 to 8 carbon atoms; R2means unsubstituted or one-deputizing five - or six-membered heteroaromatic cycle, linked through a carbon atom in the cycle with the specified amino group, and five - or six-membered heteroaromatic cycle contains 1 or 2 heteroatoms, chosen from a number of sulfur, oxygen or nitrogen and one atom is a nitrogen atom adjacent to the carbon atom linked with the amino group, and the cycle is monocyclic or condensed with the phenyl by two carbon atoms in the cycle, and the specified one-deputizing heteroaromatic cycle is one-deputizing for the carbon atom in the cycle, which is not adjacent to the carbon atom linked with the amino group, and Deputy selected from the group comprising halogen or (ness.)alkyl.

14. The compound according to any one of claims 1 to 13, selected from the group including

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-is)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(R)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-chloropyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-4-methylpyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-methylpyridin-2-ylpropionic,

3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

(S)-N-3-cyclohexyl-N-(2-methylpyrimidin-4-yl)-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(R)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-enous the l-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-bromothiazole-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(5-chlorothiazole-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-methylsulphonyl-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

3-cyclooctyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-N-benzothiazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-(1H-benzimidazole-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-N-benzoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-CEC is hexil-2-(1-oxo-1,3-dihydroindol-2-yl)-N-quinoline-2-ylpropionic,

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-(1-oxypyridine-2-yl)propionamide and

(S)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic.

15. The compound according to any one of claims 1 to 13, selected from the group including

3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrimidine-4-ylpropionic,

N-(5-chlorothiazole-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-chloropyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyrazin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-pyridin-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-thiazol-2-ylpropionic,

(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)-N-5-methylpyridin-2-ylpropionic and

(R)-N-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydroindol-2-yl)propionamide.

16. The pharmaceutical composition intended for the treatment of type II diabetes, comprising a compound according to any one of claims 1 to 15 and headlights is asepticheski acceptable carrier and/or adjuvant.

17. A method of obtaining a pharmaceutical composition according to item 16, characterized in that the compound of the formula I according to any one of claims 1 to 15 together with a pharmaceutically acceptable carrier and/or adjuvant.

18. Compounds according to any one of claims 1 to 15 for use as therapeutically active compounds for the treatment of type II diabetes.

19. The use of compounds according to any one of claims 1 to 15 for the treatment or prophylaxis of diabetes type II.

20. The use of compounds according to any one of claims 1 to 15 when getting drugs for treatment or prevention of type II diabetes.

21. The method of prevention or therapeutic treatment of type II diabetes, and this method includes introducing the compound according to any one of claims 1 to 15 a person or an animal.

22. A method of obtaining a compound according to any one of claims 1 to 15, and this method includes the interaction of the compounds of formula 3

where a and R1have the meanings indicated in claim 1,

with the appropriate heteroaromatic an amine of the formula

H2N-R2,

where R2matter specified in claim 1,

under normal conditions the formation of amide bond, with formation of compounds of formula I

where *, A, R1and R2have the meanings indicated in claim 1.

23. Connection polucen the E. the method according to item 22.



 

Same patents:

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints
The invention relates to a method for producing 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole the hydrochloride by hydrochlorination 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole of concentrated hydrochloric acid in the environment of ethyl alcohol at 20-35With target product is separated from the reaction mixture by dilution with water, heating to 75-80With that clarification of the resulting solution activated carbon, cooling the clarified solution to 0-2With, then the selected product is filtered, washed with alcohol and dried at 70C in vacuum (120 mm RT.CT.) get 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole hydrochloride with a melting point 292-294C (with decomposition) and mass fractions of the main substance of at least 99.8%, the product yield is 80% on the original basis

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry or heterocyclic compounds, chemical technology.

SUBSTANCE: invention relates to technology for manufacturing heterocyclic compounds, in particular, to technology for manufacturing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that is known as a substance for pharmaceutical designation "thiotriazoline". Invention describes a method for preparing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that involves reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in liquid medium wherein methylene chloride is used as a liquid medium. Method provides significant elevating the yield percent of the end product, enhances its quality and significant reducing industrial consumptions.

EFFECT: improved preparing method.

4 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

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