The connection of thiazolidine pyridine type or its salt, hypoglycemic agent, antiglycation tool and the pharmaceutical agent inhibiting hyperglycemia, the nonenzymatic glycation and alsoreported, for the prevention and treatment of diabetes and diabetic complications

 

(57) Abstract:

The connection of thiazolidine pyridine type and its salt of the formula I, where X1- S; X2Is S or O; Y is CR6R7, R6and R7is a hydrogen atom, or R7together with R4form a bond; Z is C1-10-alkyl, substituted silyl group; or A - B (A is a divalent C1-6-rich or C2-6unsaturated hydrocarbon group, possibly substituted by at most 3 hydroxyl, oxo and C1-7-alkilani, and B represents a radical of the formula (a-n), where each Randand Rbis a hydrogen atom, alkyl, halogen, phenyl, -naphthyl, -naphthyl, furyl, and Rwithis a hydrogen atom or a C1-7-alkyl, R1, R2and R3each represents hydrogen, and n = 0. Compound I or their pharmaceutically acceptable salts possess gipoglikemicheskoy activity and can be used for the prevention or treatment of diabetes in mammals. In addition, compounds I have antiglycation activity and are suitable for the treatment of diabetic complications. 4 C. and 5 C.p. f-crystals, 28 PL.

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The present invention relates to new thiazolidine pyridine type, with hypoglycemic the awns are suitable for treating or preventing diabetes mellitus and diabetic complications.

So far as oral hypoglycemic agents for reducing blood sugar are widely used in various sulfonylurea derivatives and derivatives biguanidine. However, these tools have disadvantages, causing severe hypoglycemic coma and appearance of milk acidosis, and therefore, their practical application should be taken all possible precautions. "Chem. Pharm. Bull., vol. 30, p.3563 (1982)", " J. Med. Chem., vol. 32, p. 421 (1989)", " J. Med. Chem., vol. 34, p.318 (1991", "J. Med. Chem., vol.. 33, p.1418 (1990), publication no past expertise Japan patent N 64586/1980 and published descriptions of European patents N 177353, 283035, 283036, 332331, 332 332 and 605228 describe the various preparations of thiazolidinediones, which give a hypoglycemic effect, and is especially suitable for the treatment of diabetes type 11, and notes that these tools produce almost no such hypoglycemic symptoms, which cause the above-mentioned oral hypoglycemic agents. However, although such compounds have the function to effectively reduce the sugar content in the blood, but not proven, that these compounds act as reducing or preventing different chronic symptoms caused by diabetes, such as diabetic nephropathy, diabetic katchen, that nonenzymatic glycosylation vital protein causes disease, followed by diabetes and atherosclerosis. In General, the reaction of reducing sugars with amino acids and proteins caused by thermal food processing or storage of food, known as the reaction of Maillard (Maillard). In the 1970s it was found that the reaction of Maillard actually invoked in vivo, and recently this reaction called glycation (glication) (see "J. Biol. Chem., vol. 252, R. 2998 (2977)"). In addition, it was confirmed that the glycation increases with such chronic hyperglycemic conditions as diabetes and it is assumed that the glycation triggers the appearance of various diabetic complications (see New Eng. J. Med. vol. 314, p. 403 (1986)"). The process of glycation is not completely clear, but it is believed that various vital proteins interact with the reducing sugars with education - non - Schiff's bases, and then rearrange Amadori happens structuring and transformation in fluorescent black materials, i.e., in AGE (end products increased glycosylation). It was found that in diabetic cataract in rats increased protein glycation of lens. In addition, it is assumed that the glycation myelin is positive tissue causes of renal dysfunction - inducing thickening of the renal glomerular basement membrane and atherosclerosis.

Brownlee et al. reported that antiglycation action aminoguanidine prevents the formation of protein AGE on the walls of the arteries in rats with diabetes, and there is an opportunity to celebrate aminoguanidine as a means to prevent diseases, including diabetes (see "Science vol. 232, R. 1629 (1986)"). However, the above function aminoguanidine is not always sufficient and the means of reaching antiglycating actions that meet the requirements of practice, has not been found yet.

On the other hand, it is known that aldozoreduktaza (AR) is the enzyme for the reduction of aldos, such as glucose and galactose, to polyols, such as sorbitol and galactic, in a living organism. It is also known that the accumulation in the bodies thus produced by the enzyme polyols induces or enhances various diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, and, consequently, inhibitors against this enzyme is suitable as a means for the treatment of these diabetic complications.

New derivatives of thiazolidine pyridine type of the present invention are thiazolidine pyridine type and their salts represented following the next formula I

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where X1represents S or O;

X2represents S, O or NH;

Y represents CR6R7/R6represents a hydrogen atom, (C1-C7)-alkyl group, or (C3-C7)-cycloalkyl group, and R7represents a hydrogen atom, (C1-C7)-alkyl group, or (C3-C7)-cycloalkyl group, or forms together with R4communication, or SO2;

Z represents a (C1-C10)-alkyl group, (C2-C10)- alkenylphenol group, (C2-C10)-alkylamino group, (C3-C7-the cycle is kinilig, cycloalkyl and cycloalkenyl groups may be substituted by at most 3 hydroxyl, oxo-, (C1-C7)-alkyl and (C1-C7-alkoxygroup/, phenyl group, biphenylene group - naftalina group - naftilan group, benzyl group, pyridyloxy group, pyrimidinyl group, pyridazinyl group, fornillo group, thienyl group, pyrrolidino group, pyrazolidine group, imidazolidinyl group, pyranyloxy group (each of the foregoing phenyl, biphenylenes, - naftilos, - naftilos, benzyl, peredelnoj, pyrimidinyl, pyridazinyl, fernilee, thienyl, pyrrolidino, pyrazolidine, imidazolidine and Pernille groups may be substituted by at most 3 hydroxyl, (C1-C7)-alkyl and (C1-C7)-CNS groups and halogen atoms), a substituted silyl group, (C1-C14)-aliphatic acyl group, (C6-C10)-aromatic acyl group or-A-B (A is a divalent saturated (C1-C6) or unsaturated (C2-C6) is a hydrocarbon group which may be substituted by at most 3 hydroxyl, oxo and (C1-C7)-alkyl groups14)-aromatic and (C4-C12) - aromatic heterocyclic group, which may contain at most 5 substituents, in General (mentioned aromatic heterocyclic group may contain at most 5 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom as the constituent elements of the heterocyclic nucleus), or (C4-C6)-heterocyclizations group (referred to heterocyclizations group can contain at most 3 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom as the constituent elements of the heterocyclic nucleus));

each of R1, R2and R3independently, represents a hydrogen atom, (C1-C7)-alkyl group (which may be substituted by a hydroxyl group), (C3-C7)-cycloalkyl group, hydroxyl group or halogen atom;

R4represents a hydrogen atom or a (C1-C7)-alkyl group, or together with R7forms a bond; and

n is 0 or 1.

The substituents of the compounds of the present invention having the formula (1), determined by illustrating examples, but the scope of the present isosteres next.

Examples (C1-C10)-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, tert-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-1-ethyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, 1-heptyl, 2-heptyl, 1 - ethyl-1,2-dimethyl-n-Pro-peel, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-methyl-2-n-heptyl, 2-propyl-1-n-heptyl, 2,4,4-trimethyl-1-n-pentyl, 1 nonyl, 2-nonyl, 2,6-dimethyl-4-n-heptyl, 3-ethyl-2, 2-dimethyl-3-n-pentyl,3,5,5-trimethyl-1-n-hexyl, 1 - decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1-n-octyl, 3,7-dimethyl-3-n-octyl, and the like.

Examples (C1-C7)-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, tert-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-1-ethyl-n-pen-Tyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, 1-heptyl, 2-heptyl, 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl and the like.

Examples (C1-C3)-alkyl groups are methyl, ethyl, n-propyl, isopropyl, and the like groups.

Examples (C2-C10)-alkenylphenol group avlimil-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-isopropylphenol, 1-methyl-1-pentenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, 1 nonenal and similar groups, 1-decenyl.

Examples (C2-C10)- alkenylphenol groups are ethinyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1 - octenyl, 1-nonenal, 1-decenyl and similar groups.

Examples (C3-C10)-cycloalkyl groups are cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, 4-methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptenyl, cyclooctyl, cyclogeranyl, cyclodecyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 1-substituted, 2-substituted and similar groups.

Examples (C3-C7)-cycloalkyl groups are cyclopropyl, 1 - methylcyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, 4 - methylcyclohexyl, cyclobutyl, cyclopentyl, ciclovia 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, cyclopentadienyl, 2-bicyclo [2.2.1] heptenyl, 2,5-bicyclo [2.2.1] heptadiene and similar groups.

Examples (C1-C7-alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n - butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, pentyloxy, hexyloxy, heptyloxy and similar groups.

Examples of the substituted silyl group include trimethylsilyl, triethylsilyl, tri-n-propulsion, three-ISOPROPYLCUMYL, tri-n-Boticelli, three-isobutyryl, tri-n-exelsior, dimethylaniline, dimethyl-n-propulsion, dimethyl-n-Boticelli, di-methylisoborneol, dimethyl-tert-Boticelli, dimethyl-n-penicilin, dimethyl-n-octylsilane, dimethylcyclohexylamine, di-methylpenicillin, dimethyl-2,3-dimethylpropylene, dimethyl-2-(bicycloheptene)silyl, dimethylbenzidine, dimethylphenylsilane, dimethyl-p-tailcall, dimethylforamide, methyldiphenylamine, triphenylsilane, diphenyl-tert-Boticelli, tribenzylamine, diphenylvinylene, diphenyl-n-Boticelli, phenylmethylsulfonyl and similar groups.

Examples (C1-C14)-aliphatic acyl groups are formyl, acetildenafil, crotonoyl and similar groups.

Examples (C6-C10), and aromatic acyl groups are benzoyl, 2-toluoyl, 3 - toluoyl, 4-toluoyl - naphtol - naphtol, cynnamoyl and similar groups.

Examples (C6-C14)-aromatic groups are phenyl, - naphthyl, - naphthyl, 1-indenyl, 2-indenyl, 3 - indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1 indanyl, 2-indanyl, 4-indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl, 9-fluorenyl and similar groups.

Examples (C4-C12)-aromatic heterocyclic groups are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 3-furutani, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 3-oxadiazol-1-yl, 3-oxadiazol-2-yl, 3-oxadiazol-3-yl, 3-oxadiazol-4-yl, 4-oxadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-accomidate-1-yl, 2-accomidate-4-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole-4-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl, 1,2,4-(2H, 4H)-triazole-3-one-2-yl, 1,2,4-(2H, 4H)-triazole-3-one-4-yl, 1,2,4-(2H, 4H)-triazole-3-one-5-yl, 1,2,4(1H, 2H)-triazole-3-one-1-yl, wounded, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridone-1-yl, 2-pyridone-3-yl, 2-pyridone-4-yl, 2-pyridone-5-yl, 2-pyridone-6-yl, 4-pyridone-1-yl, 4-pyridone-2-yl, 4-pyridone-3-yl, 3-pyridazinyl, 4-pyridazinyl, 3(2H)-pyridazinone-2-yl, 3(2H)pyridazine-4-yl, 3(2H)-pyridazine-5-yl, 3(2H)-pyridazine-6-yl, 4(1H)-pyridazine-1-yl, 4(1H)-PI-ridazine-3-yl, 4(1H)-pyridazine-5 - yl, 4(1H)-pyridazine-6-yl, 2-pyrimidinyl, 4-pyrimidinyl, 5 - pyrimidinyl, 2(1H)pyrimi-dine-1-yl, 2(1H)-pyrimidine-4-yl, 2(1H)- pyrimidine-5-yl, 2(1H)-pyrimidine-6-yl, 4(3H)-pyrimidinone-2-yl, 4(3H)-Piri-midino-3-yl, 4(3H)-pyrimidine-5-yl, 4(3H)-pyrimidinone-6 - yl, 4(1H)-pyrimidinone-1-yl, 4(1H)-pyrimidine-2-yl, 4(1H)-pyrimidine - 5-yl, 4(1H)pyrimidine-6-yl, 2-pyrazinyl, 2(1H)-pyrazin-1 - yl, 2(1H)-pyrazin-3-yl, 2(1H)-pyrazin-5-yl, 2(1H)-pyrazin-6-yl, 1,2,3-triazine-4-yl, 1,2,3-triazine-5-yl, 1,2,4-triazine-3-yl, 1,2,4-triazine-5-yl, 1,2,4-triazine-6-yl, 1,2,3,4 - tetrazine-5-yl, 1,2,4,5-tetrazine-3-yl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin, 8 - chinolin, 2-chinolin-1-yl, 2-chinolin-3-yl, 2-chinolin-4-yl, 2-chinolin-5 - yl, 2-chinolin-6-yl, 2-chinolin-7-yl, 2-chinolin-3-yl, 4-chinolin-1-yl, 4 - chinolin-2-yl, 4-chinolin-3-yl, 4-Hino-LON-5-yl, 4-chinolin-6-yl, 4 - chinolin-7-yl, 4-chinolin-8-yl, 2-benzofuranyl, 3-benzofuranyl, 4 - benzofuranyl, 5-benzofuranyl, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic, 8-ethanolic, 1-isohedron - 2-yl, 1-isohedron-3-yl, 1-isohedron-4-yl, 1-isohedron-5-yl, 1-isohedron-6-yl, 1-isohedron-7-yl, 1-isohedron-8-yl, 3-isohedron-2 - yl, 3-isohedron-4-yl, 3-isohedron-5-yl, 3-isohedron-6-yl, 3 - Yohanan-7-yl, 3-isohedron-8-yl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,7-benzothiazolyl, 1-benzimidazolyl, 2 - benzimidazolyl, 3-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 1-benzotriazolyl, 4 - benzotriazolyl, 5-benzotriazolyl, 2-benzopyranyl, 3-Ben-soberanis, 4 - benzopyranyl, 5-benzopyranyl, 6-benzopyranyl, 7-benzopyranyl, 8 - benzopyranyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5 - indolizinyl, 6-indolizinyl,7-indolizinyl, 8-indolizinyl, 2-purinol, 6 - purinol, 7-purinol, 8-purinol, 1-phthalazine, 5-phthalazine, 6 - phthalazine, 1-oxo-phthalazine-2-yl, 1-oxoproline-4-yl, 1 - acceptilation-5-yl, 1-acceptilation-6-yl, 1-acceptilation-7-yl, 1 - acceptilation-8-yl, 2-naphthyridines, 3-naphthyridines, 4-naphthyridine, 2 - hinokio-nil, 5-genoxal Nalini, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7 - indolinyl, 8-indolinyl, 1,4-benzodioxan-2-yl, 1,4-benzodioxan-5-yl, 1,4-benzodioxan-6-yl, 1,4-oxonation-2-yl, 1,4-oxonation - 5-yl, 1,4-oxonation-6-yl, 2,3-dihydro-4-benzofuranyl, 2,3-dihydro - 5-benzofuranyl, 2,3-dihydro-6-benzo-furanyl, 2,3-dihydro-7 - benzofuranyl, 1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4 - benzothiazin-4-yl, 1,4-benzothiazin-5-yl, 1,4-benzothiazin-6-yl, 1,4-benzothiazin-7-yl, 1,4-benzothiazin-8-yl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl, pyrazolo [1,5 - a] pyrimidine-2-yl, pyrazolo [1,5-a] pyrimidine-3-yl, pyrazolo [1,5-a] pyrimidine-5-yl, pyrazolo [1,5-a] -pyrimidine-6-yl, pyrazolo [1,5-a] pyrimidine-7-yl, pyrazolo [5,1-C] -[1,2,4] triazine-3-yl, pyrazolo [5,1 - c] [1,2,4] triazine-4-yl, pyrazolo [5,1-c] [1,2,4] triazine-7-yl, pyrazolo [5,1-c] [1,2,4] the triazine-8-yl, thiazolo [3,2-b] triazole-2-yl, thiazolo [3,2-b] triazole-5-yl, thiazolo [3,2-b] triazole-6-yl, benzopyrano [2,3-b] pyridine-2-yl, benzopyrano [2,3-b) pyridin-3-yl, benzopyrano [2,3-b] pyridine-4-yl, benzopyrano [2,3-b] pyridine-5-yl, benzopyrano [2,3-b] pyridine-6-yl, benzopyrano [2,3-b) pyridin-7-yl, benzopyrano [2,3-b] pyridine-8-yl, benzopyrano [2,3-b] pyridin-9-yl, 5H-benzopyrano [2,3-b] pyridine-5-on-2-yl, 5H-benzopyrano [2,3-b] pyridine-5-on-3-yl, 3H-benzopyran-but [2,3-b] pyridine-5-one-4-yl, 5H - benzopyrano [2,3-b] pyridine-5-on-6-yl, 5H-is tenil, 9-xantener, 1-phenoxathiin, 2 - phenoxethanol, 3-phenoxathiin, 4-phenoxathiin, 1-carbazolyl, 2 - carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 1-acridine, 2 - acridines, 3-acridines, 4-acridine, 9-acridine, 1-phenazine, 2 - phenazine, 3-phenazines, 4-phenazine, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl, 1-phenoxazine, 2 - phenoxazine, 3-phenoxazine,4-phenoxazine, 10-phenoxazine, 1 - thianthrene, 2-thianthrene,3-thianthrene, 4-thianthrene, 6-thianthrene, 7 - thianthrene, 8-thianthrene, 9-thianthrene and similar groups.

Examples (C4-C6)- heterocyclizations groups are 1-piperidyl, 2-piperidyl, 3 - piperidyl, 4-piperidyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3 - pyrrolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidone, 3-pyrazolidone, 4-pyrazolidone, 2-morpholinyl, 3 - morpholinyl, 4-morpholinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and similar groups.

In the present description "n" ("n" means normal, "every" ("i") means azosoedinenii, "Deut" ("s"means secondary, "t" ("t" means tertiary, "C" means cyclo"/ C-1. "Me" means methyl, "Et" means ethyl, "Pr" means propyl. "Bu" means butyl, "Pen" means pencil, "Hex" means hexyl, is symmetric carbon atom in position 5 thiazolidinones rings. Compounds having the above formula (1) include all of these optical isomers and mixtures thereof.

The following are preferred examples of (1) through (10) compounds of formula (1) of the present invention.

(1) Connection of thiazolidine pyridine-type formulas (1) and its salt, in which

X2represents S or O;

Y represents CR6R7/R6represents a hydrogen atom or a (C1-C3)-alkyl group, and R7represents a hydrogen atom or a (C1-C3)-alkyl group, or together with R4forms link);

Z represents-A-B/A is a divalent saturated (C1-C6) or unsaturated (C2-C6) is a hydrocarbon group which may be substituted with at most 3 hydroxyl, oxo and (C1-C7)-alkyl groups, and B represents a (C3-C10)-cycloalkyl, (C3-C7)-cycloalkenyl, (C6-C14)-aromatic and (C4-C12)-aromatic heterocyclic group, which, in General, can be replaced by at most 5 substituents (mentioned aromatic heterocyclic group may contain at most 5 heteroatomcontaining kernel), or (C4-C6)-heterocyclizations group (referred to heterozygosities group can contain at most 3 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom as the constituent elements of heterocyclic cores)).

Among the mentioned groups B (C3-C10)-cycloalkyl group represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptenyl, cyclooctyl, cyclogeranyl, cyclodecyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 1 - substituted or 2-substituted mentioned (C3-C7)-cycloalkenyl group is a 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, cyclopentadienyl, 2-bicyclo [2.2.1] heptenyl or 2,5-bicyclo [2.2.1] heptadiene mentioned (C6-C14)-aromatic group is a phenyl, - naphthyl, - naphthyl, 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1 indanyl, 2-indanyl, 4-indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl or 9-fluorenyl mentioned (C4-C12)- aromatic heterocyclic group represents a 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pixetell, 3-isothiazole, 4-isothiazole, 5-isothiazole, 3-furutani, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 3-oxadiazol-1-yl, 3-oxadiazol-2-yl, 3-oxadiazol-3 - yl, 3-oxadiazol-4-yl, 4-oxadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-accomidate-1-yl, 2-accomidate-4-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole-4-yl, 1,2,4-triazole-1 - yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl, 1,2,4(2H, 4H)-triazole-3 - one-2-yl, 1,2,4-(2H, 4H)-triazole-3-one-4-yl, 1,2,4-(2H, 4H)-triazole-3 - one-5-yl, 1,2,4-(1H, 2H)-Tria-Zol-3-one-1-yl, 1,2,4(1H, 2H)-triaal-3 - one-2-yl, 1,2,4-(1H,2H)-triazole-3-one-5-yl, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridone-1-yl, 2-pyridone-3-yl, 2-pyridone-4-yl, 2-pyridone-5-yl, 2-pyridone-6-yl, 4-pyridone-1-yl, 4-pyridone-2-yl, 4-pyridone - 3-yl, 3-pyridazinyl, 4-pyridazinyl, 3(2H)-pyridazinone-2-yl, 3(2H)-pyridazine-4-yl, 3(2H)-pyridazine-5-yl, 3(2H)-pyridazine-6-yl, 4(1H)-pyridazine-1-yl, 4(1H)-pyrido-Zenon-3-yl, 4(1H)-pyridazine-5 - yl, 4(1H)-pyridazine-6-yl, 2-pyrimidinyl, 4-pyrimidinyl, 5 - pyrimidinyl, 2(1H)-pyrimido-non-1-yl, 2(1H)-pyrimidine-4-yl, 2(1H)- pyrimidine-5-yl, 2(1H)-pyrimidine-6-yl, 4(3H)-pyrimidine-2-yl, 4(3H)-pyrimidine-3-yl, 4(3H)-pyrimidine-5-yl, 4(3H)-pyrimidine-6-yl, 4(1H)- pyrimidinone-1-yl, 4(1H)-pyrimidine-2-yl, 4(1H)-pyrimi-dine-5-yl, 4(1H)-pyrimidine-6-yl, 2-pyrazinyl, 3-yl, 1,2,4-triazine-5-yl, 1,2,4-triazine-6-yl, 1,2,3,4-tetrazine-5-yl, 1,2,4,5-tetrazine-3-yl, 1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-Hino-Lil, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin, 8-chinolin, 2-chinolin-1-yl, 2-chinolin-3-yl, 2-chinolin-4-yl,2 - chinolin-5-yl, 2-chinolin-6-yl, 2-chinolin-7-yl, 2-chinolin-8-yl, 4 - chinolin-1-yl, 4-chinolin-2-yl, 4-chinolin-3-yl, 4-chinolin-5-yl, 4 - chinolin-6-yl, 4-chinolin-7-yl, 4-chinolin-8-yl, 2-benzo-furanyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7 - benzofuranyl, 2-benzothiazyl, 3-benzothiazol, 4-benzothiazyl, 5 - benzothiazyl, 6-benzothiazyl, 7-benzothiazyl, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ISO-chinolin, 7-ethanolic, 8-ethanolic, 1-isohedron-2-yl, 1-ISO-chinolin-3-yl, 1-isohedron-4-yl, 1-isohedron-5-yl, 1-isohedron-6-yl, 1-isohedron-7-yl, 1-makinalar-8-yl, 3 - isohedron-2-yl, 3-isohedron-4-yl, 3-isohedron-5-yl, 3-isohedron-6-yl, 3-isohedron-7-yl, 3-isohedron-8-yl, 2-benzoxazolyl, 4 - benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 2 - benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7 - benzothiazolyl, 1-benzimidazolyl, 2-benzo-pyrazolyl, 3-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 1-benzimidazolyl, 2 - benzoyl, 3-benzopyranyl, 4-benzopyranyl, 5-benzopyranyl, 6-benzopyranyl, 7-benzopyranyl, 8 - benzopyranyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5 - indolizinyl, 6-indolizinyl, 7-in-dolishny, 8-indolizinyl, 2-purinol, 6-purinol, 7-purinol, 8-purinol, 1-phthalazine, 5-phthalazine, 6-phthalazine, 1-acceptilation-2-yl, 1-acceptilation-4-yl, 1-acceptilation-5-yl, 1-acceptilation-6-yl, 1-acceptilation-7-yl, 1-acceptilation-8-yl, 2-naphthyridines, 3-naphthyridines, 4-naphthyridine, 2-honokalani, 5-honokalani, 6-honokalani, 2-hintline, 4-hintline, 5-hintline, 6-hintline, 7-hintline, 8-hintline, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-cinline, 7-indolinyl, 8 - indolinyl, 1,4-benzodioxan-2-yl, 1,4-benzodioxan-5-yl, 1,4 - benzodioxan-6-yl, 1,4-oxonation-2-yl, 1,4-oxonation-5-yl, 1,4-oxonation-6-yl, 2,3-dihydro-4-benzofuranyl, 2,3-dihydro-5 - benzofuranyl, 2,3-dihydro-6-benzofuranyl, 2,3-dihydro-7-benzofuranyl, 1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4-benzothiazin-4-yl, 1,4-benzothiazin-5-yl, 1,4-benzothiazin-6-yl, 1,4-benzothiazin-7-yl, 1,4-benzothiazin-8-yl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7 - pteridinyl, pyrazolo [1,5-a] pyrimidine-2-yl, pyrazolo [1,5-a] pyrimidine-3-yl, pyrazolo [1,5-a]-pyrimidine-5-yl, pyrazolo [1,5-a] pari-midin-6-yl, pyrazolo [1,5-a]-pyrimidine-7-yl, feast is asin-8-yl, thiazolo [3,2-b] triazole-2-yl, thiazolo [3,2-b] triazole-5-yl, thiazolo [3,2-8] triazole-6-yl, benzopyrano [2,3-b]- pyridine-2-yl, benzopyrano [2,3-b] pyridine-3-yl, benzopyrano [2,3-b] pyridine-4-yl, benzopyrano [2,3-b] pyridine-5-yl, benzopyrano [2,3-b] pyridine-6-yl, benzopyrano [2,3-b] pyridin-7-yl, benzopyrano [2,3-b] pyridine-8-yl, benzopyrano [2,3-b] pyridin-9-yl, 5H-benzopyrano [2,3-b] pyridine-5-on-2-yl, 5H-benzopyrano [2,3-b] pyridine-5-on-3-yl, 5H-benzopyrano [2,3-b] pyridine-5-one-4-yl, 5H-benzopyrano [2,3-b] pyridine-5-on-6-yl, 5H-benzopyrano [2,3-b] pyridine-5-one-7-yl, 5H - benzopyrano [2,3-b]-pyridine-5-one-8-yl, 1-xantener, 2-xantener, 3 - xantener, 4-xantener, 9-xantener, 1-phenoxathiin, 2-phenoxethanol, 3-phenoxathiin, 4-phenoxathiin, 1-carbazolyl, 2-carbazolyl, 3 - carbazolyl, 4-carbazolyl, 9-carbazolyl, 1-acridine, 2-acridines, 3 - acridines, 4-acridine, 9-acridine, 1-phenazine, 2-phenazine, 3 - phenazines, 4-phenazine, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl, 1-phenoxazine, 2-phenoxazine, 3 - phenoxazine, 4-phenoxazine, 10-phenoxazine, 1-thianthrene, 2-thianthrene, 3-thianthrene, 4-thianthrene, 6-thianthrene, 7-thianthrene, 8 - thianthrene or 9-thianthrene, and the above-mentioned (C4-C6)- heterocyclizations group is a 1-piperidyl, 2 - piperidyl, 3-PIP is leinil, 1-pyrazolidone, 3-pyrazolidone, 4-pyrazolidone, 2-morpholinyl, 3 - morpholinyl, 4-morpholinyl, 2-tetrahydrofuranyl or 3-tetrahydrofuranyl;

each of R1, R2and R3independently, represents a hydrogen atom, (C1-C3)-alkyl group (which may be substituted by a hydroxyl group), a hydroxyl group or a halogen atom;

R4represents a hydrogen atom or a (C1-C3)-alkyl group, or together with R7forms a link;

and n is O.

(2) the Connection of thiazolidine pyridine-type formula (I) and its salt, in which

each of R1, R2and R3independently, represents a hydrogen atom, methyl group, hydroxyl group or a chlorine atom; and

B is a

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(where each of Raand Rbindependently, represents a hydrogen atom, (C1-C7)-alkyl group, (C3-C7)-cycloalkyl group, (C3-C7)-cycloalkenyl group (mentioned alkyl, cycloalkyl and cycloalkenyl group may be substituted by a hydroxyl group), GI is a, a bromine atom, triptorelin group, a nitrogroup, amino group, methylaminopropyl, dimethylaminopropyl, acetamide group, methanesulfonamido group, carboxyl group, (C1-C3)-alkoxycarbonyl group, nitrile group, karbamoilnuyu group, sulfamoyl group, fenoxaprop, benzyloxy, phenyl, - naphthyl, - naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of the above-mentioned phenyl, - naftilos, - naftilos, fernilee, thienyl, imidazolidine, peredelnoj and benzyl groups may be substituted by at most 5 substituents selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-hexyl, cyclohexyl, metoxygroup, ethoxypropan, n-propoxylate, isopropoxy, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, hydroxyl groups, fluorine atoms, chlorine, bromine, nitro and dimethylaminopropyl), 1-tetrazolyl group, 3-tetrazolyl group, 5-tetrazolyl group, thiazolidinedione-5-ilen group or thiazolidinedione-5-ylmethylene group

and Rcrepresents a hydrogen atom, (C1-C7)-alkyl group, the and pyridine-type formulas (1) and its salt, in which

each of R1, R2and R3independently, represents a hydrogen atom, methyl group, hydroxyl group or a chlorine atom; and

B is a

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(where each of Raand Rbindependently, represents a hydrogen atom, (C1-C7)-alkyl group, (C3-C7)-cycloalkyl group, (C3-C7)-cycloalkenyl group (mentioned alkyl, cycloalkyl and cycloalkenyl group may be substituted by a hydroxyl group), a hydroxyl group, (C1-C7)-alkoxygroup, (C1-C7)-allylthiourea, fluorine atom, chlorine atom, bromine atom, triptorelin group, a nitrogroup, amino group, methylaminopropyl, dimethylaminopropyl, acetamide group, methanesulfonamido group, carboxyl group, (C1-C3)-alkoxycarbonyl group, nitrile group, karbamoilnuyu group, sulfamoyl group, fenoxaprop, benzyloxy, phenyl, - naftalina - naftalina, fornillo, thienyl, imidazolidinyl, pyridyloxy or benzyl group (mentioned phenyl, - naftalina, - naftalina, furanyl the firs, selected from the group consisting of methyl, ethyl, n-sawn, ISO-propyl, cyclopropane, n-butilkoi, isobutylene, second-butilkoi, tert - butilkoi, n-hexylene, tsiklogeksilnogo group, metoxygroup, ethoxypropan, n-propoxylate, isopropoxy, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, hydroxyl groups, fluorine atoms, chlorine, bromine, nitro and dimethylaminopropyl), 1-tetrazole-function group, 3-tetrazolyl group, 5-tetrazolyl group, thiazolidinedione-5-ilen group or thiazolidinedione-5-ylmethylene group

and Rwithrepresents a hydrogen atom, (C1-C7)-alkyl group, (C3-C7)-cycloalkyl group or hydroxymethylene group).

The connection of thiazolidine pyridine-type formulas (1) and its salt, in which

X1represents S,

R1, R2and R3are hydrogen atoms;

Y represents CR6R7/R6represents a hydrogen atom or methyl group, and R7represents a hydrogen atom or together with R4forms link);

R4represents a hydrogen atom or a methyl group, or together with R7education is B>-C6) is a hydrocarbon group which may be substituted by at most 2 hydroxyl, oxo and (C1-C7)-alkyl groups (provided that the first carbon atom linked to the oxygen atom in position 5 of the pyridine ring of compounds of formula (1), is not replaced by a hydroxyl group or oxopropoxy).

(5) the Connection of thiazolidine pyridine-type formulas (1) and its salt, in which

Y represents-CH2-; and

R4represents a hydrogen atom.

(6) Connection of thiazolidine pyridine-type formulas (1) and its salt, in which

Y represents CHR7/R7forms a bond together with R4;

R4forms a bond together with R7.

(7) Connection of thiazolidine pyridine-type formula (I) and its salt, in which

A represents a

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(where m is 0 to 5,

each Rdand Reindependently, represents a hydrogen atom or methyl group, and

each of Rfand Rgindependently, represents a hydrogen atom, methyl group or hydroxyl group, or Rfand Rgtogether form oxoprop, or adjacent Rdand Rftogether form a double SV>S form together a double bond when m is equal to from 2 to 5, or adjacent Rfand Rgtogether form a triple bond).

(8) Connection of thiazolidine pyridine-type formulas (1) and its salt, in which

A represents a

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(where

m is 0-2,

each of Rdand Reindependently, represents a hydrogen atom, or methyl group, and

each of Rfand Rgindependently, represents a hydrogen atom, methyl group or hydroxyl group, or Rfand Rgtogether form oxoprop, or adjacent Rdand Rftogether form a double bond, or adjacent Rd, Rf, Reand Rgtogether form a triple bond, or adjacent groups RfS form together a double bond when m is 2, or adjacent Rfand Rgtogether form a triple bond.

(9) the Connection of thiazolidine pyridine-type formulas (1) and its salt, in which

A represents a

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or-CH=CH-CH2-

(10) Connection of thiazolidine pyridine type formula I, and its salt, in which

A represents a

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Because the connection is us is ice, and the basic nitrogen in the pyridine ring in the molecule, it can form an optionally pharmaceutically acceptable non-toxic salt with an appropriate base or acid. The compound of formula (I) can be used for the purposes of the present invention either in free form or in the form of pharmaceutically acceptable salts. Examples of basic salts are salts of alkali metals (lithium salt, sodium salt, potassium salt and the like), salts of alkaline earth metals (calcium salt, magnesium salt, etc.,), aluminium salts, ammonium salts, which can be unsubstituted or substituted by methyl, ethyl or benzyl group, salts of organic amines (salt of methylamine salt of ethylamine, dimethylamine salt, salt diethylamine, salt, trimethylamine salt of triethylamine, salt cyclohexylamine, salt, Ethylenediamine salt of bicyclohexyl, ethanolamine salt, diethanolamine salt, triethanolamine salt, salt, piperazine salt of dibenzylpiperazine, salt dehydroabietylamine, salt N,N'-bondagebrazilian, g benzathine (N,N'-dibenziletilendiaminom), salt glucamine, salt meglumine(N - methylglucamine), salt benethamine (N-benzylpenicillin), salt, tromethamine (2-amino-2-hydroxymethyl-1,3-propane diol), salt, choline,and collidine, salt of quinoline and the like salts. Examples of salts of joining acids include salts of mineral acids (hydrochloride, hydrobromide, sulphates, hydrosulfate, nitrates, phosphates, hydrogen phosphates, dihydrophosphate and the like), salts of organic acids (formate, acetate, propionate, succinate, malonate, oxalates, maleate, fumarate, malate, citrates, tartratami, lactates, glutamate, aspartate, picrate, carbonates and the like), salts, sulfones, acids (methansulfonate, bansilalpet, toluensulfonate and so on), and similar salts. Each of these salts can be obtained by known methods.

Compounds having formula I, i.e., thiazolidine pyridine type, can be obtained the following further ways of synthesis.

The solvent used in the reaction of obtaining compound is stable under the reaction conditions, and preferably are so inert, so as not to inhibit the reaction. Examples of solvents for the reaction include water, alcohols (such as methanol, ethanol, propanol, butanol and octanol), cellosolve (such as methoxyethanol and ethoxyethanol), aprotic polar organic solvents (such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylrhodamine, sulfolan and dioxane), aliphatic hydrocarbons (such as pentane, n-hexane, cyclohexane, octane, decalin and petroleum ether), aromatic hydrocarbons (such as benzene, chlorobenzene, nitrobenzene, toluene, xylene, tetralin), halogenated hydrocarbons (such as chloroform, dichloromethane and dichloroethane), ketones (such as acetone, methyl ethyl ketone and metalbulletin), lower esters of aliphatic acids (such as methyl acetate, ethyl acetate and methylpropionate), alkoxyalkane (such as dimethoxyethane and diethoxyethane), acetonitrile and the like solvents. These solvents are chosen arbitrarily depending on the chemical activity of the target response, and are used, respectively, by one or in mixtures. In some cases they are used as non-aqueous solvents using dehydrating or drying means. The above solvents are just examples of solvents that can be used in reactions of the present invention, and the present invention is not limited to these conditions.

Method 1

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In these formulas, R1, R2, R3, R6X1X2and Z have the foregoing meanings, and R8represents a hydrogen atom or a protective group for Amen is, i.e., the compound of formula (1-1) can be obtained by dehydration-condensation of the compounds of formula (II) and compounds of formula (V). The compound of formula (V) is a well-known connection, or it can be synthesized by the method described in J. Prakt. Chem.," (vol. 2, p. 253, 1909), "J. Prakt. Chem. (vol. 3, p. 45, 1919)," Chem. Ber.", (vol. 118, p. 774, 1985), and in the published German patent N DE-3045059. The compound of formula (V) in which R8represents hydrogen, can be used in this reaction after defending his primary amide proton suitable substituent (such as Tr:trityl) is well-known ways.

This reaction is usually carried out in a suitable organic solvent in the presence of base or acid. Examples of such solvents are alcohols, cellosolve, aprotic polar organic solvents, ethers, aromatic hydrocarbons, halogenated hydrocarbons, alkoxyalkane and acetonitrile.

Examples of bases and acids are organic amines (such as dimethylamine, diethylamine, Diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, ethanolamine and ethanolamine), alkoxides of metals (such is arbonet potassium, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate), organic acids (such as acetic acid, trichloroacetic acid and triperoxonane acid), inorganic acids (such as phosphoric acid and similar compounds. These materials are chosen, respectively, depending on the activity of the target response.

This reaction can be accelerated by removal of water formed during the reaction, due to the use of an appropriate dehydrating agent such as molecular sieves and anhydrous sodium sulfate, or by azeotropic distillation using traps Dean-stark.

This reaction is usually carried out at a temperature in the range of 0oC to the boiling point of the used solvent, preferably from 20oC to 120oC, for 0.5 to 30 hours.

Method 2

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In these formulas, R1, R2, R3, R6and Z have the foregoing values, R9is a (C1-C4)-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl, and Hal represents a chlorine atom, a bromine atom or an iodine atom.

The compound of formula (1), the NH, i.e., the compound of the formula (1-2e)/R4, R7=H, X1=S, X2=NH/, can be obtained by reacting thiourea with ether halogencarbonic acid of the formula (VIII).

This reaction is usually carried out in a suitable organic solvent in the presence of base or acid. Examples of the solvent used are alcohols, cellosolve and aprotic polar organic solvent, and preferably use sulfolan.

This reaction is usually carried out at a temperature in the range of 0oC to the boiling point of the used solvent, preferably from 50oC to 150oC, for 0.5-10 hours.

During the reaction formed galoidovodorodov as a by-product, but to accelerate the reaction it is possible to catch an appropriate basis. The examples used for this reason are organic amines (such as dimethylamine, diethylamine, Diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, ethanolamine and ethanolamine), inorganic alkali metal salts (such as sodium acetate and potassium acetate, and similar compounds).

Method 3

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In these Obedinenie formula (I), in which R4and R7are H, and X1and X2are S, i.e., the compound of the formula (1-2b) (R4, R7=H, X1X2=S) can be obtained by reacting dithiocarbamate ammonium ether halogencarbonic acid of the formula (VIII).

This reaction is usually carried out in water or in a suitable organic solvent or in mixtures. The examples used in this way the solvent are alcohols, cellosolve and aprotic polar organic solvents. This reaction is usually carried out at a temperature in the range -10oC to 50oC, preferably from 0o30oC, for 0.5 to 50 hours.

During this reaction as a by-product formed galoidovodorodov, but to accelerate the reaction it is possible to catch a suitable base. The examples used thus bases are organic amines (such as dimethylamine, diethylamine, Diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, ethanolamine and ethanolamine), inorganic salts of alkali metals (such as potassium carbonate, sodium carbonate, sodium acetate and potassium acetate), etc.

POI receive compound of the formula (1-2b).

Method 4

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Here in the formulas, R1, R2, R3, R6, R9, Z and Hal have the foregoing significance.

The compound of the formula I, in which R4and R7are H, X1represents S, and X2represents O, i.e., the compound of formula (l-2a)/R4, R7= H, X1= S, X2=O/, can be obtained by reacting alkanethiolate (such as potassium thiocyanate or sodium thiocyanate) with ether halogencarbonic acid of the formula (VIII), with the formation of the compounds of formula (XII), and treatment of this compound with acid.

This reaction is usually carried out in a suitable organic solvent. The examples used thus solvents are aprotic polar organic solvents.

This reaction is usually carried out at a temperature in the range from 50oC to 150oC, preferably from 80oC to 120oC, for 0.5-10 hours.

The compound of formula (XII) allocate, or it is subjected to further treatment with acid in the reaction system without selection, and obtain the target compound of the formula (1-2a). The example used for this acid is hydrochloric acid, and treatment with an acid is from 50oC to 150oC, preferably from 70oC to 100oC for 5-50 hours.

Method 5

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Here in the formulas, R1, R2, R3, R4, R6, R8X1X2, Z and Hal have the foregoing significance.

The compound of formula (I) in which R7represents hydrogen, i.e. the compound of formula (1-2) can be obtained by reacting the compounds of formula (V) with kalaidjieva formula (VI). The compound of formula (V) used here is a well-known compound, or can be synthesized by methods described in the " Ukr. Khim. Zr." (vol. l6, R. 545, 1950), "J. med. Chem.", (vol. 34, p. 1538, 1991), "J. Prakt. Chem.", (vol. 2, 79, p. 253 (1909), " J. Prakt. Chem.", (vol. 2, 99, p. 56 (1919)), or in the publication of the last examination of the Japan patent N 216882/1984. The compound of formula (V) in which R8represents a hydrogen used in the reaction, preferably, after defending his primary amide proton suitable substituent (such as Tr:trityl) in a known manner.

This reaction is usually carried out in a suitable organic solvent in the presence of a base. The examples used thus solvents are aprotic polar organic solvents, simple eamily alkali metals (for example, amide and sodium amide and potassium). These materials are chosen arbitrarily, depending on the activity of the target response.

In addition, this reaction can be performed according to the method described in "J. Amer. Chem. Soc.", (vol. 87, p. 4588, 1965), or in "J. med. Chem.", (vol. 34, p. 1538, 1991). In this case, the compound of formula (V) is entered into interaction with methylcarbonate magnesium in the atmosphere of inert gas, such as nitrogen and proton polar organic solvent such as dimethylformamide, with the formation of chelate compounds, and formed so chelate compound is then injected into interaction with halogenopyrimidines formula (VI), and obtain the connection formula (1-2). This reaction is usually carried out at a temperature in the range of 20oC to 150oC, preferably from 70oC to 100oC. the reaction Time varies depending on the materials used, but the formation of chelate compound is from 0.5 to 2 hours, and the reaction halogenopyrimidines is from 0.5 to 5 hours.

In some cases, amide group in position 3 thiazolidinones component thus obtained compounds of formula (1-2) can be split protective group is well known manner. When R8is a T Laryssa acid, or inorganic acid, such as hydrochloric acid and sulfuric acid. This reaction is carried out in the absence of solvent or in the presence of a solvent, such as ethers including tetrahydrofuran and dioxane, and halogenated solvents, including chloroform and dichloromethane, at a temperature in the range of 0oC to 100oC, preferably between 10oC to 50oC, for 0.1 to 5 hours.

Method 6

< / BR>
Here in the formulas, R1, R2, R3, R4, R8X1X2, Y and Z have the foregoing meaning, and R represents a suitable group, useplease in the reaction of nucleophilic substitution, examples of which include halogen, such as chlorine, bromine and iodine, and aromatic or aliphatic sulfonyloxy, such as p-toluensulfonate, benzolsulfonate and methysulfonylmethane.

Connection from among compounds of the formula (I) in which A represents COCH2(m=1, Rd, Re=H, Rfand Rgtogether represent oxoprop), may be obtained by using the compounds of formula (X), such as B - COCH2-Hal/Z= B-COCH3, R11= Hal, B and Hal are Deputy, described the well-known manner /for example, published UK patent N 1107677 describes the connection in which B represents a pyrrole, publishing a non-examination of the Japan patent N 85372/1986 describes the connection in which B represents oxazole or thiazole, and U.S. patent N 4167626 describes the connection in which B represents a triazole). In addition, such a connection can be obtained by halogenoalkanes B-COCH3(for example, in " Bull. Soc. Chim. Fr. p. 1760 (1973)" describes the connection in which B represents a furan, " Tetrahedron, 29(2), R. 413 (1973)" describes the connection in which B is a thiophene, " J. Heterocyclic Chem., 27(5), R. 1209 (1990)" describes the connection in which B represents a pyrrole, "Bull. Soc. Chim. Fr. RV 540 (1988)", "Bull. Soc. Chim. Fr. p. 318 (1987)", "J. Heterocyclic Chem. , 23(1), p. 275 (1986)", " "Arch. Pharm., 316(7), p. 608 (1983)" and " Synlett., (7), R. 483 (1991)" describes the connection in which B is pyrazole, "J. Heterocyclic Chem., 17(8), born 1723 (1980)" describes the connection in which B is an imidazole, and "J. Chem. Soc. C(20), R. 2005 (1976)" and "Heterocycles, 26(3), p. 745 (1987)" describes the connection in which B represents a triazole) as the source material, using well-known methods of halogenation (e.g., the method described in the publication of a non-examination of the patent Automeshing benzyl/ (for example, " Z. Chem., 9(1), R. 22 (1969)" and " Synth. Commun., 20(16), R. 2537 (1990) describe the connection in which B is a thiophene, "J. Org. Chem., 55(15), R. 4735 (1990)" and "Chem. Pharm. Bull., 17(3), p. 582 (1969) describe the connection in which B represents a pyrrole, publication laid a European patent N 506194 reveals the connection, in which B represents an imidazole, and "Chem. Ber., 117(3), R. 1194 (1984)" describes the connection in which B represents a pyrazole or triazole as starting material, the corresponding well-known reaction of reduction-oxidation (for example, to restore diisobutylaluminium and then oxidation with manganese dioxide), and get B - CHO, and then converting the thus obtained product to the B-COCH2Hal appropriate way (for example, a method described in " Tetrahedron Letters, R. 4661 (1972)"/.

The compound of the formula I can also be obtained by the coupling of compounds of formula (X) with a hydroxyl group in position 5 of the compounds of formula (IX) by reaction of nucleophilic substitution. The compound of formula (IX) protect, preferably by substitution of hydrogen R8suitable substituent (for example, Tr:Triticum).

This reaction is usually carried out in a suitable organic solvent in the presence of a base. the aromatic hydrocarbons, hydrogenated hydrocarbons, alkoxyalkane, acetonitrile, etc.

The examples used for this reason are organic amines (such as dimethylamine, diethylamine, Diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, ethanolamine and ethanolamine), alkoxides of metals (such as sodium methoxide, ethoxide sodium, isopropoxide lithium and tert-piperonyl potassium), inorganic salts and hydroxides of alkali metals (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate) and amides of alkali metals (such as sodium amide). These materials are chosen, respectively, depending on the activity of the target response.

This reaction is usually carried out at a temperature in the range -20oC to the boiling point of the employed solvent, preferably from 20oC to 150oC, for 0.5 to 30 hours.

From the amino group in position 3 of thiazolidine thus obtained compounds of formula I can be split protective group as described above in method 5.

Method 7

installed above.

Connection from among compounds having the formula I in which Y represents the SO2, i.e. the compound of formula (1-3) (Y=SO2), can be obtained by the coupling of compounds of formula (V) with the compound of the formula (XI). Pyridinesulfonamide formula (XI) can be obtained by alkylation of the hydroxyl group in position 5 5-hydroxy-2-pyridinesulfonamide acid (as described in "J. Chim. Phys. Phys. -Chim. Biol., vol. 79(3), p. 265 (1982)") as the parent compound with a suitable well-known method, and then halogenoalkanes alkylated product with a suitable halogenation agent (for example, PCl5as described in " Orq. Synth. Coll.. Vol. I, p. 84 (1941)" and "J. Amer. Chem. Soc., vol. 69 p. 1170 (1947), and SOCl2/DMF, as described in Helv. Chim. Acto., vol. 42, R. 1653 (1959)").

This reaction is usually carried out in an atmosphere of inert gas, such as nitrogen, in a suitable organic solvent in the presence of a strong base. The examples used for this purpose solvent are ethers, preferably tetrahydrofuran. Examples of the used grounds are amides of alkali metals (such as LDA-diisopropylamide lithium), an aliphatic or aromatic compounds lithium (such as n - utility, tert-boreali.

This reaction is usually carried out at a temperature in the range from -100oC to 50oC, preferably from -78oC to 20oC, for 0.1 to 10 hours.

Intermediate compounds used in the synthesis of compounds of the present invention, will receive as shown below.

< / BR>
< / BR>
< / BR>
Here in the formulas, R1, R2, R3, R6, R11and Z have the foregoing significance.

Connection from among compounds having the formula (II) in which R6represents hydrogen, can be obtained by the coupling of compounds of formula (X) with a hydroxyl group in position 5 5-hydroxypyridinone formula (IV) by nucleophilic substitution reaction with the formation of the compounds of formula (III), and oxidation hydroxymethylene group in position 2 thus obtained compounds of formula (III).

5-Hydroxypyridinone formula (IV) can be synthesized in the way described in U.S. patent N 4202901. In this method, 2-hydroxypyridine can be obtained by oxidation of 5-hydroxy-2-picoline with a suitable oxidizing agent (such as hydrogen peroxide in acetic acid) with the formation of pyridine-N-oxide, translation pyridine-N-oxide is m acyloxymethyl appropriate acid or base with the formation of 5-hydroxypyridinone. Methylseleninic product can be obtained in the way described in " J. med. Chem., vol. 20(10), p. 1528 (1977) and J. med. Chew., vol. 35(20), p.3667 (1992)", replacement product can be obtained in the way described in "Bull. Sci. Jpn. vol. . 52(1), p. 107 (1979), and bromine - or chlorine substituted product can be obtained in the way described in U.S. patent N 4025333 and in "J. med. Chem.,. vol. 17 (2), p. HS (]974)."

The stage of obtaining the compounds of formula (III) can be carried out under the same conditions as described when considering the way 6.

The stage of obtaining the compounds of formula (II) can be carried out with the use of a suitable oxidizing agent such as manganese dioxide, PCC-chlorproma pyridinium, PDC-pyridinium dichromate, DDQ - dichlorobenzidine, chloranil, the oxidant Swarna (Swern) - oxalicacid-sulfoxide-tertiary amine, and a complex of sulfur trioxide with pyridine).

The compound of formula (II) can also be obtained by the coupling of compounds of formula (X) with a hydroxyl group in position 5 hydroxypyridinone formula (XIII) by reaction of nucleophilic substitution. Hydroxypyridinone formula (XIII) can be obtained in the way described in the publication of the last examination of the Japan patent N 273659/1990, or putarray pyridinium). The stage of obtaining the compounds of formula (II) is carried out by reacting substance in a suitable organic solvent or in the presence of a base. The examples used for this purpose solvents are aprotic polar organic solvents, ethers, aromatic hydrocarbons, haloesters hydrocarbons, alkoxyalkane and acetonitrile, and among these solvents preferred for use is dimethylformamide (DMF). Examples of the used grounds are organic amines (such as dimethylamine, diethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, ethanolamine, ethanolamine, catcher acid H:- 3,4-dihydro-2H-pyrido [1,2-a] pyrimidine-2-he and catcher acid 9M:-9-methyl-3,4-dihydro-2H-pyrido[1,2-a] pyrimidine-2-one) and inorganic hydrides, hydroxides and salts of alkali metals (such as sodium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate), and among these compounds preferred for use are diisopropylethylamine, catcher acid 9M and sodium bicarbonate. These materials are selected appropriately, depending on the activity of the target reaction. This reaction usually is for 0.5-5 hours.

The compound of formula (II) (R6=H) obtained by the above method can then be modified in the compound of formula (II) (R6H) by alkylation formyl group with a suitable alkylating agent, for well-known method.

This stage can be carried out according to the method of using diazomethane, as described in " Tetrahedroh Letters, p. 955 (1963)", and "Chem. Ber., vol. 40, p. 479 (1907)" method using halogenated alkyl, as described in Synth. Commun. vol. 14(8), p.743 (1984), or by the method using alkylate, as described in " J. Orq. Chem. vol. 30, p. 226 (1965)".

< / BR>
Here in the formulas, R1, R2, R3, R6, R9, Z and Hal have the foregoing meanings, and R10is a OR9/R9is installed above the value/ or (C1-C3)-alkyl, such as methyl, ethyl, n-propyl and isopropyl.

Ester halogenated carboxylic acids of the formula (VIII) can be obtained by the interaction of halogenopyrimidines with the ester of malonic acid or a lower ester allocates acid by known methods with the formation of the compounds of formula (VII), and by halogenation thus obtained compounds.

Halogenosilanes fo halogennitroethylenes formula (VI) can be obtained by halogenoalkanes of acyloxymethyl, described for the synthesis of compounds of formula (III) or (IV) with a suitable halogenation agent such as thionylchloride, oxychlorine phosphorus, trihalogen phosphorus, pentavalent phosphorus, hydrochloric acid and Hydrobromic acid). It can also be obtained by halogenoalkanes pyridine-N-oxide, as an initial matter, oxyhalogenation phosphorus, benzosulphochloride or p - toluensulfonate, by the method which is described in U.S. patent N 5202321, " J. Org. Chem. vol. 27, p. 3856 (1962)", or "J. Org. Chem., vol. 38, p.927 (1375). "

Connection from among the compounds having formula (VII) in which R10is a (C1-C3)-alkyl, can be obtained by the interaction of halogenopyrimidines formula (VI) with the lowest ether allocates acid, such as methylacetoacetate and ethylacetoacetate, in the presence of a suitable base (such as sodium hydroxide, potassium hydroxide, sodium methoxide, ethoxide sodium, sodium amide, potassium amide, diisopropylamide, utility, metallic sodium and potassium carbonate), by the method which is described in " J. Amer. Chem. Soc., vol. 64, p.435 (1942)".

Connection from among compounds having the formula (VII) in which R10is a OR9can be obtained saintmalo, in the presence of a suitable base, what was mentioned above, according to this method, which is described in "J. Amer. Chem. Soc., vol. 74, R. 831 (1952)", and " Orq. Synth. Coll., vol. 3, p.705 (1955)".

Stage of synthesis of the compounds of formula (VIII) can be carried out using a suitable halogenation agent such as bromine and N-chlorosuccinimide) in the presence of a suitable base (such as sodium hydroxide, sodium methoxide and potassium carbonate) by this method, which is described in " J. Amer. Chem. Soc., vol. 71, p. 3107 (1949) and Tetrahedron Letters. vol. 28, p. 5505 (1987)".

The compound of formula (VIII) can be also obtained by the interaction of halogenopyrimidines formula (VI) with diazo acetic ether in the presence of copper catalyst by this method, which is described in " Zur. Russ. Fiz-Chim., vol. 21, p. 851 (1951)".

< / BR>
Here in the formulas, R1, R2, R3, R6, R8X1and Z have the foregoing significance.

The compound of formula (1-1) (in which R4and R7together are a bond), obtained as described above may be modified in the compound of the formula (1-2) (R4, R7=H) through the recovery of a double bond between the pyridine ring and thiazolidinone ring (for example, by catalytic hydrin connection or by using an amalgam of magnesium or sodium in methanol).

Catalytic hydrogenation is usually carried out in alcohols, cellosolve, aprotic polar organic solvents, ethers, alkoxyamino, lower esters of aliphatic acids or lower aliphatic acids, and it is preferable to use, in particular, methanol, ethanol, methoxyethanol, di-methylformamide, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or acetic acid, as the sole solvent or in a mixture. Examples of the used catalysts are palladium black, palladium-on-coal and platinum oxide. This reaction may proceed at normal temperature and under normal pressure, but it is preferable to conduct the reaction at elevated temperature and at elevated pressure, depending on the activity of the target response.

Recovery metalloboranes complex is done using borohydride sodium, borohydride potassium, borohydride lithium, borohydride of Tetramethylammonium or borohydride zinc in an aprotic polar organic solvent at a temperature in the range of 0oC to 150oC, preferably from 0oC to 30oC. When such restoration undesirable side reactions can be suppressed by using cobalt R'-bipyridyl or 1,10-phenanthroline (see WIPO 93/13095).

< / BR>
Here

R1, R2, R3, R4, R6, R8X1X2and Z have the foregoing significance.

The compound of the formula (1-2) (R4, R7=H) can be modified in the compound of the formula (1-2) (R4H, R7=H) by alkylation in position 5 thiazolidine suitable alkylating agent (such as halogenated alkyl, including methyliodide or ethyliodide, alkylsulfate, including dimethylsulfate or diethylsulfate, and esters of aliphatic or aromatic sulfonic acids, such as metaltail or metalmaniac) in accordance with well known methods.

This reaction is usually carried out in a suitable organic solvent in the presence of a base. Examples of the used solvents are aprotic polar organic solvents, ethers, alkoxyalkane and similar solvents, and among these particularly preferred solvents are tetrahydrofuran and dimethoxyethane. Examples of the base include amides of alkali metals (such as diisopropylamide lithium (LDA) and potassium amide and aliphatic or aromatic compounds lithium (such as n-utility, tert - utility CLASS="ptx2">

This reaction is usually carried out at a temperature in the range from - 20oC to 100oC, preferably from -10oC to 30oC, for 0.1 to 10 hours.

< / BR>
Here

R1, R2, R3, R6and Z are installed above

The compound of formula (l-2e)/X1=S, X2=NH/ can be modified in the compound of the formula (1-2a)/X1= S, X2=0) by hydrolysis of aminogroup in position 2 of thiazolidine in accordance with known methods.

This reaction is usually carried out in a suitable organic solvent in the presence of water or acid. The examples used in this case solvents are alcohols, cellosolve, aprotic polar organic solvents, ethers, alkoxyalkane, etc., and particularly preferable to use methanol, ethanol, methoxyethanol, sulfolane, dioxane and dimethoxyethane. The examples used in this case, the acid are inorganic acids such as hydrochloric acid, sulfuric acid and Hydrobromic acid). These materials are chosen appropriately, depending on the activity of the target response.

The above reaction is usually carried out at a temperature of from 50oC achasov.

< / BR>
Here

R1, R2, R3, Y and Z have videoscanine values.

The compound of formula (1C) (X1=O, X2=S) can be modified in the compound of formula (1d) (X1=0, X2=0) by oxidation of tocography in position 2 of thiazolidine in accordance with well known methods.

This reaction is carried out using a suitable oxidant such as hydrogen peroxide, organic peroxide, including peracetic acid, derbentina acid, metachlorobenzoic acid, nonoperational acid, nonoperational acid, monumentality acid and similar acids, ion mercury, bromine, chlorine and metaperiodate acid), usually in water or in a solvent such as polar aprotic solvents (e.g. dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylrhodamine, sulfolane, and N, N-dimethylimidazolidine), ethers (e.g. tetrahydrofuran and dioxane) and alkoxyalkane (for example, dimethoxyethane and diethoxyethane). These materials are chosen, respectively, depending on the activity of the target response, and use, respectively, by one or in combination.

This reaction is usually carried out at temperatures what about the 100oC, for 0.5 to 30 hours.

The compound of formula (I) can be transformed into the form of a corresponding N-oxide by oxidation of the nitrogen atom on the pyridine ring with a suitable oxidizing agent in accordance with the well known manner. Examples of the oxidizing agent used in this method are hydrogen peroxide (used in acetic acid or triperoxonane acid at a temperature of from 0oC to 100oC, preferably from 50oC to 80oC for 1-20 hours, preferably from 3 to 10 hours, optionally in the presence of catalytic amounts of sulfuric acid to accelerate the reaction), peracetic acid (used in water or acetic acid optionally in an organic solvent, such as tetrahydrofuran or ethyl acetate, at a temperature of from 0oC to 100oC, preferably from 40oC to 80oC for 1-10 hours, preferably 3-5 hours), derbentina acid or metachlorobenzoic acid (used as an organic solvent, such as chloroform or benzene, at a temperature of from 0oC to 50oC, preferably between 10oC to 30oC, for 0.1 to 3 hours, not more than 2 weeks), and nonoperational acid or monophase 10oC to 50oC, preferably from 0oC to 30oC, for 0.5 to 50 hours, preferably from 1 to 10 hours). Such oxidizing agents may be used in combination. Such N-oxide products can also be converted into corresponding compounds of pyridine by restoring the nitrogen atom on the pyridine ring with a suitable reducing agent in accordance with the well known manner. Examples of the reducing agent used in this method are hydrogen in catalytic hydrogenation (working in an organic solvent, such as acetic acid, acetic anhydride, methanol or ethanol, optionally, their mixtures, at a temperature of from 0oC to 100oC, preferably between 10oC to 70oC, at a pressure of from atmospheric to 30 ATM, preferably from normal pressure to 10 atmospheres, in the presence of a catalyst, such as Raney Nickel, Urushibara Nickel, palladium-on-coal or platinum oxide), iron (work in acetic acid at a temperature of from 50oC to 100oC, preferably from 70oC to 80oC, for 0.5 to 5 hours, preferably from 1 to 2 hours), zinc (work in acetic acid, optionally in the presence of catalytic amounts of sulfuric acid), trichlor or ethyl acetate, at a temperature of from 0oC to 100oC, preferably from 20oC to 80oC, for 0.5 to 5 hours, preferably from 1 to 3 hours), triethylphosphine, triphenylphosphine and triethylphosphite (working in an organic solvent such as ethyl acetate, at a temperature of from 150oC to 300oC, for 0.5-10 hours), and sulphur and sulphur dioxide (working in an organic solvent such as benzene or chlorobenzene, at a temperature of from 150oC to 200oC, for 0.5 to 30 hours).

The above-mentioned compound (II), (III), (IV), (VI), (VII), (VIII), (IX) and (X) are new compounds and are suitable as intermediates for obtaining the compounds of formula (I) of the present invention.

In table. 1-16 examples of compounds having formula (1-1), (1-2) and (1-3) of the present invention. In addition, the pyridine-N-oxide obtained by oxidation of the nitrogen atom on the pyridine ring, and the salts formed during the processing of nitrogen bases on thiazolidinone ring a well known manner, are also compounds of the present invention.

As can be seen from the following test results, the compound (I) or their pharmaceutically acceptable salts of the present invention possess hypoglycemic aktivnosti, grease or disintegrators for the prevention or treatment of diabetes in mammals, including humans, mice, rats, rabbits, dogs, monkeys, cows, horses, pigs, etc., the Compound (I) or their pharmaceutically acceptable salts of the present invention can also be applied in combination with various oral hypoglycemic agents such as derivatives of insulin, sulfonylurea derivatives and derivatives biguanidine, and inhibitors alsoreported.

In addition, as is evident from the following test results, the compound (I) or their pharmaceutically acceptable salts of the present invention have antiglycation activity and properties of inhibition alsoreported, and, therefore, are suitable for the prevention or treatment of diabetic complications, including diabetic eye disease (diabetic cataract, diabetic retinopathy, and so on), diabetic nephropathy, diabetic nephropathy, diabetic gangrene, etc.

The compound (I) of the present invention can be included in various suitable compositions depending on the method of introduction. Compounds of the present invention can be administered in form as sodium salt or potassium salt).

The pharmaceutical composition of the present invention is administered preferably orally in the form of the compounds of the present invention or in the form of powders, granules, tablets or capsules prepared by mixing the compounds of the present invention with a suitable pharmaceutically acceptable carrier (such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, tragacanth resin, polyvinylpyrrolidone or CMC-Ca), excipients (such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine, or microcrystalline cellulose), lubricant (such as magnesium stearate, talc, polyethylene glycol or silica) and the baking powder (such as potato starch).

However, the pharmaceutical composition of the present invention is not limited to the purpose for oral administration, and is acceptable for parenteral administration. For example, you can enter it in the form of suppositories prepared using an oil base, such as cocoa butter, polyethylene glycol, lanolin or triglyceride of fatty acids, in the form of a transdermal therapeutic ointments prepared with the use of medical paraffin oil, white petrolatum, vystavlennogo using one or several substances, selected from the group consisting of polyethylene glycol, fundamentals of hydrogel, distilled water for injection and excipient, such as lactose or corn starch, or in the form of a composition for administration through mucous membranes, such as ocular mucosa, nasal mucosa and oral mucosa.

Daily dose of the compounds of the present invention is 0.05-50 mg, preferably from 0.1 to 10 mg per kg of body weight of the patient, and administered one to three times per day. Dose, of course, may vary depending on age, weight or stage of disease of the patient.

Now the present invention will be described more in detail with the help of test cases that evaluate pharmacological activity of the compounds of the present invention, examples of the preparation of compounds and examples of the formulation. However, it should be borne in mind that the present invention is not limited to such specific examples.

Example 1

Getting 5-((5-(2-oxo-2-(2-phenyl-5-methyl-4 - oxazolyl)ethoxy)-2-pyridyl)methylidene) thiazolidin-2,4-dione (compound N I-1A-1)

< / BR>
Stage 1

Getting 5-(2-oxo-2-(2-phenyl-5-methyl-4-oxazolyl) ethoxy) 2 - pyridinemethanol (compound N 111-1)

< / BR>anola hydrochloride (compound N IV-I) (obtained by the method, described in U.S. patent N 4202901) and 7,00 g (25 mmol) of 4-bromoacetyl-5-methyl-2-phenyloxazole (obtained from 4-acetyl-5-methyl-2-phenyloxazole according to the method described in " J. Chem. Soc., (C), R. 1397 (1968), and in the publication of the last examination of the Japan patent N 85372 (1986)). To the resulting solution add 5,18 g of anhydrous potassium carbonate and the resulting solution was stirred at room temperature for 4 hours. This reaction solution using an evaporator at 60oC and reduced pressure the solvent is distilled off and the thus obtained viscous residue is extracted with 100 ml of chloroform. Thus obtained solution was washed with brine and dried over anhydrous magnesium sulfate. After removal by filtration of the drying agent residue formed during the distillation of the solvent under reduced pressure, subjected to column chromatography on silica gel (eluent 50% ethyl acetate in benzene, then ethyl acetate, and finally with 5% methanol in chloroform), and obtain 2.58 g (31,9%) yellow-brown powder of the desired product (compound N III-1). So pl. 133 - 134oC.

M.-C. (FAB) m/e 325(M+H)+< / BR>
1H NMR (CDCl3) : is 2.74(3H, s), 3,5 (1H), 4,74 (2H, s), 5,44 (2H, s), 7.3 to 7.4 (2H, m), of 7.48-7,51 (3H, m), 8,04-of 8.06 (2H, m), 8.34 per-8,35 (1H, m).

Macovescu, hold her in dimethylformamide or chloroform in the presence of a base such as sodium hydride or triethylamine, and receive connections NN (III-2) to(III-5). (Table to stage 1 of example 1 are provided in the end of the description, where Z corresponds to the substituents in the compound of formula (III).

III-21H-NMR (CD>Cl3) : of 3.45 (3H, s), 4.2V (1H) and 4.65 (2H, s), of 5.15 (2H, s), 7,2-7,4 (2H, m), and 8.2 and 8.3 (1H, m).

III-31H-NMR (CDCl3) : 3,3 (1H, s) and 4.65 (2H, s), of 5.15 (2H, s), 7,1-7,3 (2H, m), 7,3-7,5 (5H, m), and 8.2 and 8.3 (1H, m).

III-4 1H-NMR (CDCl3) : of 3.7 (1H), and 4.75 (2H, s), 7,1-8,5 (8H, m).

III-5 1H-NMR (CDCl3: 1,1 (9H, s), and 4.5 (2H, s), 6,9-8,2 (13H, m).

Stage 2

Getting 5-(2-oxo-2-(2-phenyl-5-methyl-4-oxazolyl) ethoxy) 2-pyridinecarboxamide (compound N-II-1)

< / BR>
In 5 ml of anhydrous chloroform was dissolved 0.15 g (0.47 mmol) of the compound N III-1. To this solution was added 340 mg of active manganese dioxide, and the resulting solution was stirred at room temperature for 5 days. After determining the disappearance of the original substance according to thin-layer chromatography of the residual oxidizing agent is removed by filtration. Thus obtained solution is treated with activated charcoal and the solvent is distilled off under reduced pressure. Obtain 0.11 g (7H)+.

1H NMR (CDCl3) : is 2.74 (3H, s) 5,54 (2H, s), of 7.36-7,38 (1H, m), 7,49-7,52 (3H, m), 7,97-to 7.99 (1H, m), with 8.0 and 8.1 (1H, m), 8,53-8,54 (1H, m), 10,04 (1H, s).

In the same way described above, receive connections NN (II-2) to(II-5). (Table to stage 2 of example 1 are provided in the end of the description, where Z corresponds to the substituents in the compound of formula (II).

II-21H-NMR (CDCl3) : 3,48 (3H, c in), 5.25 (2H, s), and 7.3 and 7.6 (1H, m), 7,8-8,0 (1H, m), and 8.4 to 8.5 (1H, m), for 9.90 (1H, s).

II-31H-NMR (CD>Cl3) : of 5.17 (2H, s), 7,3-7,5 (6H, m), 7,8 and 8.1 (1H, m), and 8.4 to 8.5 (1H, m), for 9.90 (1H, s).

II-41H NMR (CD>Cl3) : of 7.2 to 8.3 (7H, m), 8.6 out of 8.8 (1H, m), becomes 9.97 (1H, s).

In 29 ml of dimethylformamide, dehydrated by molecular sieves, dissolved 0,756 g (6,14 mmol) 5-hydroxy-2-pyridine carbaldehyde (compound N XIII-1) (obtained by the method described in the publication of the last examination of the Japan patent N 273659(1990) and 1,72 g (6,14 mmol) 4-bromoacetyl-5-methyl-2-phenyloxazole, and the resulting solution stirred at room temperature. To this solution is gradually added 1.6 ml (of 9.21 mmol) diisopropylethylamine, and the resulting solution stirred at room temperature for 2.5 hours. After determining thin-layer chromatography the end of the reaction it received in resultset over anhydrous sodium sulfate. After removal by filtration of the drying agent under reduced pressure, the solvent is distilled off. Thus obtained residue is subjected to column chromatography on silica gel (50% ethyl acetate in hexane), and get 1,318 g (61%) of the desired product (compound N II-1).

In the same way described above, receive connections NN (II-6) to(II-18). (These compounds are described in the table at the end of the description, where Z corresponds to the substituents in the compound of formula (II).

II-6

1H NMR (CDCl3) : 2,35 (3H, s), 2,61 (3H, s) 5,38 (2H, s), 7,16 (3H, m), 7,80 (3H, m), 8,40 (1H, m), 9,86 (1H, s).

II-7

1H NMR (CDCl3) : to 2.42 (3H, s), 2,68 (3H, s), of 5.48 (2H, s), 7,33 (3H, m), of 7.90 (3H, m), and 8.50 (1H, m), 9,96 (1H, s).

II-8

1H NMR (CD>Cl3) : of 2.68 (3H, s), 5,44 (2H, s) 6,86 (1H, m), 7,55 (1H, m), 7,87 (1H, m), with 8.05 (2H, m), 8,51 (1H, m), 9,99 (1H, s).

II-9

1H NMR (CDCl3) : is 2.74 (3H, s), the 5.51 (2H, s), 7,1-8,5 (12H, m), there is a 10.03 (1H, s).

II-10

1H NMR (CDCl3) : of 2.68 (3H, s), 5,46 (2H, s), from 7.24 (3H, m), 7,95 (3H, m), and 8.5 (1H, m), there is a 10.03 (1H, s).

II-11

1H NMR (CD>Cl3) : and 2.83 (3H, s) 5,52 (2H, s), 7,35 (3H, m), a 7.85 (5H, m), and 8.50 (2H, m), becomes 9.97 (1H, s).

II-12

1H NMR (CDCl3) / : 2,70 (3H, s) 5,49 (2H, s), 7,40 (2H, m), to 7.93 (4H, m), to 8.45 (1H, m), 9,96 (1H, s).

II-13

1H NMR (CDCl3) : 2,70 (3H2-phenyl-5-methyl-4-oxazolyl) ethoxy)-2-pyridyl)methylidene) thiazolidin-2,4-dione (compound N I-1A-1)

< / BR>
In 10 ml of toluene, dehydrated molecular sieve, suspended 0.15 g (0.47 mmol) of compound N (II-1) and 0.11 g of thiazolidinedione. To this solution was added to 8.4 mg of glacial acetic acid and then to 7.9 mg of piperidine, and the resulting solution stirred at 130oC for 15 hours. After determining according to thin-layer chromatography disappearance of the original substances precipitated precipitated substance is dissolved, adding to the reaction mixture of chloroform and methanol. Thus obtained solution was washed with brine and dried over anhydrous magnesium sulfate. After removal by filtration of the drying agent to remove the solvent under reduced pressure and the resulting residue is subjected to column chromatography on silica gel (eluent chloroform, and then 5% methanol in chloroform). Obtain 0.18 g (94,1%) of the desired product as a pale brown powder (compound N I-1A-1).

So pl. 229-231oC.

M.-C. (FAB) m/e 422 (M+H)+< / BR>
1H NMR (d6-DMSO) : 2,69 (3H, s), the 5.65 (2H, s), and 7.5 and 7.6 (4H, m), 7,78-7,81 (2H, m), of 7.9 to 8.0 (2H, m), 8,49-charged 8.52 (1H, m), with 12.3 (1H, Shir. C).

In the same way described above, receive connections NN (I-1A-2)-(I-la-32). (Table to stage 3 of example 1 are provided in the end of the description, where Z sootin, C) a 7.5 and 7.6 (1H, m), to 7.77-7,83 (2H, m), 8,51-charged 8.52 (1H, m), 12,3 (1H).

I-1A-3

1H NMR (d6-DMSO) : at 5.27 (2H, s), 7,34-7,49 (5H, m), to 7.59-to 7.61 (1H, m), 7,78-to 7.84 (2H, m), 8,54-8,55 (1H, m), 12,3 (1H). (see connection examples 1-1A-6 to 1-1A-32 in the end of the description).

I-1a-6

1H NMR (DMSO, 500 MHz) : 2,40 (3H, s), 2,68 (3H, s), the 5.65 (2H, s), 7,40 (2H, m), 7,55 (1H, m), 7,80 (2H, m), to 7.93 (2H, m), charged 8.52 (1H, m).

I-1A-7

1H NMR (CDCl3, 500 MHz) : to 2.46 (3H, s) of 2.75 (3H, s) 5,52 (2H, s), 7,35 (3H, m), 7,55 (2H, m), of 7.70 (1H, s), 7,88 (2H, m), 8,55 (1H, s).

I-1A-8

1H NMR (CDCl3, 500 MHz) : 2,70 (3H, s), the 5.45 (2H, s), to 6.88 (1H, m), 7,46 (1H, m), 7,54 (1H, m), 7,72 (1H, m), of 8.06 (2H, m), charged 8.52 (1H, m).

I-1A-9

1H NMR (CDCl3, 500 MHz) : was 2.76 (3H, s) 5,52 (2H, s), was 7.45 (5H, m), of 7.75 (4H, m), 8,15 (3H, m), 8,65 (1H, m).

I-1a-10

1H NMR (CDCl3, 500 MHz) : is 2.74 (3H, s) 5,49 (2H, s), 7,21 (2H, m), 7,29 (1H, m), 7,46 (1H, m), 7,72 (1H, m), with 8.05 (2H, m), charged 8.52 (1H, m), and 9.4 (1H SHS).

I-1a-11

1H NMR (CDCl3, 500M Hz) : and 2.79 (3H, s), of 5.55 (2H, m), 7,2-7,5 (3H, m), 7,56 (1H, m), of 7.90 (4H, m), 8,15 (1H, m), 8,55 (2H, m).

I-1a-12

1H NMR (CDDl3, 500 MHz): is 2.74 (3H, s) 5,49 (2H, s), 7,16 (1H, m), of 7.48 (3H, m), 7,71 (1H, m), 8,00 (2H, m), charged 8.52 (1H, m).

I-1a-13

1H NMR (CDCl3, 500 MHz) : 2,72 (3H, s), 3,88 (3H, s) 5,49 (2H, s) 6,70 (2H, m), to 7.15 (1H, m), 7,25 (1H, m), 7,35 (1H, m), 8,00 (2H, m), 8,35 (1H, s).

Example 2

Getting 5-((5-(2-oxo-2-(2-phenyl-5-methyl - dehydrated molecular sieve, dissolve to 0.48 g (1.1 mmol) 5-((5-(2-oxo-2-(2-phenyl-5-methyl-4 - oxazolyl) ethoxy)-2-pyridyl)methylidene)thiazolidin-2,4-dione (compound N I-1A-1). To this solution was added 0.9 g of 10% palladium charcoal and conduct catalytic reduction at room temperature under hydrogen pressure of 7 ATM for 5 days. After removal of catalyst by filtration the solvent is distilled off under reduced pressure and get the remainder, and thus obtained residue is subjected to column chromatography on silica gel (eluent of 5% methanol in chloroform). Get 0,38 g (26,3%) of the desired product as a pale yellow powder (compound I N-2A-1).

So pl. 56-62oC.

M.-C. (FAB) m/e 424 (M+H)+.

1H NMR (CDCl3) : to 2.67 (3H, s), 3,26 (1H, DD, J=10,3, 15.7 Hz), 3,6-7 (1H, DD, J= 3,8, 15.7 Hz), was 4.76 (1H, DD, J=3,8, 10,3 Hz), are 5.36 (2H, s), 7,06-was 7.08 (1H, m), 7,1-7,2 (1H, m), 7,42-7,44 (3H, m), 7,97-to 7.99 (2H, m), 8,23-8,24 (1H, m), and 8.4 (1H, Shir. C ).

In the same way described above, receive connections NN (I-2A-2) and (I-2A-4)-(I-2A-25). (Table for example 2 are given in the end of the description, where Z corresponds to the substituents in the compound of formula (I-2A).

I-2a-2

1H NMR (d6-DMSO) : to 3.34 (1H, DD, J-10, 15 Hz), 3,49 (3H, s), of 3.73 (1H, DD, J=5, 15 Hz), a 4.83 (1H, DD, J=5, 10 Hz), 5,19 (2H, s), 7,11-7,14 (1H, m), 7,33 and 7.36 (1H, m), 8,32-8,35 (1H, B>3, 90 MHz) : 2,44 (3H, s), of 2.72 (3H, in), 3.75 (2H, m), the 4.90 (1H, m), of 5.48 (2H, s), 7,31 (3H, m), 7,92 (3H, m), 8,35 (1H, m).

I-2A-5

1H NMR (CDCl3, 90 MHz) : 2,40 (3H, s), 2,70 (3H, s), 3,50 (2H, m), 4,80 (1H, m), 5,38 (2H, s), 7,25 (3H, m), 7,83 (3H, m), 8,29 (1H, m).

Example 3

Getting 5-((5-(2-hydroxy-2-(2-phenyl-5-methyl-4-oxazolyl; ethoxy) -2-pyridyl) methyl) thiazolidine-2,4-dione (compound N I-2A-3)

< / BR>
In 5 ml of methanol, dehydrated molecular sieve, dissolved 200 mg (0.47 mmol) 5-((5-(2-oxo-2-(2-phenyl-5-methyl-4-oxazolyl) ethoxy)-2-pyridyl)methyl)thiazolidine-2,4-dione (compound N I-2A-1). To this solution add a 21.5 mg of sodium borohydride and the resulting solution was stirred at room temperature for 1 day. Reaction stop saturated aqueous ammonium chloride and the reaction mixture is extracted with chloroform. Thus obtained reaction product is washed with salt brine and dried with anhydrous magnesium sulfate. After removal by filtration of the drying agent, the solvent is distilled off under reduced pressure and get the remainder, and thus obtained residue is subjected to column chromatography on silica gel (eluent 10% methanol in chloroform). Obtain 203 mg (quantitative yield) of the desired product as a pale-brown is (d6-DMSO) : to 2.46 (3H, s) to 3.33 (1H, DD, J=10,0, the 15.6 Hz), of 3.69 (1H, DD, J =3,4, 15.6 Hz), 4,24 (1H, DD, J=4,6, 9.5 Hz), 4,37 (1H, DD, J= 7,6, 9.5 Hz), to 4.81 (1H, DD, J=3,4, 10,0 Hz), 5,10 (1H, DD, J=4,6, and 7.6 Hz), 7,10-to 7.15 (1H, m), 7,2-7,3 (1H, m), of 7.4 to 7.7 (3H, m), 7.95 is-with 8.05 (2H, m), 8,25-8,30 (1H, m), and 8.7 (1H, Shir.with. ).

In the same way as described above, were obtained the following compounds N (I-1a-40) to (I-1a-46) (see table at the end of the description, where Z corresponds to the substituents in the compounds of the formula I-1A).

In the same way as described above, were obtained the following compounds N (I-2A-30) to (I-1a-34) (see table at the end of the description, where Z corresponds to the substituents in the compounds of formula (I-2A).

Example 4

Getting 5-((5-(2-hydroxy-2-(2-phenyl-5-methyl-4 - oxazolyl)etoki)-2-pyridyl)methylidene)rhodanine (compound N I-1B-1)

< / BR>
In 10 ml of toluene, dehydrated molecular sieve, suspended 200 mg (of 0.62 mmol) of the compound N II-1 and 91 mg of Rodnina and the resulting suspension was dissolved by heating. To this solution while cooling water is added to 11.2 mg of glacial acetic acid and then to 10.6 mg of piperidine and the resulting solution was stirred at room temperature for 2 days. After determining thin-layer chromatography disappearance of the original substances precipitated precipitated crystals at 50oC for 2.5 hours to obtain 220 mg (81,1%) of the desired product as a yellow powder (compound N I-1B-1). In addition, from the filtrate after removal of the crystalline substance extracted a further 50 mg of the target product.

So pl. 217,5-218,5oC.

M.-C. (FAB) m/e 438(M+H)+.

1H NMR (d6-DMSO) : 2,69 (3H, s), to 5.66 (2H, s), of 7.5 to 7.7 (5H, m), 7,8-7,9 (1H, m), with 8.0 and 8.1 (2H, m), an 8.5 and 8.6 (1H, m) to 13.6 (1H, Shir. C.).

Example 5

Getting monoethanolamine 5-((5-(2-oxo-2-(2 - phenyl-5-methyl-4-oxazolyl)ethoxy)-2-pyridyl)methylidene)thiazolidin - 2,4-dione (compound N I-1a-1-1)

< / BR>
0.2 g (0.48 mmol) of Compound N I-1A-1 is dissolved in 6 g of tetrahydrofuran at 30-40oC. To this solution are added dropwise 1.0 g of methansulfonate and the resulting solution was stirred at room temperature. After about 5 minutes, it begins to fall the yellow precipitate of methansulfonate. After stirring the reaction mixture at room temperature for 30 minutes, it was stirred at 0-5oC for another 30 minutes. Sediment methansulfonate separated by filtration and washed with 1 g of cold tetrahydrofuran. After drying in vacuum at 60oC for 1 hour to obtain 0.2 g (0,39 mmol, 81,4%) of pale yellow powder of the desired product.

So pl. 231oC.


< / BR>
35,0 g (83.1 mmol) of the Compound N I-1A-1 is dissolved in 1751 g of tetrahydrofuran at 60oC. After cooling this solution to 25oC added dropwise 146 g 41% of hydrogen chloride in alcohol, and the resulting solution was stirred at room temperature. After about five minutes, it begins to precipitate yellow precipitate of the hydrochloride. After stirring the reaction mixture at room temperature for 30 minutes, added dropwise 875 g of diethyl ether for 30 minutes. After stirring the reaction mixture at room temperature for 30 minutes it was stirred for further 30 minutes at 3-5oC. the precipitated hydrochloride is separated by filtration and dried in vacuum at 30oC for 2 hours, get 32,4 g (70,8 mmol, 85,6%) of pale yellow powder of the desired product.

So pl. 240-242oC.

Test example 1. The definition of hypoglycemic action

Mice KK and KKAy, models of NIDDM (males, age 6-7 weeks) (Nakamura, Proc. Jpn. Acad. 38, 348-352, 1962; lwatsuka et ai., Endocrinoi Jpn., 17 23-35, 1970) buy from Nihon Clea. They create the possibility of free access to high-calorie food (CMF, Oriental Yeast) and water. Examined mice weighing about 40 g

Blood (20 μl) taken from retroorbital atant. Glucose determine glucose oxydase method (glucose analyzer 11, Bekman). Check the group of 3-4 mice with glucose levels in the blood, more than 200 mg/DL, at which glucose levels in the blood, is not reduced by more than 10% within 24 hours after a single oral administration of 0.5% carboxymethylcellulose (CMC) in physiological solution.

All tested compounds suspended in 0.5% carboxymethylcellulose (CMC) in saline solution, administered to mice orally. Blood taken before injection and 24 hours after administration of retroorbital sinus, and measure glucose levels in the blood, the above-mentioned method. Hypoglycemic activity is expressed as the percent reduction of glucose in the blood is calculated before injection and 24 hours after injection ( see results mouse QC and mouse Chau at the end of the description).

< / BR>
< / BR>
Compounds of the present invention detect hypoglycemic activity, essentially, in the same or greater extent than CS-045 and CP-86325, with whom they compare, and which are used as control compounds. Glibenclamide (insulin-secreting tool) does not detect hypoglycemic activity when tested this is trust 5 weeks) (Tokuyama, Y. et al., Diabetes, 1447-1457, 1995) were purchased from Genetic Models Inc. They were given an unlimited abundance of energy-dense mixture (CMF, Oriental Yeast (Asian yeast) and water. Has been studied a group of 4 mice with maintenance of blood glucose over 200 mg/DL. The compounds suspended in 0.5% saline solution of carboxymethyl cellulose (CMC), was administered to mice orally once daily for 14 days. Before the introduction (day 0) at 4, 7 and 14 days, blood samples (20 l) selected from the retro-orbital sinus, was dissolved in 60 units of solution of heparin sodium and centrifuged in microcentrifuge. The concentration of glucose in the supernatant was determined by the method of oxidation of glucose (Glucose Analyzer 11, Beckman). Hypoglycemic activity expressed as a percentage reduction in blood glucose, calculated before and during the above mentioned days after injection.

The compounds of this invention exhibit hypoglycemic activity (see table. And at the end of the description).

Test example 2. Definition antiglycating action

When a patient with diabetes high glucose concentration persists for a long time, some types of proteins are the nonenzymatic glycation. It is assumed that the exposed glycation proteins induce diabeteszentrum, the quantity of such a protein can be determined using fluorescence in accordance with previous reports (Doi et al. , Proc. Natl. Acad. Sci. USA., 89, 2873-2877, 1992; Mitsuhoshi et al. . Diabetes, vol. 42, 826-832, 1993). Experimental procedure modify as follows. Five percent bovine serum albumin (BSA) contained in 0.5 M glucose-6-phosphate-2Na (5% BSA-0.5 M G6P), sterilized by filtration (pore size of 0.45 µm filter) and incubated at 37oC; material positive control incubated with 1% dimethyl sulfoxide (DMSO) at 37oC; the empty incubated at 4oC. All tested compounds dissolved in DMSO (the final concentration of DMSO less than 1%), add in 5% BSA-0.5 M G6P. After 10-day incubation with 5% BSA-0.5 M G6P connection with the positive control and the empty cialiswhat against 2 liters of phosphate buffered saline for 24 hours (molecular weight fractions 12000-14000). Cialisovernight the solution was diluted with water 4 times and determine the fluorescence (exp. 370 nm-EXM. 440 nm). The concentration of protein in delisounal solution (10 μl which is diluted with distilled water up to 20 times) is determined by the method of Lowry and Express fluorescence per mg protein. Control (100%) is a positive control minus "dummy".

Antigel/BR> Compounds of the present invention find stronger antiglycation activity than aminoguanidine used as control material. CS-045 and CP-86325 not find antiglycation activity.

Test example 3. The determination of the activity of inhibiting alsoreported

Prepare AR from kidneys of rats as follows. The kidneys of rats pour chilled ice saline to remove blood, and then homogenized in a Teflon homogenizer with 3 volumes of cold 5 mm Tris-HCl buffer (pH of 7.4). The homogenate was centrifuged at 45000 x g for 40 minutes to remove insoluble materials and supernatant fraction is used as a sample alsoreported (AR).

The definition of AR and action check connections

The activity of the AR test according to the modified method Inukai et al., (Jpn. J. Pharmacol. , 61, 221-227, 1993). The absorption of nikotinamidadenindinukleotida (NADPH) (340 nm) as oxidant cofactor for AR-define spectrometer (UV-240, Shimodzu, Kyoto). Tests carried out in 0.1 M sodium phosphate (pH 6,2) containing 0.4 M lithium sulfate, 0.15 M NADPH, the enzyme, and various concentrations of tested compounds and 10 mm DL-glyceraldehyde. The control sample contains all of the above is dagid). The reaction rate was measured at 30oC for 2 minutes. All tested compounds dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO in the reaction mixture never exceeds 1%. The effect of inhibitors was evaluated as the concentration check connection required for 50% inhibition of enzyme activity (IC50).

The result of these tests is the fact that the compounds of the present invention find satisfactory activity inhibition alsoreported.

Example composition 1

Tablets

The compound of the present invention is 1.0 g

Lactose - 5.0 g

Powder, crystalline cellulose - 8.0 g

Corn starch - 3.0 g

Hydroxypropylcellulose - 1.0 g

SMS-Sa - 1.5 grams

Magnesium stearate - 0.5 g

Just - 20,0 g

All the above components are mixed in the usual way, and then tabletirujut; obtain 100 tablets each containing 10 mg of active ingredient.

Example composition 2

Capsules

The compound of the present invention is 1.0 g

Lactose - 3.5 grams

Crystalline cellulose, powder, 10.0 g

Magnesium stearate - 0.5 g

Just - 15.0 g

The above components are mixed on the 10 mg of the active ingredient.

Example of part 3

Soft capsules

The compound of the present invention to 1.00 g

PEG (polyethylene glycol) 400 - to 3.89 g

The triglyceride of saturated fatty acid - 15,00 g

Mint oil - 0.01 g

Polysorbate 80 - 0.10 g

All of 20.00 g

The above compounds are mixed and fill this mixture in the usual way, soft gelatin capsules No. 3. and get 100 soft capsules, each containing 10 mg of active ingredient.

Example of part 4

Ointment

The compound of the present invention to 1.0 g (10.0 g)

Medical paraffin oil - 10,0 g (10.0 g)

Cetanol - 20,0 g (20,0 g)

White petrolatum to 68.4 g (59,4 g)

Ethylparaben - 0.1 g (0.1 g)

1-Menthol - 0.5 g (0.5 g)

Just - 100.0 g

The above components are mixed in the usual way and get a 1% (10%) ointment.

Example of part 5

Suppository

The compound of the present invention is 1.0 g

.Witepsol H15*- 46,9 g

.Witepsol H35*with 52.0 g

Polysorbate 80 0.1 g

Just - 100.0 g

*Brand triglycerides

The above components are mixed in the molten state in the usual way and pour out in the form of suppositories, then cooled for solidification and progranulin

The compound of the present invention is 1.0 g

Lactose - 6.0 g

Crystalline cellulose, powder, 6.5 g

Corn starch - 5.0 g

Hydroxypropylcellulose - 1.0 g

Magnesium stearate - 0.5 g

Just - 20,0 g

The above components granularit in the usual way and pack, get 100 packages, each of which contains 200 mg of the granules, and thus, each pack contains 10 mg of active ingredient.

Industrial applicability

Since the compounds of the present invention possess hypoglycemic action, antiglycation activity and activity inhibition alsoreported and have low toxicity, they are suitable for the prevention or treatment of diabetic complications, including diabetic eye disease (such as diabetic cataract and diabetic retinopathy), diabetic neuropathy, diabetic nephropathy, diabetic gangrene, etc.,

1. The connection of thiazolidine pyridine type and its salt of the General formula I

< / BR>
in which X1represents S;

X2Is S or O;

Y - CR6R7(R6and R7each is a hydrogen atom, or R7together with R4forms link);

ZB>1-C7) -CNS groups), substituted silyl group; or a-b (A is a divalent (C1-C6) - rich or (C2-C6) unsaturated hydrocarbon group which may be substituted by at most three hydroxyl, oxo and (C1-C7) -alkyl groups, and is a

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
each of Raand Rbindependently represents a hydrogen atom, (C1-C7) -alkyl group which may be substituted by a hydroxyl group or exography, halogen atom, phenyl, -naphthyl, -naphthyl, furyl, each of these groups - phenyl, -naphthyl, -naphthyl, Shrila can be replaced by stands, a methoxy group, benzyloxycarbonyl, a hydroxyl group, a halogen and a phenyl group), and Rcrepresents a hydrogen atom or a (C1-C7) -alkyl group;

R1, R2and R3each is hydrogen;

R4is a hydrogen atom or together with R7forms a link;

n = O.

2. The compound and its salt under item 1, where X1represents S, Y-CR6R7(R6represents a hydrogen atom, and R3is a hydrogen atom or together with R4forms SUB>-C6) is a saturated hydrocarbon group which may be substituted by hydroxyl or exography.

3. The compound and its salt under item 1, where Y represents-CH2-, and R4- the hydrogen atom.

4. The compound and its salt under item 1, where the Y - CHR7(R7together with R4forms a bond, and R4together with R7forms link.

5. The compound and its salt under item 1, where a is a

< / BR>
where m = 0,1;

each of Rdand Reindependently is a hydrogen atom;

each of Rfand Rgindependently a hydrogen atom or a hydroxyl group, or Rfand Rgtogether form oxoprop.

6. The compound and its salt under item 1, where a represents a-CH2-CH2-

< / BR>
7 Hypoglycemic agent, characterized in that it contains as active agent a compound of thiazolidine pyridine type or its salt under item 1.

8. Antiglycation means, characterized in that it contains as active agent a compound of thiazolidine pyridine type or its salt under item 1.

9. The pharmaceutical agent inhibiting hyperglycemia, determinationby the glycation and alsoreported, for the prevention and treatment sagarnaga of thiazolidine pyridine type or its salt under item 1, in an effective amount.

Priority signs:

28.03.94 - derived thiazolidine pyridine type formula I

or its salt

< / BR>
where X1-S;

X2Is S or O;

Y - CR6R7(each of R6and R7is hydrogen or R7and R4together form a bond);

Z-C1-C10-alkyl (the alkyl may be substituted by at most three C1-C7-alkoxygroup), substituted silyl group or a-C (A-bivalent1-C6-saturated hydrocarbon group which may be substituted by at most three hydroxyl or exography, and a group of the formula

< / BR>
where each of Raand Rbindependently of each other a hydrogen atom, a C1-C7-alkyl, phenyl;

Rcis a hydrogen atom or a C1-C7-alkyl;

R1, R2and R3-hydrogen atoms;

R4is a hydrogen atom or forms a bond together with R7;

n = 0;

29.11.94 - derived thiazolidine type formula I

or its salt

< / BR>
where X1-S;

X2Is S or O;

Y-CR6R7(each of R6and R7is hydrogen or R7or R4together form a bond);

Z-C1-C10-alkyl, which is In (A - divalent C1-C6saturated hydrocarbon group which may be substituted by at most three hydroxyl or exography, and a group of the formula

< / BR>
where each of Raand Rbindependently of each other a hydrogen atom, a C1-C7-alkyl, halogen atom, phenyl, -naphthyl, furyl (mentioned phenyl, naphthyl and furyl may be replaced by metelli, methoxypropane, halogen and fenelli);

Rcis a hydrogen atom or a C1-C7-alkyl;

R1, R2and R3-hydrogen atoms;

R4is a hydrogen atom or forms a bond together with R7;

n = 0.

 

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The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to 3-/1-diazolidinyl butyl-4-piperazinil/ 1H-indazols formula I

< / BR>
where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R5is hydrogen or lower alkyl;

X is halogen;

m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use
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