The preparation and use of ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids as inhibitors of the matrix metalloproteinase and tace (tnf--converting enzyme)


 

The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formulawhere W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, withis a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is phenyl and n=1-6, thienyl and group-OR2where R2is the o substituted by halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts. These compounds are inhibitors of matrix metalloproteinase and TACE enzyme carrying out the conversion factortumor necrosis. Proposed methods of inhibition of pathological changes mediated by matrix metalloproteinases, and TNT--converting enzyme (TACE) and pharmaceutical composition comprising these compounds. 4 C. and 7 C.p. f-crystals, 1 table.

Description text in facsimile form (see drawings) T TC

Claims

1. Ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acid having the formulawhere W and X are both carbon, or W is nitrogen, and X is carbon; T is nitrogen; U represents CR1'where R1'represents hydrogen or ALK is t a

this

is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally have one or two substituent R1where permissible;
Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2;
R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2'group-NO2group -(CH2)nZ', where Z' is phenyl and n=1-6, thienyl, and the group-OR2'where R2' represents alkyl with 1-8 carbon atoms;
R represents alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur;
R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl or heteroaryl, with asepticheski acceptable salt.

2. Connection on p. 1, in which W and X are both carbon, or its pharmaceutically acceptable salt.

3. Connection on p. 2, in which

is phenyl or pyrazole, each of which optionally has one or two substituent R1,
or its pharmaceutically acceptable salt.

4. Connection on p. 1, which is selected from the group consisting of
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)-amino] -7-trifloromethyl-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)-amino] -8-trifloromethyl-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxy-benzazolyl)-amino] -6-bronchioles-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxy-benzazolyl)-amino] -7-bronchioles-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxy-benzazolyl)-amino] -6-trifloromethyl-quinoline-3-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)-pyridine-3-ylmethylamino]-7-trifloromethyl-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -8-tert-butylphenol-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -8-methylinosine-3-carbon is hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -8-(1-methylethyl)quinoline-3-carboxylic acid,
hydroxyamide 4-[ethyl-(4-methoxybenzenesulfonyl)amino]-8-vinylpyridin-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)-amino] -6-nitroquinoline-3-carboxylic acid,
hydroxyamide 4-[methyl-(4-methoxybenzenesulfonyl)-amino] -8-bronchioles-3-carboxylic acid,
hydroxyamide 4-{methyl-[4-(pyridine-4-yloxy)-benzazolyl]amino}-6-eothinon-3-carboxylic acid,
hydrochloric acid hydroxyamide 4-{methyl-(4-(pyridin-4-yloxy)benzazolyl]amino}-6-eothinon-3-carboxylic acid,
hydroxyamide 4-[methyl-(4-methoxybenzenesulfonyl)amino] -6-phenylethyl-quinoline-3-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-8-methoxyquinoline-3-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -8-bronchioles-3-carbonate acid,
hydroxyamide 4-[(4-methoxy-benzazolyl)-pyridine-3-ylmethylamino] -8-benzyl-quinoline-3-carboxylic acid,
hydroxyamide 4-[(4-methoxy-benzazolyl)-pyridine-3-ylmethylamino] -8-eothinon-3-carboxylic acid,
hydroxyamide 4-[(4-methoxy-benzazolyl)-pyridine-3-ylmethylamino] -8-phenylindolin-3-carboxylic acid,
hydroxyamide 4-[(4-methoxy-benzazolyl)-pyridine-3-elmet the Mino]-7-trifloromethyl-quinoline-3-carboxylic acid,
hydroxyamide 4-[pyridin-3-ylmethyl-(toluene-4-sulfonyl)-amino]-7-trifloromethyl-quinoline-3-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydrochloric acid hydroxyamide 4-[(4-methoxybenzenesulfonyl)-pyridine-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4 b]pyridine-5-carboxylic acid,
hydrochloric acid hydroxyamide 4-[(4-methoxybenzenesulfonyl)-pyridine-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[benzyl-(4-methoxybenzenesulfonyl)amino] -1-phenyl-3-methyl-1H-pyrazolo[3,4 b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydrochloric acid hydroxyamide 4-[(4-methoxybenzenesulfonyl)-pyridine-3-ylmethylamino] -1-phenyl-3-methylamino] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-4-ylmethylamino] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1-isopropyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1-benzyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)amino]-1-benzyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)-2-titelmelodie] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)-3-titelmelodie] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1-(2,4-acid)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1-(2-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid,
hydroxyamide 4-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-{ methyl-[4-(phenoxybenzenesulfonyl)amino]-1,3-dimethyl-1 is Teal-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[methyl-(4-propiloxibenzoat)-amino] -1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-1-ethyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino] -1-tert.-butyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-1-methyl-3-tert.-butyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-3-methylisothiazolone[5,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-3-methylisoxazole[5,4-b]pyridine-5-carboxylic acid,
hydroxyamide 7-[(4-methoxybenzenesulfonyl)pyridine-3-ylmethylamino]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid,
hydroxyamide 4-{[4-(4-chlorphenoxy)benzazolyl]-methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-{[4-(4-chlorphenoxy)benzazolyl]-methylamino}-3-metriso is 3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-3-methylisothiazolone[5,4-b]pyridine-5-carboxylic acid,
hydroxyamide 4-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and
hydroxyamide 4-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-3-methylisoxazole[5,4-b]pyridine-5-carboxylic acid,
or its pharmaceutically acceptable salt.

5. Connection on p. 1, which is selected from the group consisting of
hydroxyamide 7-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid,
hydroxyamide 4-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-7-methyl-1,8-naphthiridine-3-carboxylic acid,
hydroxyamide 7-{methyl-[4-(4-pyridyloxy)benzazolyl]amino}-2,3-dimethylimidazo[4,5-b]pyridine-6-carboxylic acid,
hydroxyamide 2-methyl-4-{ methyl-[4-(4-pyridyloxy)-benzazolyl] amino}thieno[3,4-b]pyridine-3-carboxylic acid and
hydroxyamide 5-methyl-7-{ methyl-[4-(4-pyridyloxy} benzazolyl] amino}thieno[3,2-b]pyridine-6-carboxylic acid,
or its pharmaceutically acceptable salt.

6. The method of inhibition of pathological changes mediated by matrix metalloproteinases, guideuse the number of connections on p. 1 or its pharmaceutically acceptable salt.

7. The method according to p. 7, which affected the state of pathological changes mediated by the action of matrix metalloproteinases, occurs when atherosclerosis, atherosclerosis plaque formation, reduction of coronary thrombosis associated with perforation of atherosclerotic plaques, re-stenosis, osteopenia, mediated MMP, inflammatory diseases of the Central nervous system, skin aging, angiogenesis, metastasis of tumors, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease system, proteinuria, aortic aneurysm, degenerative depletion of cartilage tissue after traumatic injury, joint disease of the nervous system, accompanied by demyelination, liver cirrhosis, glomerulonephritis, premature rupture of fetal membranes, inflammatory bowel disease or caries.

8. The method according to p. 7, which affected the state of pathological changes mediated by the action of matrix metalloproteinases, takes place at the age of retinal degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy Neonode the purpose of the eye and the rejection of the transplant of the cornea.

9. The method of inhibition of pathological changes mediated by TNF--converting enzyme (TACE), in need of him mammal, which includes an introduction to the specified mammal therapeutically effective amounts of compounds on p. 1 or its pharmaceutically acceptable salt.

10. The method according to p. 10, where the affected state pathological changes occurs in rheumatoid arthritis, rejection of the transplant, cachexia, anorexia, inflammation, fever, resistance to insulin, septic shock, congestive heart failure, inflammatory disease of the Central nervous system, inflammatory bowel disease or HIV infection.

11. The pharmaceutical composition inhibiting matrix metalloproteinases and TNF--converting enzyme (TACE), including a connection on p. 1 or its pharmaceutically acceptable salt, and a pharmaceutical carrier.

Priority items:
06.10.1997 on PP.1-7, 10, 12;
06.04.1998 on PP.8-9, 11.

 

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The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

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R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

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Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

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The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

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Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

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