Pyridine compounds and their pharmaceutical use
First Claim
1. A compound of the formula whereinR1 and R2 are the same or different and each is hydrogen, lower alkyl, lower alkoxy, cyano, lower alkoxycarbonyl, carboxy, lower haloalkyl, hydroxy(lower)alkyl, hydroxy, nitro, amino, mono or di(lower)alkylamino, protected hydroxy or lower alkyl substituted by protected hydroxy;
- X is a single bond or a group of the formula selected from the group consisting of wherein R4 is hydrogen or acyl;
ring A is heterocycle or arylene wherein said heterocycle and arylene may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino which may be substituted by suitable substituent(s); and
R3 is a group of the formula selected from the group consisting of wherein R5 is hydrogen, lower alkyl, lower alkylthio, amino which may be substituted by suitable substituent(s) or aromatic heterocyclic group, or when
may form a bicyclic group selected from the group consisting of
wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl, R6 and R7 are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy, acyl or amidino which may be substituted by suitable substituent(s), and R8 is thiazolinyl or pyridyl, or a pharmaceutically acceptable salt thereof.
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Abstract
A compound of formula (I) wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NOS(nitric oxide synthasey)-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-ependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
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Citations
11 Claims
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1. A compound of the formula
wherein R1 and R2 are the same or different and each is hydrogen, lower alkyl, lower alkoxy, cyano, lower alkoxycarbonyl, carboxy, lower haloalkyl, hydroxy(lower)alkyl, hydroxy, nitro, amino, mono or di(lower)alkylamino, protected hydroxy or lower alkyl substituted by protected hydroxy; -
X is a single bond or a group of the formula selected from the group consisting of wherein R4 is hydrogen or acyl;
ring A is heterocycle or arylene wherein said heterocycle and arylene may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino which may be substituted by suitable substituent(s); and
R3 is a group of the formula selected from the group consisting of wherein R5 is hydrogen, lower alkyl, lower alkylthio, amino which may be substituted by suitable substituent(s) or aromatic heterocyclic group, or when
may form a bicyclic group selected from the group consisting of
wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl,R6 and R7 are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy, acyl or amidino which may be substituted by suitable substituent(s), and R8 is thiazolinyl or pyridyl, or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
wherein said ring A may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino, or a pharmaceutically acceptable salt thereof. -
4. The compound of claim 1 wherein R3 is
wherein R5, R6 and R7 are as defined in claim 1, or a pharmaceutically acceptable salt thereof. -
5. The compound of claim 4 wherein
R5 is hydrogen, lower alkyl, lower alkylthio, amino, mono or di(lower)alkylamino, acylamino, cyanoamino or 5-membered aromatic heteromonocyclic group containing sulfur atom or oxygen atom, or - may form a bicyclic group selected from the group consisting of
wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl, andR6 and R7 are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy or amidino which may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and cyano, or a pharmaceutically acceptable salt thereof.
- may form a bicyclic group selected from the group consisting of
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6. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
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7. A method of inhibiting NOS-mediated diseases comprising therapeutically administering a pharmaceutical composition comprising said compound of claim 1 or a pharmaceutically acceptable salt thereof.
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8. A method of treating a NOS-mediated disease comprising therapeutically administering a pharmaceutical composition comprising said compound of claim 1 or a pharmaceutically acceptable salt thereof.
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9. The method as claimed in claim 8, wherein said NOS-mediated disease is selected from the group consisting of adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-dependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoperosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, and ulcer.
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10. A method of inhibiting nitric oxide synthase comprising administering said compound of claim 1.
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11. The method of claim 10, wherein said compound is selected from the group consisting of 2-guanidino-4-methyl-5-(4-methoxypyridin-2-yl)thiazole, (5-(4-methoxypyridin-2-yl)-2-methylphenyl)guanidine dihydrochloride, N-(3-(4-methoxypyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride, 2-amino-7-(4-methoxypyridin-2-yl)quinoline dihydrochloride, 2-amino-7-(4-methylpyridin-2-yl)quinoline dihydrochloride, and 7-(4-methoxypyridin-2-yl)-2-methylaminoquinoline dihydrochloride.
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Specification