Pyridine compounds and their pharmaceutical use

• US 6,521,643 B1
• Filed: 08/17/2001
• Issued: 02/18/2003
• Est. Priority Date: 02/17/1999
• Status: Expired due to Fees

• Current Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Tomishima, Masaki, Take, Kazuhiko
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US09/913,715
• Time in Patent Office: 550 Days
• Field of Search: 514/336, 514/340, 514/342, 514/343, 514/345, 514/354, 546/268.4, 546/276.4, 546/279.7, 546/281.7, 546/290, 546/304, 546/314, 546/339
• US Class Current: 514/336
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/58 Amidines
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/63 One oxygen atom
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/85 : in position 3
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

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.

Claims

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.

2. The compound of claim 1 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 or mono or di(lower)alkylamino, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein ring A is a ring selected from the group consisting of

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, and

R⁶ 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.

6. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.

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.

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.

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.

10. A method of inhibiting nitric oxide synthase comprising administering said compound of claim 1.

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.