Naphthyridine derivatives and pharmaceutical compositions thereof

• US 5,817,670 A
• Filed: 01/30/1997
• Issued: 10/06/1998
• Est. Priority Date: 08/29/1994
• Status: Expired due to Fees

• Current Assignee: Yamanouchi Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Yamanouchi Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Niwa, Akira, Okamoto, Yoshinori, Iwata, Masahiro, Takayama, Kazuhisa, Isomura, Yasuo, Aoki, Motonori
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/776,295
• Time in Patent Office: 614 Days
• Field of Search: 546/122, 546/123, 514/300
• US Class Current: 514/300
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

1,8-Naphthyridine derivatives represented by the following general formula (I), salts thereof, hydrates thereof and solvates thereof. ##STR1## They have an activity to inhibit type IV phosphodiesterase and are useful as agents for the prevention and treatment of respiratory diseases, inflammatory diseases accompanying organ transplantation, systemic or local arthropathy, proliferative diseases, micturition-related diseases and diseases in which tumor necrosis factor (TNF) and other cytokine (IL-1, IL-6 or the like) are concerned.

Claims

1. A 1,8-naphthyridine derivative represented by the following Formula (I), a salt thereof, a hydrate thereof or a solvate thereof ##STR113## each symbol in the formula represents the following meaning:

X;

an oxygen atom or a sulfur atom,

R¹ is a lower alkyl group which may be substituted with a group described in the A group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, an aryl group which may be substituted with a group described in the B group, an aralkyl group which may be substituted with a group described in the B group, a five- or six-membered monocyclic heteroaryl group, or a five- or six membered monocyclic heteroaryl-lower alkyl group,

R² is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a trihalogenomethyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkylcarbonylamino group, an aryl group or a cycloalkyl group,

R³ and R⁴ ;

may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a trihalogenomethyl group, a nitro group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkylcarbonylamino group, an aryl group or a cycloalkyl group,

R⁵ ;

a hydrogen atom,

R⁶ ;

an aryl group which may be substituted with a group described in the C group, a five- or six-membered monocyclic heteroaryl group which may be substituted with a group described in the C group, a cycloalkyl group or an adamantyl group;

the A group is halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyl group, a carbamoyl group or a mono- or di-lower alkylcarbamoyl group;

The B group is a lower alkyl group or a group described in the A group;

The C group is a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group or a lower alkylcarbonylamino group, or a lower alkyl group which may be substituted with these groups, with the proviso that, when each of R¹, R² and R⁴ is a methyl group and each of R³ and R⁵ is a hydrogen atom, R⁶ represents an aryl group which is substituted with a group described in the C group, a five- or six-membered monocylic heteroaryl group which may be substituted with a group described in the C group, a cycloalkyl group, or an adamantyl group.

2. The 1,8-naphthyridine derivative or a salt thereof according to claim 1, wherein

R¹ is a lower alkyl group which may be substituted with a group described in the A group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a phenyl group, a phenyl-lower alkyl group, a pyridyl group or a pyridyl-lower alkyl group, and

R², R³ and R⁴ may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a trihalogenomethyl group, a phenyl group or a cycloalkyl group, and

R⁶ is a phenyl group which may be substituted with a group described in the C group, a thienyl group, a thiazolyl group, a cycloalkyl group or an adamantyl group, and

C group is a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group or a lower alkylcarbonylamino group, or a lower alkyl group which may be substituted with a halogen atom or hydroxyl group.

3. The 1,8-naphthyridine derivative or a salt thereof according to claim 2, wherein

R¹ is a lower alkyl group which may be substituted with a group selected from a cyano group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyl group or a carbamoyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a phenyl group, a phenyl-lower alkyl group, a pyridyl group or a pyridyl-lower alkyl group, and

R⁶ is a phenyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, an amino group or a trifluoromethyl group, thienyl group, thiazolyl group, a cycloalkyl group or an adamantyl group, and

R², R³ and R⁴ may be the same or different from one another and each represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group or a phenyl group.

4. The 1,8-naphthyridine derivative or a salt thereof according to claim 1, wherein R⁶ is a phenyl group which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group or an amino group.

5. The 1,8-naphthyridine derivative or a salt thereof according to claim 1, wherein R⁶ is a cycloalkyl group or an adamantyl group.

6. The 1,8-naphthyridine derivative or a salt thereof according to claim 1, wherein X is an oxygen atom.

14. A pharmaceutical composition which comprises the 1,8-naphthyridine derivative as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.

15. The pharmaceutical composition according to claim 14, which is a type IV phosphodiesterase inhibitor.

16. The pharmaceutical composition according to claim 15, which is a type IV phosphodiesterase inhibitor that is a preventive or therapeutic agent for respiratory diseases comprising bronchial asthma, chronic bronchitis, pneumonia and adult respiratory distress syndrome (ARDS).

17. The pharmaceutical composition according to claim 15, which is a type IV phosphodiesterase inhibitor that is a preventive or therapeutic agent for inflammatory diseases comprising atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocyclitis, gingivitis, periodontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (myasthenia gravis, multiple sclerosis and neuritis), hepatitis, cicatrization, nephritis including proliferative nephritis, peritonitis, pleurisy, scleroderma and burn injury.

18. The pharmaceutical composition according to claim 16 wherein said bronchial asthma is atopic asthma.

19. A method for inhibiting the activity of type IV phosphodiesterase in a patient which comprises administering to said patient a type IV phosphodiesterase inhibiting amount of the pharmaceutical composition of claim 14.

20. A method for treating a respiratory disease in a patient which comprises administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 14.

7. A naphthyridine derivative selected from the group consisting of 4-(3-chlorophenyl)-7-ethyl-1,5-dimethyl-1,8-naphthyridin-2(1H)-one or a salt thereof, 4-(3-bromophenyl)-1-ethyl-5,7-dimethyl-1,8-naphthyridin-2-(1H)-one or a salt thereof, 4-(3-bromophenyl)-1,7-diethyl-5-methyl-1,8-naphthyridin-2(1H)-one or a salt thereof, 1,7-diethyl-5-methyl-4-phenyl-1,8-naphthyridin-2(1H)-one or a salt thereof, 4-cyclohexyl-1-ethyl-1,8-naphthyridin-2(1H)-one or a salt thereof and 4-(3-bromophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2-(1H)-one or a salt thereof.

8. The naphthyridine derivative of claim 7 which is 4-(3-Chlorophenyl)-7-ethyl-1,5-dimethyl-1,8-naphthyridin-2(1H)-one or a salt thereof.

9. The naphthyridine derivative of claim 7 which is 4-(3-bromophenyl)-1-ethyl-5,7-dimethyl-1,8-naphthyridin-2(1H)-one or a salt thereof.

10. The naphthyridine derivative of claim 7 which is 4-(3-bromophenyl)-1,7-diethyl-5-methyl-1,8-naphthyridin-2(1H)-one or a salt thereof.

11. The naphthyridine derivative of claim 7 which is 1,7-diethyl-5-methyl-4-phenyl-1,8-naphthyridin-2(1H)-one or a salt thereof.

12. The naphthyridine derivative of claim 7 which is 4-cyclohexyl-1-ethyl-1,8-naphthyridin-2(1H)-one or a salt thereof.

13. The naphthyridine derivative of claim 7 which is 4-(3-bromophenyl)-1-ethyl-7-methyl-1,8-naphthyridine-2(1H)-one or a salt thereof.