Tetrahydroisoquinoline derivative

• US 8,735,425 B2
• Filed: 09/09/2010
• Issued: 05/27/2014
• Est. Priority Date: 03/26/2008
• Status: Expired due to Fees

• Current Assignee: Daiichi Sankyo Company Limited
• Original Assignee: Daiichi Sankyo Company Limited
• Inventors: Uto, Yoshikazu, Karasawa, Hiroshi, Takaishi, Kiyosumi
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US12/878,170
• Publication Number:
  US 20110034481A1
• Time in Patent Office: 1,356 Days
• Field of Search: None
• US Class Current: 514/310
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 217/06 : with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a compound or a pharmacologically acceptable salt thereof having an excellent DGAT inhibitory effect and feeding suppressant effect. The present invention provides a compound represented by the general formula (I), or pharmacologically acceptable salt thereof:

[wherein,
R¹ represents a phenylaminocarbonyl group that may be substituted with 1 to 5 group(s) independently selected from Substituent Group A, a benzoxazol-2-yl group that may be substituted with 1 to 3 group(s) independently selected from Substituent Group A, or the like; R² independently represents a C₁-C₆ alkyl group; R³ represents a group represented by the formula —C(═O)—O—R⁴ or the like; R⁴ represents a hydrogen atom, a C₁-C₆ alkyl group that may be substituted with 1 to 3 group(s) independently selected from Substituent Group B, or the like; X represents an oxygen atom, a methylene group, or a group represented by the formula —NH—, or the like; L represents a single bond, a methylene group, or the like; . . . represents a single bond or a double bond; m represents 1 or 2; n represents an integer of 0 to 5; Substituent Group A represents a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ halogenated alkyl group, a C₁-C₆ alkoxy group, or the like; and Substituent Group B represents a C₃-C₆ cycloalkyl group, a phenyl group, a carboxyl group, or the like].

Claims

1. A compound of formula (II), or a pharmacologically acceptable salt thereof:

2. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R is a phenyl group optionally substituted with 1 to 3 groups each independently selected from a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ halogenated alkyl group, a C₁-C₆ alkoxy group, and a C₁-C₆ halogenated alkoxy group or a C₃-C₆ cycloalkyl group.

3. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 3-methylphenyl group, a 3-ethylphenyl group, a 3-methoxyphenyl group, a 3-ethoxyphenyl group, a 4-trifluoromethylphenyl group, a 3-trifluoromethoxyphenyl group, a 3,4-difluorophenyl group, a 2-fluoro-5-methoxyphenyl group, a 2,4,5-trifluorophenyl group, a 3,4,5-trifluorophenyl group or a cyclopentyl group.

4. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 3-methylphenyl group, a 3-ethylphenyl group, a 3-methoxyphenyl group, a 3-ethoxyphenyl group, a 3-trifluoromethoxyphenyl group, a 3,4-difluorophenyl group, a 2-fluoro-5-methoxyphenyl group or a 2,4,5-trifluorophenyl group.

5. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein the compound of formula (II) is

trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-ethoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(2,4,5-trifluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-(3-phenyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-trifluoromethoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3,4-difluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(2-fluoro-5-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-(3-m-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester or

trans-6-[3-(3-ethyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

6. The compound according to claim 1, wherein the compound of formula (II) is

trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-ethoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(2,4,5-trifluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-(3-phenyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-trifluoromethoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3,4-difluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(2-fluoro-5-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-[3-(3-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester,

trans-6-(3-m-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester or

trans-6-[3-(3-ethyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

7. The compound according to claim 6, wherein the compound is trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

8. The compound according to claim 6, wherein the compound is trans-6-[3-(3-ethoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

9. The compound according to claim 6, wherein the compound is trans-6-[3-(2,4,5-trifluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

10. The compound according to claim 6, wherein the compound is trans-6-[3-(3,4-difluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

11. The compound according to claim 6, wherein the compound is trans-6-[3-(2-fluoro-5-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

12. The compound according to claim 6, wherein the compound is trans-6-(3-m-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

13. The compound according to claim 6, wherein the compound is trans-6-[3-(3-ethyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

14. The compound according to claim 1, wherein the compound is trans-6-[3-(2-methoxy-5-methyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

15. The compound according to claim 1, wherein the compound is trans-6-[3-(5-ethoxy-2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

16. The compound according to claim 1, wherein the compound is trans-6-(3-p-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

17. The compound according to claim 1, wherein the compound is trans-6-(3-o-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

18. The compound according to claim 1, wherein the compound is trans-6-[3-(3,4-dimethyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

19. A pharmaceutical composition comprising a compound or pharmacologically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, wherein the compound or pharmacologically acceptable salt is trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

21. The pharmaceutical composition according to claim 19, wherein the compound or pharmacologically acceptable salt is trans-6-[3-(2-methoxy-5-methyl-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

22. The pharmaceutical composition according to claim 19, wherein the compound or pharmacologically acceptable salt is trans-6-[3-(2,4,5-trifluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

23. The pharmaceutical composition according to claim 19, wherein the compound or pharmacologically acceptable salt is trans-6-(3-p-tolyl-ureido)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester.

24. A method for treating diabetes comprising administering a pharmacologically effective amount of a compound or pharmacologically acceptable salt thereof according to claim 1 to a warm-blooded animal.

25. A method for treating adiposity or obesity comprising administering a pharmacologically effective amount of a compound or pharmacologically acceptable salt thereof according to claim 1 to a warm-blooded animal.

26. The method according to claim 24, wherein the warm-blooded animal is a human.

27. The method according to claim 25, wherein the warm-blooded animal is a human.

28. A method for treating diabetes comprising administering a pharmacologically effective amount of a compound according to claim 7 or pharmacologically acceptable salt thereof to a human.

29. A method for treating diabetes comprising administering a pharmacologically effective amount of a compound according to claim 14 or pharmacologically acceptable salt thereof to a human.

30. A method for treating diabetes comprising administering a pharmacologically effective amount of a compound according to claim 9 or pharmacologically acceptable salt thereof to a human.

31. A method for treating diabetes comprising administering a pharmacologically effective amount of a compound according to claim 16 or pharmacologically acceptable salt thereof to a human.

32. A method for treating adiposity or obesity comprising administering a pharmacologically effective amount of a compound according to claim 7 or pharmacologically acceptable salt thereof to a human.

33. A method for treating adiposity or obesity comprising administering a pharmacologically effective amount of a compound according to claim 14 or pharmacologically acceptable salt thereof to a human.

34. A method for treating adiposity or obesity comprising administering a pharmacologically effective amount of a compound according to claim 9 or pharmacologically acceptable salt thereof to a human.

35. A method for treating adiposity or obesity comprising administering a pharmacologically effective amount of a compound according to claim 16 or pharmacologically acceptable salt thereof to a human.

36. A method for treating hypertriglyceridemia comprising administering a pharmacologically effective amount of a compound or pharmacologically acceptable salt thereof according to claim 1 to a warm-blooded animal.

37. The method according to claim 36, wherein the warm-blooded animal is a human.

38. A method for treating hypertriglyceridemia comprising administering a pharmacologically effective amount of a compound according to claim 7 or pharmacologically acceptable salt thereof to a human.

39. A method for treating hypertriglyceridemia comprising administering a pharmacologically effective amount of a compound according to claim 14 or pharmacologically acceptable salt thereof to a human.

40. A method for treating hypertriglyceridemia comprising administering a pharmacologically effective amount of a compound according to claim 9 or pharmacologically acceptable salt thereof to a human.

41. A method for treating hypertriglyceridemia comprising administering a pharmacologically effective amount of a compound according to claim 16 or pharmacologically acceptable salt thereof to a human.