Alxr agonist compound

Patent metadata

Field	Value
Publication number	US-2016145249-A1
Application number	US-201414903349-A
Country	US
Kind code	A1
Filing date	Jul 8, 2014
Priority date	Jul 9, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

The present invention provides a compound having ALXR agonist activity. Specifically, the invention provides a compound having ALXR agonist activity represented by general formula (I) wherein all the symbols are as defined in the specification, a salt thereof, a solvate thereof, or a prodrug thereof as well as an agent containing the same as an active ingredient for preventing and/or treating an ALXR-associated disease, such as an inflammatory bowel disease, an autoimmune disease, a chronic inflammatory disease, asthma, pulmonary fibrosis, atopic dermatitis, ischemia-reperfusion injury, myocardial infarction, or Alzheimer's disease.

First claim

1 . A compound represented by general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof:

wherein
A is a bond, —C(═O)—, —(C(R 5 ) 2 ) m —, —CH═CH—, or —C(═O)NH— (wherein R 5 represents a hydrogen atom, a hydroxyl group, a methoxy group, or an ethoxy group, and m represents an integer of 1 or 2),
ring L represents a phenyl group or a pyridyl group,
R 1 represents (1) a tert-butyl group or (2) a phenyl group, pyridyl group, or thienyl group optionally substituted with one to three Ys (wherein Y represents a hydroxyl group, a halogen atom, a cyano group, a C 1-4 alkyl group, a C 1-4 alkoxy group, or a phenoxy group),
R 2 represents a hydrogen atom, a C 1-3 alkyl group, a cyano group, —(C(R 6 ) 2 ) p OH (wherein R 6 represents a hydrogen atom or a methyl group, and p represents an integer of 1 or 2), or —(CH 2 ) q COR 7 (wherein R 7 represents a hydroxyl group, a methyl group, an amino group, a methoxy group, or an ethoxy group, and q represents an integer of 0 or 1),
R 3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-4 alkyl group, a cyano group, or —NHR 8 (wherein R 8 represents a hydrogen atom, an acetyl group, or a methylsulfonyl group), and
R 4 represents a hydroxyl group, a halogen atom, a C 1-4 alkyl group, or an amino group, and
n represents an integer of 0 to 3,
with the proviso that a plurality of Ys, R 4 s, R 5 s, and R 6 s may be the same or different, respectively.

2 . The compound according to claim 1 , wherein A is a bond.

3 . The compound according to claim 1 , wherein R 3 is a hydrogen atom or a hydroxyl group.

4 . The compound according to claim 1 , wherein R 2 is a hydrogen atom, a methyl group, or —CH 2 OH.

5 . The compound according to claim 1 , wherein R 1 is a phenyl group or pyridyl group optionally substituted with one Y.

6 . The compound according to claim 1 , wherein n is 0.

7 . The compound according to claim 1 , wherein the compound represented by general formula (I) is represented by general formula (I-1):

wherein
R 1-1 represents a phenyl group or pyridyl group optionally substituted with one Y,
ring L 1 represents a phenyl group or a pyridyl group (wherein the ring L 1 is not substituted except for trifluoromethyl group and —NH— group attached thereto),
R 2-1 represents a hydrogen atom or a methyl group,
R 3-1 represents a hydrogen atom or a hydroxyl group, and
other symbols are as defined in claim 1 .

8 . The compound according to claim 7 , wherein in the general formula (I-1), the formula

9 . The compound according to claim 8 , wherein the compound represented by general formula (I-1) is
(1) 4-[4-(3-pyridyl)-1,3-thiazol-2-yl]-N-[4-(trifluoromethyl)phenyl]-1-piperidinecarboxamide, (2) 4-[4-(3-fluorophenyl)-5-methyl-1,3-thiazol-2-yl]-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-1-piperidinecarboxamide, (3) 4-[4-(3-fluorophenyl)-5-methyl-1,3-thiazol-2-yl]-N-[4-(trifluoromethyl)phenyl]-1-piperidinecarboxamide, (4) 4-(4-benzoyl-1,3-thiazol-2-yl)-N-[4-(trifluoromethyl)phenyl]-1-piperidinecarboxamide, or (5) 4-(4-phenyl-1,3-thiazol-2-yl)-N-[5-(trifluoromethyl)-2-pyridyl]-1-piperidinecarboxamide.

10 . A pharmaceutical composition comprising a compound represented by general formula (I) as defined in claim 1 , a salt thereof, a solvate thereof, or a prodrug thereof as an active ingredient.

11 . A method for preventing and/or treating an ALXR-associated disease, comprising administering an effective dose of a compound represented by general formula (I) as defined in claim 1 , a salt thereof, a solvate thereof, or a prodrug thereof to a patient in need thereof.

12 . The method according to claim 11 , wherein the ALXR-associated disease is an inflammatory bowel disease, an autoimmune disease, a chronic inflammatory disease, asthma, pulmonary fibrosis, atopic dermatitis, ischemia-reperfusion injury, myocardial infarction, or Alzheimer's disease.

13 . A method for agonizing ALXR activity, comprising administering an effective dose of a compound represented by general formula (I) as defined in claim 1 , a salt thereof, a solvate thereof, or a prodrug thereof to a patient with a disease that can be prevented and/or treated by agonizing ALXR activity.

14 . The method according to claim 11 , wherein the compound represented by general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof is used in combination with a medicine selected from steroids, anti-TNFα antibodies, anti-IL-6 antibodies, anti-IgE antibodies, nonsteroidal anti-inflammatory drugs, immunosuppressants, sulfasalazine, and mesalazine.

15 . The method according to claim 12 , wherein the compound represented by general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof is used in combination with a medicine selected from steroids, anti-TNFα antibodies, anti-IL-6 antibodies, anti-IgE antibodies, nonsteroidal anti-inflammatory drugs, immunosuppressants, sulfasalazine, and mesalazine.

16 . The method according to claim 13 , wherein the compound represented by general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof is used in combination with a medicine selected from steroids, anti-TNFα antibodies, anti-IL-6 antibodies, anti-IgE antibodies, nonsteroidal anti-inflammatory drugs, immunosuppressants, sulfasalazine, and mesalazine.

Assignees

• Ono Pharmaceutical Co

Inventors

• Terakado Masahiko
• Hirobe Masaya
• Iwahashi Maki
• Tani Kousuke
• Sugiyama Tetsuya

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title