HETERO COMPOUND

• US 20090076070A1
• Filed: 10/02/2008
• Published: 03/19/2009
• Est. Priority Date: 04/03/2006
• Status: Active Grant

• Current Assignee: Astellas Pharma Incorporated
• Original Assignee: Astellas Pharma Incorporated
• Inventors: HARADA, Hironori, Fujita, Kazuya, Hattori, Kazuyuki, Abe, Yoshito, Morokata, Tatsuaki, Tsutsumi, Hideo, Morita, Masataka, Itani, Hiromichi, Imada, Sunao
• Granted Patent: US 7,678,820 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 413/04 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 471/04 : Ortho-condensed systems

Abstract

[Problems] To provide a useful compound as an active ingredient for a preventing and/or treating agent for rejection in the transplantation of an organ, bone marrow, or a tissue, an autoimmune disease, or the like, which has an excellent S1P₁ agonist activity.

[Means for Solving] Since the compound of the invention has an S1P₁ agonist activity, it is useful as an active ingredient for a treating or preventing agent for a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue, a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, a nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer and leukemia.

Claims

1. A compound represented by the formula (I):

2. The compound according to claim 1, which is represented by the formula (II):

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is (C₁-C₆)alkyl which may contain halogen as a substituent.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R² is —

CN, halogen;

or (C₁-C₆)alkyl which may be substituted with halogen or —

OH.

5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R⁵ is —

H;

or (C₁-C₆)alkyl which may be substituted with at least one —

C(═

O)NR^XR^Y.

6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein X is a single bond, —

CH₂—

or —

O—

.

7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a following ring;

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, as an active ingredient.

11. The compound according to any one of claim 1 to 8, used for treatment and/or prevention of rejection in transplantation of organ/tissue in human or animal, autoimmune disease, multiple sclerosis, rheumatism, psoriasis, asthma, atopy, Alzheimer'"'"'s disease, tumor, or leukemia.

12. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient.

13. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, which is S1P₁ agonist.

15. A method for treating and/or preventing rejection in transplantation of organ/bone marrow/tissue in human or animal, graft-versus-host disease rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia, said method comprising administeration of the compound according to any one of claims 1 to 8, to a subject suffering from aforementioned disease.

16. Use of the compound according to any one of claims 1 to 8, for the manufacture of an agent for treating and/or preventing rejection in transplantation of organ/bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.

17. Use of the compound according to any one of claims 1 to 8, for treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, for the use for treating and/or preventing rejection in transplantation of an organ/bone marrow/tissue in human or animal, or graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.

8. A compound or a pharmaceutically acceptable salt thereof selected from the following:

5-(5-[3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole;

5-(5-[3-(trifluoromethyl)-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole;

6-{5-[3-bromo-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl}-1H-benzimidazole;

5-(5-[4-phenoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-benzimidazole;

2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indole-1-yl)acetamide;

4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride;

6-{5-[3-(difluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;

2-(4-{5-[3-chloro-4-(2,2,2-trifluoro-1-methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide;

2-(4-{5-[4-cyclopentyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{4-[2-fluoro-1-(fluoromethyl)ethoxy]-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-(4-{5-[3-cyano-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine-3-yl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{5-chloro-6-[2-fluoro-1-(fluoromethyl)ethoxy]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-methyl-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-(4-{5-[4-isopropyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-{4-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-[4-(5-{3-methyl-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide; and

2-[4-(5-{3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]-N-(2-hydroxyethyl)acetamide;

5-(5-{3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-benzimidazole; and

5-(5-{3-chloro-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-benzimidazole.

9. A compound selected from the following:

5-(5-[3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;

5-(5-[3-(trifluoromethyl)-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;

6-{5-[3-bromo-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride;

5-(5-[4-phenoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-benzimidazole;

2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indole-1-yl)acetamide;

4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride;

6-{5-[3-(difluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;

2-(4-{5-[3-chloro-4-(2,2,2-trifluoro-1-methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide;

2-(4-{5-[4-cyclopentyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{4-[2-fluoro-1-(fluoromethyl)ethoxy]-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-(4-{5-[3-cyano-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine-3-yl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{5-chloro-6-[2-fluoro-1-(fluoromethyl)ethoxy]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-[4-(5-{3-methyl-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-(4-{5-[4-isopropyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

2-{4-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-[4-(5-{3-methyl-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide;

N-(2-hydroxyethyl)-2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide; and

2-[4-(5-{3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]-N-(2-hydroxyethyl)acetamide;

5-(5-{3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride; and

5-(5-{3-chloro-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride.