US 7,678,820 B2Granted

Hetero compound

AssigneeAstellas Pharma Inc.

InventorsHironori Harada, Kazuyuki Hattori, Kazuya Fujita, Masataka Morita, Sunao Imada, Yoshito Abe, Hiromichi Itani, Tatsuaki Morokata, Hideo Tsutsumi

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Abstract

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. 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.

Claims12

Dependent claims

A compound represented by the formula (I):

or a pharmaceutically acceptable salt thereof, wherein
ring A is
X is a single bond, —CH2—, —NR3—, —O—, —S—, —S(═O)—, or —S(═O)2—;
R1 is halogen, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, (C3-C8)heterocycloalkyl, or optionally substituted (C1-C6)alkyl or optionally substituted (C2-C6)alkenyl, each of which may contain halogen, —CONH2, aryl, or (C3-C8)cycloalkyl as a substitutent;
R2 is —CN, —O—(C1-C6)alkyl, —C(═O)H or halogen, or optionally substituted (C1-C6)alkyl which may be substituted with halogen or —OH wherein when —X— is a single bond, R1 and R2 may in combination form a 5-membered ring and may further contain (C1-C6)alkyl as an optional substituent;
R3 is —H, wherein R3 may form morpholino, 1-pyrrolidinyl or 3,4-dehydropiperidin-1-yl, together with R1 and nitrogen;
R4 is
wherein any one of the bonds from the R4 ring is bound to the oxadiazole ring;
R5 is —H, R0—(C1-C6)alkyl-, R0—(C1-C6)alkyl-O—, R0—(C1-C6)alkyl-C(═O)—, R0—(C1-C6)alkyl-S(═O)2—, R0—O—(C1-C6)alkyl-, R0—C(═O)—(C1-C6)alkyl-, R0—S(═O)2—(C1-C6)alkyl-, (C2-C6)alkenyl-, —C(═O)H, —ORX, —S(═O)2RX, halogen, ═O, —NRXRY, or —C(═O)NRXRY, wherein R0—(C1-C6)alkyl-means (C1-C6)alkyl which may be substituted with at least one group each selected from R0, wherein R0—CN, —C(═O)NRXRY, —NHRX, —SRX, —S(═O)2RX or —ORX;
and
RX and RY may be the same or different and are —H, or (C1-C6)alkyl which may be optionally substituted with —OH, —NH2 (which may be protected with a protecting group) or heteroaryl, wherein RX may form (C3-C8)heterocycloalkyl, together with RY and nitrogen.

8 more elements

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

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

20 more elements

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 1-1H-indole-1-yl)acetamide;
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 1-1H-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 1-1H-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-{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-13-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;
or
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.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/244,102Filed 2 Oct 2008 · continuation in part
Priority: JP 2006-1025443 Apr 2006
Published: US 2009/0076070 A119 Mar 2009
Granted: 16 Mar 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes