Bicyclic compound and use thereof for medical purposes

Patent metadata

Field	Value
Publication number	US-8962868-B2
Application number	US-201314081286-A
Country	US
Kind code	B2
Filing date	Nov 15, 2013
Priority date	Jul 28, 2009
Publication date	Feb 24, 2015
Grant date	Feb 24, 2015

Abstract

Since a compound represented by the general formula (I) (wherein definition of each group is as described in the specification), a salt thereof, a solvate thereof, or a prodrug thereof has strong and sustaining intraocular pressure lowering activity and, further, has no side effect on eyes such as ocular stimulating property (hyperemia, corneal clouding etc.), aqueous humor protein rise etc., it has high safety, and can be an excellent agent for preventing and/or treating glaucoma etc.

First claim

The invention claimed is:

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

wherein R 1 represents (1) COOH, (2) COOR 2 , (3) CH 2 OH, or (4) CONR 3 R 4 , R 2 represents a C1-C6 alkyl group optionally substituted with a hydroxy group, ONO 2 or a C1-4 alkoxy group, R 3 and R 4 each represent independently a hydrogen atom, or a C1-4 alkyl group optionally substituted with ONO 2 , R 5 represents a halogen atom, a hydroxy group, or a C1-4 alkoxy group, Z represents (1) —(CH 2 ) m —, (2) —(CH 2 ) n —CH═CH—, (3) —(CH 2 ) p -A-CH 2 —, or (4) ring 1, A represents an oxygen atom, or a sulfur atom, W represents a C1-6 alkyl group optionally substituted with 1 to 5 substituents selected from the group consisting of (1) a hydroxy group, (2) an oxo group, (3) a halogen atom, (4) a C1-4 alkyl group, (5) a C1-4 alkoxy group, (6) ring 2, (7) —O-ring 2, and (8) —S-ring 2, ring 1 and ring 2 each represent independently a C3-10 carbocycle or a 3- to 10-membered heterocycle, optionally substituted with 1 to 5 substituents selected from the group consisting of (1) a halogen atom, (2) CF 3 , (3) OCF 3 , (4) a C1-4 alkoxy group, (5) a C1-4 alkyl group, (6) a hydroxy group, and (7) a nitrile group, m represents an integer of 1 to 6, n represents an integer of 1 to 4, p represents an integer of 1 to 4,

represents a single bond or a double bond,

represents α configuration,

represents β configuration, and

represents α configuration, β configuration or an arbitrary mixture of them or a salt thereof.

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

wherein all symbols represent the same meanings as those described in claim 1
or a salt thereof.

3. The compound according to claim 2 , which is represented by the general formula (I-2):

wherein R 6 and R 7 each represent independently a hydrogen atom, a hydroxy group, a halogen atom, a C1-4 alkyl group or a C1-4 alkoxy group, R 6 and R 7 may be taken together to form an oxo group, Y represents —CH 2 —, —O— or —S—, and other symbols represent the same meanings as those described in claim 1
or a salt thereof.

4. The compound according to claim 3 , wherein the ring 2 is a C3-7 carbocycle; or a salt thereof.

5. The compound according to claim 3 , wherein Z is (1) —(CH 2 ) m —, or (2) —(CH 2 ) p -A-CH 2 —, and other symbols represent the same meanings as those described claim 1 ; or a salt thereof.

6. The compound according to claim 3 , wherein the compound represented by the general formula (I-2) is a compound selected from:
(1) 4-{(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic acid,
(2) ethyl 4-{(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,
(3) 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,
(4) 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic acid,
(5) 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,
(6) 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic acid, and
(7) 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate;
or a salt thereof.

7. A pharmaceutical composition containing a compound represented by the general formula (I) according to claim 1 , or a salt thereof.

8. The pharmaceutical composition according to claim 7 , which is a FP agonist.

9. The pharmaceutical composition according to claim 7 , which is an agent for treating an ocular disease.

10. The pharmaceutical composition according to claim 9 , wherein the ocular disease is glaucoma, ocular hypertension, macular edema, macular degeneration, retina and optic nerve tensile force rise, myopia, hypermetropia, astigma, dry eye, amotio retinae, cataract, intraocular pressure rise due to trauma or inflammation, intraocular pressure rise due to a drug, or intraocular pressure rise after operation.

11. A method of treating an ocular disease, comprising administering an effective amount of a compound represented by the general formula (I) according to claim 1 , or a salt thereof to a mammal.

Assignees

• Ono Pharmaceutical Co

Inventors

• Kambe Tohru
• Maruyama Toru
• Yamane Shinsaku
• Nakayama Satoshi
• Tani Kousuke

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P27/10

  for accommodation disorders, e.g. myopia · CPC title

• A61P27/12

  for cataracts · CPC title

• A61P27/02

  Ophthalmic agents · CPC title