Therapeutic substituted cyclopentanes

Patent metadata

Field	Value
Publication number	US-9765065-B2
Application number	US-201715425470-A
Country	US
Kind code	B2
Filing date	Feb 6, 2017
Priority date	Jul 3, 2007
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Disclosed herein are compounds having formula (I) wherein a dashed line represents the presence or adsence of a bond; Y is an organic acid functional group, or an amide or ester thereof; or Y is hydroxymethyl or an ester thereof; or Y is a tetrazolyl functional group; A is —(CH 2 ) 6 —, cis —CH 2 CH═CH—(CH 2 ) 3 —, or —CH 2 C═C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH 2 ) m —Ar—(CH 2 ) o —, wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 —CH 2 — may be replaced by S or O, and 1 —CH 2 —CH 2 — may be replaced by —CH═CH— or —C≡C—; U 1 and U 2 are independently selected from —H, ═O, —OH, —F, —Cl, and —CN; and B is aryl or heteroaryl, for use as acular hypotensive agent.

First claim

The invention claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Y is CO 2 R 4 or CONR 5 R 6 , wherein R 4 , R 5 , and R 6 are independently H or C 2 -C 6 alkyl; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group;
A is cis —CH 2 CH═CH—(CH 2 ) 3 — or —CH 2 C≡C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH 2 ) m —Ar—(CH 2 ) o — wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 —CH 2 — may be replaced by S or O, and 1 —CH 2 —CH 2 — may be replaced by —CH═CH— or —C≡C—;
U 1 is selected from —H, —OH, —F, —Cl, and —CN;
U 2 is —OH; and
B is aryl or heteroaryl.

2. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Y is CO 2 R 4 or CONR 5 R 6 , wherein R 4 , R 5 , and R 6 are independently H or C 2 -C 6 alkyl; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group;
U 1 is selected from —H, —OH, —F, —Cl, and —CN;
U 2 is —OH; and
B is aryl or heteroaryl.

3. The compound according to claim 1 , wherein B is substituted phenyl or pyridinyl.

4. The compound according to claim 1 , wherein U 1 is —F.

5. The compound according to claim 1 , wherein U 1 is —Cl.

6. The compound according to claim 1 , wherein U 1 is —CN.

7. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Y is CO 2 R 4 or CONR 5 R 6 , wherein R 4 , R 5 , and R 6 are independently H or C 2 -C 6 alkyl; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group;
A is cis —CH 2 CH═CH—(CH 2 ) 3 — or —CH 2 C≡C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH 2 ) m —Ar—(CH 2 ) o — wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 —CH 2 — may be replaced by S or O, and 1 —CH 2 —CH 2 — may be replaced by —CH═CH— or —C≡C—; and
B is aryl or heteroaryl.

8. The compound according to claim 7 , wherein B is selected from the group consisting of:

9. The compound according to claim 1 selected from the group consisting of:
5-(3-((1R,2S,3R,5R)-5-fluoro-3-hydroxy-2-(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
Isopropyl 5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylate;
5-(3-((1S,2S,3R,5R)-5-cyano-3-hydroxy-2-(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-2#3,5-dichlorophenyl)ethynyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-2-(3-ethylphenyl)ethynyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-2-((3-(but-3-enyl)phenyl)ethynyl)-5-chloro-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(thiophen-2-ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(thiophen-3-ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-2-ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-3-ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-4-ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
5-(3-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-((3-(3-hydroxypropyl)phenyl)ethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;
2-(2-((1R,2S,3R,5R)-5-chloro-2-((3,5-dichlorophenyl)ethynyl)-3-hydroxycyclopentyl)ethylthio)thiazole-4-carboxylic acid; and
2-(2-((1R,2S,3R,5R)-5-chloro-3-hydroxy-2-(phenylethynyl)cyclopentyl)ethylthio)thiazole-4-carboxylic acid;

or a pharmaceutical salt thereof.

Assignees

• Allergan Inc

Inventors

• Old David W
• Ngo Vinh X
• Holoboski Mark
• Posner Mari

Classifications

• A61P43/00

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

• A61K31/5575

  having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha · CPC title

• C07D333/40

  Thiophene-2-carboxylic acid · CPC title

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• C07D257/04

  Five-membered rings · CPC title