Modulators of the relaxin receptor 1

Patent metadata

Field	Value
Publication number	US-9452973-B2
Application number	US-201314398830-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	May 4, 2012
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R 1 , and R 2 are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.

First claim

The invention claimed is:

1. A compound or pharmaceutically acceptable salt thereof, having the formula

where

are each phenyl;
m, n, o, and p are integers independently chosen from 0, 1, and 2 and each of

is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
X and Y are independently chosen from O and S;
R 8 and R 9 are independently chosen from hydrogen and C 1 -C 4 alkyl;
R 10 , R 21 , and R 31 are each 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 2 alkyl)amino-, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 20 is C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, —SR 7 , —SOR 7 , or —SO 2 R 7 , where R 7 is C 1 -C 10 carbyhdryl or C 1 -C 10 haloalkyl;
R 30 is hydrogen or R 30 is C 1 -C 8 carbhydryloxy or C 1 -C 8 carbhydrylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxyl.

2. The compound or salt of claim 1 , wherein the compound is selected from the group consisting of:

3. A method for treating
myocardial ischemia-reperfusion injury, cardiac fibrosis, acute congestive heart failure, post-infarction heart, or myocardial infarction in a patient, the method comprising administering to the patient an effective amount of a compound or salt of claim 1 .

4. The method of claim 2 , wherein the compound is selected from the group consisting of:

5. A compound or salt thereof of claim 1 , having the formula

where:
R 10 , R 21 , and R 31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 2 alkyl)amino-, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 20 is C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, —SR 7 , —SOR 7 , or —SO 2 R 7 , where R 7 is C 1 -C 10 alkyl or C 1 -C 10 haloalkyl;
R 30 is hydrogen or R 30 is C 1 -C 8 alkoxy or C 1 -C 8 alkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

6. A compound or salt thereof of claim 5 , wherein R 20 is SO 2 CF 3 .

7. A compound or pharmaceutically acceptable salt thereof of claim 1 , having the formula

where:
R 10 and R 21 are each 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 2 alkyl)amino-, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 20 is C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, —SR 7 , —SOR 7 , or —SO 2 R 7 , where R 7 is C 1 -C 10 carbhydryl or C 1 -C 10 haloalkyl; and
R 3 is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF 3 , SO 2 CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl mono- and di-C 1 -C 6 alkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

8. A compound or salt of claim 1 , wherein m, n, o, and p are all 0, X and Y are both 0; and R 8 and R 9 are both hydrogen.

9. A compound or salt of claim 1 , wherein R 20 is C 1 -C 6 haloalkyl, —S(C 1 -C 6 haloalkyl), or —SO 2 (C 1 -C 6 haloalkyl).

10. A compound or salt thereof of claim 9 wherein R 10 , R 21 , and R 31 are each 0 substituents.

11. A compound or salt thereof of claim 9 , wherein R 20 is CF 3 , SCF 3 , or SO 2 CF 3 , and R 30 is C 2 -C 6 alkoxy or C 2 -C 6 alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and —CF 3 .

12. A compound or salt of claim 1 , where R 30 is C 1 -C 8 alkoxy or C 1 -C 8 alkylthio, and R 31 is absent or cyano.

13. A compound or salt of claim 1 , where R 20 is C 1 -C 6 haloalkyl, —S(C 1 -C 6 haloalkyl), or —SO 2 (C 1 -C 6 haloalkyl); and R 21 is absent.

14. A compound or salt thereof of claim 5 , wherein R 10 , R 21 , and R 31 are each 0 substituents; R 20 is CF 3 , SCF 3 , or SO 2 CF 3 , and R 30 is C 2 -C 6 alkoxy or C 2 -C 6 alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and —CF 3 .

15. A compound or salt of claim 7 , wherein R 10 and R 21 are both 0 substituents and R 3 is phenyl substituted with one meta-position substituent.

16. A compound or salt of claim 7 , wherein R 10 and R 21 are both 0 substituents and R 20 is CF 3 , SCF 3 , or SO 2 CF 3 .

17. A compound or salt of claim 7 , wherein R 20 is CF 3 or SO 2 CF 3 ; and
R 3 is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF 3 , SO 2 CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl mono- and di-C 1 -C 6 alkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

18. A compound or salt thereof, wherein the compound is selected from

Assignees

• The Us Secretary Dept Of Health And Human Service
• Univ Florida Int
• Us Health

Inventors

• Marugan Juan Jose
• Xiao Jingbo
• Ferrer-Alegre Marc
• Chen Catherine
• Southall Noel
• Zheng Wei
• Agoulnik Alexander
• Agoulnik Irina

Classifications

• C07C2601/16

  the ring being unsaturated · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07C271/28

  to a carbon atom of a non-condensed six-membered aromatic ring · CPC title

• C07C237/30

  having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D211/26

  with hydrocarbon radicals, substituted by nitrogen atoms · CPC title