Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase

Patent metadata

Field	Value
Publication number	US-9963439-B2
Application number	US-201414912479-A
Country	US
Kind code	B2
Filing date	Aug 20, 2014
Priority date	Aug 20, 2013
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism. The compositions comprise compounds of formula (I). A repreid50000060307390 IB/345 nullsents aryl optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; X is a bond, —CH 2 —, —CHR 5 —, —C═CHR 4 —, —NR 4 —, —N═O—R 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, or —C(NR 4 )—, or X is of formula (a), (b) or (c), wherein each n is independently 1, 2, or 3; each R 4 is independently hydrogen or C 1-6 alkyl; R 5 is independently hydrogen, C 1-6 alkyl, or —OR 6 , where R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyL C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; Y is C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkylylene moiety.

First claim

We claim:

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein
A represents phenyl optionally substituted with one or two groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;
X is —CH 2 —, —CHR 5 —, —NR 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, or —C(NR 4 )—, or X is of formula

 wherein
each n is independently 1, 2, or 3;
each R 4 is independently hydrogen or C 1-6 alkyl;
R 5 is independently hydrogen, C 1-6 alkyl, or —OR 6 , where R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl;

Y is C 1-6 alkylene or C 2-6 alkenylene moiety;
R 1 is C 3-12 cycloalkyl optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —S(O) 2 R 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)OR 7 , or —N(R 7 )C(O)N(R 7 ) 2 , wherein each R 7 is independently hydrogen or C 1-6 alkyl;
R 2 is halogen, C 1-6 alkyl, or —OR 8 , where R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —S(O) 2 R 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)OR 7 , or —N(R 7 )C(O)N(R 7 ) 2 , wherein each R 7 is independently hydrogen or C 1-6 alkyl; and
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, or —NR 2 ,
and each R is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1-6 alkyl.

2. The compound according to claim 1 , wherein
X is —CH 2 —, —CHR 5 —, —NR 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, —C(NR 4 )—, wherein
each R 4 is independently hydrogen or C 1-6 alkyl; and
R 5 is independently hydrogen, C 1-6 alkyl, or —OR 6 , where R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl.

3. The compound according to claim 1 , wherein
X is —CH 2 — or —CHR 5 —, wherein R 5 is independently hydrogen, C 1-6 alkyl, or —OR 6 , where R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl.

4. The A compound according to claim 3 , wherein X is —CH 2 —.

5. The compound according to claim 1 , wherein
X is —NR 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, —C(NR 4 )—, wherein each R 4 is independently hydrogen or C 1-6 alkyl.

6. The compound according to claim 5 , wherein X is —O—, —S—, —SO—, —SO 2 —, —C(O)—, or —C(NR 4 )—.

7. The compound according to claim 5 , wherein X is —O—, —S—, —SO—, or —SO 2 —.

8. The compound according to claim 5 , wherein X is —O—.

9. The compound according to claim 5 , wherein X is —S—, —SO—, or —SO 2 —.

10. The compound according to claim 8 , wherein X is —C(O)—.

11. The compound according to claim 1 , wherein X is of formula

and each n is independently 1 or 2.

12. The compound according to claim 11 , wherein each n is independently 1.

13. The compound according to claim 1 , wherein X is —CH 2 —, —NH—, —S—, —SO 2 —, —C(O)—,

14. The compound according to claim 1 , wherein X is —CH 2 —, —NH—, —S—, —SO 2 —, —C(O)—,

15. The compound according to claim 1 , wherein Y is C 1-4 alkylene or C 2-4 alkenylene.

16. The compound according to claim 1 , wherein Y is C 1-4 alkylene.

17. The compound according to claim 16 , wherein Y is methylene, ethylene, or propylene.

18. The compound according to claim 17 , wherein Y is methylene or ethylene.

19. The compound according to claim 1 , wherein Y is C 2-4 alkenylene.

20. The compound according to claim 19 , wherein Y is —CH═CH—, —CH 2 CH═CH—, or —CH═CHCH 2 —.

21. The compound according to claim 1 , wherein Y is methylene, ethylene, or —CH═CH—.

22. The compound according to claim 1 , wherein R 3 is hydrogen, C 1-6 alkyl, —OR, or —NR 2 ,
and each R is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-12 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1-6 alkyl.

23. The compound according to claim 22 , wherein R 3 is hydrogen or C 1-6 alkyl.

24. The compound according to claim 23 , wherein R 3 is hydrogen.

25. The compound according to claim 23 , wherein R 3 is C 1-6 alkyl.

26. The compound according to claim 22 , wherein R 3 is —NR 2 .

27. The compound according to claim 26 , wherein each R is independently hydrogen or C 1-6 alkyl optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1-6 alkyl.

28. The compound according to claim 22 , wherein R 3 is —OR.

29. The compound according to claim 28 , wherein R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-12 cycloalkyl, heterocycly

Assignees

• Univ Washington Through Its Center For Commercialization
• Univ Of Montana

Inventors

• Diaz Philippe
• Isoherranen Nina
• Buttrick Brian
• Guilloteau Nicolas

Classifications

• C07C2603/74

  Adamantanes · CPC title

• C07C229/42

  with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains · CPC title

• C07C323/62

  having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton · CPC title

• C07D317/30 Primary

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C69/734

  Ethers · CPC title