Novel and specific inhibitors of cytochrome p450 26 retinoic acid hydroxylase

Patent metadata

Field	Value
Publication number	US-2016200703-A1
Application number	US-201414912479-A
Country	US
Kind code	A1
Filing date	Aug 20, 2014
Priority date	Aug 20, 2013
Publication date	Jul 14, 2016
Grant date	—

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 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

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;
R 1 is 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 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 hydrogen, 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 heteroaryIC 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;
or R 1 and R 2 together with the atoms to which they are attached form a C 3-12 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each 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 ; 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 . A compound according to claim 1 , wherein A is optionally substituted phenyl having the formula:

3 . A compound according to claim 1 , wherein A is optionally substituted naphthyl having the formula:

4 . A compound according to any one of claims 1 - 3 , wherein
X is —CH 2 —, —CHR 5 —, —NR 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, —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; 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.

5 . A compound according to claim 4 , 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 1-5 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.

6 . A compound according to claim 4 , 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.

7 . A compound according to claim 6 , wherein X is —CH 2 —.

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

9 . A compound according to claim 8 , wherein X is —O—, —S—, —SO—, —SO 2 —, —C(O)—, or —C(NR 4 )—.

10 . A compound according to claim 8 , wherein X is —O—, —S—, —SO—, or —SO 2 —.

11 . A compound according to claim 8 , wherein X is —O—.

12 . A compound according to claim 8 , wherein X is —S—, —SO—, or —SO 2 —.

13 . A compound according to claim 8 , wherein X is —C(O)—.

14 . A compound according to claim 4 , wherein X is of formula

and each n is independently 1 or 2.

15 . A compound according to claim 14 , wherein each n is independently 1.

16 . A compound according to any one of claims 1 - 3 wherein X is a bond.

17 . A compound according to any one of claims 1 - 3 , wherein X is a bond, —CH 2 —, —NH—, —S—, —SO 2 , —C(O)—,

18 . A compound according to any one of claims 1 - 3 , wherein X is —CH 2 —, —NH—, —S—, —SO 2 —, —C(O)—,

19 . A compound according to any one of claims 1 - 18 , wherein Y is C 1-6 alkylene or C 2-6 alkenylene.

20 . A compound according to claim 19 , wherein Y is C 1-4 alkylene or C 2-4 alkenylene.

21 . A compound according to claim 19 , wherein Y is C 1-4 alkylene.

22 . A compound according to claim 21 , wherein Y is methylene, ethylene, or propylene.

23 . A compound according to claim 22 , wherein Y is methylene or ethylene.

24 . A compound according to claim 19 , wherein

Assignees

• Univ Washington Ct Commerciali
• Univ Montana

Inventors

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

Classifications

• C07C69/616

  polycyclic · CPC title

• C07C69/734

  Ethers · CPC title

• C07C229/44

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

• C07C69/738

  Esters of keto-carboxylic acids {or aldehydo-carboxylic acids} · CPC title

• C07C2103/74

  Chemistry & Metallurgy · mapped topic