Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same

Patent metadata

Field	Value
Publication number	US-2017190732-A1
Application number	US-201715459492-A
Country	US
Kind code	A1
Filing date	Mar 15, 2017
Priority date	Dec 18, 2012
Publication date	Jul 6, 2017
Grant date	—

Abstract

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

First claim

What is claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is selected from (C 1 -C 4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C 1 -C 4 alkyl)C(O), and HO(C 1 -C 4 alkyl)C(O);
R 2 is ═O, H, or OR a , where R a is selected from H, optionally substituted C 1 -C 4 alkyl, or optionally substituted aryl, with the proviso that when R 2 is ═O, R 8 is not present;
R 3 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 4 is independently selected from H and unsubstituted C 1 -C 4 alkyl;
R 5 is substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 6 is H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 1 -C 4 alkoxy;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, or an optionally substituted morpholinyl ring;
R 8 , when present, is H or optionally substituted C 1 -C 4 alkyl;
- - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5 or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present; and,
- - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 16 -C 17 , with the proviso that when present, the R 1 is not ═O.

2 . The compound of claim 1 , wherein one or both of R 6 or R 7 , when present and other than H, are in the beta configuration.

3 . The compound of claim 1 or 2 , wherein the R 3 group is selected from the group consisting of H, methyl, and trifluoromethyl.

4 . The compound of one of the preceding claims, wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring.

5 . The compound of one of the preceding claims, wherein R 7 is H.

6 . The compound of one of the preceding claims, wherein R 5 is substituted methyl.

7 . The compound of one of the preceding claims, wherein the C 5 —H is in the alpha position.

8 . The compound of one of preceding claims 1 - 6 , wherein the C 5 —H is in the beta configuration and R 5 group is in the beta configuration.

9 . The compound of one of the preceding claims, wherein R 6 is H.

10 . The compound of one of the preceding claims, wherein R 2 is ═O, methoxy or H.

11 . The compound of one of the preceding claims, wherein R 4 is methyl.

12 . The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

13 . The compound of claim 12 wherein R b is methyl.

14 . The compound of claim 12 or 13 , wherein R 1 is beta-methoxy.

15 . The compound of claim 12 or 13 , wherein R 1 is beta-spirooxirane.

16 . The compound of claim 12 or 13 , wherein R 1 is beta-cyano.

17 . The compound of claim 12 or 13 , wherein R 1 is ═O.

18 . The compound of claim 12 or 13 , wherein R 1 is beta-nitro.

19 . The compound of claim 12 or 13 , wherein R 1 is beta-CH 3 C(O)—.

20 . The compound of claim 12 or 13 , wherein R 1 is beta-HOCH 2 C(O)—.

21 . The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

22 . The compound of claim 21 , wherein R b is methyl.

23 . A pharmaceutically acceptable salt of a compound of one of the preceding claims.

24 . A prodrug of a compound of one of the preceding claims.

25 . A compound of Formula (II):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is selected from (C 1 -C 4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C 1 -C 4 alkyl)C(O), and HO(C 1 -C 4 alkyl)C(O);
R 2 is ═O, H, or OR a , where R a is selected from H, optionally substituted C 1 -C 4 alkyl, or optionally substituted aryl, with the proviso that when R 2 is ═O, R 8 is not present;
R x is ═O or OR d , where R d is H or C(O)R e , where R e is optionally substituted C 1 -C 22 alkyl or optionally substituted C 2 -C 22 alkenyl, with the proviso that when R x is OH, it is in the beta configuration (and when R x is R d , with R d being C(O)R e , then it is preferably in the beta configuration);
R 4 is independently selected from H and unsubstituted C 1 -C 4 alkyl;
R 5 is substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 6 is H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 1 -C 4 alkoxy;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, or an optionally substituted morpholinyl ring;
R 8 , when present, is H or optionally substituted C 1 -C 4 alkyl;
- - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5 or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present; and,
- - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 16 -C 17 , with the proviso that when present, the R 1 is not ═O,
provided that the compound does not have one of the following structures:

or alternatively provided that: (i) when R x is ═O, a C═C bond is present between C 4 -C 5 , and R 5 is CH 2 OCH 3 , then R 1 is selected from methoxy, spirooxirane, cyano, nitro, and CH 3 C(O)—; and/or (ii) when R x is beta-OH, a C═C bond is present between C 5 -C 6 , and R 5 is CH 2 OCH 3 , then R 1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH 2 C(O)—.

26 . The compound of claim 25 , wherein R x is OH in the beta configuration.

27 . The compound of claim 25 , wherein R x is ═O.

28 . The compound of one of preceding claims 25 - 27 , wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring.

29 . The compound of one of preceding claims 25 - 28 , wherein R 7 is in the beta position.

30 . The compound of one of preceding claims 25 - 29 , wherein R 5 is substituted methyl.

31 . The compound of one of preceding claims 25 - 30 , wherein the C 5 —H is in the alpha configuration and R 5 is in the beta configuration.

32 . The compound of one of preceding claims 25 - 30 , wherein the C 5 —H is in the beta configuration and R 5 is in the beta configuration.

33 . The compound of one of preceding claims 25 - 32 , wherein R 6 is H.

34 . The compound of one of preceding claims 25 - 33 , wherein R 2 is ═O, methoxy or H.

35 . The compound of one of preceding

Assignees

• Univ Washington
• Sage Therapeutics Inc

Inventors

• Covey Douglas
• Robichaud Albert Jean

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/06

  Antimigraine agents · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title