IP Library › Patent Application 16316851
Patent Application
App. No. 16/316,851

C7, C12, AND C16 SUBSTITUTED NEUROACTIVE STEROIDS AND THEIR METHODS OF USE

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Patent No.
US None
App. No.
16/316,851
Abstract

Described herein are neuroactive steroids of Formula (I), Formula (V), or Formula (IX) or a pharmaceutically acceptable salt thereof; wherein each instance of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11a , R 11b , R 12 , R 16 , R 17 , R 19 , and are as herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia.

Claims (73)

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond as valency permits;

each of R 2 , R 4 , R 6 , R 11a , and R 11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an heterocyclic or heteroaryl ring; and R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together form oxo;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

R 5 is absent or hydrogen; and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond; when both of are single bonds, then R 5 is hydrogen; and when one of the is a double bond, R 5 is absent;

R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, or —C(O)R B1 , —C(O)CH 2 R B1 , or —C(O)CH 2 CH 2 R B1 , wherein R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl;

R 19 is hydrogen or alkyl; and

R 7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 .

2 - 5 . (canceled)

6 . The compound of claim 2 , wherein R 3 is C 1 -C 6 alkyl.

7 . (canceled)

8 . The compound of claim 2 , wherein the compound of Formula (I) is a compound of Formula (II-c) or (II-d):

9 . (canceled)

10 . The compound of claim 8 , wherein R 7 is —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH 2 OCH 3 .

11 . The compound of claim 8 , wherein R 17 is —OCH 3 , —CN, or —C(O)CH 3 .

12 . (canceled)

13 . The compound of claim 8 , wherein R 17 is —C(O)CH 2 R B1 .

14 - 17 . (canceled)

18 . The compound of claim 13 , wherein R B1 is

19 - 31 . (canceled)

32 . A compound of Formula (V):

or a pharmaceutically acceptable salt thereof,

wherein represents a single or double bond as valency permits;

each of R 2 , R 4 , R 6 , R 11a , and R 11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an heterocyclic or heteroaryl ring; and R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

R 5 is absent or hydrogen; and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond; when both of are single bonds, then R 5 is hydrogen; and when one of the is a double bond, R 5 is absent;

R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, —C(O)R B1 , —C(O)CH 2 R B1 , or —C(O)CH 2 CH 2 R B1 , wherein R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl;

R 19 is hydrogen or alkyl;

and R 12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 .

33 - 35 . (canceled)

36 . The compound of claim 32 wherein R 3 is C 1 -C 6 alkyl.

37 . (canceled)

38 . The compound of claim 32 , wherein the compound of Formula (V) is a compound of Formula (VI-c) or (VI-d):

39 . (canceled)

40 . The compound of claim 38 , wherein R 12 is —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH 2 OCH 3 .

41 . The compound of claim 38 , wherein R 17 is —OCH 3 , —CN, or —C(O)CH 3 .

42 . (canceled)

43 . The compound of claim 38 , wherein R 17 is —C(O)CH 2 R B1 .

44 - 47 . (canceled)

48 . The compound of claim 43 , wherein R B1 is

49 - 57 . (canceled)

58 . A compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond as valency permits;

each of R 2 , R 4 , R 6 , R 11a , and R 11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an heterocyclic or heteroaryl ring; and R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together form oxo;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

R 5 is absent or hydrogen; and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond; when both of are single bonds, then R 5 is hydrogen; and when one of the is a double bond, R 5 is absent;

R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, —C(O)R B1 , —C(O)CH 2 R B1 , or —C(O)CH 2 CH 2 R B1 , wherein R B1 is hydrogen, —OH, —N(R A1 ) 2 , alkoxy, aryl, or heteroaryl;

R 19 is hydrogen or alkyl;

and R 16 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 .

59 . (canceled)

60 . (canceled)

61 . The compound of claim 58 , wherein R 3 is C 1 -C 6 alkyl.

62 . (canceled)

63 . The compound of claim 58 , wherein the compound of Formula (IX) is a compound of Formula (X-c) or (X-d):

64 . (canceled)

65 . The compound of claim 63 , wherein R 16 is —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH 2 OCH 3 .

66 . The compound of claim 63 , wherein R 17 is —OCH 3 , —CN, or —C(O)CH 3 .

67 . (canceled)

68 . The compound of claim 63 , wherein R 17 is —C(O)CH 2 R B1 .

69 - 72 . (canceled)

73 . The compound of claim 68 , wherein R B1 is

74 - 81 . (canceled)

82 . A compound of claim 1 , selected from the group consisting of:

83 . A pharmaceutically acceptable salt of a compound of claim 1 selected from the group consisting of:

84 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

85 - 99 . (canceled)

100 . A composition for use in treating disorders related to GABA function in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1 .

101 . A method of treating a CNS-related disorder in a subject in need thereof, comprising an effective amount of a compound of claim 1 .

102 . The method of claim 101 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

103 - 104 . (canceled)

105 . A compound of claim 32 , selected from the group consisting of:

106 . A compound of claim 58 , selected from the group consisting of:

107 . A pharmaceutically acceptable salt of a compound of claim 32 , selected from the group consisting of:

108 . A pharmaceutically acceptable salt of a compound of claim 58 , selected from the group consisting of: