US2019233465A1PendingUtilityA1
C7, c12, and c16 substituted neuroactive steroids and their methods of use
Est. expiryJul 11, 2036(~10 yrs left)· nominal 20-yr term from priority
Inventors:Albert Jean RobichaudGabriel Martinez BotellaBoyd L. HarrisonFrancesco G. SalituroAndrew GriffinMaria Jesus Blanco-Pillado
C07J 43/003C07J 41/0094C07J 7/002C07J 7/003C07J 1/0029C07J 41/005C07J 7/006A61P 25/00
65
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Claims
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
exact text as granted — not AI-modifiedWhat is claimed is:
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:Join the waitlist — get patent alerts
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