US2021087223A1PendingUtilityA1
Compositions and methods for treating cns disorders
Est. expiryOct 16, 2034(~8.2 yrs left)· nominal 20-yr term from priority
C07J 75/00C07D 249/18A61K 31/58A61K 9/0053C07J 13/007A61P 25/00C07D 295/033C07D 231/14C07D 249/04C07J 43/003A61K 9/0019C07J 9/00
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Claims
Abstract
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein , R 1 , R 2a , R 2b , R 3 and A are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
2 . The compound of claim 1 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl (e.g., haloalkyl).
3 . The compound of any one of the preceding claims, wherein R 1 is methyl or CF 3 .
4 . The compound of any one of the preceding claims, wherein R 2a is methyl.
5 . The compound of any one of the preceding claims, wherein R 2b is hydrogen.
6 . The compound of any one of the preceding claims, wherein R 2a is methyl and R 2b is hydrogen.
7 . The compound of any one of the preceding claims, wherein represents a single bond.
8 . The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (II) or Formula (III):
or a pharmaceutically acceptable salt thereof, wherein A, R 1 , R 2a , and R 2b are defined as for Formula (I).
9 . The compound of any one of the preceding claims, wherein the compound of Formula (II) is a compound of Formula (II-a) or Formula (II-b):
or a pharmaceutically acceptable salt thereof, wherein A and R 1 are defined as for Formula (I).
10 . The compound of any one of the preceding claims, wherein the compound of Formula (III) is a compound of Formula (III-a) or Formula (III-b):
or a pharmaceutically acceptable salt thereof, wherein A and R 1 are defined as for Formula (I).
11 . The compound of any one of the preceding claims, wherein A is heterocyclyl or heteroaryl (e.g., nitrogen-containing heterocyclyl or a nitrogen-containing heteroaryl).
12 . The compound of any one of the preceding claims, wherein A is monocyclic or bicyclic.
13 . The compound of any one of the preceding claims, wherein A is substituted with at least one R A , wherein R A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 1-6 haloalkyl, halogen, cyano, —OR A6 , —C(═O)OR A6 , —SR B6 , —S(═O)R B6 , or S(═O) 2 R B6 , wherein R A6 is hydrogen or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or C 1-6 haloalkyl, and R B6 is C 1-6 alkyl or C 3-6 carbocyclyl.
14 . The compound of claim 13 , wherein R A is C 1-6 alkyl, halogen, or cyano.
15 . The compound of any one of claims 13 - 14 , wherein A is substituted with 1-3 instances of R A .
16 . A compound of the Formula (IV):
or a pharmaceutically acceptable salt thereof wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen;
R A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 1-6 haloalkyl, halogen, cyano, —OR A6 , —C(═O)OR A6 , —SR B6 , —S(═O)R B6 , or S(═O) 2 R B6 , wherein R A6 is hydrogen or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or C 1-6 haloalkyl, and R B6 is C 1-6 alkyl or C 3-6 carbocyclyl;
n is 0, 1, 2 or 3; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
17 . The compound of claim 16 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl (e.g., haloalkyl).
18 . The compound of any one of claims 16 - 17 , wherein R 1 is methyl or CF 3 .
19 . The compound of any one of claims 16 - 18 , wherein R 2a is methyl.
20 . The compound of any one of claims 16 - 19 , wherein R 2b is hydrogen.
21 . The compound of any one of claims 16 - 20 , wherein R 2a is methyl and R 2b is hydrogen.
22 . The compound of any one of claims 16 - 21 , wherein represents a single bond.
23 . The compound of claims 16 - 22 , wherein the compound of Formula (IV) is a compound of Formula (V) or Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein A, R 1 , R 2a , R 2b , R A , and n are defined as for Formula (IV).
24 . The compound of any one of claims 16 - 23 , wherein the compound of Formula (V) is a compound of Formula (V-a) or Formula (V-b):
or a pharmaceutically acceptable salt thereof, wherein A, R 1 , R 2 , R b , R A , and n are defined as for Formula (IV).
25 . The compound of any one of claims 16 - 24 , wherein the compound of Formula (VI) is a compound of Formula (VI-a) or Formula (VI-b):
or a pharmaceutically acceptable salt thereof, wherein A, R 1 , are defined as for Formula (I).
26 . The compound of any one of the preceding claims, wherein A is selected from:
27 . The compound of any one of the preceding claims, wherein A is selected from:
28 . The compound of any one of the preceding claims, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
29 . A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.
30 . A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
31 . A method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of any one of the preceding claims to a subject in need thereof, wherein the subject experiences sedation and/or anesthesia within two hours of administration.
32 . The method of claim 31 , wherein the subject experiences sedation and/or anesthesia within one hour of administration.
33 . The method of claim 31 , wherein the subject experiences sedation and/or anesthesia instantaneously.
34 . The method of claim 31 , wherein the compound is administered by intravenous administration.
35 . The method of claim 31 wherein the compound is administered chronically.
36 . The method of claim 31 , wherein the subject is a mammal.
37 . The method of claim 36 , wherein the subject is a human.
38 . The method of claim 31 , wherein the compound is administered in combination with another therapeutic agent.
39 . A method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
40 . A method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
41 . A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition comprising a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
42 . A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent.
43 . The method of claim 42 , 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.
44 . The method of claim 42 , wherein the compound is administered orally.
45 . The method of claim 42 , wherein the compound is administered intramuscularly.
46 . The method of claim 42 , wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.
47 . The method of claim 42 , wherein the CNS-related disorder is a sleep disorder, an eating 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.
48 . The method of claim 42 , wherein the CNS-related disorder is depression (e.g., post-partum depression).
49 . The method of claim 42 , wherein the CNS-related disorder is tremor (e.g., essential tremor).
50 . The method of claim 42 , wherein the CNS-related disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge-eating disorder, cachexia).
51 . A kit comprising a solid composition comprising a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is aryl, heterocyclyl or heteroaryl;
R 1 is C 1-6 alkyl;
R 2a is C 1-6 alkyl;
R 2b is hydrogen or C 1-6 alkyl;
or R 2a and R 2b are joined to form an oxo (═O) group;
or R 2a and R 2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring));
R 3 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R 3 is absent; and a sterile diluent.Join the waitlist — get patent alerts
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