19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF
Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
represents a single or double bond;
R 1 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;
R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, or —OR A2 , wherein R A2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;
R 3a is hydrogen or —OR A3 , wherein R A3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;
each instance of R 4a and R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, alkoxy, halogen, or —OR A4 , wherein R A4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 is in the alpha or beta configuration; and provided if the between C5 and C6 is a double bond, R 4b is absent;
A is one of the following formulae:
each instance of R 5 is, independently, halogen, —NO 2 , —CN, —OR GA , —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —OC(═O)R GA , —OC(═O)OR GA , —C(═O)N(R GA ) 2 , —N(R GA )C(═O)R GA , —OC(═O)N(R GA ) 2 , —N(R GA )C(═O)OR GA , —S(═O) 2 R GA , —S(═O) 2 OR GA , —OS(═O) 2 R GA , —S(═O) 2 N(R GA ) 2 , or —N(R GA )S(═O) 2 R GA ; substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-4 carbocylyl, substituted or unsubstituted 3- to 4-membered heterocylyl, or optionally two R GA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring;
each instance of R AN is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, —C(═O)R GA , —C(═O)OR GA , —C(═O)N(R GA ) 2 , —S(═O) 2 R GA , —S(═O) 2 OR GA , —S(═O) 2 N(R GA ) 2 , —S(O)R GA , e.g., —S(═O)R GA , —S(═O)OR GA , —S(═O)N(R GA ) 2 , or a nitrogen protecting group;
each instance of R GA is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
p is 1 or 2; and
e is 0, 1, 2, 3, 4, or 5;
provided that when A is (A-2), (A-3), or (A-5), e is 1, 2, 3, 4, or 5.
2 . A compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
3 . A compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
4 . A compound of Formula (IV):
or a pharmaceutically acceptable salt thereof.
5 . A compound of claim 1 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 5 , wherein R AN is substituted or unsubstituted hydrogen, substituted or unsubstituted C 1-6 alkyl, —C(═O)R GA , —C(═O)OR GA , —C(═O)N(R GA ) 2 , or —S(═O) 2 R GA .
7 . A compound of claim 1 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 7 , wherein the compound is of Formula (VI-a):
9 . The compound of claim 1 , wherein e is 1.
10 . The compound of claim 1 , wherein R 5 is substituted or unsubstituted C 1-6 alkyl.
11 . The compound of claim 1 , wherein R 5 is —CH 3 .
12 . The compound of claim 1 , wherein R 5 is OR GA wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.
13 . The compound of claim 1 , wherein R 5 is OH.
14 . The compound of claim 1 , wherein R 5 is —S(═O) 2 R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.
15 . The compound of claim 1 , wherein R 5 is —S(═O) 2 CH 3 .
16 . The compound of claim 1 , wherein R 5 is —C(═O)R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.
17 . The compound of claim 1 , wherein R 5 is —C(═O)CH 3 .
18 . The compound of claim 1 , wherein R 5 is —C(═O)N(R GA ) 2 wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.
19 . The compound of claim 1 , wherein R 5 is —C(═O)NHCH 3 .
20 . The compound of claim 1 , wherein between C5 and C6 is a double bond and R 4b is absent.
21 . The compound of claim 1 , wherein between C5 and C6 is a single bond.
22 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
23 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
24 . A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
25 . The method of claim 24 , 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, tinnitus, or status epilepticus.
26 . The method of claim 24 wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.
27 . The method of claim 24 wherein the compound is administered chronically.