19-NOR neuroactive steroids and methods of use thereof
Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (1): 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, and status epilepticus.
1. A method of treating a sleep disorder or a mood disorder in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof or (b) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient:
wherein:
represents a single or double bond as valency permits;
A is of Formula (A-1) or Formula (A-2):
wherein the point of attachment is at G 1 or G 2 in Formula (A-1) and the point of attachment is at G 2 or G 3 in Formula (A-2);
G 1 is N, NR N1 , O, S, C, or C—R G1 as valency permits;
G 2 is N, NR N2 , O, S, C, —C═N—, or C—R G2 as valency permits;
G 3 is N, NR N3 , O, S, C, or C—R G3 as valency permits;
G 4 is N, NR N4 , C—R G4 , or C—(R G4 ) 2 as valency permits;
G 5 is N, NR N5 , C—R G5 , or C—(R G5 ) 2 as valency permits;
G 6 is N, NR N6 , C—R G6 , or C—(R G6 ) 2 as valency permits;
G 7 is N, NR N7 , C—R G7 , or C—(R G7 ) 2 as valency permits;
each instance of R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , and R G7 is, independently, hydrogen, 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 , —N(R GA )S(═O) 2 R GA , —S(═O)R GA , —S(═O)OR GA , —OS(═O)R GA , —S(═O)N(R GA ) 2 , —N(R GA )S(═O)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 3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R N1 , R N2 , R N3 , R N4 , R N5 , R N6 , and R N7 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, 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;
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 carbocylyl;
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, substituted or unsubstituted C 3-6 carbocylyl, or —OR A2 , wherein R A2 is hydrogen or 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 carbocylyl; and
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 carbocylyl, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;
each of R 4a or R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or halogen;
provided when bond p is a double bond, then bond q is a single bond, provided when bond q is a double bond, then bond p is a single bond and R 4b is absent; and provided when both bonds p and q are single bonds, then the hydrogen at C5 is in the alpha or beta configuration.
2. The method of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is one of the following formulae:
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound is of one of the following formulae:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is of Formula (II-b):
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound is one of the following formulae:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound is one of the following formulae:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the compound is of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein the compound is of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound is of Formula (III-b1):
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is of Formula (IV-a):
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is of Formula (IV-a1):
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is of one of the following formulae:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is selected from the group consisting of:
18. The method of claim 1 , wherein the compound is selected from the group consisting of:
19. The method of claim 1 , wherein the method is a method of treating a sleep disorder.
20. The method of claim 19 , wherein the sleep disorder is insomnia.
21. The method of claim 1 , wherein the method is a method of treating a mood disorder.
22. The method of claim 1 , wherein the mood disorder is depression.
23. The method of claim 22 , wherein the depression is postnatal depression.
24. The method of claim 23 , wherein the compound or pharmaceutical composition is administered orally.