Compositions and methods for treating CNS disorders
Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 and 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.
1. A compound of the Formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom;
R 1 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 carbocyclyl;
each of R 2a and R 2b is independently selected from 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 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A )(R B ), or —OR A2 , wherein each of R A and R B 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R A and R B , together with the nitrogen atom to which they are attached form a ring or R 2a and R 2b , together with the carbon atom to which they are attached form a ring; 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, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3a is hydrogen, —N(R A )(R B ), 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, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and
R 3b is hydrogen or —N(R A )C(O)R A3 ; or
R 3a and R 3b are joined to form an oxo (═O) group;
each of R 4a and R 4b is independently selected from hydrogen or halogen;
R 5 is hydrogen, unsubstituted C 1-6 alkyl, or —CH 2 OR A5 , wherein R A5 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, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R 6 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 6 is absent.
2. A compound of the Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom;
R 1 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, 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, substituted or unsubstituted C 3-6 carbocyclyl, —N(R A )(R B ), or —OR A2 , wherein each of R A and R B 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 carbocyclyl, or substituted or unsubstituted heterocyclyl, or R A and R B , together with the nitrogen atom to which they are attached form a ring; 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 carbocyclyl;
R 3a is hydrogen, —N(R A )(R B ), 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 —N(R A )C(O)R A3 ; or
R 3a and R 3b are joined to form an oxo (═O) group;
R 4 is hydrogen or halogen;
R 5 is hydrogen, unsubstituted C 1-6 alkyl, or —CH 2 OR A5 , wherein R A5 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 6 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 6 is absent.
3. The compound of claim 2 , wherein the compound of Formula (I) is a compound of Formula (I-a):
wherein:
n is 0, 1, 2, 3, 4, 5, or 6; and
each R a is independently halogen, cyano, C 1-6 alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA or —OR AA , wherein R AA is 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 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
two R a groups, together with the atoms with which they are attached form a ring.
4. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-b):
5. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-b-i) or (I-b-ii):
6. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-c):
7. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-c-i) or (I-c-ii):
8. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-f):
9. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-d-i) or (I-d-ii):
10. The compound of claim 2 , wherein A is a 5-10-membered ring.
11. The compound of claim 10 , wherein A is phenyl, naphthyl, furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, or triazole.
12. The compound of claim 2 , wherein R 1 is unsubstituted C 1-6 alkyl.
13. The compound of claim 12 , wherein R 1 is —CH 3 .
14. The compound of claim 1 , wherein the compound is:
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
16. A method of treating an anxiety disorder or depression in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein the anxiety disorder is a generalized anxiety disorder (GAD).
18. The method of claim 16 , wherein, wherein the method is a method of treating depression.