Compositions and methods for treating CNS disorders
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein , A, R 1 , R 2 , and R 3 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, e.g., for treating a subject suffering from a disease or disorder described herein.
1. A method of therapeutic treatment for a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I-c):
wherein:
n is 0, 1, 2, 3, 4, or 5;
Ring A is aryl or heteroaryl;
R 3A is C 1-6 alkyl;
R 1 is hydrogen, C 1-3 alkyl, C 2-6 alkenyl, or C 3-6 carbocyclyl;
R 2 is absent or hydrogen;
R a is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , —S(O) 2 R D , or —OR Y , wherein R Y is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , or —S(O) 2 R D ;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; and
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the CNS-related disorder is selected from epilepsy, status epilepticus, depression, and tremor.
2. The method of claim 1 , wherein the compound of Formula (I-c) is a compound of Formula (I-c-i), (I-c-ii), (I-c-iii), or (I-c-iv):
3. The method of claim 1 , wherein the compound of Formula (I-c) is selected from
4. The method of claim 1 , wherein the compound is administered orally.
5. The method of claim 1 , wherein the compound is administered intramuscularly.
6. The method of claim 1 , wherein the CNS-related disorder is depression, and wherein the depression is postpartum depression.
7. The method of claim 1 , wherein the CNS-related disorder is tremor, and wherein the tremor is essential tremor.
8. A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of Formula (I-c):
wherein:
n is 0, 1, 2, 3, 4, or 5;
Ring A is aryl or heteroaryl;
R 3A is C 1-6 alkyl;
R 1 is hydrogen, C 1-3 alkyl, C 2-6 alkenyl, or C 3-6 carbocyclyl;
R 2 is absent or hydrogen;
R a is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , —S(O) 2 R D , or —OR Y , wherein R Y is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , or —S(O) 2 R D ;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; and
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the compound is administered orally or intramuscularly.
9. The method of claim 8 , wherein the compound of Formula (I-c) is a compound of Formula (I-c-i), (I-c-ii), (I-c-iii), or (I-c-iv):
10. The method of claim 8 , wherein the compound of Formula (I-c) is selected from
11. The method of claim 8 , wherein the compound is administered orally.
12. The method of claim 8 , wherein the compound is administered intramuscularly.