Neuroactive steroids, compositions, and uses thereof
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein R 1a and R 1b 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 Formula (III):
wherein:
one of R 1a and R 1b is halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R h )(R i ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ) and the other one is hydrogen; or
R 1a and R 1b are taken together with the carbon to which they are attached to form C(═O);
one of R 2a and R 2b is chloro, fluoro, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen;
R 3 is hydrogen or C 1 -C 6 alkyl;
each R a is hydrogen or C 1 -C 6 alkyl;
each R b and R c is independently hydrogen or C 1 -C 6 alkyl, or
R b and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring;
each R f and R g is independently hydrogen or C 1 -C 6 alkyl, or
R f and R g , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur; and
each R h is unsubstituted C 1 -C 4 alkyl;
each R i is hydrogen, substituted methyl or C 2 -C 6 alkyl, or
R h and R i , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring.
2. The compound of claim 1 , wherein the compound is a compound of Formula (IIIb):
wherein:
one of R 1a and R 1b is halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R h )(R i ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen; or
R 1a and R 1b are taken together with the carbon to which they are attached to form C(═O);
one of R 2a and R 2b is chloro, fluoro, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen;
each R a is hydrogen or C 1 -C 6 alkyl;
each R b and R c is independently hydrogen or C 1 -C 6 alkyl, or
R b and R c , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring;
each R f and R g is independently hydrogen or C 1 -C 6 alkyl, or
R f and R g , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur; and
each R h is unsubstituted C 1 -C 4 alkyl;
each R i is hydrogen, substituted methyl or C 2 -C 6 alkyl, or
R h and R i , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring.
3. The compound of claim 1 , wherein R 1a and R 1b are taken together with the carbon to which they are attached to form C(═O).
4. The compound of claim 1 , wherein R 2a or R 2b is hydroxy, alkyl, or alkoxy.
5. The compound of claim 1 , wherein R 1a and R 1b are taken together with the carbon to which they are attached to form C(═O) and R 2a or R 2b is hydroxy, alkyl, or alkoxy.
6. The compound of claim 1 , wherein R 1a or R 1b is hydroxy, alkyl, or alkoxy.
7. The compound of claim 6 , wherein R 1a is hydroxy.
8. The compound of claim 6 , wherein R 1a is alkoxy.
9. The compound of claim 1 , wherein R 1a or R 1b is hydroxy, alkyl, or alkoxy and R 2a or R 2b is hydroxy, alkyl, or alkoxy.
10. The compound of claim 4 , wherein R 2a is alkyl.
11. The compound of claim 4 , wherein R 2a is alkoxy.
12. The compound of claim 1 , wherein R 3 is C 1 -C 6 alkyl.
13. The compound of claim 1 selected from:
14. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.