NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF
Described herein are neuroactive steroids of the Formula (I): (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 the Formula (I):
wherein:
R 1a is hydrogen, halo, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R b )(R c ), —OC(O)N(R b )(R c ), —OC(O)OR a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c );
R 1b is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R d )(R e ), —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 );
wherein one of R 1a and R 1b 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, form a 3-7-membered heterocyclic ring; and
each R d and R e is hydrogen, substituted methyl or C 2 -C 6 alkyl, or
R d and R e , 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 the Formula (Ib):
wherein:
R 1a is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R b )(R c ), —OC(O)N(R b )(R c ), —OC(O)OR a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c );
R 1b is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R d )(R e ), —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 );
wherein one of R 1a and R 1b 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, form a 3-7-membered heterocyclic ring; and
each R d and R e is hydrogen, substituted methyl or C 2 -C 6 alkyl, or
R d and R e , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring.
3 . The compound of claim 1 , wherein one of R 1a or R 1b is hydroxy, alkyl, or alkoxy.
4 . The compound of claim 3 , wherein one of R 1a or R 1b is hydroxy.
5 . The compound of claim 3 , wherein one of R 1a or R 1b is alkoxy.
6 . The compound of claim 5 , wherein R 1a is methoxy.
7 . The compound of claim 1 , selected from:
8 . A compound of the Formula (II):
wherein:
R 2a is hydrogen, chloro, fluoro, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6 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 );
R 2b is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6 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 );
wherein one of R 2a and R 2b 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, form a 3-7-membered heterocyclic ring; and
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.
9 . The compound of claim 8 , wherein the compound is a compound of the Formula (IIb):
wherein:
R 2a is hydrogen, chloro, fluoro, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6 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 );
R 2b is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6 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 );
wherein one of R 2a and R 2b 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, form a 3-7-membered heterocyclic ring; and
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.
10 . The compound of claim 8 , wherein R 2a or R 2b is alkyl, methoxy, substituted ethoxy, or C 3 -C 6 alkoxy.
11 . The compound of claim 10 , wherein R 2a is alkyl, methoxy, substituted ethoxy, or C 3 -C 6 alkoxy.
12 . The compound of claim 9 , wherein R 2b is hydrogen.
13 . The compound of claim 8 , selected from:
14 . 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.
15 . The compound of claim 14 , 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.
16 . The compound of claim 14 , wherein R 1a and R 1b are taken together with the carbon to which they are attached to form C(═O).
17 . The compound of claim 14 , wherein R 2a or R 2b is hydroxy, alkyl, or alkoxy.
18 . (canceled)
19 . The compound of claim 14 , wherein R 1a or R 1b is hydroxy, alkyl, or alkoxy.
20 - 24 . (canceled)
25 . The compound of claim 14 , wherein R 3 is alkyl.
26 . The compound of claim 14 , selected from:
27 - 39 . (canceled)
40 . A pharmaceutical composition comprising a compound of Formula (I), (Ib), (II), (IIb), (III), or (IIIb), and a pharmaceutically acceptable excipient.
41 - 52 . (canceled)