Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally related pentacylic steroids

1. A method of treating convulsions related to GABA A receptor function in a mammal, said method comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition containing a steroid or D-homosteroid and at least one pharmaceutically acceptable carrier, wherein the steroid or D-homosteroid is a compound of Formula (A)

wherein

R 2 is selected from the group consisting of hydrogen, alkoxy, and substituted or unsubstituted morpholine

R 3a is hydroxyl or carboxyl;

R 3b is hydrogen, alkyl, alkenyl, or alkynyl optionally substituted with halo, hydroxyl, or substituted or unsubstituted aryl;

R 5 is α- or β-hydrogen;

R 10 is hydrogen or C 1-4 alkyl;

R 15 is hydrogen or oxo;

R 6 , R 11 and R 12 are independently hydrogen or oxo;

L 3a is selected from the group consisting of a bond, C 1-3 alkyl, heterosubstituted C 1-3 alkyl, or alkoxy;

X 4 -X 5 -X 6 is selected from the group consisting of

X 9 -X 11 -X 12 is selected from the group consisting of

X 40 is a bond or a carbon atom; and

E is a 5- or 6-membered carbocyclic ring in the β-configuration in relation to the C and D rings, comprising a hydrogen bond acceptor and (i) the carbons at C(13) and C(17) when X 40 is a bond, or (ii) the carbons at C(13) and C(17a) when X 40 is carbon.

2. The method of claim 1 wherein the hydrogen bond acceptor is selected from the group consisting of keto, cyano, acyl, ═CHX 1 , —OX 2 , —C(O)X 2 , epoxide, an E ring alkene bond, and combinations thereof; X 1 is selected from the group consisting of hydrogen, cyano, hydrocarbyl, substituted hydrocarbyl and acyl; and X 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and acyl.

3. The method of claim 2 wherein the E ring hydrogen bond acceptor is selected from the group consisting of keto, cyano, methylene, methoxy, acetyl, ═CHCN, ═CHC(O)CH 3 , epoxide, an E ring alkene bond, and combinations thereof.

4. The method of claim 1 wherein the C(3) substituent is a carboxyl in the α-configuration or a sulfate.

5. The method of claim 2 wherein L 3a is selected from the group consisting of a bond, methylene, ethylene, methoxy, and ethoxy and R 3a is hydroxyl.

6. The method of claim 2 wherein

X 4 -X 5 -X 6 is

X 9 -X 11 -X 12 is

7. The method of claim 1 wherein

R 2 is hydrogen;

R 3b is hydrogen;

R 10 is hydrogen or β-methyl;

R 15 is hydrogen;

R 6 , R 11 and R 12 are independently hydrogen or oxo;

L 3a is a bond; and

X 40 is a bond.

8. The method of claim 7 wherein the hydrogen bond acceptor is selected from the group consisting of keto, cyano, methylene, methoxy, acetyl, ═CHCN, ═CHC(O)CH 3 , epoxide, an E ring alkene bond, and combinations thereof.

9. The method of claim 1 wherein the steroid or D-homosteroid is Formula (B)

wherein

R 3a is hydroxyl or carboxyl; and

R 5 is α- or β-hydrogen.

10. The method of claim 9 wherein the E ring comprises a hydrogen bond acceptor selected from the group consisting of keto, cyano, acyl, ═CHX 1 , —OX 2 , —C(O)X 2 , epoxide, an E ring alkene bond, and combinations thereof; X 1 is selected from the group consisting of hydrogen, cyano, hydrocarbyl, substituted hydrocarbyl and acyl; and X 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and acyl.

11. The method of claim 10 wherein the hydrogen bond acceptor is selected from the group consisting of keto, cyano, methylene, methoxy, acetyl, ═CHCN, ═CHC(O)CH 3 , epoxide, and combinations thereof.

12. The method of claim 10 wherein the hydrogen bond acceptor comprises an E ring alkene bond.

13. The method of claim 9 wherein the steroid or D-homosteroid is Formula (C)

wherein

R 5 is α- or β-hydrogen;

R 50 is selected from the group consisting of hydrogen, keto, cyano, acyl, ═CHX 1 , —OX 2 , —C(O)X 2 , epoxide, an E ring alkene bond, and combinations thereof; X 1 is selected from the group consisting of hydrogen, cyano, hydrocarbyl, substituted hydrocarbyl and acyl; and X 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and acyl, provided that when R 50 is hydrogen at least one pair of E ring atoms share a double bond; and

E is a 6-membered carbocyclic ring wherein the dashed lines represent optional double bonds provided E comprises no more than 2 double bonds and provided each carbon ring atom of E is sp 2 or sp 3 hybridized.

14. The method of claim 13 wherein R 50 is selected from the group consisting of hydrogen, keto, cyano, methylene, methoxy, acetyl, ═CHCN, ═CHC(O)CH 3 , epoxide, and combinations thereof, provided that when R 50 is hydrogen at least one pair of E ring atoms share a double bond.

15. The method of claim 9 wherein the steroid or D-homosteroid is Formula (D)

wherein

R 5 is α- or β-hydrogen;

R 50 is selected from the group consisting of hydrogen, keto, cyano, acyl, ═CHX 1 , —OX 2 , —C(O)X 2 , epoxide, an E ring alkene bond, and combinations thereof; X 1 is selected from the group consisting of hydrogen, cyano, hydrocarbyl, substituted hydrocarbyl and acyl; and X 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and acyl, provided that when R 50 is hydrogen at least one pair of E ring atoms share a double bond; and

E is a 5-membered carbocyclic ring wherein the dashed lines represent optional double bonds provided E comprises no more than 2 double bonds and provided each carbon ring atom of E is sp 2 or sp a hybridized.

16. A method of treating convulsions related to GABA A receptor function in a mammal, said method comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition containing a steroid or D-homosteroid and at least one pharmaceutically acceptable carrier, wherein said steroid or D-homo steroid is selected from the group consisting of

17. A method of treating convulsions related to GABA A receptor function in a mammal, said method comprising administering a therapeutically effective amount of a pharmaceutical composition containing a steroid or D-homosteroid and at least one pharmaceutically acceptable carrier, wherein said steroid or D-homosteroid is a compound of Formula (A)

wherein

R 2 is selected from the group consisting of hydrogen, alkoxy, and substituted or unsubstituted morpholine

R 3a is selected from the group consisting of sulfate, phosphate, and phosphonate;

R 3b is hydrogen, alkyl, alkenyl, or alkynyl optionally substituted with halo, hydroxyl, or substituted or unsubstituted aryl;

R 5 is α- or β-hydrogen;

R 10 is hydrogen or C 1-4 alkyl;

R 15 is hydrogen or oxo;

R 6 , R 11 and R 12 are independently hydrogen or oxo;

L 3a is selected from the group consisting of a bond, C 1-3 alkyl, heterosubstituted C 1-3 alkyl, or alkoxy;

X 4 -X 5 -X 6 is selected from the group consisting of

X 9 -X 11 -X 12 is selected from the group consisting of

X 40 is a bond or a carbon atom; and

E is a 5- or 6-membered carbocyclic ring in the β-configuration in relation to the C and D rings, comprising a hydrogen bond acceptor and (i) the carbons at C(13) and C(17) when X 40 is a bond, or (ii) the carbons at C(13) and C(17a) when X 40 is carbon.

18. The method of claim 17 wherein L 3a is a bond and R 3a is in the β-configuration.

19. The method of claim 17 wherein the hydrogen bond acceptor is selected from the group consisting of keto, cyano, acyl, ═CHX 1 , —OX 2 , —C(O)X 2 , epoxide, an E ring alkene bond, and combinations thereof; X 1 is selected from the group consisting of hydrogen, cyano, hydrocarbyl, substituted hydrocarbyl and acyl; and X 2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and acyl.