GANAXOLONE DERIVATIVES FOR TREATMENT OF CENTRAL NERVOUS SYSTEMS DISORDERS

摘要

The present invention is directed to Ganaxolone prodrugs with increased aqueous solubility and oral bioavailability relative to Ganaxolone and that enable development of stable extended release formulations which offer a significant therapeutic advantage and improved patience compliance by enabling treatments with lower doses over prolonged periods of time.

主权项

1. A compound of Formula Wherein X1 is selected from the group consisting of (C═O)R1, (C═O)—(CH2)nCO2−M+, (C═O)—(CH2)nCO2R, (C═O)—(CH2)mO(C═O)R, (C═O)—(CH2)nOR, (C═O)—CH═CH—CO2R, (C═O)—CH═CH—CO2−M+, (C═O)—(CH2)nN(R)2, (C═O)—(CH2)n(C═O)N(R)2, (C═O)—(CH2)mN(C═O)R, (C═O)—(CHR4)N(R)2, (P═O)—(O−M+)2, (P═O)—(OC(R2)2O(C═O)YR1)2, (C═O)—N(CH2CO2R)2, (C═O)—O(C(R2)2)mO(C═O)R, C(R2)2O(C═O)R1, C(R2)2O(C═O)OR1, C(R2)2O(P═O)—(O−M+)2, C(R2)2O(P═O)—(OC(R2)2O(C═O)YR1)2, C(R2)2O(C═O)(CHR)N(R)2, C(R2)2O(C═O)N(R)2, C(R2)2O(C═O)N(CH2CO2R)2, R is H, alkyl or arylalkyl; R1 is alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl; R2 is hydrogen or methyl; R3 is methyl, isopropyl or t-butyl; R4 is an amino acid; R5 is alkyl or alkyl-OH M+ is Hydrogen, Na+, K+, Ca++, Mg++, R4N+, R5NH3+, (R5)2NH2+, (R5)3NH+, or (R5)4N+; Y is O, NH, or CH2; n is an integer from 0-6; m is an integer from 1-6; and p is an integer from 2-6; or a pharmaceutically acceptable salt thereof.