Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same

A compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O);
• R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present;
• Rx is ═O or ORd, where Rd is H or C(O)Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, with the proviso that when Rx is OH, it is in the beta configuration (and when Rx is Rd, with Rd being C(O)Re, then it is preferably in the beta configuration);
• R4 is independently selected from H and unsubstituted C1-C4 alkyl;
• R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
• R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
• R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring;
• R8, when present, is H or optionally substituted C1-C4 alkyl;
• - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5—H substituent is not present;
• and,
• - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O,
• provided that the compound does not have one of the following structures:
• or alternatively provided that:
• (i) when Rx is ═O, a C═C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and CH3C(O)—;
• and/or (ii) when Rx is beta-OH, a C═C bond is present between C5-C6, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH2C(O)—.

A method of inducing anesthesia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O);
• R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present;
• R3 is H, optionally substituted C1-C4 alkyl, optionally C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, or optionally substituted aryl;
• R4 is independently selected from H and unsubstituted C1-C4 alkyl;
• R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl,
• R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
• R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring;
• R8, when present, is H or optionally substituted C1-C4 alkyl;
• - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5—H substituent is not present;
• and,
• - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O.

A method for treating disorders related to GABA function in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O);
• R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present;
• R3 is H, optionally substituted C1-C4 alkyl, optionally C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, or optionally substituted aryl;
• R4 is independently selected from H and unsubstituted C1-C4 alkyl;
• R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl,
• R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
• R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring;
• R8, when present, is H or optionally substituted C1-C4 alkyl;
• - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5—H substituent is not present;
• and,
• - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O.

A method of inducing anesthesia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O);
• R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present;
• Rx is ═O or ORd, where Rd is H or C(O)Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, with the proviso that when Rx is OH, it is in the beta configuration (and when Rx is Rd, with Rd being C(O)Re, then it is preferably in the beta configuration);
• R4 is independently selected from H and unsubstituted C1-C4 alkyl;
• R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
• R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
• R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring;
• R8, when present, is H or optionally substituted C1-C4 alkyl;
• - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5—H substituent is not present;
• and,
• - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O,
• provided that the compound does not have one of the following structures:
• or alternatively provided that:
• (i) when Rx is ═O, a C═C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and CH3C(O)—;
• and/or (ii) when Rx is beta-OH, a C═C bond is present between C5-C6, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH2C(O)—.

A method for treating disorders related to GABA function in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O);
• R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present;
• Rx is ═O or ORd, where Rd is H or C(O)Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, with the proviso that when Rx is OH, it is in the beta configuration (and when Rx is Rd, with Rd being C(O)Re, then it is preferably in the beta configuration);
• R4 is independently selected from H and unsubstituted C1-C4 alkyl;
• R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
• R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
• R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring;
• R8, when present, is H or optionally substituted C1-C4 alkyl;
• - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5—H substituent is not present;
• and,
• - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O,
• provided that the compound does not have one of the following structures:
• or alternatively provided that:
• (i) when Rx is ═O, a C═C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and CH3C(O)—;
• and/or (ii) when Rx is beta-OH, a C═C bond is present between C5-C6, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH2C(O)—.