GABAA modulating neurosteroids

A compound represented by Formula (I):

• including pharmaceutically acceptable esters, salts and acid addition salts thereof, wherein:
• R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, sulfonamido, halogen, alkoxy, alkyl, alkenyl, or alkynyl and all R groups can be optionally substituted;
• R1 is one of alkyl, alkenyl, arylkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, isothiocyano, azidoalkyl, arylalkyl, arylalkenyl, aryl, arylkylalkynyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl and all R1 groups can be optionally substituted;
• R2 is one of hydroxyl, alkoxy, alkanoyloxy, aminocarbonyloxy or alkoxycarbonyloxy;
• azido, or NCS;
• R3 is hydrogen, or when a double bond is present between C4 and C5 of the steroid ring system, then R3 is not present;
• R4 is one of hydrogen or lower alkyl,
• R5 is —CH(X)—R6;
• and
• X is one of N3, CN, or NCS,
• R6 is independently H, optionally substituted C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted aryl, optionally substituted arylkyl, optionally substituted C(O)—C1-10alkyl, optionally substituted C(O)—C2-10alkenyl, optionally substituted C(O)—C2-10alkynyl;
• and the dotted lines indicate that a single or double bond may be present.

A compound represented by Formula (I):

• including pharmaceutically acceptable esters, salts and acid addition salts thereof, wherein:
• R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, sulfonamido, halogen, alkoxy, alkyl, alkenyl, or alkynyl and all R groups can be optionally substituted;
• R1 is one of hydrogen, alkyl, alkenyl, arylkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, isothiocyano, azidoalkyl, arylalkyl, arylalkenyl, aryl, arylkylalkynyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl and all R1 groups can be optionally substituted;
• R2 is N3;
• R3 is hydrogen, or when a double bond is present between C4 and C5 of the steroid ring system, then R3 is not present;
• R4 is one of hydrogen or lower alkyl,
• R5 is one of —C(O)CH2N3, —C(O)CH2Br, or —C(O)CH3;
• and
• the dotted lines indicate that a single or double bond may be present.

A compound selected from one of the following, including pharmaceutically acceptable esters, salts and acid addition salts thereof:

• 17β-[2-(4-tolyl)ethynyl]-5α-androstane-3α-ol;
• 17β-(2-methoxycarbonylethynyl)-5α-androstane-3β-ol;
• 17β-(2-bromoethynyl)-5α-androstane-3α-ol;
• 17β-(3-hydroxy-1-butynyl)-5α-androstane-3α-ol;
• 17β-(3-oxo-1-butynyl)-5α-androstan-3α-ol;
• 17β-[1-hydroxy-3-(4-methoxyphenyl)-2-propynyl]-5α-androstan-3α-ol;
• 17β-(1-hydroxy-2,3-butadienyl)-5α-androstane-3-ol;
• 17β-(1-methoxy-2-propynyl)-5α-androstan-3a-ol;
• 17β-(1-hydroxy-2-propynyl)-5α-androstan-3-ol;
• 3α-Azido-5α-pregnan-20-one;
• 3α-Azido-21-bromo-5α-pregnan-20-one;
• or
• 3α,21-di-azido-5α-pregnan-20-one.

A method of inducing anesthesia;

• treating stress, treating anxiety, treating pre-menstrual syndrome, treating post-natal depression, and treating seizures;
• ameliorating attacks of anxiety, ameliorating muscle tension, or ameliorating depression common with patients suffering from central nervous system abnormalities, comprising
• administering to a patient a compound represented by Formula (I):
• including pharmaceutically acceptable esters, salts and acid addition salts thereof, wherein:
• R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, sulfonamido, halogen, alkoxy, alkyl, alkenyl, or alkynyl and all R groups can be optionally substituted;
• R1 is one of alkyl, alkenyl, arylkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, isothiocyano, azidoalkyl, arylalkyl, arylalkenyl, aryl, arylkylalkynyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl and all R1 groups can be optionally substituted;
• R2 is one of hydroxyl, alkoxy, alkanoyloxy, aminocarbonyloxy, alkoxycarbonyloxy;
• azido, or NCS;
• R3 is hydrogen, or when a double bond is present between C4 and C5 of the steroid ring system, then R3 is not present;
• R4 is one of hydrogen or lower alkyl,
• R5 is one of —CH(OR6)R7, —C≡C-aryl, —C≡C—CH(OR6)R8, or —C≡C—C(O)R8;
• R6 is independently H, optionally substituted C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted aryl, optionally substituted arylkyl, optionally substituted C(O)—C1-10alkyl, optionally substituted C(O)—C2-10alkenyl, optionally substituted C(O)—C2-10alkynyl
• R7 is independently allene, optionally substituted alkynyl, optionally substituted arylkylalkynyl, optionally substituted alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl;
• R8 is independently H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, arylalkyl, aryl, all of which may be optionally substituted;
• and
• the dotted lines indicate that a single or double bond may be present;
• or
• a compound represented by Formula (I) above, including pharmaceutically acceptable esters, salts and acid addition salts thereof, wherein:
• R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, sulfonamido, halogen, alkoxy, alkyl, alkenyl, or alkynyl and all R groups can be optionally substituted;
• R1 is one of alkyl, alkenyl, arylkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, isothiocyano, azidoalkyl, arylalkyl, arylalkenyl, aryl, arylkylalkynyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl and all R1 groups can be optionally substituted;
• R2 is one of hydroxyl, alkoxy, alkanoyloxy, aminocarbonyloxy, alkoxycarbonyloxy;
• azido, or NCS;
• R3 is hydrogen, or when a double bond is present between C4 and C5 of the steroid ring system, then R3 is not present;
• R4 is one of hydrogen or lower alkyl,
• R5 is —CH(X)—R6;
• and
• X is one of N3, CN, or NCS,
• R6 is independently H, optionally substituted C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted aryl, optionally substituted arylkyl, optionally substituted C(O)—C1-10alkyl, optionally substituted C(O)—C2-10alkenyl, optionally substituted C(O)—C2-10alkynyl;
• and the dotted lines indicate that a single or double bond may be present;
• or
• a compound represented by Formula (I) above, including pharmaceutically acceptable esters, salts and acid addition salts thereof, wherein:
• R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, sulfonamido, halogen, alkoxy, alkyl, alkenyl, or alkynyl and all R groups can be optionally substituted;
• R1 is one of alkyl, alkenyl, arylkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, isothiocyano, azidoalkyl, arylalkyl, arylalkenyl, aryl, arylkylalkynyl, alkanoyloxyalkynyl, heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl and all R1 groups can be optionally substituted;
• R2 is N3;
• R3 is hydrogen, or when a double bond is present between C4 and C5 of the steroid ring system, then R3 is not present;
• R4 is one of hydrogen or lower alkyl,
• R5 is one of —C(O)CH2N3, —C(O)CH2Br, or —C(O)CH3;
• and
• the dotted lines indicate that a single or double bond may be present;
• or
• a compound selected from one of the following, including pharmaceutically acceptable esters, salts and acid addition salts thereof:
• 17β-[2-(4-tolyl)ethynyl]-5α-androstane-3α-ol;
• 17β-(2-methoxycarbonylethynyl)-5α-androstane-3β-ol;
• 17β-(2-bromoethynyl)-5α-androstane-3α-ol;
• 17β-(3-hydroxy-1-butynyl)-5α-androstane-3α-ol;
• 17β-(3-oxo-1-butynyl)-5α-androstan-3α-ol;
• 17β-[1-hydroxy-3-(4-methoxyphenyl)-2-propynyl]-5α-androstan-3α-ol;
• 17β-(1-hydroxy-2,3-butadienyl)-5α-androstane-3-ol;
• 17β-(1-methoxy-2-propynyl)-5α-androstan-3a-ol;
• 17β-(1-hydroxy-2-propynyl)-5α-androstan-3-ol;
• 3α-Azido-5α-pregnan-20-one;
• 3α-Azido-21-bromo-5α-pregnan-20-one;
• or
• 3α,21-di-azido-5α-pregnan-20-one.