Method, compositions, and compounds for modulating brain excitability

A method for modulating excitability of the central nervous system as mediated by the ability to regulate chloride ion channels associated with the GABA-benzodiazepine receptor complex comprising administering to a patient in need of such treatment a central nervous system [excitabiilty] excitability modulating pharmaceutically effective amount of a [3-hydroxylated-5-reduced] neuroactive steroid compound that activates the GABA-benzodiazepine receptor-chloride ionophore complex by attaching to a brain receptor site other than any previously known recognition site of said complex, but associated with and still activating said complex, of the formula ##STR23## wherein R1 is selected from the group consisting of hydroxyl, ##STR24## wherein R7, R8, and R9 are individually a C.sub.1 -C.sub.20 straight chain aliphatic radical, [C.sub.1 ] a C.sub.3 -C.sub.20 branched chain aliphatic radical, [or] a C.sub.3 -C.sub.10 cyclic aliphatic radical, [or C.sub.3 ] a C.sub.6 -C.sub.10 aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, [piperidinyl, pyridinyl, furanyl, thiphenyl] piperidyl, pyridyl, furyl, thienyl , and [pyrzinyl] pyrazinyl , and Y is --O-- or --S--;

• R2 is selected from the group consisting of OH, acetyl, [2-hydroxyethanonyl] 2-hydroxyethanoyl , 1-hydroxyethyl, ##STR25## wherein Y, R7, and R9 are as defined previously and R10, R11,R12, R13, R14, R15, R18, R19, R20, and R21 are individually a C.sub.1 -C.sub.20 straight chain aliphatic radical, [C.sub.1 ] a C.sub.3 -C.sub.20 branched chain [alipahtic] aliphatic radical, [or] a C.sub.3 -C.sub.10 cyclic aliphatic radical [or C.sub.3 ] , a C.sub.6 -C.sub.10 aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, [piperidinyl, pyridinyl, furanyl, thiophenyl] piperidyl, pyridyl, furyl, thienyl , and pyrazinyl with the provisos that
• (1) R10, R11, and R12 may also individually be an amide ##STR26## radical wherein R16 and R17 individually are a C.sub.1 -C.sub.20 straight chain aliphatic radical, [C.sub.1 ] a C.sub.3 -C.sub.20 branched cain aliphatic radical, [or] a C.sub.3 -C.sub.10 cyclic aliphatic radical, [or C.sub.3 ] a C.sub.6 -C.sub.10 aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, [piperidinyl, pyridinyl, furanyl, thienyl] piperidyl, pyridyl, furyl, thienyl , and pyrazinyl, and n=1 to 8 and
• (2) R20 and R21 may also individually by [H] hydrogen, or ##STR27## wherein R22 is [H or] hydrogen, a C.sub.1 -C.sub.20 straight chain aliphatic radical, [C.sub.1 ] a C.sub.3 -C.sub.20 branched chain aliphatic radical, [or] a C.sub.3 -C.sub.10 cyclic aliphatic radical, [or C.sub.3 ] a C.sub.6 -C.sub.10 aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, [piperidinyl, pyridinyl, furanyl, thiophenyl] piperidyl, pyridyl, furyl, thienyl , and pyrazinyl[, and n is an integer of 1 to 8];
• R3 is selected from the group consisting of hydrogen, hydroxy, keto, [C.sub.1 -C.sub.18 alkyloxy,] aryloxy, [and] amino , and C.sub.1 -C.sub.18 alkyloxy ;
• and
• R4, R5, and R6 individually are selected from the group consisting of [C.sub.1 -C.sub.18 alkyl,] aryl, halo, [and] trifluoroalkyl , and C.sub.1 -C.sub.18 alkyl .