Method, compositions, and compounds for modulating brain excitability

Abstract

Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-ammobutyric acid/benzodiazepine receptor-chloride ionpore (GBR) complex.

We claim: 
     
       1. 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.]. .Iadd.excitability .Iaddend.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 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiphenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and .[.pyrzinyl.]. .Iadd.pyrazinyl.Iaddend., and Y is --O-- or --S--; R2 is selected from the group consisting of OH, acetyl, .[.2-hydroxyethanonyl.]. .Iadd.2-hydroxyethanoyl.Iaddend., 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 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain .[.alipahtic.]. .Iadd.aliphatic .Iaddend.radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical .[.or C 3  .]..Iadd., a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiophenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., 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 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched cain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thienyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and pyrazinyl, and n=1 to 8 and   (2) R20 and R21 may also individually by .[.H.]. .Iadd.hydrogen, .Iaddend.or ##STR27##  wherein R22 is .[.H or.]. .Iadd.hydrogen, .Iaddend.a C 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiophenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and pyrazinyl.[., and n is an integer of 1 to 8.].;   R3 is selected from the group consisting of hydrogen, hydroxy, keto, .[.C 1  -C 18  alkyloxy,.]. aryloxy, .[.and.]. amino.Iadd., and C 1  -C 18  alkyloxy.Iaddend.; and   R4, R5, and R6 individually are selected from the group consisting of .[.C 1  -C 18  alkyl,.]. aryl, halo, .[.and.]. trifluoroalkyl.Iadd., and C 1  -C 18  alkyl.Iaddend..   
     
     
       2. The method of claim 1 wherein said pharmaceutically effective amount is sufficient to alleviate stress in said patient. 
     
     
       3. The method of claim 1 wherein said pharmaceutically effective amount is sufficient to alleviate anxiety in said patient. 
     
     
       4. The method of claim 1 wherein said pharmaceutically effective amount is sufficient to alleviate seizure activity in said patient. 
     
     
       5. The method of claim 1 wherein said pharmaceutically effective amount is from about 50 mg to about 500 mg per dosage unit. 
     
     
       6. A compound of the formula: ##STR28## wherein R1 is selected from the group consisting of hydroxyl, ##STR29## wherein R7, R8, and R9 are individually a C 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperdinyl, pyridinyl, furanyl, thiphenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and .[.pyrzinyl.]. .Iadd.pyrazinyl.Iaddend., and Y is --O-- or --S--; R2 is selected from the group consisting of OH, acetyl .[.2-hydroxyethanonyl.]. .Iadd.2-hydroxyethanoyl.Iaddend., 1-hydroxyethyl, ##STR30##  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 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain .[.alipahtic.]. .Iadd.aliphatic .Iaddend.radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic .[.radicla.]. .Iadd.radical.Iaddend., .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiophenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and pyrazinyl with the provisos that   (1) R10, R11, and R12 may also individually be an amide ##STR31##  radical wherein R16 and R17 individually are a C 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiophenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and pyrazinyl, and n=1 to 8 and   (2) R20 and R21 may also individually be .[.H.]. .Iadd.hydrogen .Iaddend.or ##STR32##  wherein R22 is .[.H or .]. .Iadd.hydrogen, .Iaddend.a C 1  -C 20  straight chain aliphatic radical, .[.C 1  .]. .Iadd.a C 3  .Iaddend.-C 20  branched chain aliphatic radical, .[.or.]. .Iadd.a .Iaddend.C 3  -C 10  cyclic aliphatic radical, .[.or C 3  .]. .Iadd.a C 6  .Iaddend.-C 10  aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, .[.piperidinyl, pyridinyl, furanyl, thiophenyl.]. .Iadd.piperidyl, pyridyl, furyl, thienyl.Iaddend., and pyrazinyl.[., and n is an integer of 1 to 8.].;   R3 is selected from the group consisting of hydrogen, hydroxy, keto, .[.C 1  -C 18  alkyloxy,.]. aryloxy, .[.and.]. amino.Iadd., and C 1  -C 18  alkyloxy.Iaddend.; and   R4, R5, and R6 individually are selected from the group consisting of .[.C 1  -C 18  alkyl,.]. aryl, halo, .[.and.]. trifluoroalkyl.Iadd., and C 1  -C 18  alkyl.Iaddend.;   except when .[.R1 is hydroxyl, R3 and.]. R6 .[.are each hydrogen,.]. .Iadd.is halo .Iaddend.and R4 and R5 are each CH 3 , then R2 is not acetyl.[.,2-hydroxyethanonyl, or 1-hydroxyethyl.]. .Iadd.or 2-hydroxyethanoyl and R3 is not β-hydroxyl.Iaddend..   
     
     
       7. A method of treating the symptoms of premenstrual syndrome and post natal depression comprising administering to a patient in need thereof a premenstrual syndrome or post nasal depression treating effective amount of a compound of claim 6. 
     
     
       8. The method of claim 7 wherein said effective amount is sufficient to maintain the amount of progesterone or its metabolites in a patient to whom such dosage is given at a level substantially equivalent to the level of progesterone or its metabolites prior to the onset of menses for the treatment of premenstrual syndrome, or prior to birth for the treatment of postnatal depression. 
     
     
       9. A method of treating the frequency and occurrence of convulsions comprising administering to a patient in need thereof a convulsion combatting effective amount of a compound of claim 6. 
     
     
       10. A method of modulating the excitability of neuron activity in animals comprising administering to an animal in need thereof a neuron activity excitability modulating effective amount of a compound of claim 6.