Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers

A method for treating or preventing nerve cell death comprising the administration to a mammal exhibiting symptoms of nerve cell death or susceptible to nerve cell death, an effective amount of a compound having the formula:

• ##STR27## or a tautomer thereof, wherein R and R.sup.1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, carbocyclic aryl, alkaryl, aralkyl or heterocyclic, X.sup.3 and X.sup.4 are the same or different and are selected from the group consisting of hydrogen, hydroxy, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C.sub.2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido;
• wherein R and R.sup.1 are optionally substituted by hydroxy, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C.sub.2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido;
• x and y are the same or different and are 0, 1, 2, 3 or 4.

A method for treating or preventing a disease of the nervous system in which the pathophysiology of the disorder involves excessive release of a neurotransmitter from neuronal cells comprising the administration to a mammal exhibiting symptoms of such disorders or susceptible to such disorders, an effective amount of a compound having the formula:

• ##STR28## or a tautomer thereof, wherein R, R.sup.1, R.sup.4 and R.sup.5 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, carbocyclic aryl, alkaryl, aralkyl or heterocyclic;
• wherein R, R.sup.1, R.sup.4 or R.sup.5 are each optionally substituted by hydroxy, acetate, oxo, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C.sub.2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, sulfonato or carbamido.

A method for treating or preventing a disease of the nervous system in which the pathophysiology of the disorder involves excessive release of a neurotransmitter from neuronal cells comprising the administration to a mammal exhibiting symptoms of such disorders or susceptible to such disorders, an effective amount of a compound having the formula:

• ##STR29## or a tautomer thereof, wherein R and R.sup.1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, carbocyclic aryl, alkaryl, aralkyl or heterocyclic, X.sup.3 and X.sup.4 are the same or different and are selected from the group consisting of hydrogen, hydroxy, acetate, oxo, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C.sub.2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, sulfonato or carbamido;
• wherein R and R.sup.1 are optionally substituted by hydroxy, acetate, oxo, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C.sub.2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido;
• x and y are the same or different and are 0, 1, 2, 3 or 4.

A method of treating or preventing a disease selected from the group consisting of Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's diease, olivopontocerebellar atrophy, HIV-induced dementia, HIV-induced blindness, or multi-infarct demetia, the method comprising administering to a mammal exhibiting symptoms of said disease or susceptible to said disease an effective of a compound having the formula:

• ##STR30## or a tautomer thereof, wherein R, R.sup.1, R.sup.4 and R.sup.5 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, carbocyclic aryl, alkaryl, aralykl or heterocyclic, wherein R, R.sup.1, R.sup.4 and R.sup.5 may be optionally substituted by hydroxy, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido.

A method of treating or preventing a disease selected from the group consisting of Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's diease, olivopontocerebellar atrophy, HIV-induced dementia, HIV-induced blindness, or multi-infarct demetia, the method comprising administering to a mammal exhibiting symptoms of said disease or susceptible to said disease an effective of a compound having the formula:

• ##STR31## or a tautomer thereof, wherein R and R.sup.1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, carbocyclic aryl, alkaryl, aralkyl or heterocyclic, X.sup.3 and X.sup.4 are the same or different and are selected from the group consisting of hydrogen, hydroxy, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido;
• wherein R and R.sup.1 may be optionally substituted by hydroxy, amino, lower C.sub.1-6 alkyl, lower C.sub.1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, or carbamido;
• x and y are the same or different and are 0, 1, 2, 3 or 4.