Therapeutic substituted guanidines

A method of treating nerve cell death, stroke, heart attack, brain or spinal cord trauma, brain or spinal cord ischemia or heart attack comprising administering to a mammal in need of such treatment an effective amount of a compound of the following formula I:

• ##STR10## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubsuituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently halogen, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyithio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof, with the exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidine and N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.

A method of inhibiting NMDA receptor-ion channel related neurotoxicity or susceptible thereto in a mammal exhibiting such neurotoxicity comprising administering to the mammal an effective amount of a compound of the following formula II:

• ##STR11## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
• and with at least one of R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being alkylsulfinyl or alkylsulfonyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof.

A method of treating nerve cell death, stroke, heart attack, brain or spinal cord trauma, brain or spinal cord ischemia or heart attack comprising administering to a mammal in need of such treatment an effective amount of a compound of the following formula II:

• ##STR12## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted allylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
• and with at least one of R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being alkylsulfinyl or alkylsulfonyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof.

A method of treating a mammal suffering from nerve cell degeneration resulting from hypoxia, hypoglycemia, brain or spinal cord ischemia or brain or spinal cord trauma, comprising administering to the mammal an effective amount of a compound of the following formula I:

• ##STR13## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently halogen, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof, with the exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidine and N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.

A method of treating a mammal undergoing surgery where neurological deficit is a potential complication, comprising administering to the mammal a treatment effective amount of the following formula I:

• ##STR14## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, to 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
• n is an integer of from 0-3;
• or a pharrnaccutically acceptable salt thereof, with the exclusion of N-(2,4-di-iodo-5-hydroxphenyl)-N'-(2-tolyl)-guanidine and N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.

A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto comprising administering to the mammal an effective amount of a compound of the following formula:

• ##STR18## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalcyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3 R.sup.4, and each R.sup.5 substituent are each independently nitro, cyano, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkanoyl, substituted or unsubstituted carboxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl, with at least one of R.sup.3, R.sup.4, R.sup.5 being nitro, cyano, substituted or unsubstituted alkanoyl or substituted or unsubstituted carboxyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof, with the exclusion of N-(2,4-di-iodo-5-hydxroxyphenyl)-N'-(2-tolyl)-guanidine and N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.

A method of treating a mammal suffering from nerve cell death, stroke, heart attack, brain or spinal cord trauma, brain or spinal cord ischemia comprising administering to the mammal a treatment effective amount of the following formula:

• ##STR19## wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
• R.sup.1 and R.sup.2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms;
• R.sup.3, R.sup.4, and each R.sup.5 substituent are each independently nitro, cyano, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkanoyl, substituted or unsubstituted carboxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl, with at least one of R.sup.3, R.sup.4, R.sup.5 being nitro, cyano, substituted or unsubstituted alkanoyl or substituted or unsubstituted carboxyl;
• n is an integer of from 0-3;
• or a pharmaceutically acceptable salt thereof, with the exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidine and N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.