N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists

A neuroprotecting asymmetrical N,N'-disubstituted guanidine which exhibits a high binding activity with respect to the PCP receptor in the NMDA receptor-channel complex and is selected from the group consisting of N-(1-naphthyl)-N'-(o-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(m-isopropylphenyl)guanidine, N-(1-naphthyl)-N'-(m-methoxyphenyl)guanidine, N-(1-naphthyl)-N'-(4-indanyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine, N-(m-ethylphenyl)-N'-(o-iodophenyl)guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)-guanidine, N-(m-ethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-methoxyphenyl)guanidine, N-(m-ethylphenyl)-N'-(4-indanyl)guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-tolyl)guanidine, N-(o-ethylphenyl)-N'-(o-iodophenyl)guanidine, N-(o-ethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-isopropylphenyl)-guanidine, N-(o-ethylphenyl)-N'-(m-methoxyphenyl)guanidine, N-(o-ethylphenyl)-N'-(4-indanyl)guanidine, N-(o-ethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-tolyl)guanidine, N-(o-iodophenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-methoxyphenyl)-guanidine, N-(o-iodophenyl)-N'-(4-indanyl)guanidine, N-(o-iodophenyl)-N'-(o-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-ethylphenyl)-guanidine, N-(o-isopropylphenyl)-N'-(m-tolyl)guanidine, N-(o-isopropylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-isopropyl-phenyl)-N'-(m-methoxyphenyl)guanidine, N-(o-isopropylphenyl)-N'-(4-indanyl)guanidine, N-(o-isopropylphenyl)-N'-(o-ethylphenyl)guanidine, N-(o-isopropylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-isopropylphenyl)-N'-(m-tolyl)guanidine, N-(m-isopropylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(m-isopropylphenyl)-N'-(4-indanyl)guanidine, N-(m-isopropylphenyl)-N'-(o-ethylphenyl)-guanidine, N-(m-isopropylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-methoxyphenyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(4-indanyl)guanidine, N-(4-indanyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine, N-(2,4-di-iodo-5-hydroxyphenyl)-N'(2-tolyl)guanidine, N-(1-naphthyl)-N'-(3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-nitro-3-ethylphenyl)-guanidine, N-(1-naphthyl)-N'-[3-(1-hydroxy-ethyl)phenyl]guanidine, N-(4-fluoronaphthyl)-N'-(3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-tolyl)guanidine, N-(1-naphthyl)-N'-(3-trifluoromethylphenyl)guanidine, N-(m-trifluoromethyl-phenyl)-N'-(m-tolyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(o-isopropylphenyl)-guanidine, N-(m-trifluoromethylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-methoxy-phenyl)guanidine, N-(m-trifluoromethylphenyl)-N' -(4-indanyl)guanidine, N-(m-trifluoromethyl-phenyl)-N'-(o-ethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;

• N-(7-fluoronaphthyl)-N'-(3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(1-naphthyl)-N'-(4-fluoro-2-isopropyl-phenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4fluoro-2-isopropylphenyl)-guanidine;
• N-(4-fluoronaphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(6-methoxy-4-fluoro-3-ethyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(1-naphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(coumarin-8-yl)-N-(3-ethylphenyl)-guanidine;
• N-(coumarin-8-yl)-N'-(3-tolyl)guanidine;
• N-(quinolin-8-yl)-N'-(3-ethylphenyl)guanidine and N-(quinolin-8-yl)-N'-(3-tolyl)guanidine;
• or a physiologically acceptable salt thereof.

A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal a symmetrical N,N'-disubstituted guanidine selected from the group consisting of N,N'-Bis(3-trifluoromethylphenyl)guanidine, N,N'-Bis(4-fluoro-3-ethylphenyl) guanidine;

• N,N'-Bis(3,5-diethylphenyl)guanidine;
• N,N'-Bis(3-nitrophenyl)guanidine;
• N,N'-Bis(4-fluoro-3-nitrophenyl)guanidine;
• N,N'-Bis(3-nitro-5-ethylphenyl)guanidine;
• N,N'-Bis(3-azidophenyl)guanidine;
• N,N'-Bis(quinolin-8-yl)guanidine and N,N'-Bis(coumarin-8-yl)guanidine;
• or a physiologically acceptable salt thereof;
• wherein said N,N'-disubstituted guanidine possesses a high affinity for the PCP receptor of a nerve cell, and wherein said N,N'-disubstituted guanidine is administered in an amount effective to inhibit the neurotoxicity.

A method of inhibiting NMDA receptor-ion channel related neurotoxicity in a mammal exhibiting such neurotoxicity or susceptible thereto, comprising administering to the mammal exhibiting such neurotoxicity or susceptible thereto an effective ammount of an asymmetrical N,N'-disubstituted guanidine selected from the group consisting of N-(1-naphthyl)-N'-(o-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(m-isopropylphenyl)guanidine,N-(1-naphthyl)-N'-(m-methox yphenyl)-guanidine, N-(1-naphthyl)-N'-(4-indanyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine,N-(m-ethylphenyl)-N'-(o-iodophenyl )guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(o-isopropylphenyl)-guanidine, N-(m-ethylphenyl)-N'-(m-isopropylphenyl) guanidine, N-(m-ethylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(m-ethylphenyl)-N'-(4-indanyl)guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-tolyl)guanidine, N-(o-ethylphenyl)-N'-(o-iodophenyl)guanidine, N-(o-ethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-isopropylphenyl)-guanidine, N-(o-ethylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(o-ethylphenyl)-N'-(4-indanyl)guanidine, N-(o-ethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-tolyl)-guanidine, N-(o-iodophenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-methoxyphenyl)-guanidine, N-(o-iodophenyl)-N'-(4-indanyl)guanidine, N-(o-iodophenyl)-N'-(o-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-ethylphenyl)-guanidine, N-(o-isopropylphenyl)-N'-(m-tolyl)guanidine, N-(o-isopropylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-isopropylphenyl)-N'-(m-methoxyphenyl)guanidine,N-(o-isopropylphenyl)- N'-(4-indanyl)guanidine, N-(o-isopropylphenyl)-N'-(o-ethylphenyl)guanidine, N-(o-isopropylphenyl)-N' -(m-ethylphenyl)guanidine, N-(m-isopropylphenyl)-N'-(m-tolyl)guanidine, N-(m-isopropylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(m-isopropylphenyl)-N'-(4-indanyl)guanidine, N-(m-isopropylphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-isopropylphenyl)-N'-(m-ethylphenyl)-guanidine, N-(m-methoxyphenyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(4-indanyl)guanidine, N-(4-indanyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine,N-(2,4-di-iodo-5-hydroxyphenyl)-N' (2-tolyl)guanidine, N-(1-naphthyl)-N'-(3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-nitro-3-ethylphenyl)-guanidine, N-(1-naphthyl)-N'-[3-(1-hydroxyethyl)phenyl]-guanidine, N-(4-fluoronaphthyl)-N'-(3-ethyl-phenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-tolyl)guanidine, N-(1-naphthyl)-N'-(3-trifluoromethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-tolyl)-guanidine, N-(m-trifluoromethyl-phenyl)-N'-(o-isopropylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-methoxyphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(4-indanyl)-guanidine, N-(m-trifluoromethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(o-iodophenyl)guanidine,N-(1-naphthyl)-N'-( 4-fluoro-3-trifluoromethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;

• N-(7-fluoronaphthyl)-N'-(3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(1-naphthyl)-N'-(4-fluoro-2-isopropylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-2-isopropylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N' -(6-methoxy-3-ethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(6-methoxy-4-fluoro-3-ethyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;N-(1-n aphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(coumarin-8-yl)-N-(3-ethylphenyl)-guanidine;
• N-(coumarin-8-yl)-N'-(3-tolyl)guanidine;
• N-(quinolin-8-yl)-N'-(3-ethylphenyl)guanidine and N-(quinolin-8-yl)-N'-(3-tolyl)guanidine;
• or a pharmaceutically acceptable salt thereof, wherein said N,N'-disubstituted guanidine possesses a high affinity for the PCP receptor of a nerve cell.

A method for treating a disease of the nervous system in which the pathophysiology of the disorder involves excessive excitation of nerve cells by agonists of NMDA receptors comprising the administration to a mammal exhibiting symptoms of such disorders or susceptible to such disorders, a symmetrical N,N'-disubstituted guanidine selected from the group consisting of N,N'-Bis(3-trifluoromethylphenyl)guanidine, N,N'-Bis(4-fluoro-3-ethylphenyl)guanidine;

• N,N'-Bis(3,5-diethylphenyl) guanidine;
• N,N'-Bis(3-nitrophenyl)guanidine;
• N,N'-Bis(4-fluoro-3-nitrophenyl)guanidine;
• N,N'-Bis(3-nitro-5-ethylphenyl)guanidine;
• N,N'-Bis(3-azidophenyl)guanidine;
• N,N'-Bis(quinolin-8-yl)guanidine and N,N'-Bis(coumarin-8-yl)guanidine;
• or a physiologically acceptable salt thereof;
• wherein said N,N'-disubstituted guanidine possesses a high affinity for the PCP receptor of a nerve cell, and wherein said N,N'-disubstituted guanidine is administered in an amount effective to treat said disease.

A method for treating a disease of the nervous system in which the pathophysiology of the disorder involves excessive excitation of nerve cells by agonists of NMDA receptors comprising the administration to a mammal exhibiting symptoms of such disorders or is susceptible to such disorders, an effective amount of an asymmetrical N,N'-disubstituted guanidine selected from the group consisting of N-(1-naphthyl)-N'-(o-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(m-isopropylphenyl)guanidine, N-(1-naphthyl)-N'-(m-methoxyphenyl)guanidine. N-(1-naphthyl)-N'-(4-indanyl)guanidine, N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine,N-(m-ethylphenyl)-N'-(o-iodophenyl )-guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)-guanidine, N-(m-ethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(m-ethylphenyl)-N'-(4-indanyl)guanidine, N-(m-ethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-tolyl)guanidine,N-(o-ethylphenyl)-N'-(o-iodophenyl )guanidine, N-(o-ethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-ethylphenyl)-N'-(m-isopropylphenyl)-guanidine, N-(o-ethylphenyl)-N'-(m-methoxyphenyl)guanidine, N-(o-ethylphenyl)-N'-(4-indanyl)guanidine, N-(o-ethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-tolyl)guanidine, N-(o-iodophenyl)-N'-(o-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-methoxyphenyl)-guanidine, N-(o-iodophenyl)-N'-(4-indanyl)guanidine, N-(o-iodophenyl)-N'-(o-ethylphenyl)guanidine, N-(o-iodophenyl)-N'-(m-ethylphenyl)-guanidine, N-(o-isopropylphenyl)-N'-(m-tolyl)guanidine, N-(o-isopropylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(o-isopropylphenyl)-N'-(m-methoxyphenyl)guanidine, N-(o-isopropylphenyl)-N'-(4-indanyl)guanidine,N-(o-isopropylphenyl)-N'-(o- ethylphenyl)guanidine, N-(o-isopropylphenyl)-N'-(m-ethylphenyl)guanidine,N-(m-isopropylphenyl)-N' -(m-tolyl)guanidine, N-(m-isopropylphenyl)-N'-(m-methoxyphenyl)-guanidine, N-(m-isopropylphenyl)-N'-(4-indanyl)guanidine, N-(m-isopropylphenyl)-N'-(o-ethylphenyl)-guanidine, N-(m-isopropylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-methoxyphenyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(4-indanyl)guanidine, N-(4-indanyl)-N'-(m-tolyl)guanidine, N-(m-methoxyphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-ethylphenyl)-N'-(m-tolyl)guanidine,N-(2,4-di-iodo-5-hydroxyphenyl)-N' (2-tolyl)guanidine, N-(1-naphthyl)-N'-(3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-nitro-3-ethylphenyl)-guanidine, N-(1-naphthyl)-N'-[3-(1-hydroxyethyl)phenyl]guanidine, N-(4-fluoronaphthyl)-N'-(3-ethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-tolyl)guanidine, N-(1-naphthyl)-N'-(4-bromo-3-tolyl)guanidine, N-(1-naphthyl)-N'-(3-trifluoromethylphenyl)guanidine, N-(m-trifluoromethyl-phenyl)-N'-(m-tolyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(o-isopropylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-isopropylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-methoxy-phenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(4-indanyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(o-ethylphenyl)guanidine, N-(m-trifluoromethylphenyl)-N'-(m-ethylphenyl)guanidine, N-(m-trifluoro-methylphenyl)-N'-(o-iodophenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine, N-(1-naphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;

• N-(7-fluoronaphthyl)-N'-(3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(2-isopropylphenyl)guanidine;
• N-(1-naphthyl)-N'-(4-fluoro-2-isopropyl-phenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-2-isopropylphenyl)-guanidine;
• N-(4-fluoronaphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(6-methoxy-3-ethylphenyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(6-methoxy-4-fluoro-3-ethyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-tolyl)guanidine;
• N-(4-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(1-naphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(7-fluoronaphthyl)-N'-(4-fluoro-3-trifluoromethylphenyl)guanidine;
• N-(coumarin-8-yl)-N-(3-ethylphenyl)-guanidine;
• N-(coumarin-8-yl)-N'-(3-tolyl)guanidine;
• N-(quinolin-8-yl)-N'-(3-ethylphenyl)guanidine and N-(quinolin-8-yl)-N'-(3-tolyl)guanidine having a high affinity for the PCP receptor of the NMDA receptor-channel complex.