Therapeutic guanidines

Abstract

The present invention provides therapeutically useful substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such guanidines.

1 . (canceled)  
     
     
         2 . A compound having the following Formula IA:  
       
         
           
           
               
               
           
         
       
       wherein 
 R and R 1  are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;  
 or pharmaceutically acceptable salts thereof  
 
     
     
         3 . A compound of  claim 2  wherein at least one of R and R 1  is substituted or unsubstituted carbocyclic aryl or substituted or unsubstituted aralkyl.  
     
     
         4 . A compound of  claim 2  selected from the group of: 
 N-(4-sec-butylphenyl)-N-benzylguanidine;    N-(5-acenaphthyl)-N-benzylguanidine;    N-(3-acenaphthyl)-N-benzylguanidine;    N-(5-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;    N-(3-acenaphthyl)-N-(4-isopropylbenzyl)guanidine;    N-(4-cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine;    N-(4-cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(2-fluorenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(4-sec-butylphenyl)-N-(cinnamylmethylene)guanidine;    N-(4-n-butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(3-biphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(5-indanyl)-N-(4-tert-butylbenzyl)guanidine;    N-(3-trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;    N-(3-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine;    N-(methoxy-1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;    N-(1-naphthyl)-N-(4-tert-butylbenzyl)guanidine;    N-(3-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(4-chloro-1-naphthyl)-N-(4-tert-benzyl)guanidine;    N-(4-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(4-iodophenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(1-naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine;    N-(5-acenaphthyl)-N-(3-phenoxybenzyl)guanidine;    N-(3-trifluoromethylphenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(3-methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine;    N-(5-acenaphthyl)-N-(3-iodobenzyl)guanidine;    N-(5-acenaphthyl)-N-(cinnamyl)guanidine;    N-(5-acenaphthyl)-N-(4-iodobenzyl)guanidine; and    N-(5-acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine,    or pharmaceutically acceptable salts thereof.    
     
     
         5 . A compound of the following Formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R is selected from the group consisting of fluorenyl, phenanthracenyl, anthracenyl and fluoranthenyl;  
 R 1  is substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, 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 heteroatoms;  
 R 2  and R 3  are each independently hydrogen or a group as defined for R 1  above;  
 or pharmaceutically acceptable salts thereof.  
 
     
     
         6 . A compound of  claim 5  wherein R 1  is substituted or unsubstituted carbocyclic aryl.  
     
     
         7 . A compound of  claim 5  selected from the group of: 
 N,N′-bis(2-fluorenyl)guanidine;    N,N′-bis(2-fluorenyl)-N-methylguanidine;    N,N′-bis(2-fluorenyl)-N,N′-dimethylguanidine;    N,N′-bis(anthracenyl)guanidine;    N,N′-bis(anthracenyl)-N-methylguanidine;    N,N′-bis(anthracenyl)-N,N′-dimethylguanidine;    N,N′-bis(phenanthracenyl)guanidine;    N,N′-bis(phenanthracenyl)-N-methylguanidine;    N,N′-bis(phenanthracenyl)-N,N′-dimethylguanidine;    N,N′-bis(fluoranthenyl)guanidine;    N,N′-bis(fluoroanthenyl)-N-methylguanidine;    N,N′-bis(fluoroanthenyl)-N,N′-dimethylguanidine;    N-(anthracenyl)-N′-(1-adamantyl)guanidine;    N-(anthracenyl)-N′-(1-adamantyl)-N-methylguanidine;    N-(anthracenyl)-N′-(1-adamantyl)-N′-methylguanidine;    N-(anthracenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;    N-(anthracenyl)-N′-(2-adamantyl)guanidine;    N-(anthracenyl)-N′-(2-adamantyl)-N-methylguanidine;    N-(anthracenyl)-N′-(2-adamantyl)-N′-methylguanidine;    N-(anthracenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;    N-(phenanthracenyl)-N′-(1-adamantyl)guanidine;    N-(phenanthracenyl)-N′-(1-adamantyl)-N-methylguanidine;    N-(phenanthracenyl)-N′-(1-adamantyl)-N′-methylguanidine;    N-(phenanthracenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;    N-(phenanthracenyl)-N′-(2-adamantyl)guanidine;    N-(phenanthracenyl)-N′-(2-adamantyl)-N-methylguanidine;    N-(phenanthracenyl)-N′-(2-adamantyl)-N′-methylguanidine;    N-(phenanthracenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;    N-(fluorenyl)-N′-(1-adamantyl)guanidine;    N-(fluorenyl)-N′-(1-adamantyl)-N-methylguanidine;    N-(fluorenyl)-N′-(1-adamantyl)-N′-methylguanidine;    N-(fluorenyl)-N′-(1-adamantyl)-N,N′-dimethylguanidine;    N-(fluorenyl)-N′-(2-adamantyl)guanidine;    N-(fluorenyl)-N′-(2-adamantyl)-N-methylguanidine;    N-(fluorenyl)-N′-(2-adamantyl)-N′-methylguanidine; and    N-(fluorenyl)-N′-(2-adamantyl)-N,N′-dimethylguanidine;    or pharmaceutically acceptable salts thereof.    
     
     
         8 - 10 . (canceled)  
     
     
         11 . A compound having the following Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein 
 each R is independently halo, hydroxy, amino, nitro, substituted or unsubstituted alkyl having from 3 to about 10 carbon atoms, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl having 3 to about 10 carbon atoms, or substituted or unsubstituted alkynyl having 3 to about 10 carbon atoms, at least one R group is a meta or para substituent;  
 n is an integer of from 1 to 5;  
 R 1  is substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted aryloxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least 5 ring atoms, substituted or unsubstituted aralkyl having at least 5 ring atoms, 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 heteroatoms;  
 R 2  and R 3  are each independently hydrogen or a group as defined for R 1  above; or R 2  and R 3  are taken together to form a substituted or unsubstituted alkylene linkage of from 2 to about 6 carbon atoms; and wherein said compound exhibits high inhibition of glutamate release;  
 or pharmaceutically acceptable salts thereof.  
 
     
     
         12 . A compound of  claim 11  selected from the group of: 
 N,N′-di-(4-sec-butylphenyl)guanidine;    N,N′-di-(4-sec-butylphenyl)-N-methylguanidine;    N,N′-di-(4-sec-butylphenyl)-N,N′-dimethylguanidine;    N-(2-naphthyl)-N′-(4-isopropylphenyl)guanidine;    N-(2-naphthyl)-N′-(4-isopropylphenyl)-N-methylguanidine;    N-(2-naphthyl)-N′-(4-isopropylphenyl)-N′-methylguanidine;    N-(2-naphthyl)-N′-(4-isopropylphenyl)-N,N′-dimethylguanidine;    N,N′-bis(4-tert-butylphenyl)guanidine;    N,N′-bis(4-tert-butylphenyl)-N-methylguanidine;    N,N′-bis(4-tert-butylphenyl)-N′-methylguanidine;    N,N′-bis(4-tert-butylphenyl)-N,N′-dimethylguanidine;    N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)guanidine;    N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N-methylguanidine;    N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N′-methylguanidine;    N-(4-sec-butylphenyl)-N′-(2,3,4-trichlorophenyl)-N,N′-dimethylguanidine;    N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)guanidine;    N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N-methylguanidine;    N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N′-methylguanidine;    N-(4-methoxy-1-naphthyl)-N′-(2,3,4-trichlorophenyl)-N,N′-dimethylguanidine;    N,N′-bis-(4-sec-butylphenyl)-2-iminopyrimidazolidine;    N,N′-bis(3-biphenyl)guanidine;    N,N′-bis(3-biphenyl)-N-methylguanidine;    N,N′-bis(3-biphenyl)-N′-methylguanidine;    N,N′-bis(3-biphenyl)-N,N′-dimethylguanidine;    N,N′-di-(3-tert-butylphenyl)guanidine;    N,N′-di-(3-tert-butylphenyl)-N-methylguanidine;    N,N′-di-(3-tert-butylphenyl)-N′-methylguanidine;    N,N′-di-(3-tert-butylphenyl)-N,N′-dimethylguanidine;    N,N′-bis-(4-methoxy-1-naphthyl)guanidine;    N,N′-bis-(4-methoxy-1-naphthyl)-N-methylguanidine;    N,N′-bis-(4-methoxy-1-naphthyl)-N′-methylguanidine;    N,N′-bis-(4-methoxy-1-naphthyl)-N,N′-dimethylguanidine;    N,N′-bis-(3-sec-butylphenyl)guanidine;    N,N′-bis-(3-sec-butylphenyl)-N-methylguanidine;    N,N′-bis-(3-sec-butylphenyl)-N′-methylguanidine;    N,N′-bis-(3-sec-butylphenyl)-N,N′-methylguanidine;    N,N′-bis(4-n-butylphenyl)-N-methylguanidine;    N,N′-bis(4-n-butylphenyl)-N′-methylguanidine;    N,N′-bis(4-n-butylphenyl)-N,N′-dimethylguanidine;    N,N′-(sec-butylphenyl)-N′-(n-pentyl)guanidine;    N,N′-bis(3-benzyloxyphenyl)guanidine;    N,N′-bis(3-benzyloxyphenyl)-N-methylguanidine;    N,N′-bis(3-benzyloxyphenyl)-N,N′-dimethylguanidine;    N,N′-bis(4-benzyloxyphenyl)guanidine;    N,N′-bis(4-benzyloxyphenyl)-N-methylguanidine;    N,N′-bis(4-benzyloxyphenyl)-N,N′-dimethylguanidine;    N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)guanidine;    N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N-methylguanidine;    N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N′-methylguanidine; and    N-(3-benzyloxyphenyl)-N′-(4-benzyloxyphenyl)-N,N′-dimethylguanidine;    or pharmaceutically acceptable salts thereof.    
     
     
         13 - 15 . (canceled)  
     
     
         16 . A method for treating a disorder of the nervous system in which the pathophysiology of the disorder involves excessive or inappropriate release of a neurotransmitter from neuronal cells comprising administering to a mammal exhibiting symptoms of said disorder or susceptible to said disorder an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         17 . A method for treating nerve cell death comprising administering to a mammal exhibiting symptoms of nerve cell death or susceptible to nerve cell death an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         18 . A method for treating a person who has suffered or is suffering from a stroke, or who is susceptible to a stroke, comprising administering to the person an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         19 . A method of treating a disease of the cardiovascular system comprising administering to a mammal suffering from or susceptible to a cardiovascular disease an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         20 . A method of modulating the release of excess endogenous neurotransmitters from a subject comprising administering to the subject an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         21 . A method for treating a disease in which the pathophysiology of the disease involves inappropriate cellular secretion comprising administering to a mammal suffering from or susceptible to said disease an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         22 . A method for 1) blocking voltage-activated calcium channels of mammalian neuronal cells; 2) blocking voltage-activated sodium channels of mammalian neuronal cells; 3) blocking voltage sensitive calcium channels of mammalian cardiac cells; 4) blocking voltage-activated sodium channels of mammalian cardiac cells; 5) blocking voltage-activated calcium channels of mammalian smooth or skeletal muscle cells; or 6) blocking voltage-activated sodium channels of mammalian smooth or skeletal muscle cells, comprising administering to said cells an effective amount of a compound of  claim 2 ,  5 , or  11 .  
     
     
         23 . A method for diagnosing a selected disease the pathophysiology of which involves ion-channel excitation or activity comprising administering to a mammal suffering from the disease a detection effective amount of a labeled compound of  claim 2 ,  5 , or  11 .  
     
     
         24 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 2 ,  5 , or  11  and a pharmaceutically acceptable carrier.