N,n'-di-1 naphthylguanidine hcl (nagh) and n,n'-di-p-nitrophenylguanidine hcl (nad) treatment for stroke at delayed timepoints

Abstract

A composition and method of treating stroke by administration of a novel sigma agonist is presented. Twenty-four hours after MCAO, systemic administration of several novel sigma agonists including: Bromo-DTG; Chloro-DTG; N,N′-di-1-Naphthylguanidine hydrochloride (NAGH); N,N′-di-p-Nitrophenylguanidine HCL (NAD) or vehicle were injected subcutaneously daily for 3 days. Rats treated with Bromo-DTG and Chloro-DTG had no significant improvements in any of the motor or cognitive tests while NAGH treated rats showed improved vertical movement and had significantly less motor asymmetry and bias than vehicle treated rats. Sigma receptor agonist NAGH also was found to exert its long-term neuroprotective effects by preserving both gray matter and white matter tracts. Both NAD and NAGH, when administered 24 hours after experimental stroke, reduced neural damage and enhanced behavioral recovery thirty days later which suggests that NAGH and NAD potentially extend the therapeutic window of stroke several fold over the current treatments.

What is claimed is: 
     
         1 . A method of treating stroke at a delayed timepoint comprising:
 administering a therapeutically effective amount of a sigma agonist selected from the group consisting of N,N′-di-1-Naphthylguanidine hydrochloride (NAGH) or N,N′-di-p-Nitrophenylguanidine hydrochloride (NAD) to a patient in need thereof.   
     
     
         2 . The method of  claim 1 , wherein the sigma agonist is administered at least 12 hours after stroke. 
     
     
         3 . The method of  claim 1 , wherein the sigma agonist is NAGH. 
     
     
         4 . The method of  claim 3 , wherein the therapeutically effective amount is between about 0.86 mg/kg and 8.6 mg/kg. 
     
     
         5 . The method of  claim 4 , wherein the NAGH is administered at least once per day. 
     
     
         6 . The method of  claim 5 , wherein the NAGH is administered for at least 3 days 
     
     
         7 . The method of  claim 1 , wherein the sigma agonist is NAD. 
     
     
         8 . The method of  claim 7 , wherein the therapeutically effective amount is between about 2.8 mg/kg and 8.6 mg/kg. 
     
     
         9 . The method of  claim 8 , wherein the NAD is administered at least once per day. 
     
     
         10 . The method of  claim 9 , wherein the NAD is administered for at least 3 days. 
     
     
         11 . A method of reducing infarct volume long term in a patient suffering from a neurological disorder comprising:
 administering a therapeutically effective amount of a sigma agonist selected from the group consisting of N,N′-di-1-Naphthylguanidine hydrochloride (NAGH) or N,N′-di-p-Nitrophenylguanidine hydrochloride (NAD) to a patient in need thereof   
     
     
         12 . The method of  claim 11 , wherein the neurological disorder is stroke. 
     
     
         13 . The method of  claim 11 , wherein the sigma agonist is administered at least 12 hours after stroke. 
     
     
         14 . The method of  claim 11 , wherein the sigma agonist is NAGH. 
     
     
         15 . The method of  claim 14 , wherein the therapeutically effective amount is between about 0.86 mg/kg and 8.6 mg/kg. 
     
     
         16 . The method of  claim 15 , wherein the NAGH is administered at least once per day. 
     
     
         17 . The method of  claim 16 , wherein the NAGH is administered for at least 3 days. 
     
     
         18 . The method of  claim 11 , wherein the sigma agonist is NAD. 
     
     
         19 . The method of  claim 18 , wherein the therapeutically effective amount is between about 2.8 mg/kg and 8.6 mg/kg. 
     
     
         20 . The method of  claim 19 , wherein the NAD is administered at least once per day. 
     
     
         21 . A compound comprising formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 3  are cyclic compounds selected from the group consisting of phenyl and naphthyl; 
         wherein R 2  and R 4  are selected from the group consisting of Cl, Br, hydrogen, and NO 2 ; 
         or a salt thereof. 
       
     
     
         22 . The compound of  claim 21 , wherein the composition is selected from the group consisting of N,N′-di-1-Naphthylguanidine (NAGH), N,N′-di-p-Nitrophenylguanidine (NAD), N,N′ -di-p-Bromophenylguanidine (Bromo-DTG), N,N′-di-m-Chlorophenylguanidine (Chloro-DTG), and salts thereof 
     
     
         23 . The compound of  claim 21 , wherein R 1  and R 3  are both phenyl. 
     
     
         24 . The compound of  claim 23 , wherein R 2  and R 4  are both Cl. 
     
     
         25 . The compound of  claim 24 , wherein each Cl group is meta to the guanidine group. 
     
     
         26 . The compound of  claim 23 , wherein the R 2  and R 4  are both Br. 
     
     
         27 . The compound of  claim 26 , wherein each Br group is para to the guanidine group. 
     
     
         28 . The compound of  claim 23 , wherein the R 2  and R 4  are both NO 2 . 
     
     
         29 . The compound of  claim 28 , wherein each NO 2  group is para to the guanidine group. 
     
     
         30 . The compound of  claim 21 , wherein the compound comprises formula (II): 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         31 . The compound of  claim 21 , wherein R 1  and R 3  are both napthyl. 
     
     
         32 . The compound of  claim 32 , wherein R 2  and R 4  are hydrogen. 
     
     
         33 . The compound of  claim 21 , wherein the compound comprises formula (III): 
       
         
           
           
               
               
           
         
         or a salt thereof.