Agent for treatment of cerebral ischemic diseases

Abstract

A pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases, which comprises two components, i.e. an astrocyte function-improving agent, preferably a compound represented by the formula (I): (wherein R 6 is hydroxy, etc., (1) n is 1, R 11 is hydrogen and R 5 is (alkyl of which one carbon atom is substituted by fluorine)—CH 2 — or (2) n is 0 or 1, R 11 is hydrogen, etc., and R 5 is alkyl, etc.) and a thrombolytic agent, preferably tissue plasminogen activator, as active ingredients. The pharmaceutical composition of the present invention exhibits a synergistic therapeutic effect compared to independent administration of an astrocyte function-improving agent and a thrombolytic agent.

1 . A pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases, which comprises an astrocyte function-improving agent and a thrombolytic agent as active ingredients.  
     
     
         2 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in  claim 1 , wherein the astrocyte function-improving agent is a compound represented by the formula (I):  
       
         
           
           
               
               
           
         
         wherein R 6  is hydroxy, C1-4 alkoxy, C1-4 alkoxy substituted by one phenyl group, or NR 9 R 10    
         in which R 9  and R 10  are independently 
 (i) hydrogen,  
 (ii) C1-4 alkyl,  
 (iii) phenyl,  
 (iv) phenyl substituted by C1-4 alkoxy or carboxy  
 (v) 4- to 7-membered heterocycle comprising one nitrogen atom,  
 (vi) C1 -4 alkyl substituted by (a) phenyl, (b) phenyl substituted by C1-4 alkoxy or carboxyl or (c) 4- to 7-membered heterocycle comprising one nitrogen atom,  
 (vii) 4- to 7-membered heterocycle comprising one or two nitrogen atoms or 4- to 7-membered heterocycle comprising one nitrogen atom and one oxygen atom, when taken together with the nitrogen atom bonded to R 9  and R 10 , or  
 (viii) amino acid residue, when taken together with the nitrogen atom bonded to R 9  and R 10 ;  
 
         n, R 11  and R 5  are  
         (1) n is 1; R 11  is hydrogen;  
         R 5  is (C1-10 alkyl of which one carbon atom is substituted by one to three fluorine atoms)—CH 2 —, wherein R 5  does not represent —(CH 2 ) 5 —, F—(CH 2 ) 6 —, F—(CH 2 ) 7 — or F 3 C—(CH 2 ) 2 —, or  
         (2) n is 0 or 1;  
         R 11  is hydrogen or chlorine;  
         R 5  is: 
 C3-10 alkyl,  
 C3-10 alkenyl,  
 C2-10 alkoxy,  
 C2-10 alkylthio,  
 C3-7 cycloalkyl,  
 phenyl,  
 phenoxy,  
 F—(CH 2 ) m — (m is an integer of 5 to 7), F 3 C—(CH 2 ) 2 —,  
 (C2-10 alkyl substituted by one or two chlorine atoms)—CH 2 —,  
 (C1-5 alkyl substituted by one or two substituents selected from the group consisting of C1-4 alkoxy, C3-7 cycloalkyl, phenyl and phenoxy)—CH 2 —; or  
 
         R 5  and R 11 , taken together, are C3-10 alkylidene, or a non-toxic salt or hydrate thereof.  
       
     
     
         3 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in  claim 1  or  2 , wherein the astrocyte function-improving agent is (R)-2-propyloctanoic acid, and a non-toxic salt or hydrate thereof.  
     
     
         4 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in any one of  claims 1  to  3 , wherein the thrombolytic agent is tissue plasminogen activator or urobilinogen.  
     
     
         5 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in any one of  claims 1  to  4 , wherein the thrombolytic agent is tissue plasminogen activator.  
     
     
         6 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in any one of  claims 1  to  5 , wherein the cerebral ischemic disease is cerebral infarction, cerebral hemorrhage, subarachnoid hemmorhage or white matter disorders.  
     
     
         7 . The pharmaceutical composition for the treatment and/or prevention of cerebral ischemic diseases as claimed in any one of  claims 1  to  5 , wherein the cerebral ischemic disease is cerebral infarction.  
     
     
         8 . A pharmaceutical composition for the treatment and/or prevention of cerebral infarction, which comprises (R)-2-propyloctanoic acid or a non-toxic salt or hydrate thereof as an astrocyte function-improving agent and tissue plasminogen activator as a thrombolytic agent.  
     
     
         9 . A method for treating cerebral ischemic diseases, which comprises simultaneously administering an astrocyte function-improving agent and a thrombolytic agent.  
     
     
         10 . A method for treating cerebral ischemic diseases, which comprises administering an astrocyte function-improving agent after the administration of a thrombolytic agent.