Compounds having triple activities of thrombolysis, antithrombotic and radical scavenging

Abstract

wherein the definitions of T, Q, R1 and R2 are described herein. The compound of the present invention simultaneously has triple functions of thrombolysis, free radical scavenging and thrombus-targeting/antithrombosis. The present invention also relates to a pharmaceutical composition comprising the compound, and a preparation method and a nanostructure of the compound.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein T represents a linking arm having at least two groups for linking; 
         Q represents a peptide having thrombolytic activity; and 
         R 1  and R 2  represent C 1-4  alkyl groups, wherein R 1  and R 2  are the same or different. 
       
     
     
         2 . The compound of  claim 1 , wherein at least one of the groups for linking is an amino group and the remaining groups for linking are carboxyl groups or amino groups. 
     
     
         3 . The compound of  claim 2 , wherein the linking arm is L-Lys, L-Asp, or L-Glu. 
     
     
         4 . The compound of  claim 1 , wherein the peptide having thrombolytic activity is selected from a group consisting of an oligopeptide containing a PA (Pro-Ala) sequence, a PAK (Pro-Ala-Lys) sequence, an AKP (Ala-Lys-Pro) sequence or a KAP (Lys-Ala-Pro) sequence, and a peptide having repeated units of the PAK sequence, the AKP sequence or the KAP sequence. 
     
     
         5 . The compound of  claim 4 , wherein the oligopeptide having the PA (Pro-Ala) sequence is a tripeptide having the following formula Q1 or Q2:
   Pro-Ala-AA  (Q1)
     AA-Ala-Pro  (Q2)
   wherein AA is selected from a group consisting of L-Ala, L-Val, L-Trp, L-Tyr, L-Pro, L-Phe, Gly, L-Ser, L-Ile, L-Thr, L-Lys, L-Leu, L-Gln, L-Asn, L-Asp, and L-Glu.   
     
     
         6 . The compound of  claim 1 , wherein R 1  and R 2  both are methyl groups. 
     
     
         7 . The compound of  claim 6 , wherein the linking arm is L-Lys, L-Asp, or L-Glu, and the peptide having thrombolytic activity is a tripeptide having a PA (Pro-Ala) sequence. 
     
     
         8 . The compound of  claim 7 , wherein the compound having the following formula Ia, Ib, Ic, Id, Ie, If, Ig, or Ih: 
       
         
           
           
               
               
           
         
         wherein AA is selected from a group consisting of L-Ala, L-Val, L-Trp, L-Tyr, L-Pro, L-Phe, Gly, L-Ser, L-Ile, L-Thr, L-Lys, L-Leu, L-Gln, L-Asn, L-Asp, and L-Glu. 
       
     
     
         9 . A pharmaceutical composition, comprising the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the compound is in the form of a nanospherical structure. 
     
     
         11 . A method for performing thrombolysis, NO free radical scavenging or antithrombotic therapy in a subject, comprising administrating to the subject an effective amount of the pharmaceutical composition of  claim 9 . 
     
     
         12 . A method of treating stroke or cerebral infarction, comprising administrating to a subject in need an effective amount of the pharmaceutical composition of  claim 9 . 
     
     
         13 . A preparation method of the compound having the formula I of  claim 1 , comprising the following steps:
 (1) providing a compound having the following formula II:   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  represent C 1-4  alkyl groups, and R 1  and R 2  are the same or different; 
         (2) providing the linking arm T having at least two groups for linking, and the peptide Q having thrombolytic activity, wherein the linking arm having a first group for linking and a second group for linking; 
         (3) coupling the carboxyl group of the compound having the formula II with the first group for linking of the linking arm T to form a compound having the following formula IM-1: 
       
       
         
           
           
               
               
           
         
         under an appropriate reaction condition; and 
         (4) coupling the peptide Q having thrombolytic activity with the compound having the formula IM-1 under an appropriate reaction condition, wherein one terminal of the peptide Q having thrombolytic activity is coupled to the second group for linking of the linking arm T to form the compound having the formula I. 
       
     
     
         14 . The preparation method of  claim 13 , wherein the first group for linking is an amino group, and the second group for linking is a carboxyl group or an amino group. 
     
     
         15 . The preparation method of  claim 14 , wherein the linking arm is L-Lys, L-Asp, or L-Glu. 
     
     
         16 . The preparation method of  claim 13 , wherein the peptide having thrombolytic activity is selected from a group consisting of an oligopeptide having a PA (Pro-Ala) sequence, a PAK (Pro-Ala-Lys) sequence, an AKP (Ala-Lys-Pro) sequence or a KAP (Lys-Ala-Pro) sequence, and a peptide having repeated units of the PAK sequence, the AKP sequence or the KAP sequence. 
     
     
         17 . The preparation method of  claim 16 , wherein the oligopeptide having the PA (Pro-Ala) sequence is a tripeptide having the following formula Q1 or Q2:
   Pro-Ala-AA  (Q1)
     AA-Ala-Pro  (Q2)
   wherein AA is selected from a group consisting of L-Ala, L-Val, L-Trp, L-Tyr, L-Pro, L-Phe, Gly, L-Ser, L-Ile, L-Thr, L-Lys, L-Leu, L-Gln, L-Asn, L-Asp, and L-Glu.   
     
     
         18 . The preparation method of  claim 13 , wherein R 1  and R 2  both are methyl groups.