Compounds having triple activities of thrombolysis, antithrombotic and radical scavenging

Abstract

The present invention relates to a compound simultaneously having triple activities of thrombolysis, antithrombosis and free radical scavenging, as well as the preparation method, composition, and applications thereof. The compound is represented by the formula I shown below: wherein the definitions of T, Q, R 1 and R 2 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.