Novel reagents and method for conjugating biological molecules

Abstract

A compound of the general formula X—[NR—CO—Ar—CO—(CH═CH) n —(CH 2 ) 2 -L] m (I) in which X represents a polymer; R represents a hydrogen atom or an alkyl, aryl or alkyl-aryl group; Ar represents an unsubstituted or substituted heteroaryl or aryl group; n represents 0 or an integer of from 1 to 4; L represents a leaving group; and m represents an integer of from 1 to 8. The compounds find use in the conjugation of biological molecules.

1 . A compound of the general formula:
   X—[NR—CO—Ar—CO—(CH═CH) n —(CH 2 ) 2 -L] m   (I)
   in which X represents a polymer; R represents a hydrogen atom or an alkyl, aryl or alkyl-aryl group; Ar represents an unsubstituted or substituted heteroaryl or aryl group; n represents 0 or an integer of from 1 to 4; L represents a leaving group; and m represents an integer of from 1 to 8.   
     
     
         2 . A compound as claimed in  claim 1 , in which X is a polyalkylene glycol, polyvinylpyrrolidone, polyacrylate, polymethacrylate, polyoxazoline, polyvinylalcohol, polyacrylamide, polymethacrylamide, HPMA copolymer, polyester, polyacetal, poly(ortho ester), polycarbonate, poly(imino carbonate), polyamide, copolymer of divinylether-maleic anhydride and styrene-maleic anhydride, polysaccharide, or protein. 
     
     
         3 . A compound as claimed in  claim 2 , in which X is a polyalkylene glycol. 
     
     
         4 . A compound as claimed in  claim 3 , in which X is a polyethylene glycol. 
     
     
         5 . A compound as claimed in  claim 1 , in which n is 0. 
     
     
         6 . A compound as claimed in  claim 1 , in which L represents —SR′, —SO 2 R′, —OSO 2 R′, —N + R′ 3 , —N + HR′ 2 , —N + H 2 R′, halogen, or —OØ, in which R′ represents a hydrogen atom or an alkyl, aryl or alkyl-aryl group and Ø represents a substituted aryl group containing at least one electron withdrawing substituent. 
     
     
         7 . A compound as claimed in  claim 6 , in which L represents —SO 2 R′ in which R′ represents a p-tolyl group. 
     
     
         8 . A compound as claimed in  claim 7 , in which X is a polyethylene glycol. 
     
     
         9 . A compound as claimed in  claim 1 , in which Ar represents a phenyl group optionally-substituted by one or more of the same or different substituents selected from the group consisting of alkyl, —CN, —NO 2 , —CO 2 R″, —COH, —CH 2 OH, —COR″, —OR″, —OCOR″, —OCO 2 R″, —SR″, —SOR″, —SO 2 R″, —NHCOR″, —NR″COR″, —NHCO 2 R″, —NR″.CO 2 R″, —NO, —NHOH, —NR″.OH, —C═N—NHCOR″, —C═N—NR″.COR″, —N + R″ 3 , —N + H 3 , —N + HR″ 2 , —N + H 2 R″, halogen, —C≡CR″, —C═CR″ 2 , and —C═CHR″, in which each R″ independently represents a hydrogen atom or an alkyl, aryl, or alkyl-aryl group. 
     
     
         10 . A compound as claimed in  claim 9 , in which Ar represents an unsubstituted phenyl group. 
     
     
         11 . A compound as claimed in  claim 10 , in which X is a polyethylene glycol. 
     
     
         12 . A compound as claimed in  claim 1 , in which the compound has the general formula:
   X—[NH—CO—Ar—CO—(CH═CH) n —(CH 2 ) 2 —SO 2 R′] m   (Ia)
   in which R′ represents a hydrogen atom or an unsubstituted or substituted alkyl, aryl or alkyl-aryl group.   
     
     
         13 . A compound as claimed in  claim 12 , in which Ar represents an unsubstituted phenyl group. 
     
     
         14 . A compound as claimed in  claim 13 , in which X is a polyethylene glycol. 
     
     
         15 . A compound as claimed in  claim 12 , in which n represents 0. 
     
     
         16 . A compound as claimed in  claim 12 , in which m represents 1. 
     
     
         17 . A compound as claimed in  claim 12 , in which R′ represents a p-tolyl group. 
     
     
         18 . A compound as claimed in  claim 12 , having the formula:
   X—NH—CO—Ar—CO—(CH 2 ) 2 —SO 2 R′
   in which X is a polyethylene glycol, Ar represents an unsubstituted phenyl group, and R′ represents a p-tolyl group.