New effector conjugates, methods for their preparation and their pharmaceutical use

Abstract

Conjugates of epothilones and epothilone derivatives (as effectors) with suitable saccharides or saccharide derivatives (as recognition units) are described. Their production is carried out by the recognition units being reacted with suitable linkers, and the compounds that are produced are conjugated to the effectors. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.

1 - 10 . (canceled)  
   
   
       11 . A linker-recognition unit of formula (III 1 ):  
     
       
         
         
             
             
         
       
     
     in which 
 RG 1  represents an O═C═N group or an S═C═N group or an O═C═N—CH 2  group or an S═C═N—CH 2  group;  
 R 22a  and R 22b , independently of one another, are hydrogen, C 1 -C 20  alkyl, C 1 -C 20  acyl, C 1 -C 20  acyloxy, aryl, aralkyl, hydroxy, alkoxy, CO 2 H, CO 2 alkyl, halogen, CN, NO 2 , NH 2 , or N 3 , and  
 EG is a recognition unit of formula (IV):  
                     
 in which  
 R 24  is a group CH 2 OPG 4  or a group CO 2 R 26 ,  
 PG 1 , PG 2 , PG 3 , and PG 4 , independently of one another, are hydrogen or a protective group PG,  
 R 26  is hydrogen, C 1 -C 20  alkyl, C 1 -C 20  alkenyl, C 4 -C 7  cycloalkyl, which can contain an oxygen atom, aryl, aralkyl, tris(C 1 -C 20  alkyl)silyl, bis(C 1 -C 20  alkyl)-arylsilyl, (C 1 -C 20  alkyl)-diarylsilyl, or tris(aralkyl)-silyl;  
 or a linker-recognition unit of formula (III 2 ):  
                     
 in which  
 RG 2  represents an HO—CH 2  group or an HNR 23 —CH 2  group; and  
 R 22a , R 22b  and EG have the meanings that are mentioned above; but with the condition that the following compounds are not included:  
 (4-Hydroxymethyl)phenyl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside;  
 (2-Hydroxymethyl)phenyl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside;  
 (4-Hydroxymethyl)phenyl-2,3,4-tri-O-acetyl-β-D-glucuronide-6-methyl ester;  
 (2-Hydroxymethyl)phenyl-2,3,4-tri-O-acetyl-β-D-glucuronide-6-methyl ester;  
 (4-Hydroxymethyl)phenyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside;  
 (2-Hydroxymethyl-4-nitro)phenyl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside;  
 (4-Hydroxymethyl-2-nitro)phenyl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside;  
 (2-Hydroxymethyl-4-nitro)phenyl-2,3,4-tri-O-acetyl-β-D-glucuronide-6-methyl ester;  
 (4-Hydroxymethyl-2-nitro)phenyl-2,3,4-tri-O-acetyl-β-D-glucuronide-6-methyl ester;  
 (2-Chloro-4-hydroxymethyl)phenyl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside;  
 (2-Chloro-4-hydroxymethyl)phenyl-2,3,4-tri-O-acetyl-β-D-glucuronide-6-methyl ester;  
 or a linker-recognition unit of formula (III 3 ):  
                     
 in which  
 RG 3  represents a Hal-C(═O)—CH 2  group or a Hal-C(═S)—CH 2  group or an R 27 —C(═O)—O—C(═O)—CH 2  group or an R 27 —C(═O)—O—C(═S)—CH 2  group or a  
                     
 group or a  
                     
 group;  
 R 27  is C 1 -C 10  alkyl, aryl or aralkyl; and  
 R 22a , R 22b  and EG have the meanings that are mentioned above; but with the condition that the following compounds are not included:  
 2,5-Dioxopyrrolidin-1-yl-[4-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-benzyl]carbonate;  
 2,5-Dioxopyrrolidin-1-yl-[2-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-benzyl]carbonate;  
 2,5-Dioxopyrrolidin-1-yl-[4-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)-methyluronate)benzyl]carbonate;  
 4-Nitrophenyl-[2-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)methyluronate)-benzyl]carbonate;  
 2,5-Dioxopyrrolidin-1-yl-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-benzyl]carbonate;  
 4-Nitrophenyl-[2-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-5-nitrobenzyl]carbonate;  
 4-Nitrophenyl-[2-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)methyluronate)-5-nitrobenzyl]carbonate;  
 4-Nitrophenyl-[4-methoxy-5-nitro-2-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)methyluronate)benzyl]carbonate;  
 4-Nitrophenyl-[4-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)methyluronate)-5-nitrobenzyl]carbonate;  
 4-Chlorophenyl-[2-((2,3,4-tri-O-acetyl-β-D-glucopyranosyl)methyluronate)-5-nitrobenzyl]carbonate.  
 
   
   
       12 - 22 . (canceled)  
   
   
       23 . A conjugate compound according to  claim 11 , wherein, in each instance, aryl is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl, benzoxazolyl, which are optionally substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, —NH 2 , —NO 2 , —N 3 , —CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl, or C 1 -C 20 -acyloxy groups.  
   
   
       24 . A conjugate compound according to  claim 11 , wherein the aralkyl groups, in each case, are selected from the group consisting of benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl, which are optionally substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, —NO 2 , —N 3 , —CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl, or C 1 -C 20 -acyloxy groups.  
   
   
       25 . A conjugate compound according to  claim 11 , wherein the protective groups PG are each selected from: tris(C 1 -C 20  alkyl)silyl, bis(C 1 -C 20  alkyl)-arylsilyl, (C 1 -C 20  alkyl)-diarylsilyl, tris(aralkyl)-silyl, C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 4 -C 7 -cycloalkyl which optionally contains an oxygen atom in the ring, aryl, C 7 -C 20 -aralkyl, C 1 -C 20 -acyl, aroyl, C 1 -C 20 -alkoxycarbonyl, C 1 -C 20 -alkylsulfonyl, arylsulfonyl or the amino protective groups Alloc, Boc, Z, benzyl, f-Moc, Troc, Stabase or benzostabase.