16-Halogen-epothilone derivatives, method for producing them and their pharmaceutical use

Abstract

A compound of formula C, BC and ABC.

1 - 60 . (canceled)  
     
     
         61 . A compound of formula C, BC or ABC  
       
         
           
           
               
               
           
         
       
       wherein 
 R 8′ , R 8  are, each independently, a halogen atom or a cyano group,  
 R 7′  is a hydrogen atom,  
 T′ is a group OR 20 , a halogen atom, an azido group or a protected amino group,  
 R 20  is a hydrogen atom or a protective group PG 2 ,  
 R 21  is a hydroxy group, halogen, a protected hydroxy group OPG 3 , a phosphonium halide radical PPh 3   + Hal − , a phosphonate radical P(O)(OQ) 2  or a phosphine oxide radical P(O)Ph 2 ,  
 Ph is phenyl,  
 Q is C 1 -C 10  alkyl or phenyl,  
 U is an oxygen atom, two alkoxy groups OR 23 , a C 2 -C 10  alkylene-α,ω-dioxy group, which can be straight-chain or branched, H/OR 9  or a grouping CR 10 R 11 ,  
 R 23  is a C 1 -C 20  alkyl radical,  
 R 9  is hydrogen or a protective group PG 3 ,  
 R 10 , R 11  are, each independently, hydrogen, a C 1 -C 20  alkyl, aryl, C 7 -C 20  aralkyl radical or together with the methylene carbon atom are a 5- to 7-membered carbocyclic ring  
 PG 14  is a hydrogen atom or a protective group PG,  
 R 1a′ , R 1b′ , are the same or different and mean hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl, or together a —(CH 2 ) m  group,  
 R 2a′ , R 2b′  are, each independently, hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl or together a —(CH 2 ) n  group,  
 R 3  is hydrogen, C 1 -C 10  alkyl, aryl, or C 7 -C 20  aralkyl,  
 G is an oxygen atom or a group —CH 2 ,  
 R 4a , R 4b ,  
 R 4a′ , R 4b′  are, each independently, hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl or together a —(CH 2 ) p  group,  
 D-E is  
                     
 R 5  is hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl, CO 2 H, CO 2 -alkyl, CH 2 OH, CH 2 O-alkyl, CH 2 O-acyl, CN, CH 2 NH 2 , CH 2 N(alkyl, acyl) 1,2 , or CH 2 Hal,  
 R 6 , R 7  are, each independently, a hydrogen atom, or together an additional bond or an oxygen atom,  
 R 13  is CH 2 OR 13a , CH 2 -Hal, CHO, CO 2 R 13b , or COHal,  
 R 14  is hydrogen, OR 14a , Hal, or OSO 2 R 14b ,  
 R 13a , R 14a  is hydrogen, SO 2 -alkyl, SO 2 -aryl, SO 2 -aralkyl or together a —(CH 2 ) o  group or together a CR 15a R 15b  group,  
 R 13b , R 14b  is hydrogen, C 1 -C 20  alkyl, aryl, or C 7 -C 20  aralkyl,  
 R 15a , R 15b  are, each independently, hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl or together a —(CH 2 ) q  group,  
 Hal is F, Cl, Br, or I,  
 m is 2, 3, 4 or 5,  
 n is 2, 3, 4 or 5,  
 p is 2, 3, 4 or 5,  
 o is 2 to 4,  
 q is 3 to 6,  
 Z is an oxygen atom or H/OR 12 ,  
 R 12  is hydrogen or a protective group PG 2 .  
 
     
     
         62 . A compound of claim  60 , which is of formula C.  
     
     
         63 . A compound of claim  60 , which is of formula BC.  
     
     
         64 . A compound of claim  60 , which is of formula ABC.  
     
     
         65 . A compound of claim  60 , wherein 
 PG is an alkyl- and/or aryl-substituted silyl, C 1 -C 20  alkyl, C 4 -C 7  cycloalkyl, which can contain an oxygen atom in the ring, aryl, C 7 -C 20  aralkyl, C 1 -C 20  acyl or aroyl,    PG 2  is an acyl group containing 1 to 20 carbon atoms, and/or    PG 2 , PG 3  are, each independently, a methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, acetyl, propionyl, butyryl or benzoyl radical.    
     
     
         66 . A compound of claim  60 , wherein PG 2  is a tert-butyldimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl radical.