Epothilone derivatives, process for their production, and their pharmaceutical use

Abstract

Disclosed are epothilone compounds of formula I, which are useful as pharmaceutical compounds for treating, for example, malignant tumors and chronic inflammatory diseases and are useful in anti-angiogenesis therapy.

1 - 22 . (canceled)  
     
     
         23 . An epothilone compound of formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 R 4  means hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl,  
 R 5  means hydrogen, C 1 -C 10  alkyl, aryl, C 7 -C 20  aralkyl,  
 wherein, for R 4  and R 5 , aryl is phenyl, wherein said phenyl is 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 and/or C 1 -C 20  acyloxy groups, and  
 wherein, for R 4  and R 5 , aralkyl is benzyl or phenylethyl, wherein said benzyl or phenylethyl is 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 and/or C 1 -C 20  acyloxy groups,  
 R 6 , R 7  each mean a hydrogen atom, or together mean an additional bond to result in a double bond on the ring between their two positions or together mean an oxygen atom to provide an epoxide ring,  
 R 8  means a methyl group or hydrogen,  
 and at the same time, R 1a  and R 1b  together stand for a trimethylene group, R 2  stands for a phenyl or benzyl radical, and X stands for a 2-pyridyl, or  
 at the same time R 1a  and R 1b  together stand for a trimethylene group, R 2  stands for a methyl, ethyl or propyl group and X stands for a 2-pyridyl, or  
 at the same time R 1a  and R 1b  in each case stand for a methyl group, R 2  stands for a methyl, ethyl or propyl radical, and X stands for a 2-pyridyl,  
 wherein the nitrogen atom and/or the sulfur atom in X can be present in oxidized form, and  
 wherein, if R 2  and R 8  in each case mean a methyl radical, X can be only one 2-pyridyl radical that is optionally oxidized on the nitrogen atom,  
 or a stereoisomer thereof.  
 
     
     
         24 . A compound according to  claim 23 , in which R 8  is a hydrogen atom.  
     
     
         25 . A compound according to  claim 23 , in which R 8  is a methyl group.  
     
     
         26 . A compound according to  claim 23 , in which R 2  is an ethyl group.  
     
     
         27 . A compound according to  claim 23 , in which R 2  is a propyl group.  
     
     
         28 . A compound according to  claim 24 , in which R 2  is a propyl group.  
     
     
         29 . A compound according to  claim 23 , in which R 5  is a methyl group.  
     
     
         30 . A compound according to 23, in which X is 2-pyridyl that is oxidized on the nitrogen atom.  
     
     
         31 . A compound according to  claim 23 , in which R 1a  and R 1b  in each case stand for a methyl group.  
     
     
         32 . A compound according to  claim 23 , in which R 1a  and R 1b  together stand for a trimethylene group.  
     
     
         33 . A compound according to  claim 23 , in which R 6  and R 7  together mean an oxygen atom to provide an epoxide ring.  
     
     
         34 . A compound according to  claim 30 , in which R 6  and R 7  together mean an oxygen atom to provide an epoxide ring.  
     
     
         35 . A compound according to  claim 31 , in which R 6  and R 7  together mean an oxygen atom to provide an epoxide ring.  
     
     
         36 . A compound according to  claim 32 , in which R 6  and R 7  together mean an oxygen atom to provide an epoxide ring.  
     
     
         37 . A compound of formula I of  claim 23 , which is: 
 (4S,7R,8S,9S,13(E or Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione,    (1(S or R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1(R or S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (4S,7R,8S,9S,13(E or Z),16S(E))-4,8-Dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione,    (1(S or R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1(R or S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (4S,7R,8S,9S,13(E or Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)-9,13-dimethyl-cyclohexadec-13-ene-2,6-dione,    (1(S or R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1(R or S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (4S,7R,8S,9S,13(E or Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,    (1(S or R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1(R or S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-10-ethyl-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (4S,7R,8S,9S,13(E or Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)-9,13-dimethyl-cyclohexadec-13-ene-2,6-dione,    (1(S or R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1(R or S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-10-ethyl-3-(2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-7-propyl-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,    (1S,3S(E),7S,10R,11S,12S,16R)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1R,3S(E),7S,10R,11S,12S,16S)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1S,3S(E),7S,10R,11S,12S,16R)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1R,3S(E),7S,10R,11S,12S,16S)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,    (4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-7-propyl-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,    (1R,3S(E),7S,10R,11S,12S,16R)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1S,3S(E),7S,10R,11S,12S,16S)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,    (1R,3S(E),7S,10R,11S,12S,16R)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo]14.1.0]heptadeca-5,9-dione, or    (1S,3S(E),7S,10R,11S,12S,16S)-10-Propyl-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione.    
     
     
         38 . A pharmaceutical composition comprising at least one compound of formula I according to  claim 23  and a pharmaceutically compatible vehicle.  
     
     
         39 . A pharmaceutical composition comprising a compound of  claim 37  and a pharmaceutically compatible vehicle.  
     
     
         40 . A method for preparing a pharmaceutical composition comprising bringing together a pharmaceutically acceptable carrier and a compound of formula I according to  claim 23.