Combinations comprising epothilones and pharmaceutical uses thereof

Abstract

The invention relates to a combination which comprises (a) a bisphosphonate, a platinum compound or a vasculostatic compound and (b) an epothilone derivative of formula (I), wherein A represents O or NRN, wherein RN is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease; a pharmaceutical composition, a commercial package or product comprising such a combination; the use of such a combination for the preparation of a medicament for the delay of progression or treatment of a proliferative disease and to a method of treatment of a warm-blooded animal.

1 . A combination which comprises (a) a bisphosphonate, a platinum compound or a vasculostatic compound and (b) an epothilone derivative of formula I  
       
         
           
           
               
               
           
         
       
       wherein A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, 
 in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.  
 
     
     
         2 . A combination according to  claim 1  which comprises (a) carboplatin or oxaliplatin and (b) an epothilone derivative of formula I 
 wherein A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond,  
 in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.  
 
     
     
         3 . Combination according to  claim 1  wherein a bisphosphonate is employed selected from etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.  
     
     
         4 . Combination according to  claim 3  wherein the bisphosphonate is zoledronic acid.  
     
     
         5 . Combination according to  claim 1  comprising a vasculostatic compound.  
     
     
         6 . Combination according to  claim 5  wherein the vasculostatic compound is PTK787.  
     
     
         7 . Combination according to  claim 1  comprising an epothilone derivative of formula I wherein A represents O, R is lower alkyl or hydrogen and Z is O or a bond.  
     
     
         8 . Combination according to  claim 1 , which is a combined preparation or a pharmaceutical composition.  
     
     
         9 . Method of treating a warm-blooded animal having a proliferative disease comprising administering to the animal a combination according to any  claim 1  in a quantity which is jointly therapeutically effective against a proliferative disease and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.  
     
     
         10 . Method of treating according to  claim 9  wherein a bisphosphonate is employed and the proliferative disease is hormone refractory prostate cancer with bone metastasis.  
     
     
         11 . Method of treating according to  claim 9  wherein carboplatin or oxaliplatin is employed and the proliferative disease is ovarian cancer, lung cancer, head or neck cancer, cervix cancer, prostate cancer or colon cancer.  
     
     
         12 . Method of treating according to  claim 9  wherein PTK787 is employed and the proliferative disease is ovarian cancer, lung cancer, head or neck cancer, cervix cancer, prostate cancer or colon cancer.  
     
     
         13 . A pharmaceutical composition comprising a quantity which is jointly therapeutically effective against a proliferative disease of a pharmaceutical combination according to  claim 1  and at least one pharmaceutically acceptable carrier.  
     
     
         14 . A combination according to  claim 1  for use in the delay of progression or treatment of a proliferative disease.  
     
     
         15 . Use of a combination according to  claim 1  for the preparation of a medicament for the delay of progression or treatment of a proliferative disease.  
     
     
         16 . Use of a bisphosphonate in combination with an epothilone derivative of formula I  
       
         
           
           
               
               
           
         
         in which compound A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond,  
         for the preparation of a medicament for the delay of progression or treatment of a proliferative disease.  
       
     
     
         17 . Use of cisplatin, carboplatin or oxaliplatin in combination with an epothilone derivative of formula I  
       
         
           
           
               
               
           
         
         in which compound A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond,  
         for the preparation of a medicament for the delay of progression or treatment of a proliferative disease.  
       
     
     
         18 . Use of a vasculostatic compound in combination with an epothilone derivative of formula I  
       
         
           
           
               
               
           
         
         in which compound A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond,  
         for the preparation of a medicament for the delay of progression or treatment of a disease associated with deregulated angiogenesis.  
       
     
     
         19 . Use according to  claim 18 , wherein the vasculostatic compound is PTK787.  
     
     
         20 . A commercial package comprising (a) a bisphosphonate, a platinum compound or a vasculostatic compound and (b) an epothilone derivative of formula I  
       
         
           
           
               
               
           
         
         wherein A represents O or NR N , wherein R N  is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond,  
         together with instructions for simultaneous, separate or sequential use thereof in the delay of progression or treatment of a proliferative disease.