Combination of rocaglamide and apoptosis inducing substances for the treatment of cancer

Abstract

The present invention relates to a combined preparation comprising at least one rocaglamide derivative and at least one apoptosis inducing agent, preferably from the group of substances comprising agents inducing the extrinsic apoptotic pathway, antiproliferative agents and agents which induce apoptosis in T-cells by activation induced cell death (AICD) for the treatment of cancer.

1 . A combined preparation for simultaneous, separate or sequential use comprising:
 a) at least one rocaglamide derivative of the formula (I) and/or a pharmaceutically acceptable salt thereof; and   b) one or more apoptosis inducing agents selected from the group consisting of substances comprising agents inducing the extrinsic apoptotic pathway, antiproliferative agents and agents which induce apoptosis in T-cells by activation induced cell death (AICD) for the treatment of cancer,   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from hydrogen, halogen and alkyl; 
         R 2  is selected from halogen, alkyl and alkoxy; 
         R 3  is selected from hydrogen, halogen and alkyl; 
         R 4  is selected from halogen, alkyl and alkoxy; 
         or R 2  and R 3  together form a —OCH 2 CH 2 O— unit; 
         R 5  is selected from hydroxyl, acyloxy, amino, monoalkylamino, dialkylamino and —NR 12 —CHR 13 —COOR 14 , with 
         R 12  selected from hydrogen and alkyl, 
         R 13  selected from phenyl and benzyl, where both may carry a substituent selected from the group consisting of hydroxyl, indolyl imidazolylmethyl, and alkyl which may be substituted by a group selected from OH, SH, alkoxy, thioalkoxy, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, carboxamide and hydroxyl groups; 
         or R 12  and R 13  together form a —(CH 2 ) 3 — or —(CH 2 ) 4 — group; 
           R 14 selected from alkyl and benzyl; in which case R 6  is hydrogen, or 
         R 5  and R 6  together form an oxo or hydroxyimino group; 
         R 7  is hydrogen; 
         R 8  is selected from hydrogen, —COOR 15  and CONR 16 R 17 , wherein 
         R 15  and R 16  are independently selected from hydrogen and methyl, and 
         R 17  is selected from hydrogen, methyl, 4-hydroxybutyl and 2-tetrahydrofuryl; 
         R 9  is selected from phenyl which is optionally substituted, and hetaryl which is optionally substituted; 
         R 10  is selected from hydrogen, halogen, alkyl and alkoxy, and 
         R 11  is selected from hydrogen, hydroxyl, halogen, alkoxy and alkyl; or 
         R 10  and R 11  are in ortho-position to each other and together form a —OCH 2 O— unit; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The preparation according to  claim 1 , wherein the substituents R 1  to R 14  have the following meanings:
 R 1  and R 3  each are hydrogen;   R 2  and R 4  each are independently selected from methoxy which is optionally substituted;   R 5  is selected from hydroxy, formyloxy and acetyloxy, alkylamino,   —NR 12 —CHR 13 —COOR 14 , with   R 12  being selected from hydrogen and alkyl,   R 13  being selected from: alkyl which may be substituted by: a group selected from OH, SH, alkoxy; thioalkoxy, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, carboxamide and guanidino groups; and phenyl and benzyl, which both may carry a substituent from the group hydroxy, indolyl and imidazolylmethyl;   R 14  being selected from alkyl and benzyl;   R 6  is hydrogen;   R 7  is hydrogen;   R 8  is selected from hydrogen, —COOCH 3  and CON(CH 3 ) 2 ;   R 9  is phenyl which is optionally substituted;   R 10  is methoxy;   R 11  is selected from hydrogen and hydroxy, or   R 10  and R 11  are in ortho-position to each other and together form a —OCH 2 O— unit.   
     
     
         3 . The preparation according to  claim 1 , wherein the at least one antiproliferative agent is a chemotherapeutic agent. 
     
     
         4 . The preparation according to  claim 3 , wherein the at least one chemotherapeutic agent is selected from the group comprising consisting of antimetabolites, DNA-fragmenting agents, DNA-crosslinking agents, intercalating agents, monoclonal antibodies, spindle poisons, topoisomerase I poisons, topoisomerase II poisons, and any combination thereof. 
     
     
         5 . The preparation according to  claim 4 , wherein at least one chemotherapeutic agent is selected from the group consisting of antimetabolites, intercalating agents, and any combination thereof. 
     
     
         6 . The preparation according to  claim 1 , wherein the apoptosis inducing agent is a ligand to a death receptor. 
     
     
         7 . The preparation according to  claim 6 , wherein said ligand to a death receptor is TRAIL or TNF-α. 
     
     
         8 . The preparation according to  claim 6 , wherein the ligand to a death receptor is an antibody, a fragment or a derivative thereof. 
     
     
         9 . The preparation of  claim 8 , wherein the antibody is selected from the group consisting of anti-CD95 antibody, anti-TRAIL-R1 (DR4) antibody, anti-TRAIL-R2 (DR5) antibody, anti-DR6 antibody, anti TNF-R1 antibody, anti-TRAMP (DR3) antibody, fragments thereof, and derivatives thereof. 
     
     
         10 . The preparation of  claim 1 , wherein the apoptosis inducing agent is a T-cell receptor stimulating agent. 
     
     
         11 . The preparation of  claim 10 , wherein the at least one T-cell stimulating agent is αCD3. 
     
     
         12 . A pharmaceutical composition comprising the preparation of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         13 . A method of treating a subject having cancer, comprising administering to a subject in need a therapeutically effective amount of the pharmaceutical composition of  claim 12 . 
     
     
         14 . The method of  claim 13 , wherein the cancer is a pancreatic carcinoma, a T-cell derived lymphoma or a T-cell derived leukaemia. 
     
     
         15 . A method for preparing a medicament for the treatment of cancer, wherein the medicament comprises the rocaglamide derivative of formula (I), at least one of the apoptosis inducing or antiproliferative agents of  claim 1 , and a pharmaceutically acceptable carrier, wherein the method comprises admixing in a suitable amount the rocaglamide derivative of formula (I), at least one of the apoptosis inducing or antiproliferative agents of  claim 1 , and at least one pharmaceutically acceptable carrier. 
     
     
         16 . A medicament for the treatment of cancer comprising a rocaglamide derivative of formula (I), at least one of the apoptosis inducing or antiproliferative agents of  claim 1 , and at least one pharmaceutically acceptable carrier. 
     
     
         17 . A method for treatment of cancer in a patient comprising administering the preparation of  claim 1  to the patient. 
     
     
         18 . The method of  claim 17 , wherein the patient is a human.