Product comprising a transduction inhibitor of heterotrimeric G protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer

Abstract

A composition for treating cancer comprising an anti-tumorally effective amount of a product comprising at least one transduction inhibitor of heterotrimeric G protein signals and at least one other anti-cancer agent selected from the group consisting of prenyltransferase inhibitors, taxol and its analogues, gemcitabine and camptothecin and its analogues, administered simultaneously, separately or spread over a period of time and a pharmaceutical carrier.

1 . A composition for treating cancer comprising an anti-tumorally effective amount of a product comprising at least one transduction inhibitor of heterotrimeric G protein signals and at least one other anti-cancer agent selected from the group consisting of prenyltransferase inhibitors, taxol and its analogues, gemcitabine and camptothecin and its analogues, administered simultaneously, separately or spread over a period of time and a pharmaceutical carrier.  
   
   
       2 . The composition of  claim 1  wherein the other anti-cancer agent is a prenyltransferase inhibitor.  
   
   
       3 . The composition of  claim 2  wherein the prenyltransferase inhibitor is a farnesyltransferase inhibitor.  
   
   
       4 . The composition of  claim 1  comprising at least one transduction inhibitor of heterotrimeric G protein signals of the formula  
     
       
         
         
             
             
         
       
     
     corresponding to the sub-formulae  
     
       
         
         
             
             
         
       
     
     wherein X is R 12  and Y is R 8 , or X and Y together complete a ring with 6 members, the X—Y mnixture is —CH(R 8 )—CH(R 9 )— radical; 
 R 1  is selected from the group consisting of H, alkyl and alkylthio;  
 R 2  and R 3  are individually H or alkyl;  
 R 4  is H 2  or O;  
 R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl unsubstituted or substituted by a member selected from the group consisting of alkyl, —O—R 10 —S(O) m R 10  (m is 0, 1, or 2), —N(R 10 )R( 11 ), —N—C(O)—R 10 , —NH—(SO 2 )—R 10 , —CO 2 —R 10 , C(O)—N(R 10 ) (R 11 ), and —(SO 2 )—N(R 10 ) (R 11 );  
 R 6  and R 7  are individually selected from the group consisting of H, —C(O)—NH—CHR 13 —CO 2 R 14 , alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl, the latter four unsubstituted or substituted by a member selected from the group consisting of OH, alkyl, alkoxy, —N(R 10 )(R 11 ), —COOH, —CON(R 11 ) (R 11 ), and halo, or R 6  and R 7  together form aryl or heterocycle;  
 R 8  and R 9  are individually selected from the group consisting of H, alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl unsubstituted or substituted by a member of the group consisting of  
 —OH, alkyl, alkoxy —N(R 10 )(R 11 ), —COOH, —CONR( 10 )(R 11 ) and halo;  
 or R 8  and R 9  together form aryl or heterocycle;  
 R 10  and R 11  are individually selected from the group consisting of H, aryl, heterocyclyl, alkyl, aralkyl and heterocyclylalkyl;  
 R 12  is selected from the group consisting of NR 9 , S, or O;  
 R 13  is alkyl unsubstituted or substituted by a member selected from the group consisting of alkyl, —OR 10 , —S(O) m R 10  (m is 0, 1, or 2) and —N(R 10 ) (R 11 )  
 R 14  is H or alkyl;  
 combined with at least one other anti-cancer agent selected from the group consisting of gemcitabine, taxol, taxol analogues and farnesyltransferase inhibitor selected from the group consisting of: 
 a compound of the formula  
                     
 wherein n1 is 0 or 1;  
 
 X, is independently, each time that it occurs, (CHR 11 ) n3  (CH 2 ) n4 Z (CH 2 ) n5 ;  
 Z is selected from the group consisting of O, N(R 12 ), S, and a bond;  
 n3 is, independently, each time that it occurs, 0 or 1;  
 each of n4 and n5 are, independently, each time that they occur, 0, 1, 2 or 3;  
 Y is, independently, each time that it occurs, selected from the group consisting of CO, CH 2 , CS, and a bond;  
 R 1  is selected from the group consisting of  
                     
 and N(R 24 R 25 ) each of R 2 , R 11 , and R 12  are individually, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl and an aryl unsubstituted or substituted by at least one member selected from the group consisting of R 8  or R 30 , each substituent being chosen independently of the others;  
 R 3  is, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 2-6 )alkynyl, —(C 3-6 )cycloalkyl, —(C 3-6 )cycloalkyl(C 1-6 )alkyl, —(C 5-7 )cycloalkenyl, —(C 5-7 )cycloalkenyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl, and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted by at least one R 30 , each substituent being chosen independently of the others;  
 each of R 1  and R 5  are, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 3-6 )cycloalkyl, aryl and heterocyclyl unsubstituted or substituted by at least one R 30 , each substituent being chosen independently of the others, or R 4  and R 5  when taken together with the carbon atoms to which they are attached together form aryl;  
 R 6  is, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 3-6 )cycloalkyl, —(C 3-6 ) cycloalkyl(C 1-6 )alkyl, —(C 5-7 ) cycloalkenyl, —(C 5-7 ) cycloalkenyl(c 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted by at least one member selected from the group consisting of —OH, —(C 1-6 )alkyl, —(C 1-6 )alkoxy, —N(R 8 R 9 ), —COOH, —CON(R 8 R 9 ) and halo, each substituent being chosen independently of the others;  
 R 7  is, independently, each time that it occurs, selected from the group consisting of H, ═O, ═S, H —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 3-6 )cycloalkyl, —(C 3-6 )cycloalkyl(C 1-6 )alkyl, —(C 5-7 ) cycloalkenyl, —(C 5-7 )cycloalkenyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted with at least one member selected from the group consisting of —OH, —(C 1-6 )alkyl, —(C 1-6 )alkoxy, —N(R 8 R 9 ), —COOH, —CON(R 8 R 9 ) and halo, each substituent being chosen independently of the others;  
 each of R 8  and R 9  are, independently, each time that it occurs, selected from the group consisting of H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, aryl, and aryl(C 1-6 )alkyl;  
 R 10  is C;  
 or, when n1=0, R 6  and R 7  can be taken together with the carbon atoms to which they are attached form aryl or cyclohexyl;  
 R 21  is, independently, each time that it occurs, selected from the group consisting of (C 1-6 )alkyl and aryl(C 1-6 )alkyl unsubstituted or substituted by at least one R 8  or R 30 , each substituent being chosen independently of the others;  
 R 22  is selected from the group consisting of H, (C 1-6 )alkylthio, (C 3-6 )cycloalkylthio, R 8 —CO—, and  
                     
 each of R 24  and R 25  is independently, each time that it occurs, selected from the group consisting of H, (C 1-6 )alkyl and aryl (C 1-6 ) alkyl;  
 R 30  is, independently, each time that it occurs, selected from the group consisting of —(C 1-6 )alkyl, —O—R 8 , —S(O) n6 R 8 , —S(O) n7 N(R 8 R 9 ), —N(R 8 R 9 ), —CN, —NO 2 , —CO 2 R 8 , —CON(R 8 R 9 ), —NCO—R 8 , and halogen, each of n6 and n7 is, independently, each time that it occurs, 0, 1 or 2;  
 said heterocyclyl is selected from the group consisting of azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl-N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl and thienyl;  
 said aryl radical being phenyl or naphthyl;  
 with the proviso that when n1=1, R 10  is C and R 6  is H, then R 10  and R 7  can, taken together, form  
                     
 or when n1=1, R 10  is C, and R 7  is ═O, H, or ═S, then R 10  and R 6  can, taken together, form  
                     
 with each of X 1 , X 2 , and X 3  is independently selected from the group consisting of H, halogen, —NO 2 , —NCO—R 8 , —CO 2 R 8 , —CN, and —CON(R 8 R 9 ); and  
 when R 1  is N(R 24 R 25 ), then n3 is 1, each of n4 and n5 is 0, Z is a bond, and R 3  and R 11  can, taken together, form  
                     
 n2 is an integer from 1 to 6, and each of X 4  and X 5  is independently selected from the group consisting of H, —(C 1-6 )alkyl and aryl, or X 4  and X 5  taken together, form (C 3-6 )cycloalkyl,  
 a compound of the formula  
                     
 wherein R 1  is selected from the group consisting of H, —OR 10  and —NR 11 R 12 ;  
 R 2  is H or alkyl;  
 R 3 , R 4  and R 5  are independently selected from the group consisting of H, halogen, alkyl, trihalomethyl, hydroxy, cyano and alkoxy;  
 R 6  is H or alkyl;  
 R 7  is selected from the group consisting of halogen, alkyl, hydroxyalkyl, amino, and hydroxycarbonyl;  
 R 8  and R 9  are independently selected from the group consisting of H, halogen, cyano, alkyl, trihalomethyl, alkoxy, alkylthio and dialkylamino;  
 R 10  is selected from the group consisting of H, alkyl and alkylcarbonyl;  
 R 11  is H or alkyl;  
 R 12  is selected from the group consisting of H, alkyl and alkylcarbonyl;  
 and Y is O or S; 
 and of a pharmaceutically acceptable salt of a compound of formula (II) or a compound of formula (III).  
 
 
   
   
       5 . A composition of  claim 4 , wherein the transduction inhibitor of heterotrimeric G protein signals is a compound of sub-formula (I A ) wherein: 
 R 1  is H;    R 2  and R 3  are independently H or lower alkyl;    R 4  is O;    R 5  is selected from the group consisting of H, lower alkyl, cycloalkyl and cycloalkylalkyl;    R 6  is aryl unsubstituted or substituted by a member selected from the group consisting of OH, alkyl, lower alkoxy, —N(R 10 ) (R 11 ), —COOH, —CON(R 10 ) (R 11 ) and halo;    R 10  and R 11  are independently H or lower alkyl;    and a pharmaceutically acceptable salt thereof.    
   
   
       6 . A composition of  claim 4  wherein the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals is a compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 1  is  
     
       
         
         
             
             
         
       
       R 21  is aralkyl unsubstituted or substituted by at least one member selected from the group consisting of halogen, cyano, hydroxy, alkoxy, amino, alkylamino and dialkylamino;  
       R 4  is aryl unsubstituted or substituted by at least one member of the group consisting of halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;  
       X is alkylene of 1 to 6 carbon atoms;  
       Y is CO;  
       n1=1, R 10  is C, R 6  is H and R 10  and R 7  taken together, form  
       
         
           
           
               
               
           
         
       
       each of X 1 , X 2 , and X 3  is independently H or halogen and a pharmaceutically acceptable salt thereof.  
     
   
   
       7 . The composition of  claim 4  wherein the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals is a compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 1  is OH or NH 2 ; 
 R 2  is alkyl;  
 one of R 3 , R 4  and R 5  is halogen;  
 R 6  is alkyl;  
 one of R 8  and R 9  is halogen;  
 Y is O;  
 and a pharmaceutically acceptable salt thereof.  
 
   
   
       8 . A composition of  claim 1  wherein the inhibitor of G proteins is selected from the group consisting of 
 -7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; and    -7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;    and pharmaceutically acceptable salts thereof.    
   
   
       9 . The composition of  claim 1 , wherein the anti-cancer agent is selected from the group consisting of 1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine,4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoroimidazo[1,2a](1,4)-benzodiazepine; (±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone, taxol and gemcitabine.  
   
   
       10 . The composition of  claim 1  wherein an additional anti-cancer compound, different from the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals, is selected from the group consisting of 
 -1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4)benzodiazepine;    -4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a](1,4]-benzodiazepine;    -±-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone; 
 taxol;  
 gemcitabine;  
 and a pharmaceutically acceptable salt thereof.  
   
   
   
       11 . The composition of  claim 7  wherein R 2  is methyl.  
   
   
       12 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of  claim 1 .  
   
   
       13 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of  claim 4 .  
   
   
       14 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of  claim 10.