Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor

Abstract

The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from compounds of Formula I′: Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.

1 - 55 . (canceled)  
   
   
       56 . A method of treating in a subject a disorder related to FLT3, comprising administering to the subject a therapeutically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor that is:  
     
       
         
         
             
             
         
       
     
     and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier.  
   
   
       57 . The method of  claim 56  further comprising administering to the subject a therapeutically effective amount of chemotherapy.  
   
   
       58 . The method of  claim 56  further comprising administering to the subject a therapeutically effective amount of radiation therapy.  
   
   
       59 . The method of  claim 56  further comprising administering to the subject a therapeutically effective amount of gene therapy.  
   
   
       60 . The method of  claim 56  further comprising administering to the subject a therapeutically effective amount of immunotherapy.  
   
   
       61 . A method as defined in  claim 56  wherein the farnesyl transferase inhibitor comprises a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein 
 the dotted line represents an optional bond;  
 X is oxygen or sulfur;  
 R 1  is hydrogen, C 1-12 alkyl, Ar 1 , Ar 2 C 1-6 alkyl, quinolinylC 1-6 alkyl, pyridyl-C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, aminoC 1-6 alkyl, or a radical of formula -Alk 1 -C(═O)—R 9 , -Alk 1 -S(O)—R 9  or -Alk 1 —S(O) 2 —R 9 , wherein Alk 1 is CI16alkanediyl, R 9  is hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, amino, C 1-8 alkylamino or C 1-8 alkylamino substituted with C 1-6 alkyloxycarbonyl;  
 R 2 , R 3  and R 16  each independently are hydrogen, hydroxy, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxy, aminoC 1-6 alkyloxy, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyloxy, Ar 1 , Ar 2 C 1-6 alkyl, Ar 2 oxy, Ar 2 C 1-6 alkyloxy, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl, 4,4-dimethyloxazolyl; or  
 when on adjacent positions R 2  and R 3  taken together may form a bivalent radical of formula  
   —O—CH 2 —O—  (a-1),  —O—CH 2 —CH 2 —O—  (a-2),  —O—CH═CH—  (a-3),  —O—CH 2 —CH 2 —  (a-4),  —O—CH 2 —CH 2 —CH 2 —  (a-5), or  —CH═CH—CH═CH—  (a-6);  
 R 4  and R 5  each independently are hydrogen, halo, Ar 1 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, amino, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylS(O)C 1-6 alkyl or C 1-6 alkylS(O) 2 C 1-6 alkyl;  
 R 6  and R 7  each independently are hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxy, Ar 2 oxy, trihalomethyl, C 1-6 alkylthio, di(C 1-6 alkyl)amino, or when on adjacent positions R 6  and R 7  taken together may form a bivalent radical of formula  
   —O—CH 2 —O—  (c-1), or  —CH═CH—CH═CH—  (c-2);  
 R 8  is hydrogen, C 1-6 alkyl, cyano, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonylC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyloxycarbonylC 1-6 alkyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)-aminoC 1-6 alkyl, imidazolyl, haloC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, aminocarbonylC 1-6 alkyl, or a radical of formula  
   —O—R 10    (b-1),  —S—R 10    (b-2),  —N—R 11 R 12    (b-3),  
 wherein R 10  is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, Ar 1 , Ar 2 C 1-6 alkyl, C 1-6 alkyloxycarbonylC 1-6 alkyl, a radical or formula -Alk 2 -OR 13  or -Alk 2 -NR 14 R 15 ;  
 R 11  is hydrogen, C 1-12 alkyl, Ar 1  or Ar 2 C 1-6 alkyl;  
 R 12  is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylaminocarbonyl, Ar 1 , Ar 2 C 1-6 alkyl, C 1-6 alkylcarbonylC 1-6 alkyl, a natural amino acid, Ar 1 carbonyl, Ar 2 C 1-6 alkylcarbonyl, aminocarbonylcarbonyl, C 1-6 alkyloxy-C 1-6 alkylcarbonyl, hydroxy, C 1-6 alkyloxy, aminocarbonyl, di(C 1-6 alkyl)aminoC 1-6  alkylcarbonyl, amino, C 1-6 alkylamino, C 1-6 alkylcarbonylamino, or a radical of formula -Alk 2 -OR 13  or -Alk 2 -NR 14 R 15 ; wherein Alk 2  is C 1-6 alkanediyl; R 13  is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, hydroxyC 1-6 alkyl, Ar 1  or Ar 2 C 1-6 alkyl; R 14  is hydrogen, C 1-6 alkyl, Ar 1  or Ar 2 C 1-6 alkyl; R 15  is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, Ar 1  or Ar 2 C 1-6 alkyl;  
 R 17  is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, Ar 1 ;  
 R 18  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy or halo;  
 R 19  is hydrogen or C 1-6 alkyl;  
 Ar 1  is phenyl or phenyl substituted with C 1-6 alkyl, hydroxy, amino, C 1-6 alkyloxy or halo; and  
 Ar 2  is phenyl or phenyl substituted with C 1-6 alkyl, hydroxy, amino, C 1-6 alkyloxy or halo.  
 
   
   
       62 . The method of  claim 61 , wherein said farnesyl transferase inhibitor comprises a compound of formula (I) wherein X is oxygen and the dotted line represents a bond.  
   
   
       63 . The method of  claim 61 , wherein said farnesyl transferase inhibitor comprises a compound of formula (I) wherein R 1  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy-C 1-6 alkyl or, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl; R 2  is halo, C 1-6 alkyl, C 2 -6alkenyl, C 1-6 alkyloxy, trihalomethoxy, or hydroxyC 1-6 alkyloxy; and R 3  is hydrogen.  
   
   
       64 . The method of  claim 61 , wherein said farnesyl transferase inhibitor comprises a compound of formula (I) wherein R 8  is hydrogen, hydroxy, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyloxycarbonylC 1-6 alkyl, imidazolyl, or a radical of formula —NR 11 R 12  wherein R 11  is hydrogen or C 1-12 alkyl and R 12  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkylcarbonyl, hydroxy, or a radical of formula -Alk 2 -OR 13  wherein R 13  is hydrogen or C 1-6 alkyl.  
   
   
       65 . The method of  claim 61 , wherein the farnesyl transferase inhibitor is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.