Combination of SRC Kinase inhibitors and chemotherapeutic agents for the treatment of proliferative diseases

Abstract

Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.

1 . A method for the treatment of proliferative diseases, including cancer, which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of (1) at least one anti-proliferative cytotoxic agent(s) and 2) a compound of formula I,  
       
         
           
           
               
               
           
         
         where  
         Q is thiazole;  
         Z is a single bond;  
         X 1  and X 2  together form ═O;  
         R 1  is 
 (1) hydrogen or R 6 , where R 6  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z 1 , Z 2  and one or more groups Z 3 ;  
 (2) —OH or —OR 6 ;  
 (3) —SH or —SR 6 ;  
 (4) —C(O) 2 H, —C(O) q R 6 , or —O—C(O) q R 6 , where q is 1 or 2;  
 (5) —SO 3 H or —S(O) q R 6 ;  
 (6) halo;  
 (7) cyano;  
 (8) nitro;  
 (9) —Z 4 —NR 7 R 8 ;  
 (10) —Z 4 —N(R 9 ) —Z 5 —NR 10 R 11 ;  
 (11) —Z 4 —N(R 12 )—Z 5 —R 6 ;  
 (12) —P(O) (OR 6 ) 2 ;  
 
         R 2  is hydrogen, R 6 , —Z 4 —R 6 , or —Z 13 —NR 7 R 8 ;  
         R 3  is —Z 4 —R 6  wherein Z 4  is a single bond and R 6  is heteroaryl which is unsubstituted or substituted with Z 1 , Z 2  and one or more groups Z 3    
         R 4  and R 5  are each independently 
 (1) hydrogen or R 6 ;  
 (2) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;  
 (3) —N(R 9 )Z 4 R 6 ; or  
 (4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z 1 , Z 2  and Z 3 , which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z 1 , Z 2  and Z 3 ;  
 
         R 7 , R 8 , R 9 , R 10 , R 11  and R 12  
 (1) are each independently hydrogen or R 6 ;  
 (2) R 7  and R 8  may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2  and Z 3 ; or  
 (3) any two of R 9 , R 10  and R 11  may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2  and Z 3 ;  
 
         R 13  is 
 (1) cyano;  
 (2) nitro;  
 (3) —NH 2 ;  
 (4) —NHOalkyl;  
 (5) —OH;  
 (6) —NHOaryl;  
 (7) —NHCOOalkyl;  
 (8) —NHCOOaryl;  
 (9) —NHSO 2 alkyl;  
 (10) —NHSO 2 aryl;  
 (11) aryl;  
 (12) heteroaryl;  
 (13) —Oalkyl; or  
 (14) —Oaryl;  
 
         R 14  is 
 (1) —NO 2 ;  
 (2) —COOalkyl; or  
 (3) —COOaryl;  
 
         R 15  is 
 (1) hydrogen;  
 (2) alkyl;  
 (3) aryl;  
 (4) arylalkyl; or  
 (5) cycloalkyl;  
 
         Z 1 , Z 2  and Z 3  are each independently 
 (1) hydrogen or Z 6 , where Z 6  is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z 1 , Z 2  and Z 3 ;  
 (2) —OH or —OZ 6 ;  
 (3) —SH or —SZ 6 ;  
 (4) —C(O) q H, —C(O) q Z 6 , or —O—C(O) q Z 6 ;  
 (5) —SO 3 H, —S(O) q Z 6 ; or S(O) q N(Z 9 )Z 6 ;  
 (6) halo;  
 (7) cyano;  
 (8) nitro;  
 (9) —Z 4 —NZ 7 Z 8 ;  
 (10) —Z 4 —N(Z 9 )—Z 5 —NZ 7 Z 8 ;  
 (11) —Z 4 —N(Z 10 )—Z 5 —Z 6 ;  
 (12) —Z 4 —N(Z 10 )—Z 5 —H;  
 (13) oxo;  
 (14) —O—C(O)—Z 6 ;  
 (15) any two of Z 1 , Z 2 , and Z 3  may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or  
 (16) any two of Z 1 , Z 2 , and Z 3  may together be —O—(CH 2 ) r —O—, where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;  
 
         Z 4  and Z 5  are each independently 
 (1) a single bond;  
 (2) —Z 11 —S(O) q Z 12 —;  
 (3) —Z 11 —C(O)—Z 12 —;  
 (4) —Z 11 —C(S)—Z 12 —;  
 (5) —Z 11 —O—Z 12 —;  
 (6) —Z 11 —S—Z 12 —;  
 (7) —Z 11 —O—C(O)—Z 12 —; or  
 (8) —Z 11 —C(O)—O—Z 12 —;  
 
         Z 7 , Z 8 , Z 9  and Z 10  
 (1) are each independently hydrogen or Z 6 ;  
 (2) Z 7  and Z 8 , or Z 6  and Z 10 , may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2  and Z 3 ; or  
 (3) Z 7  or Z 8 , together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2  and Z 3 ;  
 
         Z 11  and Z 12  are each independently 
 (1) a single bond;  
 (2) alkylene;  
 (3) alkenylene; or  
 (4) alkynylene; and  
 
         Z 13  is 
 (1) a single bond;  
 (2) —Z 11 —S(O) q —Z 12 —;  
 (3) —Z 11 —C(O)—Z 12 —;  
 (4) —Z 11 —C(S)—Z 12 —;  
 (5) —Z 11 —O—Z 12 —;  
 (6) —Z 11 —S—Z 12 —;  
 (7) —Z 11 —O—C(O)—Z 12 —;  
 (8) —Z 11 —C(O)—Z 12 —;  
 (9) —C(NR 13 )—;  
 (10) —C(CHR 14 )—; or  
 (11) —C(C(R 14 ) 2 )  
 provided said compound is other than a compound of formula (vii)  
                     
 where 
 R 3e  is pyridyl or pryimidinyl optionally substituted with halogen or alkyl;  
 R 50  and R 51  are each independently hydrogen, halogen or alkyl;  
 R 52  and R 53  are each independently hydrogen, halogen, alkyl or haloalkyl;  
 R 54  and R 56  are each independently hydrogen, halogen, alkyl, nitro or amino;  
 R 55  is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, or alkoxycarbonyl; and  
 n is zero or 1.  
 
 
       
     
     
         2 . A compound of  claim 1  wherein R 1  is hydrogen, halo, alkyl, aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl.  
     
     
         3 . A compound of  claim 2  wherein R 1  is hydrogen.  
     
     
         4 . A compound of  claim 3  wherein R 2  is hydrogen.  
     
     
         5 . A compound of  claim 4  wherein R 4  is hydrogen.  
     
     
         6 . A compound of  claim 5  wherein R 5  is an aryl group which is substituted with Z 1 , Z 2  and one or more groups Z 3 .  
     
     
         7 . A compound of  claim 6  wherein R 1  is hydrogen or alkyl, R 2  and R 4  are independently hydrogen or alkyl, and R 5  is aryl which is unsubstituted or substituted with Z 1 , Z 2  and one or more groups Z 3 .  
     
     
         8 . A compound of  claim 7  wherein R 5  is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.  
     
     
         9 . A compound of  claim 8  wherein R 3  is heteroaryl substituted optionally substituted with Z 1  and Z 2  and substituted with at least one group Z 3  where Z 3  is Z 6 .  
     
     
         10 . A compound of  claim 9  wherein Z 6  is heterocyclo optionally substituted with one or more hydroxyalkyl.  
     
     
         11 . The method according to  claim 1 , wherein the Compound of Formula I is ′N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.  
     
     
         12 . The method according to  claim 1  wherein the antiproliferative cytotoxic agent is administered following administration of the Formula I compound.  
     
     
         13 . The method according to  claim 1 , wherein the antiproliferative cytotoxic agent is administered prior to the administration of the Formula I compound.  
     
     
         14 . The method according to  claim 1  wherein the antiproliferative cytotoxic agent is administered simultaneously with the formula 1 compound.  
     
     
         15 . The method according to  claim 1  for the treatment of cancerous solid tumors.  
     
     
         16 . The method according to  claim 1  for the treatment of refractory tumors.  
     
     
         17 . The method according to  claim 1  wherein the anti-proliferative cytotoxic agent is selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, inhibitors of cell cycle progression, radiation and a platinum coordination complex.  
     
     
         18 . The method according to  claim 17  wherein the anti-proliferative cytotoxic agent is paclitaxel.  
     
     
         19 . A pharmaceutical composition for the treatment of cancer which comprises a synergistic combination of at least one anti-proliferative cytotoxic agent and a compound of  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         20 . The composition according to  claim 19  for the treatment of cancerous solid tumors.  
     
     
         21 . The composition according to  claim 19  for the treatment of refractory tumors.  
     
     
         22 . The composition according to  claim 19  wherein the antiproliferative cytotoxic agent is paclitaxel.