Methods for treating cancer with trka receptor tyrosine kinase antagonists

Abstract

The present disclosure relates to novel synthetic substituted heterocyclic compounds and pharmaceutical compositions containing the same, said compounds being capable of inhibiting or antagonizing TrkA receptor tyrosine kinases. In some aspects, the disclosure provides a compound having a structural formula (I): The disclosure further concerns the use of such compounds in the treatment and/or prevention of certain types of cancers, pain, inflammation, restenosis, atherosclerosis, psoriasis, thrombosis, Alzheimer's, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination.

What is claimed is: 
     
         1 . A method for treating pancreatic, liver, stomach, ovarian, breast, kidney, blood, prostate, colon, brain, neuroblastoma, or lung cancer in a patient suffering therefrom, comprising:
 a) administering to the patient a therapeutically effective amount of a compound having a structural formula (I):   
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof; 
       wherein:
 A 1  and A 2  are independently oxygen or sulfur; 
 R 1  is selected from the group consisting of hydrogen, —(CH 2 ) n halogen, —CN, —CH 3 , NH 2 , NHR a , C 1-6  alkyl, N(CHR) n C 3-10 cycloalkyl, wherein said cycloalkyl can be independently optionally substituted with 1 or 2 groups of C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 11 , and NR a SO 2 R 11 ; 
 R is selected from Hydrogen, halogen, CN, NO 2 , NH 2 , or C 1-6  alkyl; 
 R 2  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein each recited R 2  cycloalkyl or heterocycle can be independently optionally substituted with 1 or 2 groups of C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 11 , and NR a SO 2 R 11 , 
         R 3 , R 5 , R 6 , and R 9  are independently R 7 ; 
         R 4  is selected from the group consisting of: halogen, CN, NO 2 , CF 3 , —(CHR) n COOR 11 , —(CHR) n SO 2 R 11 , C 1-4  haloalkyl, —OC 1-4 -haloalkyl, C 2-6  alkyl, —(CHR) n C(O)CF 3 , —(CHR) n C(OH)(CF 3 ) 2 , —(CH 2 ) n halogen, —OR 10 , —NR 11 R 12 , —NR a COR 11 , —NR a COOR 11 , —NR a SO 2 R 11 , —NR a CONR 11 R 12 , —COR 11 , tetrazole, —(CHR) n tetrazole, —S—C 1-6  alkyl, or —CONR 11 R 12 , —C(O)OR 11 , —SO 2 NHC(═O)CH 3 , —C(CF 3 )(CF 3 )OH, —SO 2 NH 2 , —C(O)CF 3 , 
       
       
         
           
           
               
               
           
         
         R 7  and R 10  are independently selected from the group consisting of: hydrogen, halogen, CN, NH 2 , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, —C(O)CF 3 , —(CH 2 ) n halogen, —OR a , and NR a R a ; 
         R 11  and R 12  are independently selected from the group consisting of: hydrogen, NR a C(═O)R, halogen, CN, NH 2 , NHR a , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, —S—C 1-6  alkyl, —C(═O)—(O) n —R a , and —OR a , wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 
         R a  each independently represents hydrogen or C 1-6  alkyl; and 
         n represents an integer from 0 to 3. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound administered is selected from the group consisting of:
 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;   4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid;   N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;   methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;   4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid;   N-[(4-[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino phenyl)sulfonyl]acetamide;   1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and   1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1, 1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione,   
       or a salt, prodrug, or solvate thereof. 
     
     
         3 . The method according to  claim 1 , wherein the compound administered is: 
       
         
           
           
               
               
           
         
         or a salt, prodrug, or solvate thereof. 
       
     
     
         4 . The method according to  claim 1 , wherein pancreatic cancer is treated. 
     
     
         5 . The method according to  claim 1 , wherein liver cancer is treated. 
     
     
         6 . The method according to  claim 1 , wherein stomach cancer is treated. 
     
     
         7 . The method according to  claim 1 , wherein ovarian cancer is treated. 
     
     
         8 . The method according to  claim 1 , wherein breast cancer is treated. 
     
     
         9 . The method according to  claim 1 , wherein kidney cancer is treated. 
     
     
         10 . The method according to  claim 1 , wherein blood cancer is treated. 
     
     
         11 . The method according to  claim 1 , wherein prostate cancer is treated. 
     
     
         12 . The method according to  claim 1 , wherein colon cancer is treated. 
     
     
         13 . The method according to  claim 1 , wherein brain cancer is treated. 
     
     
         14 . The method according to  claim 1 , wherein neuroblastoma cancer is treated. 
     
     
         15 . The method according to  claim 1 , wherein lung cancer is treated. 
     
     
         16 . The method according to  claim 1 , wherein tumor growth of said pancreatic, liver, stomach, ovarian, breast, kidney, blood, prostate, colon, brain, neuroblastoma, or lung cancer is reduced in said patient. 
     
     
         17 . A method for treating pancreatic, liver, stomach, ovarian, breast, kidney, blood, prostate, colon, brain, neuroblastoma, or lung cancer in a patient suffering therefrom, comprising:
 a) administering to the patient a therapeutically effective amount of a compound having a structural formula (II):   
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof; 
       wherein:
 X represents N or CH; 
 R 4  is selected from the group consisting of: —C(O)OR 11 , —C(CF 3 )(CF 3 )OH, —CF 3 , —(CHR) n COOR 11 , —(CHR) n SO 2 R 11 , —(CHR) n C(OH)(CF 3 ) 2 , 
 
       
         
           
           
               
               
           
         
         R 11  is selected from the group consisting of: hydrogen, NR a C(═O)R, halogen, CN, NH 2 , NHR a , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, —S—C 1-6  alkyl, —C(═O)—(O), —R a , —OR a , or C 1-6  alkyl, wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 
         R represents hydrogen, halogen, CN, NO 2 , NH 2 , or C 1-6  alkyl; 
         R a  each independently represents hydrogen or C 1-6  alkyl; and 
         n represents 0. 
       
     
     
         18 . The method according to  claim 17 , wherein the compound administered is selected from the group consisting of:
 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;   4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid;   N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;   methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and   ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   or a salt, prodrug, or solvate thereof.   
     
     
         19 . The method according to  claim 17 , wherein the compound administered is: 
       
         
           
           
               
               
           
         
         or a salt, prodrug, or solvate thereof. 
       
     
     
         20 . The method according to  claim 17 , wherein pancreatic cancer is treated. 
     
     
         21 . The method according to  claim 17 , wherein liver cancer is treated. 
     
     
         22 . The method according to  claim 17 , wherein stomach cancer is treated. 
     
     
         23 . The method according to  claim 17 , wherein ovarian cancer is treated. 
     
     
         24 . The method according to  claim 17 , wherein breast cancer is treated. 
     
     
         25 . The method according to  claim 17 , wherein kidney cancer is treated. 
     
     
         26 . The method according to  claim 17 , wherein blood cancer is treated. 
     
     
         27 . The method according to  claim 17 , wherein prostate cancer is treated. 
     
     
         28 . The method according to  claim 17 , wherein colon cancer is treated. 
     
     
         29 . The method according to  claim 17 , wherein brain cancer is treated. 
     
     
         30 . The method according to  claim 17 , wherein neuroblastoma cancer is treated. 
     
     
         31 . The method according to  claim 17 , wherein lung cancer is treated. 
     
     
         32 . The method according to  claim 17 , wherein tumor growth of said pancreatic, liver, stomach, ovarian, breast, kidney, blood, prostate, colon, brain, neuroblastoma, or lung cancer is reduced in said patient. 
     
     
         33 . A method for reducing tumor growth of a pancreatic cancer in a patient suffering therefrom, comprising:
 a) administering to the patient a therapeutically effective amount of a compound having a structural formula (I):   
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof; 
       wherein:
 A 1  and A 2  are independently oxygen or sulfur; 
 R 1  is selected from the group consisting of hydrogen, —(CH 2 ) n halogen, —CN, —CH 3 , NH 2 , NHR a , C 1-6  alkyl, N(CHR) n C 3-10 cycloalkyl, wherein said cycloalkyl can be independently optionally substituted with 1 or 2 groups of C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 11 , and NR a SO 2 R 11 ; 
 R is selected from Hydrogen, halogen, CN, NO 2 , NH 2 , or C 1-6  alkyl; 
 R 2  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein each recited R 2  cycloalkyl or heterocycle can be independently optionally substituted with 1 or 2 groups of C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 11 , and NR a SO 2 R 11 , 
         R 3 , R 5 , R 6 , and R 9  are independently R 7 ; 
         R 4  is selected from the group consisting of: halogen, CN, NO 2 , CF 3 , —(CHR) n COOR 11 , —(CHR) n SO 2 R 11 , C 1-4  haloalkyl, —OC 1-4 -haloalkyl, C 2-6  alkyl, —(CHR) n C(O)CF 3 , —(CHR) n C(OH)(CF 3 ) 2 , —(CH 2 ) n halogen, —OR 10 , —NR 11 R 12 , —NR a COR 11 , —NR a COOR 11 , —NR a SO 2 R 11 , —NR a CONR 11 R 12 , —COR 11 , tetrazole, —(CHR) n tetrazole, —S—C 1-6  alkyl, or —CONR 11 R 12 , —C(O)OR 11 , —SO 2 NHC(═O)CH 3 , —C(CF 3 )(CF 3 )OH, —SO 2 NH 2 , —C(O)CF 3 , 
       
       
         
           
           
               
               
           
         
         R 7  and R 10  are independently selected from the group consisting of: hydrogen, halogen, CN, NH 2 , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, —C(O)CF 3 , —(CH 2 ) n halogen, —OR a , and NR a R a ; 
         R 11  and R 12  are independently selected from the group consisting of: hydrogen, NR a C(═O)R, halogen, CN, NH 2 , NHR a , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, —S—C 1-6  alkyl, —C(═O)—(O) n —R a , and —OR a , wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 
         R a  each independently represents hydrogen or C 1-6  alkyl; and 
         n represents an integer from 0 to 3. 
       
     
     
         34 . The method according to  claim 33 , wherein the compound administered is selected from the group consisting of:
 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;   4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid;   N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1, 1, 1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione;   methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate;   4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide;   4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid;   N-[(4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide;   1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione;   2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4′-bipiperidin-1′-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and   1-amino-2-(1,4′-bipiperidin-1′-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}anthracene-9,10-dione,   
       or a salt, prodrug, or solvate thereof. 
     
     
         35 . The method according to  claim 33 , wherein the compound administered is: 
       
         
           
           
               
               
           
         
         or a salt, prodrug, or solvate thereof.