Method and compositions for inhibition of adaptor protein/tyrosine kinase interactions

Abstract

The present invention relates to methods and compositions for the inhibition of adaptor protein/protein tyrosine kinase protein interactions, especially wherein those interactions involving a protein tyrosine kinase capable of complexing with a member of the SH2- and/or SH3-containing family of adaptor proteins are associated with a cell proliferative disorder. Specifically, the present invention relates to particular compounds, especially quinazoline derivative compounds, and methods utilizing such compounds.

What is claimed is:  
     
         1 . A pharmaceutical composition suitable for administration to humans which comprises the compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically salt thereof; and a pharmaceutically acceptable carrier.  
     
     
         2 . A pharmaceutical composition suitable for administration to humans which comprises the compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.  
     
     
         3 . A method of ameliorating symptoms of a cell proliferative disorder wherein the cell proliferative disorder involves a protein tyrosine kinase polypeptide/adaptor polypeptide complex with an amount of a compound sufficient to disrupt protein tyrosine kinase polypeptide/adaptor polypeptide complexes of the cell so that symptoms of the cell proliferative disorder are ameliorated; wherein said compound has either of the following formulas:  
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3  wherein the cell proliferative disorder occurs in a mammal and the compound contacts the cell within a mammal so that the symptoms of the cell proliferative disorder in the mammal are ameliorated.  
     
     
         5 . The method of  claim 3  wherein the cell proliferative disorder is a BCR-ABL-associated cancer, a glioma, a glioblastoma, a melanoma, an ovarian cancer, a breast cancer, or a prostate cancer.  
     
     
         6 . A method of ameliorating symptoms of a cell proliferative disorder wherein the cell proliferative disorder involves a protein tyrosine kinase polypeptide/adaptor polypeptide complex, comprising: contacting a cell capable of forming the protein tyrosine kinase polypeptide/adaptor polypeptide complex with an amount of the pharmaceutical composition of  claim 1  or  2  sufficient to disrupt protein tyrosine kinase polypeptide/adaptor polypeptide complexes of the cell so that symptoms of the cell proliferative disorder are ameliorated.  
     
     
         7 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are each independently hydrogen, lower alkyl, acetyl, aryl, alkylaryl or higher alkyl acid ester, and wherein at least one of R1 and R2 is other than hydrogen;  
 R3 to R12 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, mercapto or 2-methylbut-2-en-4-yl; and wherein at least one of R11 and R12 is 2-methylbut-2-en-4-yl.  
 
     
     
         8 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are both H;  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, mercapto or 2-methylbut-2-en-4-yl; and  
 R11 and R12 are each independently H or 2-methylbut-2-en-4-yl, wherein at least one of R11 and R12 is 2-methylbut-2-en-4-yl;  
 wherein at least one of R3 to R10 is other than H.  
 
     
     
         9 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are each independently aryl, alkylaryl and higher alkyl acid ester; and  
 R3 to R12 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, OH, alkoxy, nitro, fluoro, chloro, iodo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, or mercapto.  
 
     
     
         10 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1, R2, R11 and R12 are H; and  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, alkoxy, hydroxy, nitro, halo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, or mercapto, wherein at least one of R3 to R10 is other than H; 
 (a) when R4-R10 are each H, R3 may not be 2-methylbut-2-en-4-yl or 2-hydroxy-2-methylbut-4-yl;  
 (b) when R4-R6 and R8-R10 are each H, R3 and R7 may not simultaneously be 2-methylbut-2-en-4-yl;  
 (c) when R3-R4, R6-R8 and R10 are H, R5 and R9 may not simultaneously be 2-methylbut-2-en-4-yl or 3-methyl-n-butyl;  
 (d) when R3, R5-R7, R9-R10 are H, R4 and R8 may not both be 2-methylbut-2-en-4-yl or 2-methylbut-1,3-dien-4-yl, and R4 and R8 may not be 2-methylbut-2-en-4-yl and 2-methylbut-1,3-dien-4-yl.  
 
 
     
     
         11 . The compound of  claim 10 , wherein the compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R3-R5 and R7-R9 are H and either or both of R6 and R10 are 2-methylbut-2-en-4-yl.  
     
     
         12 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 at least one of R1 and R2 is acetyl;  
 R11 and R12 are H; and  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, and mercapto, wherein: 
 (a) when both R1 and R2 are acetyl; or when one of R1 and R2 is acetyl and R3-R4, R6-R8 and R10-R12 are H; R5 and R9 may not simultaneously be 2-methylbut-2-en-4-yl;  
 (b) when both R1 and R2 are acetyl and when R4-R6 and R8-R10 are H, R3 and R7 may not simultaneously be 2-methylbut-2-en-4-yl;  
 (c) when both R1 and R2 are acetyl and when R3, R5-R7, and R9-R10 are H, R4 and R8 may not simultaneously be 2-methylbut-2-en-4-yl.  
 
 
     
     
         13 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 at least one of R1 and R2 is lower alkyl;  
 R11 and R12 are H; and  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, alkenyl, alkenylcarboxy, aryl, alkylaryl, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxamide, carboxy, sulfonyl, sulfonamide, amino, and mercapto, wherein: 
 (a) when both R1 and R2 are methyl, at least one of R3 to R10 must be a group other than H;  
 (b) when both R1 and R2 are methyl, and R4-R10 are H, R3 may not be 2-methylbut-2-en-4-yl;  
 (c) when both R1 and R2 are methyl, and R4-R6 and R8-R10 are H, R3 and R7 may not simultaneously be 2-methylbut-2-en-4-yl;  
 (d) when both R1 and R2 are methyl, and R3-R4, R6-R8 and R10 are H, R5 and R9 may not simultaneously be 2-methylbut-2-en-4-yl.  
 
 
     
     
         14 . The compound of  claim 10  wherein R4 is 2-methylbut-2-en-4-yl and R3 and R5-R10 are H; or R5 is 2-methylbut-2-en-4-yl and R3-R4 and R6-R10 are H; or R6 is 2-methylbut-2-en-4-yl, and R3-R5 and R7-R10 are H.  
     
     
         15 . The Compounds: 
 (a) 2,5-Diacetoxy-3,6-di-[2-(2-methylbut-2-en-4-yl)indol-3-yl]1,4-quinone;    (b) 2,5-Diacetoxy-3,6-di-[2-(3-methyl-n-butyl)indol-3-yl]1,4-quinone;    (c) 2,5-Dihydroxy-3,6-di-[2-(3-methyl-n-butyl)indol-3-yl]1,4-quinone;    (d) 3,6-Di-[5-(bromo)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (e) 3,6-Di-[2-(allyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (f) 2,5-Dihydroxy-3,6-di-[2-(n-propyl)indol-3-yl]1,4-quinone;    (g) 3,6,-Di-[2-(aminocarbonyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (h) 2,5-Diacetoxy-3,6-di-[2 (aminocarbonyl)indol-3-yl]-1,4-quinone;    (i) 3,6-Di-[2-allylindol-3-yl)-2,5-dibenzoyloxy-1,4-quinone;    (j) 2,5-Dihydroxy-3,6-di-[2-(cyano)indol-3-yl]1,4-quinone;    (k) 2,5-Dihydroxy-3,6-di-[4-(methoxycarbonyl)indol-3-yl]1,4-quinone;    (l) 2,5-Dihydroxy-3,6-di-[5,7-(dimethoxy)indol-3-yl]1,4-quinone;    (m) 2,5-Dihydroxy-3,6-di-[4,7-(dimethoxy)indol-3-yl]1,4-quinone;    (n) 2,5-Dihydroxy-3,6-di-[5-(nitro)indol-3-yl]1,4-quinone;    (o) 3,6-Di-[4(4-chlorobenzoylamino)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (p) 3,6-di-[2-(4-chlorophenyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (q) 2,5-Dihydroxy-3,6-di-[2-(4-fluorophenyl)indol-3-yl]1,4-quinone;    (r) 2,5-Dihydroxy-3,6-di-[4,6-(dimethoxy)indol-3-yl]1,4-quinone;    (s) 2,5-Dihydroxy-3,6-di-[2-(5-hydroxy-6-methoxy)indol-3-yl]1,4-quinone;    (t) 2,5-Dihydroxy-3,6-di-[4-(cyano)indol-3-yl]1,4-quinone;    (u) 2,5-Dihydroxy-3,6-di-[5-(4-trifluoromethylphenylaminocarbonyl)indol-3 -yl]1,4-quinone;    (v) 2,5-Dihydroxy-3,6-di-[2-(4-trifluoromethylphenylaminocarbonyl)indol-3 -yl]1,4 -quinone;    (w) 3,6-Di-[2-(5-bromo-6-nitro)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (x) 2,5-Dimethoxy-3,6-di-[2-(2-methylbut-2-en-4-yl)indol-3-yl]1,4-quinone;    (y) 2,5-Dimethoxy-3,6-di-[2-(3-methyl-n-butyl)indol-3-yl]1,4-quinone.    
     
     
         16 . The compounds: 
 (a) 2,5-Dihydroxy-3,6-di-[2-(methyl)indol-3-yl]-1,4-quinone;    (b) 3,6-Di-(2-ethylindol-3-yl)-2,5-dihydroxy-1,4-quinone;    (c) 3,6-Di-(2-butylindol-3-yl)-2,5-dihydroxy-1,4-quinone;    (d) 3,6-Di-[2-(but-1-en-4-yl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (e) 2,5-Dihydroxy-3,6-di-[2-(2-methylbut-1-en-4-yl)indol-3-yl]-1,4-quinone;    (f) 2,5-Dihydroxy-3,6-di-(2-(4-methyl-n-pentyl)indol-3-yl]-1,4-quinone;    (g) 2,5-Dihydroxy-3,6-di-[2-(2-phenylethyl)indol-3-yl]-1,4-quinone;    (h) 3,6-Di-[(5-carboxy-2-ethyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (i) 3,6-Di-[[5-carboxy-2-(n-propyl)]indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (j) 3,6-Di-[[5-carboxy-2-(3-methyl-n-butyl)]indol-3-yl)-2,5-dihydroxy-1,4-quinone;    (k) 3,6-Di-[2-(4-carboxy-n-butyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (l) 3-[[5-Carboxy-2-(3-methyl-n-butyl)]indol-3-yl]-2,5-dihydroxy-6-(indol-3-yl)1,4-quinone;    (m) 3,6-Di-[(5-amino-2-ethyl)indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (n) 3,6-Di-[[5-amino-2-(n-propyl)]indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (o) 3,6-Di-[5-amino-2-(3-methyl-n-butyl)]indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (p) 2,5-Diacetoxy-3,6-di-[2-(3-methyl-n-butyl)indol-3-yl]-1,4-quinone;    (q) 3,6-Di-[[2-ethyl-5-(4-methylphenylsulfonylamino)]indol-3-yl]-2,5-dihydroxy-1,4-quinone;    (r) 2,5-Dihydroxy-3,6-di-[[5-(4-methylphenylsulfonylamino)-2-(n-propyl)]indol-3-yl]-1,4-quinone;    (s) 2,5-Dihydroxy-3,6-di-[[2-(3-methyl-n-butyl)-5-(4-methylphenylsulfonylamino)]indol-3-yl]-1,4-quinone;    (t) 2,5-Dihydroxy-3,6-di-[2-(2-methylpent-2-en-5-yl) indol-3-yl]-1,4-quinone.    
     
     
         17 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are each independently hydrogen, lower alkyl, acetyl, aryl, alkylaryl or higher alkyl acid ester,  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, aryl, alkylaryl, alkenyl, alkenylcarboxy, OH, alkoxy, nitro, halo, trihalomethyl, amide,-carboxyamide, carboxy, sulfonyl, sulfonamide, amino, mercapto, 4-methylphenylsulfonylamino, or 2-methylbut-2-en-4-yl; and  
 R11 and R12 are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, aryl, alkylaryl, alkylcarboxy, alkenylcarboxy, but-1-en-4-yl, 2-methylbut-1-en-4-yl, 4-methyl-n-pentyl, 2-phenylethyl, 2-methylpent-2-en-4-yl, and 4-carboxy-n-butyl, wherein at least one of R11 and R12 is other than hydrogen.  
 
     
     
         18 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are each independently hydrogen, lower alkyl, acetyl, aryl, alkylaryl or higher alkyl acid ester,  
 R3 to R10 are each independently H. alkyl, alkylcarboxy, aryl, alkylaryl, alkenyl, alkenylcarboxy, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxyamide, carboxy, sulfonyl, sulfonamide, amino, mercapto, 4-methylphenylsulfonylamino, or 2-methylbut-2-en-4-yl; and  
 R11 and R12 are both 3-methyl-n-butyl.  
 
     
     
         19 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R1 and R2 are each independently hydrogen, lower alkyl, acetyl, aryl, alkylaryl or higher alkyl acid ester,  
 R3 to R10 are each independently H, alkyl, alkylcarboxy, aryl, alkylaryl, alkenyl, alkenylcarboxy, OH, alkoxy, nitro, halo, trihalomethyl, amide, carboxyamide, carboxy, sulfonyl, sulfonamide, amino, mercapto, 4-methylphenylsulfonylamino, or 2-methylbut-2-en-4-yl and wherein at least one of R3 to R10 is other than hydrogen; and  
 R11 and R12 are each independently hydrogen or 3-methyl-n-butyl.  
 
     
     
         20 . A pharmaceutical composition suitable for administration to humans comprising a compound of claims  7 ,  8 ,  9 ,  10 ,  11 ,  12 ,  13 ,  14 ,  15 ,  16 ,  17 ,  18 , or  19 ; and a pharmaceutically acceptable carrier.  
     
     
         21 . A method of ameliorating symptoms of a cell proliferative disorder wherein the cell proliferative disorder involves a protein tyrosine kinase polypeptide/adaptor polypeptide complex, comprising: contacting a cell capable of forming the protein tyrosine kinase polypeptide/adaptor polypeptide complex with an amount of the pharmaceutical composition of claim  20  sufficient to disrupt protein tyrosine kinase polypeptide/adaptor polypeptide complexes of the cell so that symptoms of the cell proliferative disorder are ameliorated.