Method of treating a patient having precancerous lesions with quinazoline derivatives

Abstract

Derivatives of Quinazoline are useful for the treatment of patients having precancerous lesions. These compounds are also useful to inhibit growth of neoplastic cells.

We claim:  
     
         1 . A method of treating a patient having precancerous lesions sensitive to compounds below and in the need of treatment, comprising administering to the patient a pharmacologically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, each of which may be the same or different, are selected from a hydroxyalkyl group, an acylamino group, a carboxyl group which may be protected, or two of R1, R2, R3 or R4 may together form methylenedioxy, ethylenedioxy, or a phenyl ring;  
         R5 and R6, each of which may he the same or different, are selected from a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6 carbon atoms, an aminoalkyl grouid having from 1 to 6 carbon atoms, a carboxyalkyl group which may be protected, an alkylcarbamoyl group having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkyl group or 1,4-benzdioxylalkyl group, or further R5 and R6 may form a ring which may contain another nitrogen atom and/or oxygen atom together with the nitrogen atom to which they are bonded, which may be substituted;  
         R7 is selected from an acyl group, an alkoxyalkyl group having 2 to 8 carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which may be protected or a hydroxyalkyl group having 2 to 8 carbon atoms;  
         R8 is selected from a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted, said substitutions, which may be the same or different, are selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group having from 2 to 8 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an acyl group, an acylamino group, an alkylsulfonylamino group, a hydroiminoalkyl group, an alkyloxy-carbonylamino group, an alkyloxybarbonyloxy group or a heteroaryl group which may be substituted; or two of said substitutions may together form a saturated or unsaturated ring which may contain a nitrogen, a sulfer atom or an oxygen atom; and  
         Y is a group represented by the formula —(CH2)q— (wherein q is 0 or an integer of 1 to 8), when q is an integer of 1 to 8, each carbon atom may have from 1 to 2 substituents, or Y is a group represented by the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         2 . The method of    claim 1   , wherein R1, R2, R3, and R4, each of which may be the same or different from one another, are selected from a hydrogen atom, a cyano group, a halogen atom, or a lower alkoxy group.  
     
     
         3 . The method of    claim 2   , wherein one of R1, R2, R3 and R4 is a cyano group, a halogen atom or a methoxy group.  
     
     
         4 . The method of    claim 3   , wherein R2 is a halogen atom.  
     
     
         5 . The method of    claim 4   , wherein R2 is a chlorine atom.  
     
     
         6 . The method of    claim 5   , wherein R1, R3 and R4 are hydrogen atoms.  
     
     
         7 . The method of    claim 6   , wherein Y is a group represented by the formula —(CH2)q—, wherein q is an integer of 1 to 8.  
     
     
         8 . The method of    claim 7   , wherein R8 is benzyl group which may be substituted, said substitutions, each of which may be the same or different, are each selected from a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkenyl group, an acyl group, an acylamino group, an alkylsulfonylamino group, a hydroxyiminoalkyl group, an alkyloxycarbonylamino group, an alkyloxycarbonyloxy group or a heteroaryl group which may be substituted, or two of the substitutions may together form a saturated or unsaturated ring which may contain a nitrogen atom, a sulfer atom or an oxygen atom; and q is an integer of 1 to 8.  
     
     
         9 . The method of    claim 8   , wherein R8 is a group represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of    claim 9   , wherein R7 is a hydrogen atom.  
     
     
         11 . The method of    claim 10   , wherein R5 and R6 form a ring represented by the formula:  
       
         
           
           
               
               
           
         
         wherein R9 is selected from a hydroxyl group which may be protected, a halogen atom, a alkyl group having 1 to 8 carbon atoms, a lower alkoxy group, a carboxyl group which may be protected, a hydroxyalkyl group, a carboxyalkyl group and a heteroacyl group.  
       
     
     
         12 . The method of    claim 10   , wherein said compound is 2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl) amino-6-choroquinazolin.  
     
     
         13 . The method of    claim 1   , wherein Y is a group represented by the formula —(CH2)q—, wherein q is an integer of 1 to 8.  
     
     
         14 . The method of    claim 13   , wherein R8 is a group represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of    claim 14   , wherein one of R1, R2, R3 and R4 is a cyano group, a chlorine atom or a methoxy atom.  
     
     
         16 . The method of    claim 15   , wherein R2 is a halogen atom.  
     
     
         17 . The method of    claim 16   , wherein R2 is a chlorine atom.  
     
     
         18 . The method of    claim 17   , wherein R1, R3 and R4 are hydrogen atoms.  
     
     
         19 . The method of    claim 18   , wherein R5 and R6 form a ring which is represented by the formula:  
       
         
           
           
               
               
           
         
         wherein R9 is selected from a hydroxyl group which may be protected, a halogen atom, a alkyl group having 1 to 8 carbon atoms, a lower alkoxy group, a carboxyl group which may be protected, a hydroxyalkyl group, a carboxyalkyl group and a heteroacyl group.  
       
     
     
         20 . The method for inhibiting the growth of neoplastic cells sensitive to a compound below, comprising exposing said cells to an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, each of which may be the same or different, are selected from a hydroxyalkyl group, an acylamino group, a carboxyl group which may be protected, or two of R1, R2, R3 or R4 may together form methylenedioxy, ethylenedioxy, or a phenyl ring;  
         R5 and R6, each of which may be the same or different, are selected from a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms, a carboxyalkyl group which may be protected, an alkylcarbamoyl group having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkyl group or 1,4-benzdioxylalkyl group, or further R5 and R6 may form a ring which may contain another nitrogen atom and/or oxygen atom together with the nitrogen atom to which they are bonded, which may be substituted;  
         R7 is selected from an acyl group, an alkoxyalkyl group having 2 to 8 carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which may be protected or a hydroxyalkyl group having 2 to 8 carbon atoms;  
         R8 is selected from a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted, said substitutions, which may be the same or different, are selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group having from 2 to 8 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an acyl group, an acylamino group, an alkylsulfonylamino group, a hydroiminoalkyl group, an alkyloxy-carbonylamino group, an alkyloxybarbonyloxy group or a heteroaryl group which may be substituted; or two of said substitutions may together form a saturated or unsaturated ring which may contain a nitrogen, a sulfer atom or an oxygen atom; and  
         Y is a group represented by the formula —(CH2)q— (wherein q is 0 or an integer of 1 to 8), when q is an integer of 1 to 8, each carbon atom may have from 1 to 2 substituents, or Y is a group represented by the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         21 . The method of    claim 20    wherein R1, R2, R3 and R4 may independently be a cyano group, a halogen or a methoxy group.  
     
     
         22 . The method of    claim 21   , wherein R2 is a halogen.  
     
     
         23 . The method of    claim 22   , wherein R8 is represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of    claim 23   , wherein R5 and R6 form a ring which is represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of    claim 24   , wherein said compound is 2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl) amino-6-chloroquinazolin.  
     
     
         26 . The method of    claim 21    wherein R7 and R8 are each hydrogen; q is zero; and R5 and R6 form a substituted ring represented by the structure:  
       
         
           
           
               
               
           
         
         and R10 is hydrogen, amino, lower alkyl group, or NHCO2R11 in which R11 is a lower alkyl group.  
       
     
     
         27 . The method of regulating apoptosis in human cells, comprising exposing said cells to an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, each of which may be the same or different, are selected from a hydrogen atom, a alkoxy group having from 1 to 6 carbon atoms, a hydroxyalkyl group, a cyano group, an acylamino group, a carboxyl group which may be protected or two of R1, R2, R3 or R4 may together form methylenedioxy, ethylenedioxy, or a phenyl ring;  
         R5 and R6, each of which may be the same or different, are selected from a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxylakyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms, a carboxyalkyl group which may be protected, alkylcarbamoyl group having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkyl group or a 1,4-benzdioxylalkyl group, or further R5 and R6 may form a ring which may contain another nitrogen atom and or oxygen atom together with the nitrogen atom to which they are bonded, and which may be substituted;  
         R7 is selected from a hydrogen atom, a alkyl group having 1 to 6 carbon atoms, an acyl group, a alkoxyalkyl group having 2 to 8 carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which may be protected or a hydroxyalkyl group having 2 to 8 carbon atoms;  
         R8 is selected from a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted or a benzyl group which may be substituted, said substitutions, which may be the same or different, are selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a alkyl group having from 1 to 6 carbon atoms, a alkoxy group having from 1 to 6 carbon atoms, a alkoxyalkyl group having from 2 to 8 carbon atoms, a alkenyl group having from 2 to 8 carbon atoms, an acyl group an acylamino group, an alkylsulfonylamino group, a hydroiminoalkyl group, an alkyloxy-carbonylamino group, an alkyloxybarbonyloxy group or a heteroaryl group which may be substituted: or two of said substitutions may together from a saturated or unsaturated ring which may contain a nitrogen, a sulfer atom or an oxygen atom; and  
         Y is a group represented by the formula —(CH2)q— (wherein q is 0 or an integer of 1 to 8), when q is an integer of 1 to 8, each carbon atom may have from 1 to 2 substituents, or Y is a group represented by the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         28 . The method of    claim 26   , wherein R2 is a halogen.  
     
     
         29 . The method of    claim 27   , wherein R8 is represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of    claim 28   , wherein R5 and R6 form a ring which is represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of    claim 29   , wherein said compound is 2-(4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazolin.