Methods for synthesizing heterocycles and therapeutic use of the heterocycles for cancers

Abstract

The present invention provides methods for synthesizing novel tetrahydroquinoline derivatives that are useful for cancer chemotherapy and anti-viral applications. The present invention provides compounds useful for cancer chemotherapy and methods for the preparation of these compounds. The present invention also includes cancer chemotherapy methods.

1 : A compound having a formula of Structure 1:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkylaryl, heteroaryl, acyl, acylalkyl, carboxy, carboxamido, trialkylsilyl, aryldialkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, thio, alkylthio, arylthio, acyclthio, amino, alkylamino, dialkylamino, acylamino, arylamino, diarylamino, and carboxamido;  
 n ranges from 0 to 4;  
 X is selected from the group consisting of —O—, —S—, —S(O)—, —S(O2)-, —CH2-, —NR 10 — where R 10  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkylaryl, heteroaryl, acyl, acylalkyl, carboxy, carboxamido, trialkylsilyl, and aryldialkyl group; or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . (canceled)  
   
   
       3 : The compound of  claim 1  wherein said pharmaceutically acceptable salt is selected from the group consisting of chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, malate, citrate, benzoate, salicylate, ascorbate, and mixtures thereof.  
   
   
       4 : The compound of  claim 1  wherein the compound is in the form of a prodrug thereof.  
   
   
       5 : The compound of  claim 1  wherein the compound is in the form of a liposome delivery system.  
   
   
       6 : The compound of  claim 1  wherein R 1 , R 2 , R 3  or R 4  is substituent containing a nitrogen atom.  
   
   
       7 : The compound of  claim 1  wherein R1, R2, R3, or R4 is an alkoxy, hydroxyl, or a carboxylate ester.  
   
   
       8 : The compound of  claim 1  wherein the compound is in optically pure or enriched form.  
   
   
       9 : The compound of  claim 1  wherein the compound is a pure stereoisomer or a mixture of stereoisomers.  
   
   
       10 - 18 . (canceled)  
   
   
       19 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 1 , and a pharmaceutically acceptable carrier.  
   
   
       20 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 19 .  
   
   
       21 : The method of  claim 20  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       22 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 19 .  
   
   
       23 : A compound having a formula of Structure 2:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1 , R 2 , R 3 , and R 4  are each independently selected from the group consisting of amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, acylamino, arylamino, diarylamino, and carboxamido group;  
 R 5  is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, alkynyl, aryl, and carboxyl group;  
 n is 1 or 2; and  
 X is selected from the group consisting of —O—, —S—, or —NR 11 —, where R 11  is hydrogen, alkyl, alkenyl, aryl, alkynyl, aryl, and carboxyl group, or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       24 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 23 , and a pharmaceutically acceptable carrier.  
   
   
       25 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 24 .  
   
   
       26 : The method of  claim 25  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       27 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 24 .  
   
   
       28 : A compound having a formula of Structure 3:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2  is selected from the group consisting of hydroxyl, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, acylamino, arylamino, diarylamino, and carboxamido group;  
 R 8  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkylaryl, heteroaryl, acyl, acylalkyl, carboxy, carboxamido, trialkylsilyl, aryldialkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, thio, alkylthio, arylthio, acyclthio, amino, alkylamino, dialkylamino, acylamino, arylamino, diarylamino, and carboxamido; and  
 n is 1 or 2, or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       29 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 28 , and a pharmaceutically acceptable carrier.  
   
   
       30 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 29 .  
   
   
       31 : The method of  claim 35  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       32 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 29 .  
   
   
       33 : A compound having a formula of Structure 4:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 13 , R 12 , and R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, alkynyl, aryl, and carboxyl group, or R 13  and R 12  are connected to form a ring of 3 to 10 atoms; and  
 n is 1 or 2, or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       34 : The compound of  claim 33  wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       35 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 33 , and a pharmaceutically acceptable carrier.  
   
   
       36 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 35 .  
   
   
       37 : The method of  claim 36  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       38 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 35 .  
   
   
       39 : A compound having a formula of Structure 5:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1 , R 2 , R 3 , and R 4  is selected from the group consisting of amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, acylamino, arylamino, diarylamino, and carboxamido group;  
 R 5  is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, alkynyl, aryl, and carboxyl group; and  
 n is 0 or 1; or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       40 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 39 , and a pharmaceutically acceptable carrier.  
   
   
       41 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 40 .  
   
   
       42 : The method of  claim 41  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       43 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 40 .  
   
   
       44 : A compound having a formula of Structure 6:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X and Y are each independently selected from a group consisting of hydrogen, alkyl, akenyl, aryl, alkynyl, aryl, and carboxyl group; and  
 n is 0 or 1; or  
 a pharmaceutically acceptable salt thereof.  
 
   
   
       45 : A pharmaceutical composition for treating a disorder, symptoms or conditions thereof in a patient, comprising a therapeutically effective amount of the compound of  claim 44 , and a pharmaceutically acceptable carrier.  
   
   
       46 : A method of treating a viral infection, comprising administering to a patient in need thereof a viral infection treating effective amount of the pharmaceutical composition of  claim 45 .  
   
   
       47 : The method of  claim 46  wherein the viral infection is initiated by a virus selected from the group consisting of RNA viruses and DNA viruses.  
   
   
       48 : A method of treating a cancer excluding lung cancer, CNS cancer, and breast cancer, comprising administering to a patient in need thereof an cancer treating effective amount of the composition of  claim 45 .  
   
   
       49 : A method of making the compound of  claim 1  comprising: 
 reacting an aniline derivative having the formula:                          with a reactant selected from the group consisting of cyclic enol ethers, cyclic thioenolethers, cyclic amines, cyclic hemiacetals, and cyclic aminols to yield the compound of  claim 1 .    
   
   
       50 : The method of  claim 49  wherein the reacting step is carried out in the presence of a Lewis acid.  
   
   
       51 : The method of  claim 50  wherein the reactant is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is selected from the group consisting of O, S, NR 14  where R 14  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkylaryl, heteroaryl, acyl, acylalkyl, carboxy, carboxamido, trialkylsilyl, and aryldialkyl; and  
 Y is selected from the group consisting of HO, alkoxyl, aryloxy, heteroaryloxy, alkenoxy, alkynoxy, carboxyl, chloro, bromo, iodo, fluoro, trialkylsiloxy, thio, alkylsulfuryl, arylsulfuryl, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, arylphosphoryl, amino, alkylamino, arylamino, and carboxyamino.  
 
   
   
       52 : The method of  claim 51  wherein the Lewis acid is indium chloride in the presence of an aqueous medium.  
   
   
       53 : The method of  claim 52  wherein: 
 R 1 , R 3 , R 4 , and R of the aniline derivative is hydrogen; and    the reactant is selected from the group consisting of: