Aminoquinoline compounds having anticancer activity

Abstract

Amine compounds having activity against inflammation, fungi, unicellular parasitic microorganisms, and cancer are described. The compounds contain a monocyclic, bicyclic, or tricyclic aromatic ring having one, two, or three ring nitrogen atoms.

What is claimed is: 
     
         1 . A method for treating a neoplastic disease in a mammalian subject, comprising administering to the subject an effective amount of a compound represented by Formula IA1a or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
         p is 0 or 1, provided that if p is 1 then n must not be 0 or 1; 
         q is 0 or 1; 
         one of R 1  and R 2  is hydrogen and the other is selected from the group consisting of hydrogen, halo, methyl, and perfluoromethyl; 
         R 4  is hydrogen or halo; and 
         R 5  is selected from the group consisting of hydrogen; halo; unbranched or branched alkyl having from 1 to 6 carbon atoms unsubstituted or substituted by phenyl or phenoxy; alkoxy having from 1 to 10 carbon atoms unsubstituted or substituted by phenyl or phenoxy, provided that when substituted by phenoxy the alkoxy must have more than one carbon atom; phenyl; phenoxy; C(O)OR 6 ; C(O)NHR 6 ; or NHC(O)R 6 , wherein R 6  is alkyl having from 1 to 6 carbon atoms. 
       
     
     
         2 . The method of  claim 1  wherein R 1  is hydrogen and R 2  is hydrogen. 
     
     
         3 . The method of  claim 2 , wherein p is 1 and R 4  is hydrogen. 
     
     
         4 . The method of  claim 3 , wherein R 5  is hydrogen. 
     
     
         5 . The method of  claim 4 , selected from the group consisting of:
 N-[8-(Benzyloxy)octyl]quinolin-4-amine,   N-(6-Phenoxyhexyl)quinolin-4-amine,   N-(8-Phenoxyoctyl)quinolin-4-amine.   
     
     
         6 . The method of  claim 3 , wherein q is 0, and R 5  is alkoxy having from 1 to 6 carbon atoms unsubstituted or substituted by phenyl. 
     
     
         7 . The method of  claim 6 , wherein R 5  is in the ortho position. 
     
     
         8 . The method of  claim 7 , wherein the compound is selected from the group consisting of:
 N-{2-[2-(Hexyloxy)phenoxy]ethyl}quinolin-4-amine,   N-{3-[2-(Hexyloxy)phenoxy]propyl}quinolin-4-amine,   N-{4-[2-(Hexyloxy)phenoxy]butyl}quinolin-4-amine,   N-[3-(2-Ethoxyphenoxy)propyl]quinolin-4-amine,   N-[3-(2-Methoxyphenoxy)propyl]quinolin-4-amine,   N-{3-[2-(Benyloxy)phenoxy]propyl}quinolin-4-amine.   
     
     
         9 . The method of  claim 6 , wherein R 5  is in the meta position. 
     
     
         10 . The method of  claim 9 , wherein the compound is selected from the group consisting of:
 N-[8-(3-Methoxyphenoxy)octyl]quinolin-4-amine,   N-{4-[3-(Hexyloxy)phenoxy]butyl}quinolin-4-amine,   N-{3-[3-(Hexyloxy)phenoxy]propyl}quinolin-4-amine,   N-{12-[3-(Hexyloxy)phenoxy]ethyl}quinolin-4-amine.   
     
     
         11 . The method of  claim 6 , wherein R 5  is in the para position. 
     
     
         12 . The method of  claim 11 , wherein the compound is selected from the group consisting of:
 N-[8-(4-Methoxyphenoxy)octyl]quinolin-4-amine,   N-[6-(4-Methoxyphenoxy)hexyl]quinolin-4-amine,   N-{2-[4-(Hexyloxy)phenoxy]ethyl}quinolin-4-amine,   N-{3-[4-(Hexyloxy)phenoxy]propyl}quinolin-4-amine,   N-{4-[4-(Hexyloxy)phenoxy]butyl}quinolin-4-amine.   
     
     
         13 . The method of  claim 3 , wherein R 5  is unbranched or branched alkyl having from 1 to 6 carbon atoms. 
     
     
         14 . The method of  claim 13 , wherein the compound is selected from the group consisting of:
 N-[8-(m-Tolyloxy)octyl]quinolin-4-amine,   N-[8-(p-Tolyloxy)octyl]quinolin-4-amine,   N-[8-(o-Tolyloxy)octyl]quinolin-4-amine,   N-[8-(4-tert-Butylphenoxy)octyl]quinolin-4-amine.   
     
     
         15 . The method of  claim 3 , wherein R 5  is fluoro. 
     
     
         16 . The method of  claim 15 , wherein the compound is selected from the group consisting of:
 N-[8-(4-Fluorophenoxy)octyl]quinolin-4-amine,   N-[8-(3-Fluorophenoxy)octyl]quinolin-4-amine,   N-[8-(2-Fluorophenoxy)octyl]quinolin-4-amine.   
     
     
         17 . The method of  claim 2 , wherein p is 0. 
     
     
         18 . The method of  claim 17  wherein q is 0. 
     
     
         19 . The method of  claim 18 , wherein n is 0 
     
     
         20 . The method of  claim 19 , wherein the compound is selected from the group consisting of:
 N-(Biphenyl-4-yl)quinolin-4-amine,   N-(4-Hexylphenyl)quinolin-4-amine,   Hexyl 4-(quinolin-4-ylamino)benzoate,   N-(4-Phenoxyphenyl)quinolin-4-amine,   N-(3-Phenoxyphenyl)quinolin-4-amine,   N-(2-Phenoxyphenyl)quinolin-4-amine,   N-[4-(Quinolin-4-ylamino)phenyl]hexanamide,   N-[3-(Quinolin-4-ylamino)phenyl]hexanamide,   N-Hexyl-4-(quinolin-4-ylamino)benzamide,   N-Hexyl-3-(quinolin-4-ylamino)benzamide.   
     
     
         21 . The method of  claim 19 , wherein R 5  is alkoxy having from 1 to 10 carbon atoms unsubstituted or substituted by phenyl. 
     
     
         22 . The method of  claim 21 , wherein the compound is selected from the group consisting of:
 N-(4-Methoxyphenyl)quinolin-4-amine,   N-[4-(Benzyloxy)phenyl]quinolin-4-amine,   N-(4-Butoxyphenyl)quinolin-4-amine,   N-[4-(Hexyloxy)phenyl]quinolin-4-amine,   N-[3-(Benzyloxy)phenyl]quinolin-4-amine,   N-[3-(Hexyloxy)phenyl]quinolin-4-amine,   N-[2-(Benzyloxy)phenyl]quinolin-4-amine,   N-[2-(Hexyloxy)phenyl]quinolin-4-amine,   N-[2-Fluoro-4-(hexyloxy)phenyl]quinolin-4-amine.   
     
     
         23 . The method of  claim 18 , wherein n is 1 or 2. 
     
     
         24 . The method of  claim 23 , wherein the compound is selected from the group consisting of:
 N-Benzylquinolin-4-amine,   N-Phenethylquinolin-4-amine.   
     
     
         25 . The method of  claim 17 , wherein q is 1. 
     
     
         26 . The method of  claim 25 , wherein R 5  is alkoxy having from 1 to 10 carbon atoms. 
     
     
         27 . The method of  claim 26 , wherein the compound is selected from the group consisting of:
 N-[4-(Hexyloxy)benzyl]quinolin-4-amine,   N-[3-(Hexyloxy)benzyl]quinolin-4-amine,   N-[2-(Hexyloxy)benzyl]quinolin-4-amine,   N-[3-Fluoro-4-(hexyloxy)benzyl]quinolin-4-amine,   N-[4-(Decyloxy)benzyl]quinolin-4-amine,   N-[3-(Decyloxy)benzyl]quinolin-4-amine.   
     
     
         28 . The method of  claim 25 , wherein R 5  is phenoxy, or alkoxy having from 1 to 10 carbon atoms substituted by phenyl. 
     
     
         29 . The method of  claim 28 , wherein the compound is selected from the group consisting of:
 N-(3-Phenoxybenzyl)quinolin-4-amine,   N-[3-(Benzyloxy)benzyl]quinolin-4-amine,   N-(3-Phenethoxybenzyl)quinolin-4-amine.   
     
     
         30 . The method of  claim 1 , wherein the neoplastic disease is a hematologic cancer. 
     
     
         31 . The method of  claim 1  wherein the neoplastic disease is a solid tumor. 
     
     
         32 . The method of  claim 1  wherein the compound is administered topically to the subject. 
     
     
         33 . The method of  claim 1  wherein the compound or composition is administered systemically to the subject. 
     
     
         34 . The method of  claim 33 , wherein the compound is administered orally, rectally, parenterally, or nasally.