LPAAT-beta inhibitors and uses thereof

Abstract

The invention relates to triazines and the use thereof to inhibit lysophosphatidic acid acyltransferase β (LPAAT-β) activity. The invention further relates to methods of treating cancer using said triazines. The invention also relates to methods for screening for LPAAT-β activity.

What is claimed is:  
     
         1 . A compound of the Formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is halo, hydroxy, alkylmercapto, mercapto, alkoxy, aryloxy or substituted amino;  
 R 2 , R 3 , R 4  and R 5 , each of which may be same or different, are hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl or substituted aryl; or  
 R 2  and R 3  or R 4  and R 5 , together with the nitrogen to which they are attached, form a piperidine, piperazine, or a morpholine ring; or pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound of  claim 1 , wherein R 1  is chloro, R 2  and R 4  are hydrogen and R 3  and R 5  are phenyl; or pharmaceutically acceptable salts thereof.  
     
     
         3 . A compound of  claim 1 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is phenyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         4 . A compound of  claim 1 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is t-butyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         5 . A compound selected from the group consisting of 6-chloro-N-(4-methoxy-phenyl)-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-butyl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-isopropyl-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-tert-butyl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, (4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-naphthalen-1-yl-amine, N-tert-butyl-6-chloro-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-cyclo-hexyl-N′-isopropyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-2-methyl-propan-1-ol, 6-chloro-N-isopropyl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-chloro-phenyl)-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, N-allyl-6-chloro-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-ethanol, N-tert-butyl -6-chloro-N′-cyclopentyl-[1,3,5]triazine-2,4-di amine, 6-chloro-N-(4-methoxyphenyl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl -6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-indan-5-yl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-chloro-phenyl)-N′-propyl-[1,3,5]triazine-2,4-diamine, N-(4-chloro-phenyl)-6-methoxy-N′-propyl-[1,3,5]triazine-2,4-diamine and N-(4-chloro-phenyl)-6-methylsulfanyl-N′-phenyl-[1,3,5]triazine-2,4-diamine.  
     
     
         6 . A compound of  claim 1 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is 4-methoxyphenyl and R 5  is 4-chlorophenyl; or pharmaceutically acceptable salts thereof.  
     
     
         7 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . A method for inhibiting LPAAT-β (lysophosphatidic acid acyltransferase β) comprising contacting LPAAT-β with an effective amount of a compound of the Formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is halo, hydroxy, alkylmercapto, mercapto, alkoxy, aryloxy or substituted amino;  
 R 2 , R 3 , R 4  and R 5 , each of which may be same or different, are hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl or substituted aryl; or  
 R 2  and R 3  or R 4  and R 5 , together with the nitrogen to which they are attached, form a piperidine, piperazine, or a morpholine ring; or pharmaceutically acceptable salts thereof; thereby inhibiting LPAAT-β.  
 
     
     
         9 . The method of  claim 8 , wherein said LPAAT-β is found in an animal.  
     
     
         10 . The method of  claim 9 , wherein said animal is a mammal.  
     
     
         11 . The method of  claim 10 , wherein said mammal is a human.  
     
     
         12 . The method of  claim 8 , wherein R 1  is chloro, R 2  and R 4  are hydrogen and R 3  and R 5  are phenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         13 . The method of  claim 8 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is phenyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         14 . The method of  claim 8 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is t-butyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         15 . The method of  claim 8 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3  is 4-methoxyphenyl and R 5  is 4-chlorophenyl; or pharmaceutically acceptable salts thereof.  
     
     
         16 . The method of  claim 8 , wherein the compound is selected from the group consisting of 6-chloro-N-(4-methoxy-phenyl)-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-butyl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-isopropyl-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-tert-butyl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, (4-chloro-6-morpholin-4-yl-[1,3,5]triazin -2-yl)-naphthalen-1-yl-amine, N-tert-butyl-6-chloro-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-cyclo-hexyl-N′-isopropyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-2-methyl-propan-1-ol, 6-chloro-N-isopropyl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-chloro-phenyl)-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, N-allyl-6-chloro-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-ethanol, N-tert-butyl-6-chloro-N′-cyclopentyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-methoxyphenyl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-indan-5-yl-N′-phenyl-[1, 3,5]triazine-2,4-diamine, 6-chloro -N-(4-chloro-phenyl)-N′-propyl-[1,3,5]triazine-2,4-diamine, N-(4-chloro-phenyl)-6-methoxy-N′-propyl-[1,3,5]triazine-2,4-diamine and N-(4-chloro-phenyl)-6-methylsulfanyl-N′-phenyl-[1,3,5]triazine-2,4-diamine.  
     
     
         17 . A method of inhibiting cell proliferation comprising contacting a cell with an effective amount of a compound of the Formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is halo, hydroxy, alkylmercapto, mercapto, alkoxy, arylox or substituted amino;  
 R 2 , R, R 4  and R 5 , each of which may be same or different, are hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl or substituted aryl; or  
 R 2  and R 3  or R 4  and R 5 , together with the nitrogen to which they are attached, form a piperidine, piperazine, or a morpholine ring; or pharmaceutically acceptable salts thereof; thereby inhibiting the proliferation of the cell.  
 
     
     
         18 . The method of  claim 17 , wherein said cell is a cancer cell.  
     
     
         19 . The method of  claim 17 , wherein R 1  is chloro, R 2  and R 4  are hydrogen and R 3  and R 5  are phenyl; or pharmaceutically acceptable salts thereof.  
     
     
         20 . The method of  claim 17 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is t-butyl and R 5  is 4-chlorophenyl; or pharmaceutically acceptable salts thereof.  
     
     
         21 . The method of  claim 17 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is t-butyl and R 5  is 4-chlorophenyl; or pharmaceutically acceptable salts thereof.  
     
     
         22 . The method of  claim 17 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is 4-methoxyphenyl and R 5 is 4-chlorophenyl; or pharmaceutically acceptable salts thereof.  
     
     
         23 . The method of  claim 17 , wherein the compound is selected from the group consisting of 6-chloro-N-(4-methoxy-phenyl)-N′-p-tolyl-[1,3,5]triazine -2,4-diamine, N-butyl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-isopropyl-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-tert-butyl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, (4-chloro-6-morpholin-4-yl-[1,3,5]triazin -2-yl)-naphthalen-1-yl-amine, N-tert-butyl-6-chloro-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-cyclo-hexyl-N′-isopropyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-2-methyl-propan-1-ol, 6-chloro-N-isopropyl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-chloro-phenyl)-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, N-allyl-6-chloro-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-ethanol, N-tert-butyl-6-chloro-N′-cyclopentyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-methoxyphenyl)-N′-phenyl-[1,3,5]tri azine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-indan-5-yl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro -N-(4-chloro-phenyl)-N′-propyl-[1,3,5]triazine-2,4-diamine, N-(4-chloro-phenyl) -6-methoxy-N′-propyl-[1,3,5]triazine-2,4-diamine and N-(4-chloro-phenyl)-6-methylsulfanyl-N′-phenyl-[1,3,5]triazine-2,4-diamine.triazine-2,4-di amine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine and 6-chloro-N-indan-5-yl-N′-phenyl-[1,3,5]triazine-2,4-diamine.  
     
     
         24 . A method for treating cancer, comprising administering to an animal in need thereof, an effective amount of a compound of the Formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is halo, hydroxy, alkylmercapto, mercapto, alkoxy, aryloxy or substituted amino;  
 R 2 , R 3 , R 4  and R 5 , each of which may be same or different, are hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl or substituted aryl; or  
 R 2  and R 3  or R 4  and R 5 , together with the nitrogen to which they are attached, form a piperidine, piperazine, or a morpholine ring; or  
 pharmaceutically acceptable salts thereof;  
 wherein the cancer is treated.  
 
     
     
         25 . The method of  claim 24 , wherein R 1  is chloro, R 2  and R 4  are hydrogen and R 3  and R 5  are phenyl; or 
 pharmaceutically acceptable salts thereof    
     
     
         26 . The method of  claim 24 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is t-butyl and R 5 is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         27 . The method of  claim 24 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is t-butyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         28 . The method of  claim 24 , wherein R 1  is chloro, R 2  and R 4  are hydrogen, R 3 is 4-methoxyphenyl and R 5  is 4-chlorophenyl; or 
 pharmaceutically acceptable salts thereof.    
     
     
         29 . The method of  claim 24 , wherein said cancer is prostate, breast, lung, ovarian, brain, cervical, colon or bladder cancer.  
     
     
         30 . The method of  claim 24 , where the compound is selected from the group consisting of 6-chloro-N-(4-methoxy-phenyl)-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-butyl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-isopropyl-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, N-tert-butyl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, (4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-naphthalen-1-yl-amine, N-tert-butyl-6-chloro-N′-p-tolyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-cyclo-hexyl-N′-isopropyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-2-methyl-propan-1-ol, 6-chloro-N-isopropyl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-chloro-phenyl)-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, N-allyl-6-chloro-N′-cyclohexyl-[1,3,5]triazine-2,4-diamine, 2-(4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino)-ethanol, N-tert-butyl-6-chloro-N′-cyclopentyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(4-methoxyphenyl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo[1,3]dioxol-5-yl-6-chloro-N′-(4-chlorophenyl)-[1,3,5]triazine-2,4-diamine, 6-chloro-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N′-phenyl-[1,3,5]triazine-2,4-diamine, N-benzo [1,3]dioxol-5-yl-6-chloro-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro-N-indan-5-yl-N′-phenyl-[1,3,5]triazine-2,4-diamine, 6-chloro -N-(4-chloro-phenyl)-N′-propyl-[1,3,5]triazine-2,4-diamine, N-(4-chloro-phenyl) -6-methoxy-N′-propyl-[1,3,5]triazine-2,4-diamine and N-(4-chloro-phenyl)-6-methylsulfanyl-N′-phenyl-[1,3,5]triazine-2,4-diamine.  
     
     
         31 . A method for screening a patient for LPAAT-β activity, said method comprising detecting the presence or absence of an increased amount of LPAAT-β RNA,DNA or protein relative to a predetermined control, whereby the presence of said increased amount is indicative of cancer susceptibility in said patient.  
     
     
         32 . The method of  claim 31 , comprising detecting the presence or absence of an increased amount of LPAAT-β RNA.  
     
     
         33 . The method of  claim 31 , comprising detecting the presence or absence of an increased amount of LPAAT-β DNA.  
     
     
         34 . The method of  claim 31 , comprising detecting the presence or absence of an increased amount of LPAAT-β protein.  
     
     
         35 . A method of inhibiting cell proliferation comprising the inhibition of LPAAT-β.  
     
     
         36 . The method of  claim 35 , wherein said cell is a cancer cell.  
     
     
         37 . A vaccine preparation capable of inducing an anti-tumor immune response comprising a pharmaceutically acceptable carrier and an anti-tumor immune response-inducing effective amount of LPAAT-β protein.  
     
     
         38 . A method for screening a patient for LPAAT-β activity, said method comprising detecting the presence or absence of an increased amount of a phospholipid of defined acyl-chain composition relative to a predetermined control, whereby the presence of said increased amount is indicative of cancer susceptibility in said patient.  
     
     
         39 . The method of  claim 38 , wherein said phospholipid is phosphatidylinositol.