7-oxo-pyridopyrimidines (II)

Abstract

The present invention provides compounds of the formula: a prodrug or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and Ar 1 are those defined herein, and methods for preparation and uses thereof.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       a prodrug or a salt thereof, wherein: 
 R 1  is hydrogen or alkyl;  
 R 2  is —CR′R″—R a  (where R′ and R″ are hydrogen, hydroxyalkyl or alkyl with at least one being alkyl or hydroxyalkyl and R a  is hydroxyalkyl), R x —S—R y — (where R x  is alkyl and R y  is alkylene), alkoxy-substituted alkyl, heterocyclylalkyl or C 4 -C 5  cycloalkyl, wherein each of the hydroxy group present in R 2  can be independently in the form of an ester, a carbamate, a carbonate, or a sulfonate derivative; or  
 R 1  and R 2  together with the nitrogen atom to which they are attached form a heterocyclyl group;  
 R 3  is hydrogen, alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and  
 Ar 1  is aryl.  
 
     
     
         2 . The compound of  claim 1  wherein Ar 1  is an optionally substituted phenyl.  
     
     
         3 . The compound of  claim 2 , wherein Ar 1  is a phenyl group independently substituted with one or two halo, alkyl or methoxy groups.  
     
     
         4 . The compound of  claim 3 , wherein Ar 1  is 2-chlorophenyl, 2-methylphenyl or 2-methoxyphenyl.  
     
     
         5 . The compound according to  claim 4  of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 5 , wherein R 1  is hydrogen or methyl.  
     
     
         7 . The compound according to  claim 6 , wherein R 2  is (1,1-dimethyl-2-hydroxy)ethyl, (1,2-dimethyl-2-hydroxy)propyl, or (1-substituted piperidin-4-yl)methyl, wherein each of the hydroxy group present in R 2  can be independently in the form of an ester, a carbamate, a carbonate, or a sulfonate derivative.  
     
     
         8 . A composition comprising: 
 (a) an excipient; and    (b) a compound of the formula:                           a prodrug or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is hydrogen or alkyl;  
 R 2  is —CR′R″—R a  (where R′ and R″ are hydrogen, hydroxyalkyl or alkyl with at least one being alkyl or hydroxyalkyl and R a  is hydroxyalkyl), R x —S—R y — (where R x  is alkyl and R y  is alkylene), alkoxy-substituted alkyl, heterocyclylalkyl or C 4 -C 5  cycloalkyl, wherein each of the hydroxy group present in R 2  can be independently in the form of an ester, a carbamate, a carbonate, or a sulfonate derivative; or  
 R 1  and R 2  together with the nitrogen atom to which they are attached forming a heterocyclyl group; <R 3  is hydrogen, alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R (where R is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and  
 Ar 1  is aryl.  
   
     
     
         9 . A method for preparing a compound of  claim 1 , comprising the steps of contacting a compound of the formula Ig:  
       
         
           
           
               
               
           
         
       
       with an amine of the formula R 1 R 2 NH under conditions sufficient to produce a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1 , R 2 , R 3  and Ar 1  are those defined in  claim 1;   
 L is a leaving group;  
 n is an integer from 0 to 2; and  
 R 6  is an alkyl group.  
 
     
     
         10 . The method of  claim 9 , wherein n is 1.  
     
     
         11 . The method of  claim 9  wherein n is 2.  
     
     
         12 . A method for treating a p38 mediated disorder comprising administering to a patient in need of such treatment, an effective amount of a compound of  claim 1 .  
     
     
         13 . The method of  claim 12 , wherein said p38 mediated disorder is arthritis, Crohns disease, Alzheimer's disease, irritable bowel syndrome, adult respiratory distress syndrome or chronic obstructive pulmonary disease.  
     
     
         14 . A process for producing a pyrimidine of the formula:  
       
         
           
           
               
               
           
         
       
       comprising: 
 (a) contacting an acetal of the formula NC—CH 2 —C(OR a ) 2 , with an alkyl formate of the formula HCO 2 R in the presence of a condensation base under conditions sufficient to produce a condensed product; and  
 (b) contacting said condensed product with thiourea in the presence of a cyclization base under conditions sufficient to produce said pyrimidine of Formula II-c, wherein each of R and R a  is independently alkyl.  
 
     
     
         15 . The process of  claim 14 , wherein said condensation base is a tert-butoxide.  
     
     
         16 . The process of  claim 14 , wherein said cyclization base is an alkoxide.  
     
     
         17 . A process for producing a pyridopyrimidine of the formula:  
       
         
           
           
               
               
           
         
       
       comprising: 
 (a) contacting a pyrimidine of the formula:  
                     
  with an alkylating agent of the formula R—X 1  in the presence of an alkylating base under conditions sufficient to produce an alkylated pyrimidine of the formula:  
                     
  and  
 (b) contacting said alkylated pyrimidine of Formula II-d with an aryl acetate of the formula Ar 1 —CH 2 —CO 2 R in the presence of a cyclization base under conditions sufficient to produce said pyridopyrimidine of Formula II-e  
  or  
 (a) contacting said pyrimidine of Formula II-c with said aryl acetate of the formula Ar 1 —CH 2 —CO 2 R in the presence of a cyclization base under conditions sufficient to produce a thiol pyridopyrimidine of the formula:  
                     
  and  
 (b) contacting said thiol pyridopyrimidine of Formula III with said alkylating agent of the formula R—X 1  in the presence of an alkylating base under conditions sufficient to produce said pyridopyrimidine of Formula II,  
  wherein 
 X 1  is a leaving group;  
 each R is independently alkyl;  
 Ar 1  is aryl;  
 
 
     
     
         18 . The process of  claim 17 , wherein X 1  is halide.  
     
     
         19 . The process of  claim 17  further comprising contacting said pyridopyrimidine of Formula II with a nitrogen alkylating agent of the formula R 3 —X 2  under conditions sufficient to produce an N-substituted pyridopyrimidine of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  is alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R′ (where R′ is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl;  
 X 2  is a leaving group; and  
 Ar 1  and R are those defined in  claim 17 .  
 
     
     
         20 . The process of  claim 19 , wherein X 2  is a halogen.