Quinazolinone derivatives useful as vanilloid antagonists

Abstract

There is described a process for the manufacture of compounds of the formula I said process comprising reacting a compound of the formula II as described herein, or a salt thereof, under simultaneous or sequential condensation and cyclisation conditions with an aniline compound of the formula III, wherein R 2 and m are as defined for a compound of the formula I. Further reactions and related embodiments are also claimed and disclosed.

1 . A process for the manufacture of a quinazolinone compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1 -C 6 alkyl, (C 1 -C 6 alkyl)C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, di-(trifluoromethyl)C 1 -C 6 alkyl, R 9 —O—(C 1 -C 6 alkyl)- in which the alkyl chain is optionally substituted by trifluoromethyl, (NC)—C 1 -C 6 alkyl-, (R 10 R 11 N—)C i -C 6 alkyl-, or (C 1 -C 6 alkyl)-SO 2 —(C 1 -C 6 alkyl)-, wherein R 9 , R 10  and R 11  are each independently H or C 1 -C 6 alkyl; 
 each R 2 , independently, is halogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, cyano, a group —C(═O)—R 2a , where R 2a  is C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, R 10 R 11 N—, R 10 R 11 N—(C 1 -C 6 alkyl)-, —SO 2 —(C 1 -C 6 alkyl), R 9 —O—(C═O)—, wherein Rg 1  R 10  and R 11  are as defined above, unsubstituted or substituted phenyl wherein the substituents are 1 to 4 substituents independently selected from the group consisting of halo, hydroxy and C 1 -C 6 -alkyl, or a 5- or 6-membered saturated or unsaturated heterocyclic ring having one, two or three heteroatoms selected from N, O and S and optionally including a further substituent selected from halo; 
 R 3  is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, hydroxy-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, cyano, —C(═O)H, phenyl, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkoxy, (C 1 -C 6 alkoxycarbonylamino)C 1 -C 6 alkoxy or (C 1 -C 6 alkylcarbonylamino)C 1 -C 6 alkoxy; 
 R 4  is H; 
 R 5  is hydrogen or hydroxy; 
 R 6  is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, hydroxy-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, cyano, —C(═O)H, phenyl, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkoxy, (C 1 -C 6 alkoxycarbonylamino)C 1 -C 6 alkoxy or (C 1 -C 6 alkylcarbonylamino)C 1 -C 6 alkoxy, (amino)C 1 -C 6 alkoxy, (dimethylamino)C 1 -C 6 alkoxy, or (C 1 -C 6 alkoxycarbonyl)C 1 -C 6 alkoxy, 
 m is 1 to 5, in free form or in salt form, 
 said method or process comprising reacting a compound of the formula II, 
 
       
         
           
           
               
               
           
         
         wherein R 4 * is H, and R 1  and R 3 , R 5  and R 6  are as defined for a compound of the formula I, or a salt thereof 
         under simultaneous or sequential condensation and cyclization conditions, with an aniline compound of the formula III, 
       
       
         
           
           
               
               
           
         
         wherein R 2  and m are as defined above for a compound of the formula I, 
       
       to give a corresponding compound of the formula I. 
     
     
         2 . The process of  claim 1 , wherein m is 1 or 2. 
     
     
         3 . The process of  claim 1 , wherein R 1  is C 1 -C 6 alkyl, (C 1 -C 6 alkyl)C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)C 1 -C 6 alkyl or cyclopropyl. 
     
     
         4 . The process of  claim 1 , wherein R 5  and R 6  are both hydrogen. 
     
     
         5 . The process of  claim 1 , wherein R 3  is hydrogen, chloro, bromo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy or (C 3 -C 6 cycloalkyl)C 1 -C 4 alkoxy. 
     
     
         6 . The process of  claim 1 , wherein:
 R 1  is (C 1 -C 6 alkyl)C 1 -C 6 alkyl; and   R 3  is hydrogen.   
     
     
         7 . The process of  claim 1 , which further comprises
 acylating or etherifying a free hydroxyl group R 4 —O wherein R 4  is H with a compound of the formula (IV)
   R 4 ″—X  (IV)
 
   wherein X is OH or an active derivative thereof and R 4 ″ is an acyl moiety, to provide a compound of Formula I wherein R 4 —O is esterified hydroxy or etherified hydroxyl.   
     
     
         8 . The process of  claim 1 , further comprising a step of converting a free compound of Formula I into a salt. 
     
     
         9 . The process according to  claim 1  wherein the product is a compound of the formula Ia in free or salt form, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 1-methylethyl; 
 R 2  is cyano in p-position of the phenyl ring relatively to the phenyl carbon binding to the ring nitrogen in formula I; 
 R 3  is hydrogen; 
 R 4  is hydrogen; and 
 m is 1, 
 
       wherein the process comprises reacting a compound of the formula II, 
       
         
           
           
               
               
           
         
         wherein R 4 * is H, each of R 5  and R 6  is hydrogen and R 1  and R 3  are as defined for the compound of formula I, or a salt thereof, 
         under simultaneous or sequential condensation and cyclization conditions with an aniline compound of the formula III, 
       
       
         
           
           
               
               
           
         
         wherein R 2  and m are as defined above for the compound of formula I. 
       
     
     
         10 . The process according to  claim 1 , further comprising synthesizing the compound of the formula II wherein R 1 , R 3 , R 5  and R 6  are as defined for a compound of the formula II in  claim 1 , and R 4 * is R 1 *—C(═O)—, wherein R 1 * is selected from the group of substituents defined for R 1  as defined for a compound of the formula I in  claim 1 , 
       by oxidizing a compound of the formula VI, 
       
         
           
           
               
               
           
         
         wherein the moieties R 1 , R 3  and R 5  and R 6  are as defined for a compound of the formula II in  claim 1 , 
         wherein R 4 * and R 1 —C(═O) are different or identical, 
         to provide the corresponding compound of the formula II in free or in salt form. 
       
     
     
         11 . The process according to  claim 10  comprising oxidizing a compound of the formula VI wherein the R 1 * and R 1  are identical to each other, and the other symbols have the meanings given for a compound of the formula I in  claim 10 ,
 wherein the process further comprises hydrolyzing the oxidized compound of the formula VI to the corresponding compound of the formula II wherein R 4 * is hydrogen. 
 
     
     
         12 . The process according to  claim 11 , wherein R 1  and R 4 * in Formula (VI) are both 1-methylethyl. 
     
     
         13 . The process according to  claim 12 , further comprising synthesizing the compound of the formula VI wherein R 1 , R 3 , R 4 *, R 5  and R 6  are as defined for a compound of the formula II in  claim 12 ,
 by acylating a compound of the formula VII,   
       
         
           
           
               
               
           
         
         said expression including the free compound or a salt thereof, 
         wherein R 3 , R 5  and R 6  are as defined for a compound of the formula II in  claim 12 , 
         with an acid of the formula VIII,
   R 1 ″—COOH  (VIII)
 
 
         or a reactive derivative thereof, either simultaneously reacting the free OH and NH 2  group in formula VII or reacting these groups sequentially, then either using the same acid of formula VIII or its reactive derivative, or two different acids of the formula VIII, in the latter case the first to acylate the first, the second to acylate the second group, where in formula VIII R 1 ″ is R 1  or R 1 * as defined for a compound of the formula II in  claim 12 . 
       
     
     
         14 . The process according to  claim 1 , wherein a compound of the formula (A) 
       
         
           
           
               
               
           
         
         is reacted under simultaneous or sequential condensation and cyclization conditions with a compound of the formula (B) 
       
       
         
           
           
               
               
           
         
         to provide a compound of the formula (C)