Novel tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them

Abstract

The present invention relates to novel tricyclic compounds useful for the treatment of inflammatory conditions, diseases of the central nervous and insulin resistant diabetes.

1 - 73 . (canceled) 
     
     
         74 . A method for the preparation of a compound of general formula (1) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S; 
 each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; 
 P is oxygen or sulfur; 
 n is an integer from 0-4; 
 Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 
 X is oxygen or S(O) m ; 
 m is 0, 1 or 2; 
 Y is —C(O)NR 4 ; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring, 
 or an N-oxide thereof; comprising 
 (a) converting a compound of formula (11) 
 
       
         
           
           
               
               
           
         
       
       to the compound of formula (1). 
     
     
         75 . The method of  claim 74  wherein step (a) comprises a reaction with an amine of the formula ArNHR 4 . 
     
     
         76 . A method for the preparation of a compound of general formula (2) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S; 
 each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; 
 P is oxygen or sulfur; 
 Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 
 X is oxygen or S(O) m ; 
 m is 0, 1 or 2; 
 Y is —C(O)NR 4 ; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring, 
 
       or an N-oxide thereof, comprising converting a compound of formula (1a) 
       
         
           
           
               
               
           
         
       
       to the compound of formula (2). 
     
     
         77 . The method of  claim 76 , wherein the conversion step comprises hydrogenating the compound of formula (1a). 
     
     
         78 . The method of  claim 77 , wherein the compound of formula (1a) is hydrogenated in the presence of a catalyst. 
     
     
         79 . The method of  claim 78 , wherein the catalyst is an activated Raney nickel catalyst. 
     
     
         80 . A method for the preparation of a compound of general formula (11) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S; 
 each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; 
 P is oxygen or sulfur; 
 n is an integer from 0-4; 
 Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 
 X is oxygen or S(O) m ; 
 m is 0, 1 or 2; 
 Y is —C(O)NR 4 ; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring, 
 
       or an N-oxide thereof; comprising converting a compound of formula (10) 
       
         
           
           
               
               
           
         
       
       to the compound of formula (11), wherein FG represents substituted or unsubstituted alkyl, formyl, cyano, halogen, nitro, or amino. 
     
     
         81 . The method of  claim 80 , wherein FG is formyl. 
     
     
         82 . The method of  claim 81 , wherein the conversion step comprises oxidizing the compound of formula (10). 
     
     
         83 . The method of  claim 80 , further comprising converting the compound of formula (11) to a compound of formula (1), wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S;   each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl;   P is oxygen or sulfur;   n is an integer from 0-4;   Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;   X is oxygen or S(O) m ;   m is 0, 1 or 2;   Y is —C(O)NR 4 ;   R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring.   
     
     
         84 . A method for the preparation of a compound of general formula (10a) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m , NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S; 
 each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; 
 n is an integer from 0-4; 
 Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 
 X is oxygen or S(O) m ; 
 m is 0, 1 or 2; 
 FG is substituted or unsubstituted alkyl, formyl, cyano, halogen, nitro, or amino; 
 Y is —C(O)NR 4 ; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring, 
 
       or an N-oxide thereof, comprising converting a compound of formula (10b) 
       
         
           
           
               
               
           
         
       
       to the compound of formula (1a). 
     
     
         85 . The method of  claim 84 , wherein the converting step comprises reacting the compound of formula (10b) with chlorodifluoromethane. 
     
     
         86 . The method of  claim 84 , wherein FG is formyl. 
     
     
         87 . The method of  claim 84 , further comprising converting the compound of formula (10a) to a compound of formula (1), wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S;   each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl;   P is oxygen or sulfur;   n is an integer from 0-4;   Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;   X is oxygen or S(O) m ;   m is 0, 1 or 2;   Y is —C(O)NR 4 ;   R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring.   
     
     
         88 . A method for the preparation of a compound of general formula (10b) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S; 
 each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; 
 n is an integer from 0-4; 
 Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; 
 X is oxygen or S(O) m ; 
 m is 0, 1 or 2; 
 FG is substituted or unsubstituted alkyl, formyl, cyano, halogen, nitro, or amino; 
 Y is —C(O)NR 4 ; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring, 
 
       or an N-oxide thereof; comprising converting a compound of formula (10c) 
       
         
           
           
               
               
           
         
       
       to the compound of formula (10b). 
     
     
         89 . The method of  claim 88 , wherein the converting step comprises reducing the compound of formula (10c). 
     
     
         90 . The method of  claim 88 , wherein FG is formyl. 
     
     
         91 . The method of  claim 88 , further comprising converting the compound of formula (10b) to a compound of formula (1), wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) m —R a , —S(O) m —NR a R a , nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR a , —SR a , a protecting group and when two R 2  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR a  or S;   each occurrence of R a  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl;   P is oxygen or sulfur;   n is an integer from 0-4;   Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;   X is oxygen or S(O) m ;   m is 0, 1 or 2;   Y is —C(O)NR 4 ;   R 4  is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR 1 , —COOR 1 , substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic ring.