Indole compounds and pharmaceutical use thereof

Abstract

Provided is an agent for the treatment or prophylaxis of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection or the like.A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof:wherein each symbol is as described in the specification.

1 .- 26 . (canceled) 
     
     
         27 . A process for producing a compound of formula [I-c] 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof comprising
 hydrolyzing a compound of formula [22] 
 
       
       
         
           
           
               
               
           
         
         to remove —C(═O)R 8  on the pyrazolyl ring to form the compound of formula [I-c], 
         wherein 
         R 1  is
 (1) a hydrogen atom, 
 (2) a hydroxy group, or 
 (3) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s); 
 
         R 2  and R 3  are the same or different and each is
 (1) a hydrogen atom, or 
 (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group; 
 
 
         R 7  is
 (1) a hydrogen atom, or 
 (2) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group, and 
 (c) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s), and 
 
 
         R 8  is
 (1) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
 (c) a C 3-6  cycloalkyl group optionally substituted by C 1-6  alkoxy group(s), 
 (d) a C 6-10  aryl group, 
 (e) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by oxo group(s), 
 (f) a 5- to 8-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (i) a hydroxy group, 
 (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy group, and 
 (iv) an oxo group, 
 
 (g) a C 3-6  cycloalkyloxy group, 
 (h) a C 6-10  aryloxy group, 
 (i) a 5- or 6-membered unsaturated heterocyclyloxy group, 
 (j) a 5- or 6-membered saturated heterocyclyloxy group, and 
 (k) an amino group optionally mono- or di-substituted by substituents selected from
 (i) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6  alkoxy group, 
 (ii) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C 1-6  alkoxy group, 
 (iii) a C 1-6  alkoxy-carbonyl group optionally substituted by C 6-10  aryl group(s), and 
 (iv) a C 3-6  cycloalkyl-carbonyl group optionally substituted by C 1-6  alkoxy group(s), 
 
 
 (2) a C 1-6  alkoxy group optionally substituted by C 6-10  aryl group(s), 
 (3) a C 3-6  cycloalkyl group optionally substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, and 
 (b) a C 1-6  alkoxy group, 
 
 (4) a C 6-10  aryl group optionally substituted by C 1-6  alkyl group(s) optionally substituted by 1 to 3 halogen atoms, 
 (5) an amino group optionally mono- or di-substituted by C 1-6  alkyl group(s) optionally substituted by C 6-10  aryl group(s), 
 (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted by C 1-6  alkyl group(s), 
 (7) a 5- or 6-membered saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from
 (a) a C 1-6  alkyl group, 
 (b) a C 1-6  alkyl-carbonyl group, and 
 (c) an oxo group, 
 
 (8) a C 3-6  cycloalkyloxy group, or 
 (9) a C 6-10  aryl-carbonyl group, or 
 
         R 7  and R 8  form, together with the nitrogen atom and carbon atom they are bonded to, a 5- or 6-membered cyclic amine, on the indolyl group, that is substituted by an oxo group and optionally further substituted by 1 to 3 substituents selected from
 (a) a hydroxy group, 
 (b) a C 1-6  alkyl group optionally substituted by hydroxy group(s), 
 (c) a C 1-6  alkoxy group, and 
 (d) a C 3-6  cycloalkyl group. 
 
       
     
     
         28 . The method of  claim 27 , wherein the compound of formula [22] is prepared by condensing a compound of formula [21] 
       
         
           
           
               
               
           
         
         with a compound of formula [18] 
       
       
         
           
           
               
               
           
         
         to form the compound of formula [22]. 
       
     
     
         29 . The method of  claim 28 , wherein the compound of formula [21] is prepared by reducing a compound of formula [20] 
       
         
           
           
               
               
           
         
       
       wherein R 13  is an alkyl or benzyl group, to form the compound of formula [21]. 
     
     
         30 . The method of  claim 29 , wherein the compound of formula [20] is prepared by deprotecting a compound of formula [16] 
       
         
           
           
               
               
           
         
       
       wherein R 12  is an amino-protecting group, to remove R 12  to form a compound of formula [20]. 
     
     
         31 . The method of  claim 30 , wherein the compound of formula [16] is prepared by contacting a compound of formula [15] 
       
         
           
           
               
               
           
         
       
       with an alkylating agent in a solvent in the presence of a base to form the compound of formula [16]. 
     
     
         32 . The method of  claim 31 , wherein the compound of formula [15] is prepared by subjecting a compound of formula [14] 
       
         
           
           
               
               
           
         
       
       to a Curtius rearrangement in the presence of an alcohol of the formula R 13 OH to provide a compound of formula [15]. 
     
     
         33 . The method of  claim 32 , wherein the compound of formula [14] is prepared by deprotecting a compound of formula [13] 
       
         
           
           
               
               
           
         
       
       wherein R 11  is a carboxy-protecting group, to remove R 11  to form a compound of formula [14]. 
     
     
         34 . The method of  claim 33 , wherein the compound of formula [13] is prepared by introducing an amino-protecting group R 12  into a compound of formula [10] 
       
         
           
           
               
               
           
         
       
       to form a compound of formula [13].