Bicyclic compound, production and use thereof

Abstract

wherein, R1 is a 5- to 6-membered ring group which may be substituted; X1 is a bond or the like; ring A is a 5- to 6-membered ring group which may be substituted; ring B is a 8- to 10-membered ring group which may be substituted; X2 is a bivalent group of 1 to 4 atoms; Z1 is a bivalent cyclic ring group or the like; Z2 is a bond or the like; and R2 is an amino group, a nitrogen-containing heterocyclic group which may be substituted or the like, or a salt thereof.

1 - 56 . (canceled) 
     
     
         57 . A process for synthesizing a compound according to Formula (IIi 0 ): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 R 1  is a cyclic 5- to 6-membered ring which may be substituted; 
 X 1  is selected from the group consisting of a bond, —(CH 2 ) b —O—, and —C≡C— 
 rings A and B, together with the variables a, E 1 , E 2 , and Y″ form a benzoazocine ring system; and, 
 b is 0, 1, or 2; 
 
         comprising the steps of: 
         (a) conducting ester hydrolysis of a compound according to Formula (X): 
       
       
         
           
           
               
               
           
         
         
           wherein R 11  is C 1 -C 6  alkyl; 
         
         to obtain a compound according to Formula (II′): 
       
       
         
           
           
               
               
           
         
         (b) reacting the carboxylic acid of Formula (II′) with (PhO) 2 PON 3  and tert-butanol to obtain a compound according to Formula (IIe′): 
       
       
         
           
           
               
               
           
         
         (c) hydrolyzing a compound according to Formula (IIe′) with an aqueous acid to obtain a compound according to Formula (IIi 0 ): 
       
       
         
           
           
               
               
           
         
       
     
     
         58 . The process according to  claim 57 , wherein Y″ is selected from the group consisting of —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —CH═, —CH═CH—, —CH═CH—CH 2 —, —CH 2 CH═CH—, —CH═CH—CH═CH—, ═CH—CH═CH—, —CH 2 —CH—CH 2 —, —CH═CH—(CH 2 ) 2 —, —CH═CH—(CH 2 ) 3 —, —CH═CH—(CH 2 ) 4 —, —O—(CH 2 ) 3 —, —O—(CH 2 ) 4 —, —O—(CH 2 ) 5 —, —CH 2 —O—(CH 2 ) 2 —, —O—CH═CH—CH 2 —, —S(O) m —(CH 2 ) 3 —, —S(O) m —(CH 2 ) 4 —, —S(O) m —(CH 2 ) 5 —, —CH 2 —S(O) m —(CH 2 ) 2 —, —S(O) m —CH═CH—CH 2 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —CH═CH—CH═CH—, —CH═CH—(CH 2 ) 2 —, —NH—(CH 2 ) 3 —, —NH—(CH 2 ) 4 —, —NH—(CH 2 ) 5 —, —CH 2 —NH—(CH 2 ) 2 —, —NH—CH═CH—CH 2 —, —N═CH—CH═CH—, —CH═N—(CH 2 ) 2 —, —CH═N—CH═CH—, —N═N—(CH 2 ) 2 —, —N═N—CH═CH—, and —CH═N—N═CH—; and,
 wherein m is 0, 1, or 2. 
 
     
     
         59 . The process according to  claim 57 , wherein X 1  is a bond. 
     
     
         60 . A process for synthesizing a compound according to Formula (IIa′): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is a cyclic 5- to 6-membered ring which may be substituted; 
 X 1  is selected from the group consisting of a bond, —(CH 2 ) b —O—, and —C≡C— 
 rings A and B, together with the variables a, E 1 , E 2 , and Y″ form a benzoazocine ring system; and, 
 b is 0, 1, or 2; 
 
         comprising the steps of: 
         (i) subjecting a compound according to Formula (VIII): 
       
       
         
           
           
               
               
           
         
         wherein R 11  is C 1 -C 6  alkyl; 
         to undergo ester hydrolysis then decarboxylation to obtain a compound according to Formula (XI): 
       
       
         
           
           
               
               
           
         
         (ii) reducing the ketone of Formula (XI) with a reducing agent followed by dehydration to obtain a compound according to Formula (XII): 
       
       
         
           
           
               
               
           
         
         (iii) reacting a compound according to Formula (XII) with SO 2 Cl 2  to obtain a compound according to Formula (IIa′): 
       
       
         
           
           
               
               
           
         
       
     
     
         61 . The process according to  claim 60 , wherein Y″ is selected from the group consisting of —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —CH═, —CH═CH—, —CH═CH—CH 2 —, —CH 2 CH═CH—, —CH═CH—CH═CH—, ═CH—CH═CH—, —CH 2 —CH—CH 2 —, —CH═CH—(CH 2 ) 2 —, —CH═CH—(CH 2 ) 3 —, —CH═CH—(CH 2 ) 4 —, —O—(CH 2 ) 3 —, —O—(CH 2 ) 4 —, —O—(CH 2 ) 5 —, —CH 2 —O—(CH 2 ) 2 —, —O—CH═CH—CH 2 —, —S(O) m —(CH 2 ) 3 —, —S(O) m —(CH 2 ) 4 —, —S(O) m —(CH 2 ) 5 —, —CH 2 —S(O) m —(CH 2 ) 2 —, —S(O) m —CH═CH—CH 2 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —CH═CH—CH═CH—, —CH═CH—(CH 2 ) 2 —, —NH—(CH 2 ) 3 —, —NH—(CH 2 ) 4 —, —NH—(CH 2 ) 5 —, —CH 2 —NH—(CH 2 ) 2 —, —NH—CH═CH—CH 2 —, —N═CH—CH═CH—, —CH═N—(CH 2 ) 2 —, —CH═N—CH═CH—, —N═N—(CH 2 ) 2 —, —N═N—CH═CH—, and —CH═N—N═CH—; and,
 wherein m is 0, 1, or 2. 
 
     
     
         62 . The process according to  claim 60 , wherein X 1  is a bond. 
     
     
         63 . The process according to  claim 60 , wherein the reducing agent of step (ii) is sodium borohydride (NaBH 4 ) or catalytic hydrogen. 
     
     
         64 . A process for synthesizing a compound having the structure: 
       
         
           
           
               
               
           
         
         8-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxamide (Compound 1); 
         comprising: 
         (I) mixing 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acid (Compound A): 
       
       
         
           
           
               
               
           
         
         with dimethylformamide in tetrahydrofuran to form a first solution; 
         (II) adding thionyl chloride (SOCl 2 ) to the first solution to form a compound, in situ, having the structure: 
       
       
         
           
           
               
               
           
         
         (III) mixing 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (Compound B): 
       
       
         
           
           
               
               
           
         
         with trimethylamine in tetrahydrofuran to form a second solution; 
         (IV) adding the first solution to the second solution form a reaction mixture; 
         (V) stirring the reaction mixture of the first solution and the second solution for 1.5 hours under nitrogen atmosphere to obtain a compound having the structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         65 . The process according to  claim 64 , wherein the molar ratio of Compound A to Compound B is about 1:1. 
     
     
         66 . The process according to  claim 64 , wherein the molar ratio of Compound B to triethylamine is about 1:25. 
     
     
         67 . The process according to  claim 64 , wherein steps (I) and (II) is conducted at a temperature of about 0° C. 
     
     
         68 . The process according to  claim 64 , wherein step (III) is conducted at a temperature of about 0° C. 
     
     
         69 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof.