Spiro compounds and pharmaceutical use thereof

Abstract

The Spiro compound represented by the following general formula [Ia], its pharmaceutically acceptable salt or a solvate thereof

1 .- 21 . (canceled) 
     
     
         22 . A process for preparing a spiro compound of Formula [I]: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is a C 1 -C 6 alkyl group, a C2-C6alkenyl group, a C2-C6alkynyl group, a phenyl group, a hydroxy group, or a five-membered heteroaryl group which has at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and which is optionally substituted by a C 1 -C 6 alkyl group, or a di(C 1 -C 6 alkoxy)methyl group); 
 m1 is 0, 1 or 2; 
 m2 is 0 or 1; 
 the spiro-ring AB is optionally substituted by 1 to 5 same or different substituent(s) selected from the group consisting of:
 (1) a hydroxy group, 
 (2) a C 1 -C 6  alkyl group, 
 (3) a C 1 -C 6  alkoxy group and 
 (4) an oxo group; 
 
 n1 is 0, 1, 2, 3 or 4; 
 n2 is 1, 2, 3 or 4; 
 n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; and 
 a bond represented by the symbol:    
 
         means a single bond or a double bond with the proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C;
 
 
         wherein the process comprises hydrolyzing an intermediate according to Compound (3): 
       
       
         
           
           
               
               
           
         
         wherein R 51  is a C 1 -C 6 alkyl group and R 1′  corresponds to R 1 . 
       
     
     
         23 . The process of  claim 22  wherein the hydrolyzing is carried out in a solvent in the presence of a base. 
     
     
         24 . The process of  claim 23  wherein the solvent comprises an ether solvent, an alcoholic solvent, or a mixture thereof. 
     
     
         25 . The process of  claim 23  wherein the base comprises an aqueous solution of sodium hydroxide or potassium hydroxide. 
     
     
         26 . The process of  claim 22  wherein the compound according to Compound (3) is prepared by the process of condensing a spiro intermediate according to Compound (1): 
       
         
           
           
               
               
           
         
         with an intermediate according to Compound (2): 
       
       
         
           
           
               
               
           
         
         wherein X 51  and X 52  are the same or different and each represents a hydroxy group or a leaving group. 
       
     
     
         27 . The process of  claim 26  wherein X 52  is a leaving group and X 51  is a hydroxy group. 
     
     
         28 . The process of  claim 26  wherein the leaving group is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group. 
     
     
         29 . The process of  claim 26  wherein the condensing is carried out in the presence of a condensing reagent. 
     
     
         30 . The process of  claim 29  wherein the condensing reagent comprises 1,1′-(azodicarbonyl)dipiperidine or triphenylphosphine. 
     
     
         31 . The process of  claim 26  wherein the condensing is carried out in the presence of a solvent. 
     
     
         32 . The process of  claim 31  wherein the solvent comprises an ether solvent. 
     
     
         33 . The process of  claim 31  wherein the solvent comprises a polar solvent. 
     
     
         34 . The process of  claim 26  wherein the condensing is carried out in the presence of a base. 
     
     
         35 . The process of  claim 34  wherein the base comprises an alkali metal carbonate. 
     
     
         36 . The process of  claim 35  wherein the alkali metal carbonate is potassium carbonate or cesium carbonate. 
     
     
         37 . A process for preparing an intermediate according to Compound (1b): 
       
         
           
           
               
               
           
         
         wherein:
 the spiro-ring AB is optionally substituted by 1 to 5 same or different substituent(s) selected from the group consisting of:
 (1) a hydroxy group, 
 (2) a C 1 -C 6  alkyl group, 
 (3) a C 1 -C 6  alkoxy group and 
 (4) an oxo group; 
 
 L v1  is a leaving group; 
 m1 is 0, 1 or 2; 
 n1 is 0, 1, 2, 3 or 4; 
 n2 is 1, 2, 3 or 4; 
 n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; and 
 a bond represented by the symbol:    
 
         means a single bond or a double bond with the proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C;
 
 
         comprising reacting an intermediate according to Compound (1a): 
       
       
         
           
           
               
               
           
         
         with a halogenating agent in a solvent in the presence of an additive at room temperature or with heat. 
       
     
     
         38 . The process of  claim 37  wherein the halogenating reagent comprises N-bromosuccinimide. 
     
     
         39 . The process of  claim 37  wherein the additive comprises triphenylphosphine. 
     
     
         40 . The process of  claim 37  wherein the solvent comprises a halogenated hydrocarbon solvent. 
     
     
         41 . The process of  claim 37  wherein the solvent comprises chloroform. 
     
     
         42 . A process for preparing an intermediate according to Compound (1a-1a): 
       
         
           
           
               
               
           
         
         wherein:
 the spiro-ring AB is optionally substituted by 1 to 5 same or different substituent(s) selected from the group consisting of:
 (1) a hydroxy group, 
 (2) a C 1 -C 6  alkyl group, 
 (3) a C 1 -C 6  alkoxy group and 
 (4) an oxo group; 
 
 n1 is 0, 1, 2, 3 or 4; 
 n2 is 1, 2, 3 or 4; and 
 a bond represented by the symbol:    
 
         means a single bond or a double bond with the proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C;
 
 
         comprising: 
         (a) reacting an intermediate according to Compound (5-1): 
       
       
         
           
           
               
               
           
         
         with di(C 1 -C 6 alkyl) carbonate in a solvent in the presence of a base at room temperature or with heat to form an intermediate according to Compound (5-1a): 
       
       
         
           
           
               
               
           
         
         wherein R 51  is C 1 -C 6  alkyl; 
         (b) reacting the intermediate according to Compound (5-1a) with a reducing agent in a solvent at room temperature or with heat, or by catalytic reduction with a catalyst in an atmosphere of hydrogen to form an intermediate according to Compound (5-1b): 
       
       
         
           
           
               
               
           
         
         (c) reacting the intermediate according to Compound (5-1b) with methanesulfonyl chloride in a solvent under basic conditions at room temperature or with heat to form an intermediate according to Compound (5-1c): 
       
       
         
           
           
               
               
           
         
         wherein L v2  is a leaving group; 
         (d) reacting the intermediate according to Compound (5-1c) with a base in a solvent at room temperature or with heat to form an intermediate according to Compound (5-1d): 
       
       
         
           
           
               
               
           
         
         wherein R 100  is C 1 -C 6  alkyl; and 
         (e) reacting the intermediate according to Compound (5-1d) with a reducing agent in a solvent with cooling or at room temperature to form the intermediate of Compound (1a-1a). 
       
     
     
         43 . The process of  claim 42  wherein the di(C 1 -C 6 alkyl)carbonate of step (a) is dimethyl carbonate. 
     
     
         44 . The process of  claim 42  wherein the base of step (a) is sodium hydride or potassium tert-butoxide. 
     
     
         45 . The process of  claim 42  wherein the solvent of step (a) comprises an ether solvent. 
     
     
         46 . The process of  claim 45  wherein the ether solvent of step (a) comprises tetrahydrofuran. 
     
     
         47 . The process of  claim 42  wherein the reducing agent of step (b) comprises sodium borohydride. 
     
     
         48 . The process of  claim 42  wherein the solvent of step (b) comprises an ether solvent or an alcoholic solvent or a mixture thereof. 
     
     
         49 . The process of  claim 48  wherein the solvent of step (b) comprises tetrahydrofuran or methanol or a mixture thereof. 
     
     
         50 . The process of  claim 42  wherein the catalyst of step (b) comprises platinum oxide. 
     
     
         51 . The process of  claim 42  wherein the base of step (c) is an organic base. 
     
     
         52 . The process of  claim 51  wherein the organic base of step (c) is triethylamine or pyridine. 
     
     
         53 . The process of  claim 42  wherein the solvent of step (c) comprises a halogenated hydrocarbon. 
     
     
         54 . The process of  claim 53  wherein the halogenated hydrocarbon of step (c) is chloroform. 
     
     
         55 . The process of  claim 42  wherein the reacting of step (c) is carried out in the presence of an additive. 
     
     
         56 . The process of  claim 55  wherein the additive of step (c) comprises 4-dimethylaminopyridine. 
     
     
         57 . The process of  claim 42  wherein the base of step (d) is an organic base. 
     
     
         58 . The process of  claim 57  wherein the organic base of step (d) is 1,8-diazabicyclo[5.4.0]undec-7-ene. 
     
     
         59 . The process of  claim 42  wherein the solvent of step (d) comprises an ether solvent. 
     
     
         60 . The process of  claim 59  wherein the ether solvent of step (d) is tetrahydrofuran. 
     
     
         61 . The process of  claim 42  wherein the reducing agent of step (e) comprises diisobutylaluminum hydride. 
     
     
         62 . The process of  claim 42  wherein the solvent of step (e) comprises an ether solvent. 
     
     
         63 . The process of  claim 62  wherein the ether solvent of step (e) is tetrahydrofuran. 
     
     
         64 . A process for preparing an intermediate according to Compound (4): 
       
         
           
           
               
               
           
         
         wherein:
 m1 is 0, 1 or 2; 
 m2 is 0 or 1; 
 the spiro-ring AB is optionally substituted by 1 to 5 same or different substituent(s) selected from the group consisting of:
 (1) a hydroxy group, 
 (2) a C 1 -C 6  alkyl group, 
 (3) a C 1 -C 6  alkoxy group and 
 (4) an oxo group; 
 
 n1 is 0, 1, 2, 3 or 4; 
 n2 is 1, 2, 3 or 4; and 
 a bond represented by the symbol:    
 
         means a single bond or a double bond with the proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C;
 
 
         comprising condensing an intermediate according to Compound (1): 
       
       
         
           
           
               
               
           
         
         wherein X 51  is a hydroxy group or a leaving group; 
         with an intermediate according to Compound (20): 
       
       
         
           
           
               
               
           
         
         wherein X 52  is a hydroxy group or a leaving group. 
       
     
     
         65 . The process of  claim 64  wherein the condensing is carried out in the presence of a condensing reagent. 
     
     
         66 . The process of  claim 65  wherein the condensing reagent comprises 1,1′-(azodicarbonyl)dipiperidine or triphenylphosphine. 
     
     
         67 . The process of  claim 64  wherein the condensing is carried out in the presence of a solvent. 
     
     
         68 . The process of  claim 67  wherein the solvent comprises an ether solvent. 
     
     
         69 . The process of  claim 67  wherein the solvent comprises a polar solvent. 
     
     
         70 . The process of  claim 64  wherein the condensing is carried out in the presence of a base. 
     
     
         71 . The process of  claim 70  wherein the base comprises an alkali metal carbonate. 
     
     
         72 . The process of  claim 71  wherein the alkali metal carbonate is potassium carbonate or cesium carbonate. 
     
     
         73 . An intermediate compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 1′  is a C 1 -C 6 alkyl group, a C2-C6alkenyl group, a C2-C6alkynyl group, a phenyl group, a hydroxy group, a five-membered heteroaryl group which has at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and which may be substituted by a C1-C6alkyl group, or a di(C 1 -C 6 alkoxy)methyl group); 
 R 51  is a C 1 -C 6 alkyl group; 
 R 100  is a C 1 -C 6 alkyl group; 
 L v1  is a leaving group; 
 L v2  is a leaving group; 
 X 51  and X 52  are the same or different and each represents a hydroxy group or a leaving group; 
 m1 is 0, 1 or 2; 
 m2 is 0 or 1; 
 the spiro-ring AB is optionally substituted by 1 to 5 same or different substituent(s) selected from the group consisting of:
 (1) a hydroxy group, 
 (2) a C 1 -C 6  alkyl group, 
 (3) a C 1 -C 6  alkoxy group and 
 (4) an oxo group; 
 
 n1 is 0, 1, 2, 3 or 4; 
 n2 is 1, 2, 3 or 4; 
 n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; and 
 a bond represented by the symbol:    
 
         means a single bond or a double bond with the proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C.