Benzopiperidine derivatives

Abstract

Benzopiperidine derivatives represented by formula (I), salts thereof or hydrates thereof, processes for producing the same and drugs comprising the same: wherein the variables are as described in the specification. These compounds are useful as drugs efficacious in the prevention and treatment of these various inflammatory diseases and immunologic diseases, such as rheumatoid arthritis, atopic dermatitis, psoriasis, asthma, and rejection reaction accompanying organ transplantation.

1 . A benzopiperidine derivative represented by the following general formula (I), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  may be the same or different and each represents: 
 1) hydrogen,  
 2) optionally substituted lower alkyl;  
 3) optionally substituted lower alkenyl;  
 4) optionally substituted lower alkynyl;  
 5) optionally substituted lower cycloalkyl;  
 6) optionally substituted lower cycloalkenyl;  
 7) optionally substituted C 2-6  alkoxy;  
 8) a group represented by the following formula:  
                     wherein X and Y represent each optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom; l and m may be the same or different and each represents 0 or 1; the ring A represents an optionally substituted cycloalkyl ring optionally having one or more heteroatoms; the ring B represents a ring optionally having one or more double bonds in the ring selected from the following ones: 
 a) an optionally substituted cycloalkyl ring optionally having a heteroatom;  
 b) an optionally substituted bicycloalkyl ring optionally having a heteroatom, wherein the different atoms (bridgehead carbon atoms) in the ring B are bonded to each other via an optionally substituted C 1  or higher alkylene group optionally having a heteroatom; or  
 c) an optionally substituted spiro-hydrocarbon ring optionally having a heteroatom, wherein both ends of an optionally substituted C 1  or higher alkylene group optionally having a heteroatom are bonded to a carbon atom (bridgehead carbon atom) in the ring B;  
   
 9) a group represented by the following formula:  
                     
 wherein X 1  represents optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom;  
 l 1  is 0 or 1;  
 the ring A 1  represents: 
 a) an optionally substituted cycloalkyl ring optionally having one or more heteroatoms;  
 b) an optionally substituted cycloalkenyl ring optionally having one or more heteroatoms; or  
 c) an optionally substituted spiro-hydrocarbon ring optionally having a heteroatom, wherein both ends of an optionally substituted C 1  or higher alkylene group optionally having a heteroatom are bonded to a carbon atom (bridgehead carbon atom) in the ring A 1 ; or  
 
 10) a group represented by the following formula:  
 —(X 2 ) l     2   —Q  
 wherein X 2  represents optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom;  
 l 2  is 0 or 1;  
 Q represents: 
 a) heteroaryl consisting of one or more optionally substituted rings or aryl consisting of one or more optionally substituted rings;  
 b) optionally substituted quaternary ammonio;  
 c) a group represented by the formula:  
                     
 wherein R 5  and R 6  may be the same or different and each represents hydrogen or lower alkyl;  
 d) lower acyl;  
 e) lower acyloxy;  
 f) carbamoyl;  
 g) a group represented by the following formula:  
                     
 wherein R 7  and R 8  may be the same or different and each represents hydrogen, lower alkyl, a group represented by the formula:  
                     
 wherein R 71  represents lower alkyl, trifluoromethyl, aryl or a group represented by the formula:  
                     
 wherein R 72  and R 73  may be the same or different and each represents hydrogen, lower alkyl, lower cycloalkyl or aryl; a group represented by the following formula:  
                     
 wherein R 81  represents hydrogen, lower alkyl or aryl; a group represented by the formula:  
                     
 wherein R 74  and R 75  may be the same or different and each represents hydrogen or lower alkyl; a group represented by the formula:  
                     
 wherein R 76  represents hydrogen, lower alkyl, cyano, pyridyl or lower alkylsulfonyl; R 77  represents hydrogen or lower alkyl, or an amino protecting group;  
 h) protected hydroxy;  
 i) a group represented by the formula:  
 —S—R 82    
 wherein R 82  represents hydrogen, lower alkyl or a mercapto protecting group;  
 j) carboxy;  
 k) protected carboxy;  
 l) a group represented by the formula:  
                     
 wherein W represents oxygen or sulfur; R 83  and R 84  may be the same or different and each represents hydrogen, lower alkyl, lower cycloalkyl, cyano, aryl or a group represented by the formula:  
 —SO 2 R 85    
 wherein R 85  represents hydrogen, hydroxy, lower alkyl or aryl; or R 83  and R 84  may together form optionally substituted lower cycloalkyl optionally having one or more heteroatoms;  
 m) sulfonyl;  
 n) sulfonylamido;  
 o) azido;  
 p) formyl;  
 q) a group represented by the formula:  
                     
 wherein R 86 , R 87  and R 88  may be the same or different and each represents hydrogen, aryl, heteroaryl, optionally substituted lower alkyl, hydroxy(lower alkyl), cyano, amino, nitro, acetyl or a group represented by the formula:  
 —SO 2 R 89    
 wherein R 89  represents aryl, hydroxy, optionally substituted lower alkyl, trifluoromethyl or amino; or R 86  and R 87  may together form an optionally substituted lower cycloalkyl optionally having one or more heteroatoms;  
 r) guanidino;  
 s) hydrazino;  
 t) isocyano;  
 u) cyanate;  
 v) isocyanate;  
 w) thiocyanate;  
 x) isothiocyanate;  
 y) nitroso; or  
 z) a group represented by the formula:  
                     
 wherein R 90  and R 91  represent each hydrogen or lower alkyl, provided that the case where R 1  to R 3  each represents methyl in the case 2) of the above definition thereof is excluded;  
 R represents:  
 
 1) hydrogen;  
 2) lower alkyl;  
 3) optionally substituted arylalkyl;  
 4) optionally substituted heteroarylalkyl;  
 5) an amino protective group;  
 6) a group represented by the following formula:  
                     
 wherein X 3  represents optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom; R 9  and R 10  may be the same or different and each represents hydrogen, lower alkyl or an amino protective group; or  
 7) a group represented by the formula:  
 —X 4 —CO 2 R 11    
 wherein X 4  represents optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom; R 11  represents hydrogen, lower alkyl or a carboxy protecting group;  
 E represents N or a group represented by the formula:  
 C—R 4    
 wherein R 4  has the same meaning as 1 to 10) as defined above with respect to R 1  to R 3 ;  
 Z represents O, S, SO, SO 2  or a group represented by the following general formula:  
 N—R 12    
 wherein R 12  represents hydrogen, lower alkyl or an amino protecting group;  
 the ring G represents an optionally substituted heteroaryl ring having one or more nitrogen atoms;  
 provided that the following cases are excluded: 
 a) that in which R 1  to R 3  are each hydrogen, E is CH, Z is O, S, or SO 2  and the ring G is an unsubstituted (i.e., all of the substituents being hydrogen atoms) heteroaryl ring having one or more nitrogen atoms;  
 b) that in which R 1  to R 3  are each hydrogen, E is CH, Z is O, S, SO 2  or NH and the substituent(s) of the ring G is optionally substituted phenyl, pyridinyl, thienyl, nitro, cyano, halogeno, acetyl, methyl, ethyl, t-butyl, ethoxy, N-methylpiperazyl, naphthyl, optionally protected carboxyalkyl or amino;  
 c) that in which R 1  to R 3  are each hydrogen, E is CH, Z is NH and the ring G is unsubstituted (i.e., all of the substituents being hydrogen atoms) pyridazine; and  
 d) that in which R 1  to R 3  are each all hydrogen, E is CH, R is a group other than hydrogen, Z is NR 12  (R 12  being lower alkyl or an amino protective group) and the ring G is an optionally substituted heteroaryl ring optionally having one or more nitrogen atoms.  
 
 
       
     
     
         2 . The benzopiperidine derivative as set forth in  claim 1 , its salt or hydrates thereof, wherein Z in the formula (I) is S.  
     
     
         3 . The benzopiperidine derivative as set forth in  claim 1  its salt or hydrates thereof, wherein the ring G in the formula (I) is an optionally substituted pyrazine ring.  
     
     
         4 . A benzopiperidine derivative represented by the following general formula (II), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R, E, Z and the ring G are each as defined above;  
         U represents: 
 1) a group represented by the formula:  
                     
 wherein X, Y, l, m and the rings A and B are each as defined above; or  
 2) a group represented by the formula:  
                     
 wherein X 1 , l 1  and the ring A 1  are each as defined above.  
 
       
     
     
         5 . The benzopiperidine derivative as set forth in  claim 4 , its salt or hydrates thereof, wherein U in the general formula (II) represents: 
 1) a group represented by the formula:                          wherein X, Y, l, m and the ring B are each as defined above; and    the ring A 2  represents an optionally substituted cycloalkyl ring having one or more heteroatoms; or    2) a group represented by the formula:                          wherein X 1  and l 1  are each as defined above; and    the ring A 3  represents: 
 a) an optionally substituted cycloalkyl ring having one or more heteroatoms;  
 b) an optionally substituted cycloalkenyl ring having one or more heteroatoms; or  
 c) an optionally substituted spiro-hydrocarbon ring having one or more heteroatoms, wherein the both ends of an optionally substituted C 1  or higher alkylene group optionally having a heteroatom are bonded to a carbon atom (bridgehead carbon atom) in the ring A 3 .  
   
     
     
         6 . A benzopiperidine derivative represented by the formula (III), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R, E, Z and the ring G are each as defined above;  
         U 1  represents: 
 1) a group represented by the formula:  
                     
 wherein Y, m and the rings A 2  and B are each as defined above; or  
 2) a group represented by the following formula:  
                     
 wherein the ring A 3  is as defined above.  
 
       
     
     
         7 . The benzopiperidine derivative as set forth in  claim 1  its salt or hydrates thereof, wherein the ring G in the formula (II) or (III) is an optionally substituted pyrazine ring.  
     
     
         8 . A process for producing a derivative represented by the formula (VI), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R, E, Z, the ring G, X, Y, l, m, the ring A 2  and the ring B are each as defined above, which comprises reacting a compound represented by the following general formula (IV) or (IV′):  
         
           
             
             
                 
                 
             
           
         
         wherein R, E, Z, the ring G, X and l are each as defined above, and Lev. represents a leaving group, with a compound represented by the following formula (V):  
         
           
             
             
                 
                 
             
           
         
         wherein Y, m, the ring A 2  and the ring B are each as defined above, provided that the ring B is optionally protected, optionally followed by deblocking.  
       
     
     
         9 . A 10H-pyrazino[2,3-b][1,4]benzothiazine derivative represented by the formula (IV-1) or (IV′-1), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein Lev. is as defined above.  
       
     
     
         10 . A bicycloalkyl derivative represented by the formula (VII), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein Y, m and the rings A 2  and B are each as defined above; R 13  represents hydrogen, lower alkyl or an amino protective group; and R 14  and R 15  may be the same or different and each represents hydrogen or lower alkyl.  
       
     
     
         11 . A bicycloalkyl derivative represented by the formula (X), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein Y, m, the rings A 2  and B and R 13  are each as defined above; X 5  represents optionally substituted lower alkylene optionally having a heteroatom, optionally substituted lower alkenylene optionally having a heteroatom or optionally substituted lower alkynylene optionally having a heteroatom; l 5  is 0 or 1; and Q 1  represents carboxy, alkoxycarbonyl, sulfamoyl, amido, optionally protected hydroxy or optionally protected amino.  
       
     
     
         12 . A bicycloalkyl derivative represented by the following general formula (XI), (XII), (XIII), (XIV), (XV) or (XVI), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 13 , X 5 , l 5  and Q 5  are each as defined above; and R 14′  and R 15′  may be the same or different and each represents hydrogen or lower alkyl, provided that the following cases are excluded: that in which, in the formula (XI) or (XII), R 15′  and R 14′  are each hydrogen, l 5  is 0 and Q 1  is carboxy or ethoxycarbonyl; that in which, in the general formula (XI), R 13  is methyl, l 5  is 1, X 5  has one carbon atom and forms a double bond together with a carbon atom on the ring to which it is bonded and Q 1  is ethoxycarbonyl, 4-methoxyphenylcarbonyl or formyl, or R 13  is methyl, l 5  is 1, X 5  is unsubstituted methylene and Q 1  is ethoxycarbonyl; and that in which, in the formula (XIII), R 13  is benzyl or benzoyl, l 5  is 0 and Q 1  is ethoxycarbonyl.  
       
     
     
         13 . A bicycloalkyl derivative selected from among those represented by the formulae 1) to 3), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 13  is as defined above; and R 18  represents hydrogen, lower alkyl or a carboxy protective group, provided that the case where, in the compound of the formula 1), R 13  is methyl and R 14  is ethyl is excluded.  
       
     
     
         14 . A piperidine derivative represented by the formula (XVII) or (XVIII), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 13 , X 5 , l 5  and Q 1  are each as defined above, provided that the following cases are excluded:  
         that in which, in the general formula (XVII), X 5  is unsubstituted C 1-4  alkylene, l 5  is 0 or 1 and Q 1  is ethoxycarbonyl, or X 5  is unsubstituted C 1-3  alkylene, l 5  is 0 or 1 and Q 1  is amino protected by carbonyl; and that in which, in the formula (XVIII), l 1  is 0, Q 1  is amino optionally protected by tert-butoxycarbonyl or hydroxy optionally protected by methanesulfonyl.  
       
     
     
         15 . A piperidine derivative represented by the formula (XIX), (XX) or (XXI), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 13 , X 5 , l 5  and R 18  are each as defined above; and Me represents methyl.  
       
     
     
         16 . A piperidine derivative selected from among those represented by the formulae 1) to 3), its salt or hydrates thereof:  
       
         
           
           
               
               
           
         
         wherein R 13  and R 18  are each as defined above; and Me represents methyl.  
       
     
     
         17 . A drug comprising a benzopiperidine derivative represented by the formula (I) as set forth in  claim 1 , its pharmacologically acceptable salt or hydrates thereof.  
     
     
         18 . A drug comprising a benzopiperidine derivative, its pharmacologically acceptable salt or hydrates thereof as set forth in  claim 17 , which is a preventive or remedy for inflammatory immunologic diseases and autoimmune diseases.  
     
     
         19 . A drug comprising a benzopiperidine derivative, its pharmacologically acceptable salt or hydrates thereof as set forth in  claim 17  which is a preventive or remedy for rheumatism, collagen disease, asthma, nephritis, ischemic reflow disorders, psoriasis, atopic dermatitis or the rejection reaction accompanying organ transplantation.  
     
     
         20 . Use of a benzopiperidine compound as defined in  claim 1 , a pharmacologically acceptable salt thereof or a pharmacologically acceptable hydrate in manufacturing a pharmacological medicine.  
     
     
         21 . A pharmaceutical composition comprising a pharmacologically effective amount of a benzopiperidine compound as defined in  claim 1 , a pharmacologically acceptable salt thereof or a pharmacologically acceptable hydrate and a pharmacologically acceptable carrier.  
     
     
         22 . A method for treating inflammatory immunologic diseases or autoimmune diseases, which comprises the step of administering a pharmacologically effective amount of a benzopiperidine compound as defined in  claim 1 , a pharmacologically acceptable salt thereof or a pharmacologically acceptable hydrate to a human patient suffering from inflammatory immunologic diseases or autoimmune diseases.