Cyclic amide derivative, and its production and use

Abstract

The present invention provides a cyclic amide derivative useful as a drug for treating thrombosis, which is represented by the formula (I): wherein R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or an optionally substituted divalent chain hydrocarbon group, a represents 0, 1, or 2, X 1 represents an optionally substituted lower alkylene or an optionally substituted lower alkenylene, Y 1 represents —C(O)—, —S(O)— or —S(O) 2 —, A represents a piperazine ring which may be further substituted or a piperidine ring which may be further substituted, X 2 represents a bond or an optionally substituted lower alkylene, Y 2 represents —C(O)—, —S(O)—, —S(O) 2 — or —C(═NR 7 )—, X 3 represents an optionally substituted C 1-4 alkylene or an optionally substituted C 2-4 alkenylene, Z 3 represents —N(R 4 )—, —O— or a bond, Z 1 represents —C(R 2 )(R 2′ )—, —N(R 2 )—, etc., and Z 2 represents —C(R 3 )(R 3′ )—, —N(R 3 )—, etc., or a salt thereof.

1 . A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a cyclic hydrocarbon group which may be optionally substituted or a heterocyclic group which may be optionally substituted,
 W represents a bond or a divalent chain hydrocarbon group which may be optionally substituted, 
 a represents 0, 1, or 2, 
 X 1  represents a lower alkylene which may be optionally substituted or a lower alkenylene which may be optionally substituted, 
 Y 1  represents —C(O)—, —S(O)— or —S(O) 2 —, 
 A represents a piperazine ring which may be further substituted or a piperidine ring which may be further substituted, 
 X 2  represents a bond or a lower alkylene which may be optionally substituted, 
 Y 2  represents —C(O)—, —S(O)—, —S(O) 2 — or —C(═NR 7 )— (wherein R 7  represents a hydrogen atom, a hydroxy group which may be optionally substituted, a lower alkoxycarbonyl group or an acyl group), 
 X 3  represents a C 1-4  alkylene which may be optionally substituted or a C 2-4  alkenylene which may be optionally substituted, 
 in which two alkyl groups may be bound to each other to form an aryl ring together with carbon atoms which they attach to when X 3  represents a C 2-4  alkenylene substituted with two alkyl groups, 
 Z 3  represents —N(R 4 )—, —O— or a bond (wherein R 4  represents a hydrogen atom, a hydrocarbon group which may be optionally substituted or an acyl group), 
     
 
       represents a single bond or a double bond, when
     
 
       represents a single bond, Z 1  represents —C(R 2 )(R 2′ )—, —N(R 2 )— or —O—, and Z 2  represents —C(R 3 )(R 3′ )—, —N(R 3 )—, —O— or a bond (provided that, when Z 1  is —O—, Z 2  is other than —O—), and when
     
 
       is a double bond, Z 1  represents —C(R 2 )═ or a nitrogen atom, and Z 2  represents ═C(R 3 ) or a nitrogen atom,
 each of R 2 , R 2′ , R 3  and R 3′  represents a hydrogen atom, a hydrocarbon group which may be optionally substituted or a heterocyclic group which may be optionally substituted, respectively, or each pair of R 2  and R 3 , and R 2′  and R 3′  may be bound to each other respectively to form a ring which may be optionally substituted, or a salt thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein X 3  represents a C 1-4  alkylene which may be optionally substituted or a C 2-4  alkenylene which may be optionally substituted. 
     
     
         3 . A prodrug of the compound according to  claim 1  or  2 . 
     
     
         4 . The compound according to  claim 2 , wherein R 1  is an aryl which may be optionally substituted. 
     
     
         5 . The compound according to  claim 2 , wherein R 1  is a naphthyl which may be substituted with a halogen atom. 
     
     
         6 . The compound according to  claim 2 , wherein W is a bond. 
     
     
         7 . The compound according to  claim 2 , wherein Y 1  is —C(O)—. 
     
     
         8 . The compound according to  claim 2 , wherein —X 1 —Y 1 — is represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 2 , wherein A is a group represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein a ring A′ represents a piperazine ring which may be further substituted and a ring A″ represents a piperidine ring which may be further substituted. 
     
     
         10 . The compound according to  claim 2 , wherein X 2  is a bond. 
     
     
         11 . The compound according to  claim 2 , wherein Y 2  is —C(O)— or —C(═NR 7 )—. 
     
     
         12 . The compound according to  claim 2 , wherein 
       
         
       
       is a single bond. 
     
     
         13 . The compound according to  claim 2 , wherein Z 3  is a bond. 
     
     
         14 . The compound according to  claim 2 , wherein the group: 
       
         
           
           
               
               
           
         
       
       is represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein each symbol in the formula is as defined in  claim 1 . 
     
     
         15 . The compound according to  claim 2 , wherein the group: 
       
         
           
           
               
               
           
         
       
       is represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein each symbol in the formula is as defined in  claim 1 . 
     
     
         16 . The compound according to  claim 2 , wherein a is 2. 
     
     
         17 . The compound according to  claim 1  or  2 , wherein W is a bond, a is 2, —X 1 —Y 1 — is represented by the formula: 
       
         
           
           
               
               
           
         
       
       and X 2  is a bond. 
     
     
         18 . The compound according to  claim 17 , wherein R 1  is an aryl which may be optionally substituted, and A is a group represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein a ring A′ represents a piperazine ring which may be further substituted and a ring A″ represents a piperidine ring which may be further substituted. 
     
     
         19 . The compound according to  claim 18 , wherein R 1  is an aryl which may be substituted with 1 to 3 halogen atom(s), Y 2  is —C(O)— or —C(═NR 7 )—, 
       
         
       
       is a single bond, and Z 3  is a bond. 
     
     
         20 . The compound according to  claim 19 , wherein the group: 
       
         
           
           
               
               
           
         
       
       is represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein each symbol in the formula is as defined in  claim 1 . 
     
     
         21 . The compound according to  claim 19 , wherein the group: 
       
         
           
           
               
               
           
         
       
       is represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein each symbol in the formula is as defined in  claim 1 . 
     
     
         22 . A compound selected from a group consisting of 4-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)morpholin-3-one, 1-(4-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperazin-1-yl)piperidin-2-one, 1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one, 1-(4-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperazin-1-yl)tetrahydropyrimidin-2(1H)-one, 1-(1-{3-[(6-chloronaphthalen-2-yl)sulfonyl]}propanoyl))piperazin-4-yl)tetrahydropyrimidin-2(1H)-one and (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-1-(2-imino-1,4′-bipiperidin-1′-yl)-1-oxopropan-2-ol, or a salt thereof. 
     
     
         23 . A compound selected from a group consisting of 1′-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}-1,4′-bipiperidin-2-one, and 2-(1-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)isoindolin-1-one, or a salt thereof. 
     
     
         24 . A pharmaceutical composition comprising the compound according to  claim 1 ,  2  or  3 . 
     
     
         25 . The pharmaceutical composition according to  claim 24 , which is an anticoagulant. 
     
     
         26 . The pharmaceutical composition according to  claim 24 , which is an activated blood coagulation factor X inhibitor. 
     
     
         27 . The pharmaceutical composition according to  claim 24 , which is a medicament for preventing or treating myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or atherosclerotic obliterans. 
     
     
         28 . The pharmaceutical composition according to  claim 24 , which is a medicament for preventing or treating economy-class syndrome, thromboembolism during and post operation, or the secondary onset of deep vein thrombosis. 
     
     
         29 . Use of the compound according to  claim 1 ,  2  or  3  for manufacturing an activated blood coagulation factor X inhibitor. 
     
     
         30 . A method for preventing or treating myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or atherosclerotic obliterans, which comprises administering the compound according to  claim 1 ,  2  or  3  to a human being or an animal. 
     
     
         31 . A method for preventing or treating economy-class syndrome, thromboembolism during and post operation, or the secondary onset of deep vein thrombosis which comprises administering the compound according to  claim 1 ,  2  or  3  to a human being or an animal. 
     
     
         32 . A process for preparing the compound according to  claim 1 , which comprises reacting a compound represented by the formula (II): 
       
         
           
           
               
               
           
         
       
       wherein L represents a leaving group and the other symbols are as defined in  claim 1 , or a salt thereof with a compound represented by the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein M represents a hydrogen atom, an alkali metal, an alkali earth metal or a leaving group and the other symbols are as defined in  claim 1 , or a salt thereof, and if necessary, subjecting the resulting compound to hydrolysis, esterification, amidation, alkylation, acylation, reduction, oxidation and/or deprotection reactions.