Sulfonyl derivatives

Abstract

Described is a sulfonyl derivative represented by the following formula (I): [wherein R 1 represents a hydrogen atom, a hydroxyl group, a nitro group or the like, R 2 and R 3 each independently represents a hydrogen atom, a halogen atom or the like, R 4 and R 5 each independently represents a hydrogen atom, a halogen atom or the like, Q 1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like, Q 2 represents a single bond, an oxygen atom or the like, Q 3 represents any one of the following groups: T 1 represents a carbonyl group or the like, and X 1 and X 2 each independently represents a methine group or a nitrogen atom]; or salt thereof; or solvate thereof. The sulfonyl derivative, salt or solvate according to the present invention is novel as an excellent anticoagulant and it has strong FXa inhibitory action, rapidly exhibits sufficient and long-lasting anti-thrombus effects after oral administration and has less side effects.

1 . A sulfonyl derivative represented by the following formula (I):  
       
         
           
           
               
               
           
         
         [wherein R 1  represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A 1 -B 1 -(in which A 1  represents an amino group which may have one or two substituents, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B 1  represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group),  
         R 2  and R 3  each independently represents a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group or R 2  or R 3  may be coupled together with R 1  to form a C 1-3  alkylene or alkenylene group,  
         R 4  and R 5  each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (with the proviso that R 4  and R 5  do not represent a hydrogen atom at the same time),  
         Q 1  represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a saturated or unsaturated bicyclic or tricyclic fused ring group which may have a substituent,  
         Q 2  represents a single bond, an oxygen atom, a sulfur atom, a linear or branched C 1-6  alkylene group, a linear or branched C 2-6  alkenylene group, a linear or branched C 2-6  alkynylene group, a group —N(R 6 )—CO— (in which R 6  represents a hydrogen atom or an alkyl group), a group —N(R 7 )—(CH 2 )m- (in which R 7  represents a hydrogen atom or an alkyl group and m stands for an integer of 0 to 6) or a group of the following formula:  
         
           
             
             
                 
                 
             
           
           (which represents a divalent, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a divalent saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a divalent saturated or unsaturated dicyclic fused ring group which may have a substituent and ←C means the bonding of the carbon atom of this group to Q 1 ),  
         
         Q 3  represents any one of the following groups:  
         
           
             
             
                 
                 
             
           
           (in which when the carbon atom to which each of R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  is bonded is not adjacent to a nitrogen atom, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  each independently represents: 
 a hydrogen atom,  
 a hydroxyl group,  
 an alkyl group,  
 an alkoxyl group,  
 an alkoxyalkyl group,  
 an alkoxyalkyloxy group,  
 a hyroxyalkyl group,  
 a hydroxyalkyloxy group,  
 a hydroxyalkylsulfonyl group,  
 a formyl group,  
 a formylalkyl group,  
 a formylalkylcarbonyl group,  
 a formylalkylsulfonyl group,  
 an alkylcarbonyl group,  
 an alkylsulfonyl group,  
 an alkylcarbonylalkyl group,  
 an alkylsulfonylalkyl group,  
 a carboxyl group,  
 a carboxyalkyl group,  
 a carboxyalkyloxy group,  
 a carboxyalkylcarbonyl group,  
 a carboxyalkylsulfonyl group,  
 a carboxyalkylcarbonylalkyl group,  
 a carboxyalkylsulfonylalkyl group,  
 an alkoxycarbonyl group,  
 an alkoxycarbonylalkyl group,  
 an alkoxycarbonylalkyloxy group,  
 an alkoxycarbonylalkylcarbonyl group,  
 an alkoxycarbonylalkylsulfonyl group,  
 an amino group which may have one or two substituents, an aminoalkyl group in which the amino moiety may have one or two substituents,  
 an aminoalkyloxy group in which the amino moiety may have one or two substituents,  
 an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,  
 an aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents,  
 an aminocarbonyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents or  
 a group A 2 -B 2 - (in which A 2  represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B 2  represents a single bond, a carbonyl group or an alkylene group),  
 
           when the carbon atom to which each of R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  is bonded is adjacent to a nitrogen atom, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  each independently represents: 
 a hydrogen atom,  
 an alkyl group,  
 a hyroxyalkyl group,  
 a hyroxyalkylcarbonyl group,  
 a hydroxyalkylsulfonyl group,  
 a formyl group,  
 a formylalkyl group,  
 a formylalkylcarbonyl group,  
 a formylalkylsulfonyl group,  
 an alkylcarbonyl group,  
 an alkylsulfonyl group,  
 an alkylcarbonylalkyl group,  
 an alkylsulfonylalkyl group,  
 a carboxyl group,  
 a carboxyalkyl group,  
 a carboxyalkylcarbonyl group,  
 a carboxyalkylsulfonyl group,  
 a carboxyalkylcarbonylalkyl group,  
 a carboxyalkylsulfonylalkyl group,  
 an alkoxyalkyl group,  
 an alkoxycarbonyl group,  
 an alkoxycarbonylalkyl group,  
 an alkoxycarbonylalkylcarbonyl group,  
 an alkoxycarbonylalkylsulfonyl group,  
 an aminoalkyl group in which the amino moiety may have one or two substituents,  
 an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonylalkyl group in which the amino moiety may have one or two substituents or  
 a group A 3 -B 3  - (in which A 3  represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B 3  represents a single bond, a carbonyl group or an alkylene group),  
 
           R 8  and R 9 , R 10  and R 11 , R 12  and R 13 , and R 15  and R 16  may each be coupled together with a carbon atom which constitutes the ring and represent a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,  
           R 14  and R 17  each independently represents: 
 a hydrogen atom,  
 an alkyl group,  
 a hydroxyalkyl group,  
 a hyroxyalkylcarbonyl group,  
 a hydroxyalkylsulfonyl group,  
 an alkoxyl group,  
 an alkoxyalkyl group,  
 an alkoxyalkylcarbonyl group,  
 an alkoxyalkylsulfonyl group,  
 a formyl group,  
 a formylalkyl group,  
 a formylalkylcarbonyl group,  
 a formylalkylsulfonyl group,  
 an alkylcarbonyl group,  
 an alkylcarbonylalkyl group,  
 an alkylsulfonyl group,  
 an alkylsulfonylalkyl group,  
 a carboxyalkyl group,  
 a carboxyalkylcarbonyl group,  
 a carboxyalkylsulfonyl group,  
 a carboxyalkylcarbonylalkyl group,  
 a carboxyalkylsulfonylalkyl group,  
 an alkoxycarbonyl group,  
 an alkoxycarbonylalkyl group,  
 an alkoxycarbonylalkylcarbonyl group,  
 an alkoxycarbonylalkylsulfonyl group,  
 an amino group which may have one or two substituents,  
 an aminoalkyl group in which the amino moiety may have one or two substituents,  
 an aminoalkyloxy group in which the amino moiety may have one or two substituents,  
 an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,  
 an aminoalkyloxycarbonyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonyl group in which the amino moiety may have one or two substituents,  
 an aminocarbonylalkyl group in which the amino moiety may have one or two substituents, and  
 an aminocarbonyloxyalkyl group in which the amino moiety may have one or two substituents,  
 
           R 14  and R 12  or R 13  may be coupled together with a carbon atom constituting a ring and with a nitrogen atom to which R 14  is bonded to form a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,  
           R 17  and R 15  or R 16  may be coupled together with a carbon atom constituting a ring and with a nitrogen atom to which R 17  is bonded to form a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, and  
           a, b, d, e and g each independently stands for an integer of 0 or 1, c stands for an integer of 0 to 3, f, h and i each independently represents an integer of 1 to 3, with the proviso that the sum of a, b and c stands for an integer of 2 or 3, the sum of d and e stands for an integer of 0 or 1 and the sum of f, g and h stands for an integer of 3 to 5),  
         
         T 1  represents a carbonyl group, 
 a group —CH(R 18 )— (in which R 18  represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent) or  
 a group −C(═NOR 19 )— (in which R 19  represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent),  
 
         X 1  and X 2  each independently represents a methine group or a nitrogen atom]; salt thereof; or solvate thereof.  
       
     
     
         2 . A sulfonyl derivative according to  claim 1 , wherein the following group:  
       
         
           
           
               
               
           
         
       
       in the formula (I) is a group of the following formula:  
       
         
           
           
               
               
           
         
       
       or  
       
         
           
           
               
               
           
         
       
       (wherein R 2 , R 4 , R 5 , X 1  and X 2  have the same meanings as defined above); salt thereof; or solvate thereof.  
     
     
         3 . A sulfonyl derivative according to  claim 1  or  2 , wherein R 4  represents a halogen atom; salt thereof; or solvate thereof.  
     
     
         4 . A sulfonyl derivative according to any one of  claims 1  to  3 , wherein Q 1  represents a phenyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyrrolidinyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent or a tetrahydrothiazolopyridyl group which may have a substituent; salt thereof; or solvate thereof.  
     
     
         5 . A sulfonyl derivative according to any one of  claims 1  to  4 , wherein Q 2  represents a single bond, phenylene group, cyclohexylene group or cyclohexenylene group; salt thereof; or solvate thereof.  
     
     
         6 . A sulfonyl derivative according to any one of  claims 1  to  5 , wherein Q 3  represents a group of the following formula:  
       
         
           
           
               
               
           
         
       
       [wherein R 8 , R 9 , a, b and c have the same meanings as defined above]; salt thereof; or solvate thereof.  
     
     
         7 . A sulfonyl derivative according to any one of  claims 1  to  6 , wherein T 1  represents a carbonyl group; salt thereof; or solvate thereof.  
     
     
         8 . A medicament comprising as an effective ingredient a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         9 . An inhibitor for an activated coagulation factor X which comprises as an effective ingredient a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         10 . A coagulation inhibitor comprising as an effective ingredient a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         11 . A preventive and/or remedy for a thrombosis or embolism which comprises as an effective ingredient a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         12 . A preventive and/or remedy for cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization, formation of thrombus upon extracorporeal circulation or coagulation upon blood collection, which comprises as an effective ingredient a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         13 . A pharmaceutical composition comprising a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 ; and a pharmaceutically acceptable carrier.  
     
     
         14 . Use of a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7  as a medicament.  
     
     
         15 . Use of a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7  as an inhibitor for an activated coagulation factor X.  
     
     
         16 . Use of a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7  as a coagulation inhibitor.  
     
     
         17 . Use of a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7  as a preventive and/or remedy for a thrombosis or embolism.  
     
     
         18 . A method for treating a disease caused by a thrombosis or embolism, which comprises administering, to a patient suffering from the disease, a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .  
     
     
         19 . A method for treating cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization, formation of thrombus upon extracorporeal circulation or coagulation upon blood collection, which comprises administering, to a patient therefrom, a sulfonyl derivative, salt thereof or solvate thereof as claimed in any one of  claims 1  to  7 .