Drug compositions and methods for preventing and treating thrombosis or embolism

Abstract

Drug compositions containing a substituted diamine compound represented by formula (1): Q 1 -Q 2 -r-N(R 1 )-Q 3 -N(R 2 )  (1) wherein Q 3 represents the following group wherein Q 5 represents an alkylene group having 4 carbon atoms, R 3 represents a hydrogen atom, and R 4 represents a 3-6 membered heterocyclic group which may be substituted; are useful for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.

1 - 40 . (canceled) 
   
   
       41 . A solid drug composition comprising:
 at least one pharmaceutically acceptable additive selected from the group of additives consisting of a filler, an extender, a binder, a disintegrator, a dissolution accelerator, a humectant and a lubricant; and   a compound represented by formula (1):
   Q 1 -Q 2 -T o -N(R 1 )-Q 3 -N(R 2 )-T 1 -Q 4   (1) 
   
     wherein
 R 1  and R 2  each independently represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; 
 Q 1  represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 2  represents a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched alkynylene group having 2 to 6 carbon atoms, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 3  represents the following group 
 
     
       
         
         
             
             
         
       
       wherein Q 5  represents an alkylene group having 4 carbon atoms, R 3  represents a hydrogen atom, and R 4  represents a 3-6 membered heterocyclic group which may be substituted; 
       Q 4  represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
       T 0  represents a carbonyl or thiocarbonyl group; and 
       T 1  represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)— (wherein R′ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)-A 1 -N(R″)— (wherein A 1  represents an alkylene group which has 1 to 5 carbon atoms and may be substituted, and R″ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group), —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A 2 -C(═O)— (wherein A 2  represents a single bond or alkylene group having 1 to 5 carbon atoms), group —C(═O)-A 3 -C(═O)—NH— (wherein A 3  represents an alkylene group having 1 to 5 carbon atoms), group —C(═O)—C(═NOR a )—N(R b ), group —C(═S)—C(═NOR a )—N(R b )— (wherein R a  represents a hydrogen atom, alkyl group or alkanoyl group, and R b  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NOR c )—C(═O)—N(R d )— (wherein R c  represents a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and R d  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═N—N(R e )(R f )—C(═O)—N(R g )— (wherein R e  and R r  each independently represent a hydrogen atom, alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and R g  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—NH—C(═O)—, group —C(═S)—NH—C(═O)—, group —C(═O)—NH—C(═S)—, group —C(═S)—NHC(═S)—, group —C(═O)—NH—SO 2 —, group —SO 2 —NH—, group —C(═NCN)—NH—C(═O)—, group —C(═S)—C(═O)— or thiocarbonyl group; 
     
     a salt thereof, or an N-oxide thereof. 
   
   
       42 . A liquid drug composition, comprising:
 water, a pharmaceutically acceptable solvent or a mixture of water and a pharmaceutically acceptable solvent;   at least one additive selected from the group of additives consisting of a stabilizer, a preservative, a dissolution aid, a suspending agent and an emulsifier; and   a compound, represented by formula (1):
   Q 1 -Q 2 -T o -N(R 1 )-Q 3 -N(R 2 )-T 1 -Q 4   (1) 
   
     wherein
 R 1  and R 2  each independently represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; 
 Q 1  represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 2  represents a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched alkynylene group having 2 to 6 carbon atoms, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted, 
 Q 3  represents the following group: 
 
     
       
         
         
             
             
         
       
       wherein Q 5  represents an alkylene group having 4 carbon atoms, R 3  represents a hydrogen atom, and R 4  represents a 3-6 membered heterocyclic group which may be substituted; 
       Q 4  represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
       T 0  represents a carbonyl or thiocarbonyl group; and 
       T 1  represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)— (wherein R′ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)-A 1 -N(R″)— (wherein A 1  represents an alkylene group which has 1 to 5 carbon atoms and may be substituted, and R″ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group), —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A 2 -C(═O)— (wherein A 2  represents a single bond or alkylene group having 1 to 5 carbon atoms), group —C(═O)-A 3 -C(═O)—NH— (wherein A 3  represents an alkylene group having 1 to 5 carbon atoms), group —C(═O)—C(═NOR a )—N(R b ), group —C(═S)—C(═NOR a )—N(R b )— (wherein R a  represents a hydrogen atom, alkyl group or alkanoyl group, and R b  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NOR c )—C(═O)—N(R d )— (wherein R c  represents a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and R d  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═N—N(R e )(R f ))—C(═O)—N(R g )— (wherein R e  and R f  each independently represent a hydrogen atom, alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and R g  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—NH—C(═O)—, group —C(═S)—NH—C(═O)—, group —C(═O)—NH—C(═S)—, group —C(═S)—NHC(═S)—, group —C(═O)—NH—SO 2 —, group —SO 2 —NH—, group —C(═NCN)—NH—C(═O)—, group —C(═S)—C(═O)— or thiocarbonyl group; 
     
     a salt thereof, or an N-oxide thereof. 
   
   
       43 - 46 . (canceled) 
   
   
       47 . A method for preparing the solid drug composition according to  claim 41 , comprising mixing the compound represented by formula (1), as described in  claim 41 , with at least one pharmaceutically acceptable additive selected from the group of additives consisting of a filler, an extender, a binder, a disintegrator, a dissolution accelerator, a humectant and a lubricant. 
   
   
       48 . A method for the preparation of the liquid drug composition according to  claim 42 , comprising adding the compound represented by formula (1), as described in  claim 42 , with one selected from the group consisting of water, a pharmaceutically acceptable solvent and a mixture of water and a pharmaceutically acceptable solvent. 
   
   
       49 - 51 . (canceled) 
   
   
       52 . A method for treating and/or preventing thrombosis or embolism, comprising administering to a patient in need thereof an effective amount of a compound represented by formula (1):
   Q 1 -Q 2 -T o -N(R 1 )-Q 3 -N(R 2 )-T 1 -Q 4   (1)   
     wherein
 R 1  and R 2  each independently represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; 
 Q 1  represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 2  represents a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched alkynylene group having 2 to 6 carbon atoms, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 3  represents the following group: 
 
     
       
         
         
             
             
         
       
       wherein Q 5  represents an alkylene group having 4 carbon atoms, R 3  represents a hydrogen atom, and R 4  represents a 3-6 membered heterocyclic group which may be substituted; 
       Q 4  represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
       T 0  represents a carbonyl or thiocarbonyl group; and 
       T 1  represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)— (wherein R′ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)-A —N(R″)— (wherein A 1  represents an alkylene group which has 1 to 5 carbon atoms and may be substituted, and R″ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group), —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A 2 -C(═O)— (wherein A 2  represents a single bond or alkylene group having 1 to 5 carbon atoms), group —C(═O)-A 3 -C(═O)—NH— (wherein A 3  represents an alkylene group having 1 to 5 carbon atoms), group —C(═O)—C(═NOR a )—N(R b ), group —C(═S)—C(═NOR a )—N(R b )— (wherein R a  represents a hydrogen atom, alkyl group or alkanoyl group, and R b  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NOR c )—C(═O)—N(R d )— (wherein R c  represents a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and R d  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═N—N(R e )(R f ))—C(═O)—N(R g )— (wherein R e  and R f  each independently represent a hydrogen atom, alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and R g  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—NH—C(═O)—, group —C(═S)—NH—C(═O)—, group —C(═O)—NH—C(═S)—, group —C(═S)—NHC(═S)—, group —C(═O)—NH—SO 2 —, group —SO 2 —NH—, group —C(═NCN)—NH—C(═O)—, group —C(═S)—C(═O)— or thiocarbonyl group; 
     
     a salt thereof, or an N-oxide thereof. 
   
   
       53 . A method for treating and/or preventing cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, comprising administering to a patient in need thereof an effective amount of a compound a compound represented by formula (1):
   Q 1 -Q 2 -T o -N(R 1 )-Q 3 -N(R 2 )-T 1 -Q 4   (1)   
     wherein
 R 1  and R 2  each independently represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; 
 Q 1  represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 2  represents a single bond, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, a linear or branched alkynylene group having 2 to 6 carbon atoms, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
 Q 3  represents the following group: 
 
     
       
         
         
             
             
         
       
       wherein Q 5  represents an alkylene group having 4 carbon atoms, R 3  represents a hydrogen atom, and R 4  represents a 3-6 membered heterocyclic group which may be substituted; 
       Q 4  represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic condensed hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic condensed heterocyclic group which may be substituted; 
       T 0  represents a carbonyl or thiocarbonyl group; and 
       T 1  represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)— (wherein R′ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)-A 1 -N(R″)— (wherein A 1  represents an alkylene group which has 1 to 5 carbon atoms and may be substituted, and R″ represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group), —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A 2 -C(═O)— (wherein A 2  represents a single bond or alkylene group having 1 to 5 carbon atoms), group —C(═O)-A 3 -C(═O)—NH— (wherein A 3  represents an alkylene group having 1 to 5 carbon atoms), group —C(═O)—C(═NOR a )—N(R b ), group —C(═S)—C(═NOR a )—N(R b )— (wherein R a  represents a hydrogen atom, alkyl group or alkanoyl group, and R b  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NOR c )—C(═O)—N(R d )— (wherein R c  represents a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and R d  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═N—N(R e )(R f ))—C(═O)—N(R g )— (wherein R e  and R f  each independently represent a hydrogen atom, alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and R g  represents a hydrogen atom, hydroxyl group, alkyl group or alkoxy group), group —C(═O)—NH—C(═O)—, group —C(═S)—NH—C(═O)—, group —C(═O)—NH—C(═S)—, group —C(═S)—NHC(═S)—, group —C(═O)—NH—SO 2 — group —SO 2 —NH—, group —C(═NCN)—NH—C(═O)—, group —C(═S)—C(═O)— or thiocarbonyl group; 
     
     a salt thereof, or an N-oxide thereof. 
   
   
       54 - 59 . (canceled) 
   
   
       60 . The solid drug composition according to  claim 41 , wherein the composition is in a form selected from the group consisting of a tablet, a powder, a granule, and a capsule. 
   
   
       61 . The liquid drug composition according to  claim 42 , wherein the composition is in a form selected from the group consisting of a solution, a syrup, an elixir, an oil and an aqueous suspension. 
   
   
       62 . The method for treatment and prevention of thrombosis or embolism according to  claim 52 , wherein the effective amount of the compound represented by formula (1) is from about 1 mg to about 1 g. 
   
   
       63 . The method for treatment and prevention of cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, according to  claim 53 , wherein the effective amount of the compound represented by formula (I) is from about 1 mg to about 1 g. 
   
   
       64 . A method for treating and preventing thrombosis or embolism comprising orally administering to a patient in need thereof, an effective amount of the solid drug composition according to  claim 41 . 
   
   
       65 . A method for treating and preventing thrombosis or embolism comprising administering by injection to a patient in need thereof, an effective amount of the liquid drug composition according to  claim 42 . 
   
   
       66 . A method for treatment and prevention of cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, comprising orally administering to a patient in need thereof, an effective amount of the solid drug composition according to  claim 41 . 
   
   
       67 . A method for treatment and prevention of cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, comprising administering by injection to a patient in need thereof, an effective amount of the liquid drug composition according to  claim 42 .