Plasminogen activator inhibitor-1 inhibitor

Abstract

The present invention provides a novel compound having plasminogen activator inhibitor-1 inhibitory activity, and an inhibitor of PAI-1 comprising the compound as an active ingredient. The present invention also provides a pharmaceutical composition having an inhibitory action on PAI-1 activity and being efficacious in the prevention and treatment of various diseases whose onset is associated with PAI-1 activity.

1 . A method for treating or preventing a disease whose development is attributed to PAI-1 activity, the method comprising administering a subject being affected or potentially affected with the disease an effective amount of the compound represented by Formula (I), a salt, or a solvate thereof in a combination with a pharmacologically acceptable carrier or additive thereof: 
       
         
           
           
               
               
           
         
         wherein —R 1  and R 2  are the same or different, and each represents hydrogen, halogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         —X represents —CH═CH—; 
         -A represents a group shown in any of the following (a) to (e): 
         (a) a group represented by the following Formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are the same or different, and each represents hydrogen, substituted or unsubstituted C 1-6 -alkyl, or CF 3 ; 
         T represents a single bond, substituted or unsubstituted C 1-3 -alkylene, oxygen, —CO—, —O—C 1-3 -alkylene, or C 2-6 -alkynylene; 
         D represents substituted or unsubstituted aryl, heteroaryl, or benzo-condensed heteroaryl; substituted or unsubstituted C 3-8 -cycloalkyl or heterocycloalkyl; substituted or unsubstituted C 3-8 -cycloalkenyl or heterocycloalkenyl; or adamantyl; 
         q is an integer 1; 
         provided that when, in Formula (I), L is substituted or unsubstituted C 1-6 -alkylene-NHCO— and T is a single bond, D is not unsubstituted phenyl; 
         (b) a group represented by any of the Following Formulae (III) to (V) 
       
       
         
           
           
               
               
           
         
         wherein, in Formulae (III) to (V) above, 
         R 5  represents hydrogen or halogen; 
         R 6  represents hydrogen, C 1-6 -alkyl, or C 1-6 -hydroxyalkyl; 
         E represents a single bond or —O—C 1-6 -alkylene; 
         Ar represents substituted or unsubstituted aryl or heteroaryl; and 
         q is an integer 1; 
         (c) a group represented by the following Formula (VI) 
       
       
         
           
           
               
               
           
         
         wherein Y represents sulfur or oxygen, and E and Ar are as defined above; 
         (d) a group represented by the following Formula (VII) 
       
       
         
           
           
               
               
           
         
         wherein G represents hydrogen or C 1-6 -alkyl; 
         -L represents a single bond, substituted or unsubstituted C 1-6 -alkylene (some carbon atoms in the alkylene optionally form a cycloalkyl ring), substituted or unsubstituted C 1-6 -alkylene —O-(some carbon atoms in the alkylene optionally form a cycloalkyl ring), substituted or unsubstituted C 2-6 -alkenylene, substituted or unsubstituted C 2-6 -alkynylene, —CO—, 1,4-piperazidinyl, C 1-6 -alkylene-1,4-piperazidinyl, adamantylene, or a group represented by the following Formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein, in (CH 2 ) n  one or more carbons are optionally substituted and may form cycloalkyl with a substituent of the carbon, provided that m is an integer 0 or 1, and n is an integer 0 to 2); 
         —B is COOR 9    
         wherein R 9  represents hydrogen; or a group converted to hydrogen in vivo, which is selected from the group consisting of C 1-6 -alkyl, aryl, aralkyl, —CH(R 10 )—O—CO—R 11 , —CH(R 10 )—O—CO—OR 11 , and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 10  is hydrogen or C 1-6 -alkyl, R 11  is C 1-6 -alkyl or C 3-8 -cycloalkyl, and R 12  is C 1-6  alkyl; or 
         a heterocyclic group represented by any of the following Formulae (XI)-(XIII): 
       
       
         
           
           
               
               
           
         
         wherein Z represents oxygen or sulfur. 
       
     
     
         2 . The method according  claim 1 , wherein the compound represented by Formula (I) above is a compound wherein A is a group represented by any of the Formula (II). 
     
     
         3 . The method according to  claim 2 , wherein the compound represented by Formula (I) above is a compound represented by any of the following Formulae (Ia-1) to (Ia-4): 
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , B, X, T, D, and q are as defined above; 
       
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , B, X, T, D, and q are as defined above; and L 2  represents substituted or unsubstituted C 1-6 -alkylene-O—; 
       
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , B, X, T, D, and q are as defined above; and L 3  represents substituted or unsubstituted C 1-6 -alkylene, C 2-6 -alkenylene, or C 2-6 -alkynylene; 
       
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , B, X, T, D, and q are as defined above; and L 4  represents —CO—, or a group represented by the following formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein, in (CH 2 ) n , one or more carbons are optionally substituted and may form cycloalkyl with a substituent of the carbon, provided that m is an integer 0 or 1, and n is an integer 0 to 2). 
       
     
     
         4 . The method according to  claim 1 , wherein the compound represented by Formula (I) above is a compound represented by any of the following Formulae (Ib-III) to (Ib-V): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 5 , R 6 , B, X, L, E, Ar, and q are as defined  claim 1 . 
       
     
     
         5 . The method according to  claim 1 , wherein the compound represented by Formula (I) above is a compound represented by the following Formula (Ic): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , B, X, L, Y, E, Ar, and q are as defined  claim 1 . 
       
     
     
         6 . The method according to  claim 1 , wherein the compound represented by Formula (I) above is a compound represented by Formula (Id): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , B, X, L, and G are as defined  claim 1 . 
       
     
     
         7 . The method according to  claim 1 , wherein the disease whose development is attributed to PAI-1 activity is thrombosis in arteries; thrombosis in veins; deep-vein thrombosis (DVT) during surgical operations; disseminated intravascular coagulation syndrome (DIC); diabetic complications such as angiopathy (macroangiopathy or microangiopathy), neuropathy, retinopathy (diabetic retinopathy), or nephropathia (diabetic nephropathy); restenosis after percutaneous transluminal coronary angioplasty (PTCA); cancer; diabetes mellitus; ocular diseases such as glaucoma or oxygen-induced retinopathy; kidney disease (chronic kidney disease (CKD), nephrotic syndrome, post-renal kidney injury, or pyelonephritis); polycystic ovary syndrome; radiation damage; alopecia (calvities); splenohepatomegaly; bone-marrow regeneration; obesity, amyloidosis; arteriosclerosis; or Alzheimer's disease. 
     
     
         8 . The method according to  claim 7 , wherein the thrombosis in arteries is thrombosis in the brain (cerebral thrombosis, cerebral embolism, or transient ischemic attack), thrombosis in the heart (angina pectoris or myocardial infarction), thrombosis in the lower extremities (lower extremity acute arterial thrombosis), or thrombosis in the upper intestinal tract (upper intestinal tract arterial thrombosis); and the thrombosis in veins is thrombosis in the extremities (deep-vein thrombosis) or thrombosis occurring when a blood clot travels to the lung (pulmonary embolism). 
     
     
         9 . The method according to  claim 1 , wherein the disease whose development is attributed to PAI-1 activity is a disease accompanied by tissue fibrosis. 
     
     
         10 . The method according to  claim 9 , wherein the disease accompanied by tissue fibrosis is pulmonary fibrosis.