Platelet adp receptor inhibitors

Abstract

Novel compounds of formulae (I) to (VII), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylfulfonamide derivatives which are effective platelet ADF receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also relates to a method for preventing or treating thrombosis in a mammal comprising the step of administering a therapeutically effective amount of a compound of formulae (I) to (VIII), or a pharmaceutically acceptable salt thereof.

The claimed invention is: 
     
         1 . A compound selected from the group consisting of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII); 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl; 
 W is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 E is selected from the group consisting of H, —C 1 -C 8  alkyl, polyhaloalkyl, —C 3-8 -cycloalkyl, aryl, alkylaryl substituted aryl, heteroaryl, and substituted heteroaryl; 
 D is selected from the group consisting of —NR 1 —(C═O)—R 2 , —O—R 1 ; 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is independently selected from the group consisting of:
 H, C 1 -C 8  alkyl, polyhaloalkyl, —C 3-8 -cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, substituted heteroaryl, —(C═O)—C 1 -C 8  alkyl, —(C═O)-aryl, —(C═O)-substituted aryl, —(C═O)-heteroaryl and —(C═O)-substituted heteroaryl; 
 
 R 2  is independently selected from the group consisting of: aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or 
 R 1  and R 2  can be direct linked or can be indirectly linked through a carbon chain that is from 1 to about 8 carbon atoms in length, 
 n is an integer from 0-4, 
 m is an integer from 0 or 1, 
 y is an integer front 0-4 and 
 Q is independently C or N, wherein when Q is a ring carbon atom, each ring carbon atom is independently substituted by X, wherein 
 X is in each case a member independently selected from the group consisting of:
 hydrogen, halogen, polyhaloalkyl —OR 3 , —SR 3 , —CN, —NO 2 , —SO 2 R 3 , —C 1-10 -alkyl, —C 3-8 -cycloalkyl, aryl, aryl-substituted by 1-4 R 3  groups, amino, amino-C 1-8 -alkyl, C 1-3 -acylamino, C 1-3 -acylamino-C 1-8 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylamino C 1-8  alkyl, C 1-6  dialkylamino, C 1-6  dialkylamino C 1-8  alkyl, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-4 -alkyl, carboxy C 1-6  alkyloxy, hydroxy, hydroxy C 1-6  alkyl, and a 5 to 10 membered fused or non-fused aromatic or nonaromatic heterocyclic ring system, having 1 to 4 heteroaroms independently selected from N, O, and S, with the proviso that the carbon and nitrogen atoms, when present in the heterocyclic ring system, are unsubstituted, mono- or di-substituted independently with 0-2 R 4  groups, 
 
 wherein R 3  and R 4  are each independently selected from the group consisting of:
 hydrogen, halogen, —CN, —NO 2 , —C 1-10  alkyl, C 3-8 -cycloalkyl, aryl, amino, amino-C 1-8 -alkyl, C 1-3 -acylamino, C 1-3 -acylamino-C 1-8 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylamino C 1-8  alkyl, C 1-6  alkoxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-6 -alkyl, carboxy-C 1-6 -alkyloxy, hydroxy, hydroxy-C 1-6 -alkyl, -thio and thio-C 1-6 -alkyl; 
 
 Y is selected from the group consisting of O, S, N—OR 5 , and NR 5 , 
 wherein R 5  is selected from the group consisting of:
 H, C 1-10  alkyl, C 3-8 -cycloalkyl, NR 2 , and CN; and 
 
 Z is selected from the group consisting of NR 1  and O; 
 or pharmaceutically acceptable salts and prodrugs. 
 
     
     
         2 . A compound according to  claim 1 , wherein:
 A is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         Y is selected from the group consisting of O, S, N—OR 5  and NR 5 . 
         E is selected from the group consisting of H, or C 1-8  alkyl. 
         W is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1 , wherein;
 D is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A compound according  1 , having the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting of: 
         H, Me and 
       
       
         
           
           
               
               
           
         
         W is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         Y is selected from the group consisting of: 
         O, S, N—C≡N, NH and 
       
       
         
           
           
               
               
           
         
       
       and
 A is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , having the following formula, 
       
         
           
           
               
               
           
         
       
       wherein:
 n is an integer from 0-4; 
 X is selected from the group consisting of: 
 3-Br, 3-Cl, 4-OMe, H, 3-SO 2 Me, 3-N(Me) 2  and 3,4,-dimethyl; 
 W is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         Y is selected from the group consisting of: 
         O, N—C≡N, NH and 
       
       
         
           
           
               
               
           
         
         A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of  claim 1 , having the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of: 
 O, N—C≡N, NH and 
 
       
         
           
           
               
               
           
         
         A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1 , having the following formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of: 
 H, Me and 
 
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         W is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition for preventing or treating thrombosis in a mammal comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         10 . A pharmaceutical composition of  claim 9 , wherein said therapeutically effective amount is an amount effective to inhibit platelet aggregation in the mammal. 
     
     
         11 . A pharmaceutical composition of  claim 10 . wherein said platelet aggregation is platelet ADP-dependent aggregation. 
     
     
         12 . A pharmaceutical composition of  claim 11 , wherein said mammal is a human. 
     
     
         13 . A pharmaceutical composition of  claim 9 , wherein said compound is an effective inhibitor of [ 3 H]2-MeS-ADP ADP binding to platelet ADP receptors. 
     
     
         14 . A pharmaceutical composition for preventing or treating thrombosis in a mammal comprising a therapeutically effective amount of a compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         15 . A pharmaceutical composition of  claim 14 , wherein said therapeutically effective amount is an amount effective to inhibit platelet aggregation in the mammal. 
     
     
         16 . A pharmaceutical composition of  claim 15 , wherein said platelet aggregation is platelet ADP-dependent aggregation. 
     
     
         17 . A pharmaceutical composition of  claim 16 , wherein said mammal is a human. 
     
     
         18 . A pharmaceutical composition of  claim 14 , wherein said compound is an effective inhibitor of [ 3 H]2-MeS-ADP binding to platelet ADP receptors. 
     
     
         19 . A method for preventing or treating thrombosis in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method of  claim 19 , wherein said mammal is a human. 
     
     
         21 . A method of  claim 19 , wherein said mammal is prone to or suffers from a cardiovascular disease. 
     
     
         22 . A method of  claim 19 , wherein said cardiovascular disease is at least one selected from the group consisting of acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures resulting from angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses.