Azolidinone-vinyl fused-benzene derivatives

Abstract

The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. wherein A, X, Y, Z, R 1 , R 2 and n are as described in the description.

1 - 33 . (canceled) 
     
     
         34 . A method for the prophylaxis and/or treatment of one or more diseases or disorders selected from the group consisting of autoimmune disorders, cardiovascular diseases, viral infections, platelet aggregation, cancer, graft rejection, and lung injuries, the method comprising, administering to a subject in need thereof, an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein 
         A is a 5-8 membered heterocyclic or carbocyclic group, wherein said carbocyclic group may be fused with aryl, heteroaryl, cycloalkyl or heterocycloalkyl; 
         X is S or O; 
         Y 1  and Y 2  are independently S or O; 
         Z is S or O; 
         R 1  is H, CN, carboxy, acyl, C 1 -C 6 -alkoxy, halogen, hydroxy, acyloxy, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, alkoxycarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, amino, C 1 -C 6 -alkyl amino, ammonium, sulfonyloxy, C 1 -C 6 -alkyl sulfonyloxy, sulfonyl, C 1 -C 6 -alkyl sulfonyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfonylamino, C 1 -C 6 -alkyl sulfonylamino or carbamate; 
         R 2  is selected from the group consisting of H, halogen, acyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 2 -C 6 -alkenyl-aryl, C 2 -C 6 -alkynyl aryl, carboxy, cyano, hydroxy, C 1 -C 6 -alkoxy, nitro, acylamino, ureido, C 1 -C 6 -alkyl carbamate, sulfonylamino, sulfanyl, or sulfonyl; 
         n is 0, 1 or 2; 
         with the proviso that the following compounds are excluded: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is a lower alkyl or aralkyl and R 2  is H or a halogen. 
       
     
     
         35 . The method according to  claim 34 , wherein said one or more diseases are selected from the group consisting of Alzheimer's disease, Huntington's disease, CNS trauma, stroke and ischemic conditions. 
     
     
         36 . The method according to  claim 34 , wherein said one or more diseases are selected from the group consisting of atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstriction. 
     
     
         37 . The method according to  claim 34 , wherein said one or more diseases or disorders are selected from the group consisting of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, pancreatitis, multiorgane failure, angiogenesis, invasion metastisis, melanoma, Karposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplantation graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung and general lung airways inflammation. 
     
     
         38 . The method according to  claim 34 , wherein Y 1  and Y 2  are both oxygen. 
     
     
         39 . The method according to  claim 34 , wherein n is 1 or 2 and R 1  and R 2  are both H. 
     
     
         40 . The method according to  claim 34 , wherein, in the compound of formula (I), X is S, Y 1  and Y 2  are both O, and n is 0. 
     
     
         41 . The method according to  claim 34 , whereby the compound of formula (I) is a thiazolidinone-vinyl fused-benzene of the formula (Ia) 
       
         
           
           
               
               
           
         
         wherein Y 1 , R 1 , R 2 , Z and n are as above defined for the compound of formula (I); 
         V and W are each, independently from each other, O, S or —NR 3  wherein R 3  is H or C 1 -C 6  alkyl; 
         G is a C 1 -C 5  alkylene or a C 1 -C 5  alkenylene group; 
         o and m are each, independently from each other, 0 or 1; and 
         q is an integer from 0 to 4. 
       
     
     
         42 . The method according to  claim 41 , whereby the thiazolidinone-vinyl fused-benzene has the formula (Ib): 
       
         
           
           
               
               
           
         
         wherein Y 1 , R 1 , R 2 , V, Z, W, m, n, o, q are as above defined in the compound of formula (Ia), and p is an integer from 1 to 4. 
       
     
     
         43 . The method according to  claim 41 , whereby the thiazolidinone-vinyl fused-benzene has the formula (Ic): 
       
         
           
           
               
               
           
         
         wherein W, as well as R 1  and Y 1 , are as above defined in the compound of formula (Ia). 
       
     
     
         44 . The method according to  claim 41 , whereby the thiazolidinone-vinyl fused-benzene has the formula (Id): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , Z and n are as above defined in formula (Ia); o is 0 or 1; 
         p is an integer from 1 to 4 and q is an integer from 0 to 4. 
       
     
     
         45 . The method according to  claim 41 , wherein, in formula (Ia), Z is O, m is 0, n is 1, p is 1 or 2, q is 1, and R 1  and R 2  are each as above defined for the compound of formula (Ia). 
     
     
         46 . The method according to  claim 41 , wherein, in formula (Ia), m is 1, n is 0, p is 1 or 2, q is 0, and R 1  and R 2  are each as above defined for the compound of formula (Ia). 
     
     
         47 . The method according to  claim 41 , wherein, in formula (Ia), m is 0, n is 1, p is 1 or 2, q is 0, and R 1  and R 2  are each as defined above for the compound of formula (I). 
     
     
         48 . The method according to  claim 41 , wherein, in formula (Ia), R 1  is halogen or hydrogen. 
     
     
         49 . A method for the prophylaxis and/or treatment of one or more diseases or disorders selected from the group consisting autoimmune disorders, cardiovascular diseases, viral infections, platelet aggregation, cancer, graft rejection, and lung injuries, the method comprising administering to a subject in need thereof, an effective amount of a thiazolidinone-vinyl fused-benzene according to formula (II-a): 
       
         
           
           
               
               
           
         
         wherein A is selected from the group consisting of dioxol, dioxin, dihydrofuran, (dihydro)furanyl, (dihydro)oxazinyl, pyridinyl, isooxazolyl, oxazolyl (dihydro)napthalenyl, pyrimidinyl, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl, and oxadiazolyl; 
         R 2  is selected from the group consisting of H, halogen, acyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkenyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 2 -C 6 -alkenyl-aryl, C 2 -C 6 -alkynyl aryl, carboxy, cyano, hydroxy, C 1 -C 6 -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, and sulfonyl. 
       
     
     
         50 . The method according to  claim 49 , wherein the said one or more diseases are selected from the group consisting of Alzheimer's disease, Huntington's disease, CNS trauma, stroke and ischemic conditions. 
     
     
         51 . The method according to  claim 49 , wherein said one or more diseases are selected from the group consisting of atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstriction. 
     
     
         52 . The method according to  claim 49 , wherein said one or more diseases are selected from the group consisting of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastisis, melanoma, Karposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplantation, graft rejection, pancreatitis, multiorgane failure, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung and general lung airways inflammation.