Novel 2-Oxo-Heterocyclic Compounds And The Pharmaceutical Compositions Comprising The Same

Abstract

The present invention is related to new 2-oxo-cyclic compound, the process for preparing them and a pharmaceutical composition comprising the same. The present invention provides a pharmaceutical composition for preventing and treating the inflammatory disease comprising the pain or inflammation caused by rheumatic disease, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, and inflammatory syndrome for example, from myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, burns and scar, inflammatory Crohn's disease, Types I diabetes. therefore, it can be used as the therapeutics for treating and preventing inflammatory diseases.

1 - 15 . (canceled) 
     
     
         16 . A novel compound represented by the following general formula (I), the pharmaceutically acceptable salt or the isomer thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X is a hydroxyl group, —NHOH, —NHOCH 2 Ph, 
       
       
         
           
           
               
               
           
         
         A is an hydrogen, A1 group or 
       
       
         
           
           
               
               
           
         
         A1 is a lower alkyl, lower alkenyl, lower alkynyl, lower allyl group having C1 to C5 carbon atoms, a heterocyclic group or aromatic aryl group selected from thiophenyl group, naphtyl group, pyrrolyl group, furyl group and biphenyl group, wherein the Y in A2 substituted is a lower alkyl group, lower alkoxy group, nitro, halogen, amine, acetamide, carbonamide or sulfonamide group, M is a lower alkyl group or phenyl group substituted with R′, of which R′ is a hydrogen, lower alkyl or lower alkoxy group, m and r is independently an integer of 1 to 5 respectively; 
         p is an integer of 0, 1 or 2; 
         n is an integer of 1 to 5; and 
         dotted line   means single bond or double bond. 
       
     
     
         17 . A novel compound represented by the following general formula (IV), the pharmaceutically acceptable salt or the isomer thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X is a hydroxyl group, —NHOH, —NHOCH2Ph, 
       
       
         
           
           
               
               
           
         
         Y is a lower alkyl group, lower alkoxy group, nitro, halogen, amine, acetamide, carbonamide or sulfonamide group; M is a lower alkyl group or phenyl group substituted with R′, of which R′ is a hydrogen, lower alkyl or lower alkoxy group; 
         m and r is independently an integer of 1 to 5 respectively; 
         n is an integer of 1 to 5; and 
         dotted line   means single bond or double bond. 
       
     
     
         18 . The compound according to  claim 17 , wherein said compound is one selected from the group consisting of:
 3-[1-(2,4-Dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-yl]N-hydroxypropionamide,   N-hydroxy-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy propionamide,   N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-propionamide,   N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-pyridin-2-yl-propionamide,   N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   N-benzyloxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propionamide,   N-4-[5-(2-hydroxycarbamoyl-ethyl)-6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl]-phenyl-benzamide,   N-hydroxy-3-[1-(4-dimethylsulfonylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionamide,   N-hydroxy-3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl]-propionamide,   3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid,   3-[1-(4-benzoylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid,   3-[2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid,   N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide,   2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy-acetamide,   2-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetamide,   N-hydroxy-2-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetamide,   N-hydroxy-2-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy-acetamide,   N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy-acetamide,   [1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic acid,   (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,   (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,   [2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,   [2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,   2-[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide,   (2-oxo-1-phenethyl-piperidine-3-yl)-acetic acid,   [2-oxo-1-(3-phenyl-propyl)-piperidine-3-yl]-acetic acid,   4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy-butylamide,   4-(1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-butylamide,   N-hydroxy-4-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-butylamide, and   N-hydroxy-4-[2-oxo-1-(3-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-butylamide.   
     
     
         19 . A novel compound represented by the following general formula (V), the pharmaceutically acceptable salt or the isomer thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X is a hydroxyl group, —NHOH, —NHOCH 2 Ph, 
       
       
         
           
           
               
               
           
         
         R is a lower alkyl, lower alkenyl, lower alkynyl, lower allyl group having C1 to C5 carbon atoms, a heterocyclic group or aromatic aryl group selected from thiophenyl group, naphtyl group, pyrrolyl group, furyl group and biphenyl group; 
         n is an integer of 1 to 5; and 
         dotted line   means single bond or double bond. 
       
     
     
         20 . The compound according to  claim 19 , wherein said compound is one selected from the group consisting of:
 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,   N-Benzyloxy-3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   3-(1-Allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propionamide,   N-hydroxy-3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,   N-hydroxy-3-(1-(naphthalene-2-yl-methyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide, and   N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-propionamide.   
     
     
         21 . A pharmaceutical composition comprising an efficient amount of the compound represented by general formula (I), (IV) or (V) according to any one of  claims 16  to  20  or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to treat or prevent inflammatory diseases together with pharmaceutically acceptable carriers or diluents. 
     
     
         22 . A method for treating an inflammatory disease comprising the pain or inflammation caused by rheumatic disease and inflammatory syndrome which comprises administering a therapeutically effective amount of a compound represented by general formula (I), (IV) or (V) according to any one of  claims 16  to  20  or the pharmaceutically acceptable salt thereof. 
     
     
         23 . A method according to  claim 22 , wherein said rheumatic disease is selected from rheumatoid arthritis, spondyloarthropathies, gout, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. 
     
     
         24 . A method according to  claim 22 , wherein said inflammatory syndrome is selected from myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, burns and scar, inflammatory Crohn's disease, and Type I diabetes.