Oxa(thia)zolidine derivatives and anti-inflammatory drugs

Abstract

The present invention provides medicinal compositions characterized by containing as the active ingredient either a compound represented by a general formula (1) or a pharmaceutically acceptable composite thereof, wherein X represents oxygen or sulfur; R 1 represents hydrogen, C 1-4 alkyl, etc.; R 2 represents, e.g., phenyl optionally substituted by A 1 ; R 3 represents, e.g., hydrogen, C 1-4 alkyl optionally substituted by A 2 , or a group represented by either one of the following formulae; R represents oxygen, sulfur, or a group represented by a formula (N-G)], in particular, inhibitor of phospholipase A(2) activity; use of the composition; and compound represented by a general formula (1-1); wherein X, R 1 , R 2 , R 3 and G 1 are the same as defined in the description.

1 .- 12 . (Canceled)  
     
     
         13 . A pharmaceutical composition for an anti-inflammatory drug, and/or an anti-allergic drug, and/or an immune controlling drug, and/or an analgesic drug, the composition having as an active ingredient either a compound represented by a formula (1) or a pharmaceutically acceptable composite thereof;  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents oxygen or sulfur,  
 R 1  represents hydrogen, C 1-4  alkyl or C 1-4  haloalkyl,  
 R 2  represents phenyl optionally substituted by A 1 , naphthyl optionally substituted by A 1 , 5 to 6-membered heterocyclic group optionally substituted by A 1  containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A 1 , or a group represented by a formula (2);  
                     
 wherein Q represents —(CH 2 ) 3 —, —(CH 2 ) 4 — or —OCH 2 O—,  
 R 3  represents hydrogen, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy optionally substituted by A 2 , C 1-4  alkylcarbonyl optionally substituted by A 2 , C 1-4  alkoxycarbonyl optionally substituted by A 2 , C 2-4  alkenylcarbonyl optionally substituted by A 2 , phenyliminomethyl optionally substituted by A 3 , phenyl optionally substituted by A 3 , anilino optionally substituted by A 3 , or a group represented by the following formulae;  
                     
 wherein Y represents oxygen or sulfur, R 4  represents hydrogen or C 1-4  alkyl, R 5  represents C 1-6  alkyl optionally substituted by A 2 , C 2-6  alkenyl optionally substituted by A 2 , C 2-6  alkynyl optionally substituted by A 2 , C 1-6  alkoxy optionally substituted by A 2 , C 2-6  alkenyloxy optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)amino optionally substituted by A 2 , C 3-7  cycloalkyl optionally substituted by A 4 , C 5-7  cycloalkenyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , C 1-6  alkoxycarbonyl optionally substituted by A 2 , phenylsulfonyl optionally substituted by A 3 , C 1-6  alkoxysulfonyl optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)aminosulfonyl optionally substituted by A 2 , or 5- to 7-membered heterocyclic group optionally substituted by A 4  containing at least one atom selected from a group consisting of oxygen, sulfur and nitrogen as a heteroatom, and n represents 0, 1 or 2,  
 R represents oxygen, sulfur or a group represented by a formula of N-G, wherein G represents hydrogen, nitro, cyano, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy, C 1-4  alkylcarbonyl, phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , a group represented by a formula of NHCOR 6 , wherein R 6  represents C 1-4  alkyl or phenyl optionally substituted by A 3 , or a group represented by the following formula;  
                     
 wherein Z represents oxygen or sulfur, R 7  represents C 1-4  alkyl, C 3-7  cycloalkyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , or optionally substituted 5- to 7-membered heterocyclic group,  
 A 1  represents halogeno, amino, nitro, cyano, C 1-12  alkyl, C 2-6  alkenyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, phenyl optionally substituted by halogeno, C 1-4  alkyl or C 1-4  haloalkyl, pyridyl, thienyl, C 1-4  alkoxy, methylenedioxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, C 1-4  alkylcarbonyloxy, carbamoyl, or mono- or di-(C 1-4  alkyl)carbamoyl,  
 A 2  represents halogeno, C 1-4  alkoxy, C 1-4  alkoxy C 1-4  alkoxy, amino, mono- or di-(C 1-4  alkyl)amino, C 1-4  alkylcarbonyloxy, C 1-4  alkoxycarbonyl, halo C 1-4  alkoxycarbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4  alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally substituted by halogeno,  
 A 3  represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano, C 1-4  alkyl, C 1-4  haloalkyl, pyridyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, carbamoyl, mono- or di-(C 1-4  alkyl)carbamoyl, or C 1-4  alkoxycarbonyl C 1-4  alkylthio, and  
 A 4  represents halogeno, hydroxy, oxo, C 1-4  alkyl, halo C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, halo C 1-4  alkoxy, halo C 1-4  alkylthio, C 1-4  alkoxy C 1-4  alkoxy, C 1-4  alkylsulfonyl, C 1-4  alkoxycarbonyl, or C 1-4  haloalkoxycarbonyl,  
 provided that R is oxygen or sulfur, R 3  represents a group represented by the following formula;  
                     
 wherein Y, R 4  and R 5  are as defined above, and  
 R represents not a group represented by a formula of N-G when X is oxygen.  
 
     
     
         14 . Compounds represented by a formula (1-1);  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents hydrogen, C 1-4  alkyl or C 1-4  haloalkyl,  
 R 2  represents phenyl optionally substituted by A 1 , naphthyl optionally substituted by A 1 , 5 to 6-membered heterocyclic group optionally substituted by A 1  containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A 1 , or a group represented by a formula (2);  
                     
 wherein Q represents —(CH 2 ) 3 —, —(CH 2 ) 4 — or —OCH 2 O—,  
 R 3  represents hydrogen, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy optionally substituted by A 2 , C 1-4  alkylcarbonyl optionally substituted by A 2 , C 1-4  alkoxycarbonyl optionally substituted by A 2 , C 2-4  alkenylcarbonyl optionally substituted by A 2 , phenyliminomethyl optionally substituted by A 3 , phenyl optionally substituted by A 3 , anilino optionally substituted by A 3 , or a group represented by the following formulae;  
                     
 wherein Y represents oxygen or sulfur, R 4  represents hydrogen or C 1-4  alkyl, R 5  represents C 1-6  alkyl optionally substituted by A 2 , C 2-6  alkenyl optionally substituted by A 2 , C 2-6  alkynyl optionally substituted by A 2 , C 1-6  alkoxy optionally substituted by A 2 , C 2-6  alkenyloxy optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)amino optionally substituted by A 2 , C 3-7  cycloalkyl optionally substituted by A 4 , C 5-7  cycloalkenyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , C 1-6  alkoxycarbonyl optionally substituted by A 2 , phenylsulfonyl optionally substituted by A 3 , C 1-6  alkoxysulfonyl optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)aminosulfonyl optionally substituted by A 2 , or 5- to 7-membered heterocyclic group optionally substituted by A 4  containing at least one atom selected from a group consisting of oxygen, sulfur and nitrogen as a heteroatom, and n represents 0, 1 or 2,  
 G 1  represents nitro, cyano, C 1-4  alkylcarbonyl, benzoyl optionally substituted by A 3 , NHCOR 6 , wherein R 6  represents C 1-4  alkyl or phenyl optionally substituted by A 3 , or a group represented by the following formula;  
                     
 wherein Z represents oxygen or sulfur, R 7  represents C 1-4  alkyl, C 3-7  cycloalkyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , or optionally substituted 5- to 7-membered heterocyclic group,  
 A 1  represents halogeno, amino, nitro, cyano, C 1-12  alkyl, C 2-6  alkenyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, phenyl optionally substituted by halogeno, C 1-4  alkyl or C 1-4  haloalkyl, pyridyl, thienyl, C 1-4  alkoxy, methylenedioxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, C 1-4  alkylcarbonyloxy, carbamoyl, or mono- or di-(C 1-4  alkyl)carbamoyl,  
 A 2  represents halogeno, C 1-4  alkoxy, C 1-4  alkoxy C 1-4  alkoxy, amino, mono- or di-(C 1-4  alkyl)amino, C 1-4  alkylcarbonyloxy, C 1-4  alkoxycarbonyl, halo C 1-4  alkoxycarbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4  alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally substituted by halogeno,  
 A 3  represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano, C 1-4  alkyl, C 1-4  haloalkyl, pyridyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, carbamoyl, mono- or di-(C 1-4  alkyl)carbamoyl, or C 1-4  alkoxycarbonyl C 1-4  alkylthio, and  
 A 4  represents halogeno, hydroxy, oxo, C 1-4  alkyl, halo C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, halo C 1-4  alkoxy, halo C 1-4  alkylthio, C 1-4  alkoxy C 1-4  alkoxy, C 1-4  alkylsulfonyl, C 1-4  alkoxycarbonyl, or C 1-4  haloalkoxycarbonyl,  
 provided that R is oxygen or sulfur, R 3  represents a group represented by the following formula;  
                     
 wherein Y, R 4  and R 5  are as defined above.  
 
     
     
         15 . A method to treat inflammatory diseases or disorders, allergic diseases or auto-immune disease by administering an effective amount of a pharmaceutical composition, of a compound of formula (1) and the pharmaceutically acceptable carrier thereof, to a mammal,  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents oxygen or sulfur,  
 R 1  represents hydrogen, C 1-4  alkyl or C 1-4  haloalkyl,  
 R 2  represents phenyl optionally substituted by A 1 , naphthyl optionally substituted by A 1 , 5 to 6-membered heterocyclic group optionally substituted by A 1  containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A 1 , or a group represented by a formula (2);  
                     
 wherein Q represents —(CH 2 ) 3 —, —(CH 2 ) 4 — or —OCH 2 O—,  
 R 3  represents hydrogen, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy optionally substituted by A 2 , C 1-4  alkylcarbonyl optionally substituted by A 2 , C 1-4  alkoxycarbonyl optionally substituted by A 2 , C 2-4  alkenylcarbonyl optionally substituted by A 2 , phenyliminomethyl optionally substituted by A 3 , phenyl optionally substituted by A 3 , anilino optionally substituted by A 3 , or a group represented by the following formulae;  
                     
 wherein Y represents oxygen or sulfur, R 4  represents hydrogen or C 1-4  alkyl, R 5  represents C 1-6  alkyl optionally substituted by A 2 , C 2-6  alkenyl optionally substituted by A 2 , C 2-6  alkynyl optionally substituted by A 2 , C 1-6  alkoxy optionally substituted by A 2 , C 2-6  alkenyloxy optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)amino optionally substituted by A 2 , C 3-7  cycloalkyl optionally substituted by A 4 , C 5-7  cycloalkenyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , C 1-6  alkoxycarbonyl optionally substituted by A 2 , phenylsulfonyl optionally substituted by A 3 , C 1-6  alkoxysulfonyl optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)aminosulfonyl optionally substituted by A 2 , or 5- to 7-membered heterocyclic group optionally substituted by A 4  containing at least one atom selected from a group consisting of oxygen, sulfur and nitrogen as a heteroatom, and n represents 0, 1 or 2,  
 R represents oxygen, sulfur or a group represented by a formula of N-G, wherein G represents hydrogen, nitro, cyano, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy, C 1-4  alkylcarbonyl, phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , a group represented by a formula of NHCOR 6 , wherein R 6  represents C 1-4  alkyl or phenyl optionally substituted by A 3 , or a group represented by the following formula;  
                     
 wherein Z represents oxygen or sulfur, R 7  represents C 1-4  alkyl, C 3-7  cycloalkyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , or optionally substituted 5- to 7-membered heterocyclic group, A 1  represents halogeno, amino, nitro, cyano, C 1-12  alkyl, C 2-6  alkenyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, phenyl optionally substituted by halogeno, C 1-4  alkyl or C 1-4  haloalkyl, pyridyl, thienyl, C 1-4  alkoxy, methylenedioxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, C 1-4  alkylcarbonyloxy, carbamoyl, or mono- or di-(C 1-4  alkyl)carbamoyl,  
 A 2  represents halogeno, C 1-4  alkoxy, C 1-4  alkoxy C 1-4  alkoxy, amino, mono- or di-(C 1-4  alkyl)amino, C 1-4  alkylcarbonyloxy, C 1-4  alkoxycarbonyl, halo C 1-4  alkoxycarbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4  alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally substituted by halogeno,  
 A 3  represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano, C 1-4  alkyl, C 1-4  haloalkyl, pyridyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, carbamoyl, mono- or di-(C 1-4  alkyl)carbamoyl, or C 1-4  alkoxycarbonyl C 1-4  alkylthio, and  
 A 4  represents halogeno, hydroxy, oxo, C 1-4  alkyl, halo C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, halo C 1-4  alkoxy, halo C 1-4  alkylthio, C 1-4  alkoxy C 1-4  alkoxy, C 1-4  alkysulfonyl, C 1-4  alkoxycarbonyl, or C 1-4  haloalkoxycarbonyl,  
 provided that R is oxygen or sulfur, R 3  represents a group represented by the following formula;  
                     
 wherein Y, R 4  and R 5  are as defined above, and  
 R represents not a group represented by a formula of N-G when X is oxygen.  
 
     
     
         16 . The method according to  claim 15 , wherein the inflammatory diseases or the disorders are any of anaphylaxis, allergic inflammation, asthma, rhinitis, bronchitis, pneumonia, and adult respiratory distress syndrome, inflammatory intestine disorder, Crohn's disease, ulcerative colitis, ischemia/reperfusion injuries, vasculitis, arteriosclerosis, hepatitis, nephritis, nerve degenerative diseases, arthritis, dermatitis, solar keratosis, psoriasis, septic shock and fever.  
     
     
         17 . The method according to  claim 15 , wherein the progress of the sick condition is due to inflammatory disease or disorder that is accompanied with the enhanced phospholipase A(2) activity.  
     
     
         18 . The method according to  claim 15 , wherein the inflammatory disease or disorder is mediated by pro-inflammatory lipid mediators, such as arachidonic acid and the metabolites thereof, and/or lysophosphatidylcholine, and/or the platelet activating factor (PAF).  
     
     
         19 . The method according to  claim 18 , wherein the pro-inflammatory lipid mediators are suppressed by the inhibitor of the phospholipase A(2) activity.  
     
     
         20 . A method for treating a patient in order to reduce inflammatory and/or allergic conditions and/or sick conditions associated with auto-immune diseases and disorders, the method comprising administering to said patient a medicinal composition manufactured from a compound derivative of the formula (1)  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents oxygen or sulfur,  
 R 1  represents hydrogen, C 1-4  alkyl or C 1-4  haloalkyl,  
 R 2  represents phenyl optionally substituted by A 1 , naphthyl optionally substituted by A 1 , 5 to 6-membered heterocyclic group optionally substituted by A 1  containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A 1 , or a group represented by a formula (2);  
                     
 wherein Q represents —(CH 2 ) 3 —, —(CH 2 ) 4 — or —OCH 2 O—,  
 R 3  represents hydrogen, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy optionally substituted by A 2 , C 1-4  alkylcarbonyl optionally substituted by A 2 , C 1-4  alkoxycarbonyl optionally substituted by A 2 , C 2-4  alkenylcarbonyl optionally substituted by A 2 , phenyliminomethyl optionally substituted by A 3 , phenyl optionally substituted by A 3 , anilino optionally substituted by A 3 , or a group represented by the following formulae;  
                     
 wherein Y represents oxygen or sulfur, R 4  represents hydrogen or C 1-4  alkyl, R 5  represents C 1-6  alkyl optionally substituted by A 2 , C 2-6  alkenyl optionally substituted by A 2 , C 2-6  alkynyl optionally substituted by A 2 , C 1-6  alkoxy optionally substituted by A 2 , C 2-6  alkenyloxy optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)amino optionally substituted by A 2 , C 3-7  cycloalkyl optionally substituted by A 4 , C 5-7  cycloalkenyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , C 1-6  alkoxycarbonyl optionally substituted by A 2 , phenylsulfonyl optionally substituted by A 3 , C 1-6  alkoxysulfonyl optionally substituted by A 2 , mono- or di-(C 1-6  alkyl)aminosulfonyl optionally substituted by A 2 , or 5- to 7-membered heterocyclic group optionally substituted by A 4  containing at least one atom selected from a group consisting of oxygen, sulfur and nitrogen as a heteroatom, and n represents 0, 1 or 2,  
 R represents oxygen, sulfur or a group represented by a formula of N-G, wherein G represents hydrogen, nitro, cyano, C 1-4  alkyl optionally substituted by A 2 , C 1-4  alkoxy, C 1-4  alkylcarbonyl, phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , anilino optionally substituted by A 3 , a group represented by a formula of NHCOR 6 , wherein R 6  represents C 1-4  alkyl or phenyl optionally substituted by A 3 , or a group represented by the following formula;  
                     
 wherein Z represents oxygen or sulfur, R 7  represents C 1-4  alkyl, C 3-7  cycloalkyl optionally substituted by A 4 , phenyl optionally substituted by A 3 , benzoyl optionally substituted by A 3 , or optionally substituted 5- to 7-membered heterocyclic group,  
 A 1  represents halogeno, amino, nitro, cyano, C 1-12  alkyl, C 2-6  alkenyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, phenyl optionally substituted by halogeno, C 1-4  alkyl or C 1-4  haloalkyl, pyridyl, thienyl, C 1-4  alkoxy, methylenedioxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, C 1-4  alkylcarbonyloxy, carbamoyl, or mono- or di-(C 1-4  alkyl)carbamoyl,  
 A 2  represents halogeno, C 1-4  alkoxy, C 1-4  alkoxy C 1-4  alkoxy, amino, mono- or di-(C 1-4  alkyl)amino, C 1-4  alkylcarbonyloxy, C 1-4  alkoxycarbonyl, halo C 1-4  alkoxycarbonyl, C 1-4  alkylcarbamoyl, di-(C 1-4  alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally substituted by halogeno,  
 A 3  represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano, C 1-4  alkyl, C 1-4  haloalkyl, pyridyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfenyl, C 1-4  alkylsulfonyl, mono- or di-(C 1-4  alkyl)amino, C 1-4  haloalkoxy, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-4  haloalkoxycarbonyl, carbamoyl, mono- or di-(C 1-4  alkyl)carbamoyl, or C 1-4  alkoxycarbonyl C 1-4  alkylthio, and  
 A 4  represents halogeno, hydroxy, oxo, C 1-4  alkyl, halo C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, halo C 1-4  alkoxy, halo C 1-4  alkylthio, C 1-4  alkoxy C 1-4  alkoxy, C 1-4  alkylsulfonyl C 1-4  alkoxycarbonyl, or C 1-4  haloalkoxycarbonyl,  
 provided that R is oxygen or sulfur, R 3  represents a group represented by the following formula;  
                     
 wherein Y, R 4  and R 5  are as defined above, and  
 R represents not a group represented by a formula of N-G when X is oxygen.