Antituberculous composition comprising oxazole compounds

Abstract

The present invention provides antituberculous therapeutic drugs with a higher potency. The present invention provides also antituberculous therapeutic drugs containing oxazole compounds represented by (I) general formula (1): [wherein R 1 represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-6, and R 2 represents general formula (A) or the like, wherein R 3 represents a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or the like], optically active forms thereof or salts thereof, and drugs (II) such as primary antituberculous drugs.

1 . An antituberculous therapeutic drug comprising:
 (I) at least one selected from the group consisting of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compounds represented by general formula (1):   
       
         
           
           
               
               
           
         
       
       [wherein R 1  represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-8, and R 2  represents any group of the following general formulas (A)-(G), wherein the group represented by the general formula (A) is: 
       
         
           
           
               
               
           
         
       
       wherein R 3  represents any group of the following (1)-(6):
 (1) a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (2) a phenyl C1-6 alkoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (3) -NR 4 R 5  group, wherein R 4  represents a hydrogen atom or C1-6 alkyl group and R 5  represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-8 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (4) a phenyl C1-8 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (5) a phenoxy C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); and 
 (6) a benzofuryl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring); the group represented by the general formula (B) is: 
 
       
         
           
           
               
               
           
         
       
       wherein R 6  represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-8 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (C) is: 
       
         
           
           
               
               
           
         
       
       wherein R 7  represents a phenyl C2-10 alkenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or a biphenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (D) is: 
       
         
           
           
               
               
           
         
       
       wherein R 8  represents a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (E) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 8  is as described above); and 
       the group represented by the general formula (F) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 8  is as described above), 
       the group represented by the general formula (G) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 6  is as described above)], 
       optically active forms thereof and pharmacologically acceptable salts thereof, and
 (II) at least one. 
 
     
     
         2 . The antituberculous therapeutic drug according to  claim 1 , wherein the at least one primary antituberculous drug is selected from the group of rifampicin, rifabutin, rifapentine isoniazid, ethambutol, and pyrazinamide and salts thereof. 
     
     
         3 - 21 . (canceled) 
     
     
         22 . The antituberculous therapeutic drug according to  claim 1 , wherein the drug of (II) further comprises at least one selected from the anti-HIV drugs. 
     
     
         23 . The antituberculous therapeutic drug according to  claim 22 , wherein the at least one selected from the anti-HIV drugs is (a) a reverse transcriptase inhibitor based on a nucleic acid, (b) a reverse transcriptase inhibitor based on a non-nucleic acid or (c) a protease inhibitor. 
     
     
         24 . A medicament for dosing at an interval of 48 hours or more, wherein the medicament comprises at least one compound as active ingredient which is selected from the group consisting of:
 (I) 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compounds represented by general formula (1):   
       
         
           
           
               
               
           
         
       
       [wherein R 1  represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-6, and R 2  represents any group of the following general formulas (A)-(G), wherein the group represented by the general formula (A) is: 
       
         
           
           
               
               
           
         
       
       wherein R 3  represents any group of the following (1)-(6):
 (1) a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (2) a phenyl C1-6 alkoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (3) NR 4 R 5  group, wherein R 4  represents a hydrogen atom or C1-6 alkyl group and R 5  represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (4) a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
 (5) a phenoxy C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); and 
 (6) a benzofuryl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring); 
 
       the group represented by the general formula (B) is: 
       
         
           
           
               
               
           
         
       
       wherein R 6  represents phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (C) is: 
       
         
           
           
               
               
           
         
       
       wherein R 7  represents a phenyl C2-10 alkenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or a biphenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (D) is: 
       
         
           
           
               
               
           
         
       
       wherein R 8  represents a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); 
       the group represented by the general formula (E) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 8  is as described above); and 
       the group represented by the general formula (F) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 8  is as described above), 
       the group represented by the general formula (G) is: 
       
         
           
           
               
               
           
         
       
       (wherein R 6  is as described above)], 
       optically active forms thereof and pharmacologically acceptable salts thereof. 
     
     
         25 . A kit for tuberculosis treatment, wherein the kit comprises the medicament of  claim 24 , and at least one drug (II) selected from the group primary antituberculous drugs, is used to dose the medicament and the drugs at an interval of 48 hours or more. 
     
     
         26 - 30 . (canceled) 
     
     
         31 . The antituberculous therapeutic drug according to any one of  claims 1 ,  2  and  22 , which is in the form of a single preparation obtained by formulating oxazole compound (I) and drug (II) described above simultaneously. 
     
     
         32 . The antituberculous therapeutic drug according to any one of  claims 1 ,  2  and  22 , which is in the form of two preparations obtained by formulating oxazole compound (I) and drug (II) separately, for simultaneous administration in the same administration route. 
     
     
         33 . The antituberculous therapeutic drug according to any one of  claims 1 ,  2  and  22 , which is in the form of two preparations obtained by formulating oxazole compound (I) and drug (II) separately, for administration with time difference in the same administration route. 
     
     
         34 . The antituberculous therapeutic drug according to any one of  claims 1 ,  2  and  22 , which is in the form of two preparations obtained by formulating oxazole compound (I) and drug (II) separately, for simultaneous administration in different routes. 
     
     
         35 . The antituberculous therapeutic drug according to any one of  claims 1 ,  2  and  22 , which is in the form of one or more preparations obtained by formulating oxazole compound (I) and drug (II) separately, for administration with time difference in different administration routes.