New Benzothiazinone Derivatives and Their Use as Antibacterial Agents

Abstract

The present invention relates to novel benzothiazinone derivatives and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria. The present invention aims at the generation of new compounds with activity against mycobacteria as potential new tuberculosis drugs to overcome problems concerning resistance and drug intolerance. The solution of the present invention is a compound of formula I wherein R 1 to R 6 are as defined in the specification.

1 . A compound of formula (1): 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein R 1  and R 2  are, independently of each other, NO 2 , CN, CONR 7 R 8 , CHO, halogen, NR 7 R 8 , SO 2 NR 7 R 8 , SR 9 , OCF 3 , mono-, di- or trifluoromethyl; 
         R 3  and R 4  are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, cycloalkyl having 3-6 carbon atoms, benzyl, SR 9 , OR 9 ; 
         R 5  and R 6  are, independently of each other, a saturated or unsaturated, linear or branched aliphatic radical having 1-8 chain members, cycloalkyl having 3-6 carbon atoms, phenyl, or R 5  and R 6  together represent a bivalent radical —(CR 9   2 )m-, or R 5  and R 6  together represent a bivalent radical: 
       
       
         
           
           
               
               
           
         
         wherein m is 1-4, or represent bivalent radicals, a saturated or unsaturated mono or polyheterocyles with heteroatoms N, S, O, and substituted by)(R 10 ) x , where x is 1-4; 
         R 7 , R 8  and R 9  are, independently of each other, H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, mono-, di- or trifluoromethyl, halogen, phenyl; 
         R 10  is H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, NO 2 , NR 7 R 8 , CN, CONR 7 R 8 , COOR 9 , CHO, halogen, SO 2 NR 7 R 8 , SR 9 , OR 9 , OCF 3 , mono-, di- or trifluoromethyl, benzyl or phenyl. 
       
     
     
         2 . A 2-(2,3-R 5 R 6 -1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-(trifluoro-methyl)-1,3-benzothiazin-4-one of the formula (1) according to  claim 1 , wherein R 1  represents NO 2 , R 2  is CF 3 , R 3  and R 4  are H, and R 5  and R 6  have the meanings given in  claim 1 . 
     
     
         3 . A 2-(2,3-R 5 R 6 -1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazine-6-carbonitrile of the formula (1) according to  claim 1 , wherein R 1  represents NO 2 , R 2  is CN, R 3  and R 4  are H, and R 5  and R 6  have the meanings given in  claim 1 . 
     
     
         4 . A 2-(2,3-R 5 R 6 -1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6,8-dinitro-4-oxo-1,3-benzothiazine of the formula (1) according to  claim 1 , wherein R 1  and R 2  represent NO 2 , R 3  and R 4  are H, and R 5  and R 6  have the meanings given in  claim 1 . 
     
     
         5 . A 2-(2,3-R 5 R 6 -1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazine-6-carbamide of the formula (1) according to  claim 1 , wherein R 1  represents NO 2 , R 2  is CONH 2 , R 3  and R 4  are H, and R 5  and R 6  have the meanings given in  claim 1 . 
     
     
         6 . A compound of the formula (1) according to  claim 1  selected from the group consisting of:
 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6,8-dinitro-1,3-benzothiazine-4-one, 
 2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one, 
 2-(4,4-diethoxypiperidin-1-yl)-6,8-dinitro-1,3-benzothiazin-4-one, 
 7-methyl-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6,8-dinitro-1,3-benzothiazin-4-one, 
 2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, 
 2-(2,3-dimethyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, 
 2-(1,5-dioxa-9-azaspiro[5.5]undec-9-yl)-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one, 
 2-(1,5-dioxa-9-azaspiro[5.5]undec-9-yl)-8-nitro-4-oxo-1,3-benzothiazine-6-carbonitrile, 
 2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-4-oxo-1,3-benzothiazine-6-carbonitrile, 
 8-amino-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-oxo-1,3-benzothiazine-6-carbonitrile, and 
 8-amino-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-(trifluoromethyl)-1,3-benzothiazin-4-one. 
 
     
     
         7 . The compound of the formula (1) according to  claim 1 , wherein R 5  and R 6  are alkyl. 
     
     
         8 . A pharmaceutical composition comprising a compound of the formula (1) according to  claim 1 . 
     
     
         9 . A method of therapeutically or prophylactically treating tuberculosis in a mammal, comprising administering to the mammal a therapeutic or prophyltic dose of a pharmaceutical composition comprising a compound of formula (1) 
       
         
           
           
               
               
           
         
         Wherein R 1  and R 2  are, independently from each other, NO 2 , CN, CONR 7 R 8 , CHO, halogen, NR 7 R 8 , SO 2 NR 7 R 8 , SR 9 , OCF 3 , mono-, di- or trifluoromethyl; 
         R 3  and R 4  are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, cycloalkyl having 3-6 carbon atoms, benzyl, SR 9 , OR 9 ; 
         R 5  and R 6  are, independently of each other, a saturated or unsaturated, linear or branched aliphatic radical having 1-8 chain members, cycloalkyl having 3-6 carbon atoms, phenyl, or R 5  and R 6  together represent a bivalent radical —(CR 9   2 ) m —, or R 5  and R 6  together represent a bivalent radical: 
       
       
         
           
           
               
               
           
         
         wherein m is 1-4, or represent bivalent radicals, a saturated or unsaturated mono or polyheterocyles with heteroatoms N, S, O, and substituted by (R 10 ) X , where x is 1-4; 
         R 7 , R 8  and R 9  are, independently of each other, H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, mono-, di- or trifluoromethyl, halogen, or phenyl, or R 3  and R 4  together represent a bivalent radical —(CH 2 ) n — wherein n is 2-7; 
         R 10  is H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, NO 2 , NR 7 R 8 , CN, CONR 7 R 8 , COOR 9 , CHO, halogen, SO 2 NR 7 R 8 , SR 9 , OR 9 , OCF 3 , mono-, di- or trifluoromethyl, benzyl or phenyl.