4-Pyridone-3-carboxylic acids and/or derivatives thereof

Abstract

The invention provides 4-pyridone-3-carboxylic acids and derivatives thereof together with a method for their preparation. Also included in the invention are compositions containing said 4-pyridone-3-carboxylic acids and derivatives and the use of said compounds and compositions as antibacterial and/or antifungal agents or for animal growth promotion or improved feed utilization.

What is claimed is: 
     
       1. A compound of the formula ##STR25## or a .Iadd.pharmaceutically usable .Iaddend.salt thereof in which R 1a  denotes a cycloalkyl group having 3 to 7 carbon atoms or an amino group --NR 4  R 5 , in which R 4  and R 5  are identical or different, and denote a straight-chain or branched C 1  to C 4  alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, .Iadd.said ring selected from the group consisting of pyrrolidine, piperidine, hexamethyleneimine, morpholine and thiomorpholine, .Iaddend.   R 2  denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and   R 3a  denotes a carboxyl group or a derivative which is a nitrile, an ester.Iadd.--COOR 6  .Iaddend.or an acid amide .Iadd.--CO--NR 7  R 8 , wherein R 6 , R 7  and R 8  denote a C 1  -C 4  alkyl, .Iaddend.   the symbols A and D are nitrogen atoms and the symbols B and E remaining in each represent a carbon atom which is unsubstituted or substituted by C 1  to C 6  alkyl, C 1  to C 4  alkoxy, C 1  to C 6  alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1  to C 4  alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C 1  to C 3  alkyl, nitro or halogen, or amino substituted by carbalkoxy.   
     
     
       2. A process for the production of a 4-pyridone-3-carboxylic acid or a derivative thereof which comprises reacting .Iadd.an .Iaddend.enamine of the formula ##STR26## in which R 1  denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR 4  R 5 , in which   R 4  and R 5  are identical or different, and denote a straight-chain or branched C 1  to C 4  alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, R 2  denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and   R 3  denotes an ester or acid amide derivative of the carboxyl group, with .[.an o-halogeno-(hetero)-aryl-.]. .Iadd.a .Iaddend.carboxylic acid halide of the formula ##STR27## in which the symbols A and D are nitrogen atoms and the symbols B and E remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C 1  to C 6   alkyl, C 1  to C 4  alkoxy, C 1  to C 6  alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1  to C 4  alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C 1  to C 3  alkyl, nitro or halogen, or amino substituted by carbalkoxy .Iadd.and wherein X 1  and X 2  denote identical or different halogen atoms.Iaddend..   
     
     
       3. A medicated fodder comprising an amount of a compound as claimed in claim 1 effective for promoting growth and improving feed utilization and a nutritious material. 
     
     
       4. A process according to claim 2 in which the aprotic solvent is dioxane. 
     
     
       5. A process according to claim 2 in which the first reaction stage is carried out from 10° to 60° C. and the second reaction stage is carried out from 100° to 150° C. and the aprotic solvent is dioxane. 
     
     
       6. A process according to claim 2 in which R' is cyclopropyl or cyclohexyl. 
     
     
       7. A process according to claim 2 in which the base in the first reaction stage is triethylamine and the base in the second reaction stage is 1,8-diazabicyclo-[5.4.0]-undec-7-ene. 
     
     
       8. A process according to claim 2 in which the enamine is of the formula ##STR28## in which R 1'   denotes a tert.alkyl, a C 3 , to C 7  cycloalkyl, or a dialkyl amino group --NR 4'  --R 5' , in which   R 4'   and R 5'   denote a C 1  or C 2  alkyl group or together complete a morpholinyl radical,   R 2'   denotes a hydrogen atom or a C 1  to C 4  alkyl group or an optionally substituted benzyl or phenyl radical and   R 3  has the same meaning as in claim 2.   
     
     
       9. A process according to claim 2 in which the enamine is of the formula ##STR29## in which R 1"   denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical, R 2"   denotes a hydrogen atom or a C 1  to C 4  alkyl group and   R 3  has the same meaning as in claim 2.   
     
     
       10. A process according to claim 2 in which the .[.o-halogeno-(hetero-)aryl-.].carboxylic acid halide is a compound of the formula ##STR30## in which the symbols A, B, D and E have the same meaning as in claim 2, but the heterocyclic radical .[.optionally present.]. contains at most two nitrogen atoms. 
     
     
       11. A compound according to claim 1 in which R 1a  denotes a tert.-butyl, cyclopropyl, cyclohexyl, dimethylamino or N-morpholinyl radical. 
     
     
       12. A compound according to claim 1 of the formula ##STR31## in which A, B D and E have the same meanings as in claim 1. 
     
     
       13. A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 1 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. 
     
     
       14. A pharmaceutical composition containing as an active ingredient as antibacterially or antifungally effective amount of a compound according to claim 1 in the form of a sterile or physiologically isotonic aqueous solution. 
     
     
       15. A comparison according to claim 13 containing from 0.5 to 95% by weight of the said active ingredient. 
     
     
       16. A medicament in dosage unit form comprising an antibacterially or antifungally effective amount of a compound according to claim 1 together with an inert pharmaceutical carrier. 
     
     
       17. A medicament of claim 16 in the form of tablets, pills, dragees, capsules, ampoules, or suppositories. 
     
     
       18. A method of combating bacterial diseases in warm-blooded animals which comprises administering to the said animals an effective amount of an active compound according to claim 1 either alone or in admixture with a diluent or in the form of a medicament. .Iadd. 
     
     
       19.  A compound of the formula ##STR32## or a pharmaceutically useable salt thereof in which R 1a  denotes a cycloalkyl group having 3 to 7 carbon atoms or an amino group --NR 4  R 5 , in which R 4  and R 5  are identical or different, and denote a straight-chain or branched C 1  to C 4  alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, said ring selected from the group consisting of pyrrolidine, piperidine, hexamethyleneimine, morpholine and thiomorpholine,   R 2  denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and   R 3a  denotes a carboxyl group or a derivative which is a nitride, an ester--COOR 6  or an acid amide --CO--NR 7  R 8 , wherein R 6 , R 7  and R 8  denote a C 1  -C 4  alkyl, the symbols A, B, D and E at most represent two nitrogen atoms and the remaining symbols in each case represent a carbon atom which is unsubstituted or substituted by C 1  to C 6  alkyl, C 1  to C 4  alkoxy, C 1  to C 6  alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1  to C 4  alkyl, benzyl or phenyl said benzyl or phenyl being unsubstituted or substituted by C 1  to C 3  alkyl, nitro or halogen, or amino substituted by carbalkoxy. .Iaddend. .Iadd.   
     
     
       20.  A compound according to claim 19, wherein each of A, B, D and E is a carbon atom. .Iaddend. .Iadd.21. A compound according to claim 20 of the formula ##STR33## in which A, B, D and E have the same meanings as in claim 20. .Iaddend. 
     
     
        .Iadd.22.  A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 20 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. .Iaddend. .Iadd.23. A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 20 in the form of a sterile or physiologically isotonic aqueous solution. .Iaddend. .Iadd.24. A composition according to claim 21 containing from 0.5 to 95% by weight of the said active ingredient. .Iaddend. .Iadd.25. A medicament in dosage unit form comprising an antibacterially or antifungally effective amount of a compound according to claim 20 together with an inert pharmaceutical carrier. .Iaddend. .Iadd.26. A medicament of claim 25 in the form of tablets, pills, dragees, capsules, ampoules, or suppositories. .Iaddend. .Iadd.27. A method of combating bacterial diseases in warm-blooded animal which comprises administering to the said animals an effective amount of an active compound according to claim 20 either alone or in admixture with 
     
     
        a diluent or in the form of a medicament. .Iaddend. .Iadd.28.  A medicated fodder comprising an amount of a compound as claimed in claim 20 effective for promoting growth and improving feed utilization and a nutritious material. .Iaddend. .Iadd.29. A process for the production of a 4-pyridone-3-carboxylic acid or a derivative thereof which comprises reacting an enamine of the formula ##STR34## in which R 1  denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR 4  R 5 , in which   R 4  and R 5  can be identical or different, and denote a straight-chain or branched C 1  to C 4  alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, R 2  denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and   R 3  denotes an ether or acid amide derivative of the carboxyl group, with an o-halogeno-(hetero)-aryl-carboxylic acid halide of the formula ##STR35## in which at most two of the symbols A, B, D and E are nitrogen atoms and the symbols remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C 1  to C 6  alkyl, C 1  to C 4  alkoxy, C 1  to C 6  alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1  to C 4  alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C 1  to C 3  alkyl, nitro or halogen, or amino substituted by carbalkoxy.   
     
     
        .Iaddend. .Iadd.30.  A process according to claim 29, wherein A, B, D and E each is a carbon atom. .Iaddend. .Iadd.31. A process according to claim 30 in which the aprotic solvent is dioxane. .Iaddend. .Iadd.32. A process according to claim 30 in which the first reaction stage is carried out from 10° to 60° C. and the second reaction stage is carried out from 100° to 150° C. and the aprotic solvent is dioxane. 
     
     
        .Iaddend. .Iadd.33.  A process according to claim 30 in which R' is cyclopropyl or cyclohexyl. .Iaddend. .Iadd.34. A process according to claim 30 in which the base in the first reaction stage is triethylamine and the base in the second reaction stage is 1,8-diazabicyclo-[5.4.0]-undec-7-ene. .Iaddend. .Iadd.35. A process according to claim 30 in which the enamine is of the formula ##STR36## in which R 1  denotes a tert.alkyl, a C 3  to C 7  cycloalkyl, or a dialkyl amino group --NR 4  --R 5 , in which   R 4  and R 5  denote a C 1  or C 2  alkyl group or together complete a morpholinyl radical,   R 2  denotes a hydrogen atom or a C 1  to C 4  alkyl group or an optionally substituted benzyl or phenyl radical and   R 3  denotes an ester or acid amide derivative of the carboxyl group, with a carboxylic acid halide of the formula ##STR37## in which at most two of the symbols A, B, D and E are nitrogen atoms and the symbols remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C 1  to C 6  alkyl, C 1  to C 4  alkoxy, C 1  to C 6  alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1  to C 4  alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C 1  to C 3  alkyl, nitro or halogen, or amino substituted by carbalkoxy.   
     
     
        .Iaddend. .Iadd.36.  A process according to claim 30 in which the enamine is of the formula ##STR38## in which R 1  denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical, R 2  denotes a hydrogen atom or a C 1  to C 4  alkyl group and   R 1  denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR 4     
     
     
        R 5 . .Iaddend. .Iadd.37.  A process according to claim 30 in which the o-halogeno-aryl-carboxylic acid halide is a compound of the formula ##STR39## in which the symbols A, B, D and E have the same meaning as in claim 30. .Iaddend.