| Methods of preventing bacterial infections with florfenicol-type antibiotics -> Monitor Keywords |
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Methods of preventing bacterial infections with florfenicol-type antibioticsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Three Nitrogens And Three Carbon Atoms, Asymmetrical (e.g., 1,2,4-triazine, Etc.)Methods of preventing bacterial infections with florfenicol-type antibiotics description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060014743, Methods of preventing bacterial infections with florfenicol-type antibiotics. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This Application is a continuation-in-part of U.S. patent application Ser. No. 10/094,688, filed Mar. 8, 2002 and entitled "Novel Florfenicol-type Antibiotics." The '688 application is incorporated as if fully set forth herein. FIELD OF THE INVENTION [0002] The present invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry and medicine. In particular, it relates to novel florfenicol-type antibiotics. BACKGROUND OF THE INVENTION [0003] Florfenicol is a broad spectrum antibiotic with activity against many gram-negative and gram-positive bacteria. Florfenicol is useful for the prevention and treatment of bacterial infections due to susceptible pathogens in birds, reptiles, fish, shellfish and mammals. One of its primary uses is in the treatment of pneumonia and associated respiratory infections in cattle (often referred to generically as Bovine Respiratory Disease or BRD) caused by Mannhemia haemolytica, Pasturella multocida and(or) Haemophilus somnus. It is also indicated in the treatment of pododermatitis in cattle caused by Fusobacterium necrophorum and Bacterioides melaninogenicus, swine respiratory disease caused by Pasteurella multocida, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and(or) Mycoplasma spp., colibacillosis in chickens caused by Escherichia coli, enteric septicemia in catfish caused by Edwardsiella ictaluri, and furunculosis in salmon caused by Aeromonas salmonicida. Other genera of bacteria that have exhibited susceptibility to florfenicol include. Enterobacter, Klebsiella, Staphylococcus, Enterococcus, Bordetella, Proteus, and Shigella. In particular, chloramphenicol resistant strains of organisms such as K. pneumoniae, E. cloacae, S. typhus and E. coli are susceptible to florfenicol. [0004] Florfenicol is a structural analog of thiamphenicol, which in turn is a derivative of chloramphenicol in which the aromatic nitro group, which nitro group has been implicated in chloramphenicol-induced, non-dose related irreversible aplastic anemia in humans, is replaced with a methylsulfonyl group. Florfenicol has a fluorine atom in place of the primary hydroxyl group of chloramphenicol and thiamphenicol. This renders florfenicol less susceptible to deactivation by bacteria containing the plasmid-encoded enzyme, chloramphenicol acetyl transferase (CAT), which acetylates the primary hydroxyl group of chloramphenicol and thiamphenicol, thereby preventing them from binding to ribosomal subunits of susceptible bacteria. Ribosomal binding is the primary mechanism of action of the chloramphenicol antibiotics and results in inhibition of peptidyl transferase, which is responsible for the transfer of amino acids to growing peptide chains and subsequent protein formation in bacteria. Nonetheless, compounds having the primary hydroxyl group do have utility in the treatment of bacterial infections, as evidenced by the continuing use of chloramphenicol and thiampheniol throughout the world. [0005] In recent years, a number of bacterial genera and species have begun to exhibit some resistance to florfenicol. For example, resistance has been observed in Salmonella species (Bolton, L. F., et al., Clin. Microbiol. 1999, 37, 1348), E. coli (Keyes, K., et al., Antimicrob. Agents Chemother., 2000, 44, 421.), Klebsiella pneumoniae (Cloeckaert, A., et al., Antimicrob. Agents Chemother., 2001, 45, 2381), and in the aquacultural pathogen, Photobacterium damselae subsp. piscicida (formerly Pasteurella piscicida) (Kim, E., et al., Microbiol. Immunol., 1996, 40, 665). This resistance has been traced to a highly conserved gene (flo) that produces an antibiotic efflux pump (Flo). [0006] The emergence, and threatened spread, of resistance to florfenicol has fostered the need for new antibiotics that retain or exceed the activity of florfenicol, maintain its imperviousness to the CAT enzyme and, in addition, are not substrates for the Flo efflux pump. The compounds of the present invention are such antibiotics. SUMMARY [0007] Thus, an embodiment of this invention is a compound having the chemical formula: wherein: [0008] R.sup.1 is selected from the group consisting of --OH and --F; [0009] R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, (1C-4C)alkyl, halo, --CF.sub.3, --NH.sub.2, --CN and N.sub.3; [0010] R.sup.4 is selected from the group consisting of: --C(.dbd.R.sup.5)R.sup.6, [0011] wherein: [0012] R.sup.5 is selected from the group consisting of oxygen, N--C.ident.N, and NOR.sup.7, [0013] wherein: [0014] R.sup.7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, alicyclic and heteroalicyclic; [0015] R.sup.6 is selected from the group consisting of hydrogen, (1C-4C)alkyl, (3C-6C)cycloalkyl, (1C-4C)alkoxy, aryl, heteroaryl, alicyclic and heteroalicyclic; wherein: [0016] A.sup.1 is carbon or nitrogen; [0017] A.sup.2, A.sup.3, A.sup.4 and A.sup.5 are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that at least one of A.sup.1-A.sup.5 is not carbon, that the total number of nitrogen, oxygen and sulfur atom in the ring does not exceed 4 and that the ring is aromatic; [0018] carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C-4C)alkyl, (3C-6C)cycloalkyl, (1C-4C)alkylO--, --CF.sub.3, --OH, --CN, halo, (1C-4C)alkylS(O)--, (1C-4C)alkylS(O).sub.2--, NH.sub.2SO.sub.2--, (1C-4C)alkylNHSO.sub.2--, ((1C-4C)alkyl).sub.2NSO.sub.2--, --NH.sub.2, (1C-4C)alkylNH--, ((1C-4C)alkyl).sub.2N--, (1C-4C)alkylSO.sub.2NH--, (1C-4C)alkylC(O)--, (3C-6C)cycloalkylC(O)--, (1C-4C)alkylOC(O)--, (1C-4C)alkylC(O)NH--, --C(O)NH.sub.2, (1C-4C)alkylNHC(O)-- and ((1C-4C)alkyl).sub.2NC(O)--, wherein any of the alkyl groups in any of the substituents may optionally be substituted with a group selected from halo and --OH; [0019] if A.sup.1 is carbon and the ring does not contain oxygen or sulfur, one of the nitrogen atoms may optionally be substituted with an entity selected from the group consisting of (1C-4C)alkyl, (1C-4C)alkylS(O).sub.2-- and --NH.sub.2; wherein: [0020] A.sup.6, A.sup.7, A.sup.8, A.sup.9 and A.sup.10 are independently selected from the group consisting of carbon, nitrogen and provided that only one of A.sup.6-A.sup.10 at a time can be carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C-4C)alkyl, (3C-6C)cycloalkyl, (1C-4C)alkylO--, --CF.sub.3, --OH, --CN, halo, (1C-4C)alkylS(O)--, (1C-4C)alkylS(O)2--, NH.sub.2SO.sub.2--, (1C-4C)alkylNHSO.sub.2--, ((1C-4C)alkyl).sub.2NSO.sub- .2--, --NH.sub.2, (1C-4C)alkylNH--, ((1C-4C)alkyl).sub.2N--, (1C-4C)alkylSO.sub.2NH--, (1C-4C)alkylC(O)--, (3C-6C)cycloalkylC(O)--, (1C-4C)alkylOC(O)--, (1C-4C)alkylC(O)NH--, --C(O)NH.sub.2, (1C-4C)alkylNHC(O)--, ((1C-4C)alkyl).sub.2NC(O)-- and --OCH.sub.2O--, the oxygen atoms in the --OCH.sub.2O-- substituent being bonded to adjacent ring carbon atoms, wherein any of the alkyl groups in any of the substituents may optionally be substituted with a group selected from halo and --OH; [0021] R.sup.8 is hydrogen in all compounds, except when R.sup.2 and R.sup.3 are both F, in which case R.sup.8is hydrogen or F; and, [0022] the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown. [0023] In an embodiment of this invention, R.sup.1 is --F. [0024] In an embodiment of this invention, R.sup.2 and R.sup.3 are independently selected from the group consisting of Cl and F. [0025] In an embodiment of this invention, R.sup.8 is hydrogen. [0026] In an embodiment of this invention, R.sup.4 is --C(.dbd.R.sup.5)R.sup.6 wherein R.sup.5 and R.sup.6 are as defined above. [0027] In an embodiment of this invention, R.sup.4 is CH.sub.3C(O)--. [0028] In an embodiment of this invention, R.sup.4 is wherein: [0029] A.sup.6, A.sup.7, A.sup.8, A.sup.9 and A.sup.10 are as defined above, and, [0030] any of A.sup.6-A.sup.10 that is carbon is substituted with an entity selected from the group consisting of hydrogen, --NH.sub.2, halo-, --CN, (1C-4C)alkyl-, (1C-4C)alkylC(O)--, (1C-4C)alkylS(O)--, (1C-4C)alkylS(O).sub.2--, NH.sub.2SO.sub.2--, (1C-4C)alkylSO.sub.2NH--, (1C-4C)alkylNHSO.sub.2--, ((1C-4C)alkyl).sub.2NSO.sub.2--, wherein any of the alkyl groups in any of the substituents may optionally be substituted with halo or --OH. [0031] In an embodiment of this invention, R.sup.4 is and one, two or three of A.sup.6-A.sup.10 is/are nitrogen; and, [0032] one or two of the remaining carbon atoms in the ring is/are optionally substituted with --NH.sub.2, all other carbon atoms in the ring being unsubstituted. [0033] In a presently preferred embodiment of this invention, R.sup.4 is selected from the group consisting of: [0034] In an embodiment of this invention, R.sup.4 is as defined above. [0035] In an embodiment of this invention, R.sup.4 is and all carbon atoms and nitrogen atoms are unsubstituted. [0036] In an embodiment of this invention, R.sup.4 is and one of A.sup.2-A.sup.5 that is carbon is substituted with an --NH.sub.2 group, all other carbon and, if applicable, nitrogen atoms in the ring being unsubstituted. [0037] In a presently preferred embodiment of this invention, R.sup.4 is selected from the group consisting of: [0038] A presently preferred embodiment of this invention is a compound selected from the group consisting of: wherein the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown. 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