MXPA00002432A - 8a-AZALIDES AS VETERINARY ANTIMICROBIAL AGENTS - Google Patents
8a-AZALIDES AS VETERINARY ANTIMICROBIAL AGENTSInfo
- Publication number
- MXPA00002432A MXPA00002432A MXPA/A/2000/002432A MXPA00002432A MXPA00002432A MX PA00002432 A MXPA00002432 A MX PA00002432A MX PA00002432 A MXPA00002432 A MX PA00002432A MX PA00002432 A MXPA00002432 A MX PA00002432A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- amino
- cmo
- substituted
- hydrogen
- Prior art date
Links
- 239000004599 antimicrobial Substances 0.000 title description 5
- 241000283690 Bos taurus Species 0.000 claims abstract description 20
- 230000002265 prevention Effects 0.000 claims abstract description 11
- 201000009910 diseases by infectious agent Diseases 0.000 claims abstract description 10
- 230000000241 respiratory Effects 0.000 claims abstract description 9
- 244000144972 livestock Species 0.000 claims abstract description 7
- -1 hydroxy, amino Chemical group 0.000 claims description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 206010060945 Bacterial infection Diseases 0.000 claims description 15
- 206010057190 Respiratory tract infection Diseases 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 241000606831 Histophilus somni Species 0.000 claims description 9
- 241000204031 Mycoplasma Species 0.000 claims description 9
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 241000606750 Actinobacillus Species 0.000 claims description 7
- 241000588724 Escherichia coli Species 0.000 claims description 7
- 241000606860 Pasteurella Species 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 6
- 241000607142 Salmonella Species 0.000 claims description 6
- 206010039447 Salmonellosis Diseases 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 5
- 241000589893 Brachyspira hyodysenteriae Species 0.000 claims description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 4
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000676 alkoxyimino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000005139 alkynylsulfonyl group Chemical group 0.000 claims description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000000477 aza group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052793 cadmium Inorganic materials 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- NHFDIUPJVYYTLG-UHFFFAOYSA-N carbononitridic isocyanide Chemical compound [C-]#[N+]C#N NHFDIUPJVYYTLG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052803 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- 150000004696 coordination complex Chemical class 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 2
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 241000534944 Thia Species 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims 1
- 125000004967 formylalkyl group Chemical group 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 claims 1
- 241001465754 Metazoa Species 0.000 abstract description 9
- 230000001580 bacterial Effects 0.000 abstract description 6
- 241000282898 Sus scrofa Species 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 239000000969 carrier Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 241000606856 Pasteurella multocida Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 3
- 241001293418 Mannheimia haemolytica Species 0.000 description 3
- 230000000845 anti-microbial Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 241000606748 Actinobacillus pleuropneumoniae Species 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010038683 Respiratory disease Diseases 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 229940029983 VITAMINS Drugs 0.000 description 2
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
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- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
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- 235000014666 liquid concentrate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 244000005700 microbiome Species 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
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- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
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- 235000013343 vitamin Nutrition 0.000 description 2
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- NVEPPWDVLBMNMB-SNAWJCMRSA-N 1-methyl-2-[(E)-2-(3-methylthiophen-2-yl)ethenyl]-5,6-dihydro-4H-pyrimidine Chemical compound CN1CCCN=C1\C=C\C1=C(C)C=CS1 NVEPPWDVLBMNMB-SNAWJCMRSA-N 0.000 description 1
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6H-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl)acetic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- MYQXHLQMZLTSDB-UHFFFAOYSA-N 2-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)acetic acid Chemical compound OC(=O)CC1=CC=C2OC(CC)CC2=C1 MYQXHLQMZLTSDB-UHFFFAOYSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- OIRAEJWYWSAQNG-UHFFFAOYSA-N 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 1
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- ARHWPKZXBHOEEE-UHFFFAOYSA-N Alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
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- SPFYMRJSYKOXGV-UHFFFAOYSA-N BAY VP 2674 Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 1
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- IVUMCTKHWDRRMH-UHFFFAOYSA-N Carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229950009592 Cefquinome Drugs 0.000 description 1
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N Ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 1
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- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 description 1
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- 229960004369 Flufenamic Acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N Flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
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- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
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Abstract
8a-Azalides are useful in the treatment and prevention of bacterial respiratory and enteric infections in livestock animals, particularly in cattle and swine.
Description
8a-AZALIDES AS VETERINARY ANTIMICROBIAL AGENTS
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides methods for the treatment or prevention of enteric or respiratory bacterial infections in livestock animals.
BACKGROUND OF THE INVENTION 10 The morbidity and mortality associated with enteric and respiratory bacterial infections in cattle represent a significant economic loss for the animal husbandry industry. In livestock, especially in younger animals, stress as a result of transportation,
Dehydration, alteration or deprivation of food can cause the animals to become mildly susceptible to bacterial respiratory infections, especially if the animals are housed in full or very poorly ventilated rooms. The main bacterial pathogens causing respiratory diseases of cattle are Pasteurella haemolytica, P. multocida,
Haemophilus somnus and Mycoplasma spp. In pigs, respiratory infections are caused by Pasteurella multocida or Actinobacillus pteuropneumoniae, and Mycoplasma ssp. they are associated with considerable losses in some herds. The most common causative organisms
of enteric diseases in cattle and pigs are Escherichia coli, Treponema hyodysenteriae and Salmonella spp. The current therapeutic antimicrobial products against respiratory and enteric infections in cattle include a diverse group of conventional products effective against a broad spectrum of infectious agents, mainly among this group include tetracyclines; and a newly introduced group of products designed primarily for the treatment of bovine respiratory diseases, such as quinolones (danofloxacin, enrofloxacin), cephalosporins (cefquinome, ceftiofur), macrolides (tilmicosin), and florfenicol. Resistance to older antimicrobial agents has developed in the field. Although resistance to newer products is not yet a problem, it is known that excessive use favors the emergence of resistance over time, but the increase in the number of families of drugs, and therefore mechanisms of action, may decrease the probability of resistance development for any individual compound. Thus, there is a continuing need to discover antimicrobial compounds that are suitable for use in veterinary medicine; preferably, said compounds belong to a chemotype different from the antimicrobial agents currently used in animal or human medicine. Other desirable characteristics of a novel antimicrobial product for use in veterinary medicine include high potency against target organisms, high concentration of target tissue, and long tissue life and half plasma life.
* - 8a-Azalides are antibiotics characterized by a 15-membered lactone ring containing a nitrogen atom in the ring. A group of 8a-azalides is described in European patent application 508,699 because it has an antibacterial spectrum similar to that of erythromycin, and is active in vitro against gram positive and gram negative bacteria, including E. Coli, and H. influenzae. However, EP 508,699 does not disclose the use of 8a-azalides for the treatment and prevention of respiratory or enteric bacterial infections in livestock animals. In addition, there is no suggestion that 8a-azalides have antibacterial activity against common causative organisms of enteric and respiratory bacterial infections of swine and cattle.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for treating or preventing bacterial enteric or respiratory infection in a livestock animal comprising the administration of a therapeutically or prophylactically effective amount of an 8a-azalide to a livestock animal in need of such treatment or prevention. In a preferred embodiment the 8a-azalide has the formula I:
or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable metal complexes thereof, and said metal complex is taken from the group consisting of copper, zinc, cobalt, nickel and cadmium; wherein R1 is hydrogen; hydroxy; C1-4 alkoxy; formyl; CMO alkylcarbonyl, C-MO alkoxycarbonyl, aryloxycarbonyl, C-MO aralkoxycarbonyl, CMO alkylsulfonyl, O-arylsulfonyl wherein said CMO alkyl group is substituted by 1-3 halogen (F, Cl, Br), hydroxy, amino groups , C -? - 5 acylamino or C? -4 alkyl; or alkyl of C-MO, C2-10 alkenyl or C2-? alkynyl or substituted or unsubstituted wherein said alkyl chain, if it has more than two carbons in length, may have 1 to 2 of oxa, aia or aza embedded of the formula -NR-, in which R
¡^^^^^^ i ^ M íáíál ^ tá ?? is hydrogen or C 1-3 alkyl, and wherein said substituents are independently 1-3 of (a) aryl or heteroaryl optionally substituted by 1-3 halogen (F, Cl, Br, I), C 4 alkyl, alkoxy of C1-3 amino, C1-4 alkylamino, di (C? -) amino or hydroxy alkyl, (b) heterocyclyl substituted or unsubstituted by hydroxy, amino, C- alkylamino, di (C? -4 alkyl) ) amine, C1-4 alkylcarbonyloxy or C-? alkylcarbonylamino. ? (c) halogen (F, Cl, Br or I), (d) hydroxy not acylated or acylated by a RaC group (= O) or
R b S (O) 2 wherein Ra is hydrogen, C 1-6 alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and R b is C 1-6 alkyl or aryl, (e) C-MO alkoxy, (f) aryloxy or heteroaryloxy substituted or unsubstituted by groups 1-3 halogen, hydroxy, amino or C? -4 alquilo alkyl, (g) amino or alkylamino of C-MO not acylated or acylated by a group RaC (= 0), RaOC (= O), or RbS02, where Ra and Rb are as previously defined; (h) di (C-MO alkyl) amino, (i) arylamino, heteroarylamino, aralkylamino or heteroarylalkylamino wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halogen, hydroxy, amino or CrC alkyl groups, 0) mercapto,
(k) C 1-10 alkylthio, alkylsulfinyl or alkylsulphonyl, arylthio, aryisulfinyl or arylsulphonyl wherein said aryl group is unsubstituted or substituted by halogen, hydroxy, amino or C? -4 alkyl groups, (I) formyl , (m) Ci-io, (n) arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl or heteroarylalkylcarbonyl alkylcarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halogen, hydroxy, amino or C1-4 alkyl groups, ( o) carboxy, (p) C 1-6 alkoxycarbonyl, (q) aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarylalkoxycarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by halogen, hydroxy, amino or alkyl groups 1-3 C? -4, (r) carbamoyl or sulfamoyl wherein the N atom is unsubstituted or substituted by groups 1-2 alkyl of C?? - 6 or by an alkylene chain of
C -6, (s) cyano (t) isonitrile (u) nitro, (v) azido, (w) substituted or unsubstituted minomethyl on nitrogen or carbon with CMO alkyl, (x) oxo or
(and) thiono; R2 and R3 are independently hydrogen, C-MO alkyl, aryl; or R2 and R3 together are oxo or thiono; R4 and R5 are independently hydrogen or alkylcarbonyl; or R4 and R5 are together carbonyl; or R 4 and R 1 together are C 1 -C 3 alkylene substituted or unsubstituted by an oxo group; R6 and R7 are both hydrogen, or one of R6 and R7 is hydrogen and the other is hydroxy, an acyloxy derivative taken from the group consisting of formyloxy, C-MO alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy, or -NHR12 wherein R12 is hydrogen, arylsulfonyl or heteroarylsulfonyl substituted or unsubstituted by 1-3 halogen or C?-3 alkyl, alkylsulfonyl or -C (= O) -XA-R 13 groups, wherein X is a linking link, O or NH, A is a C1-C3 linking or alkylene linkage, R13 is hydrogen, C1-C10 alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or C3-C7 cycloalkyl, wherein any of the R13 groups other than hydrogen can be substituted by one or more of halogen, hydroxyl, C1-C3 alkoxy, cyano, isonitrile, nitro, amino, mono- or di-alkylamino of (C1-C3), mercapto, C1-C3 alkylthio, C 1 -C 3 alkylsulfinyl, C 1 -C 3 alkylsulfonyl, arylthio, arylsufinyl,
i-- > sulfamoyl, arylsulfonyl, carboxy, carbamoyl, C 1 -C 3 alkylcarbonyl or C 1 -C 3 alkoxycarbonyl; or R6 and R7 are together oxo, hydroxyimino, alkoxyimino, aralkoxyimino or aminoimino; R8 is methyl, aralkoxycarbonyl, or arylsulfonyl; R9 is hydrogen, formyl, C1-10 alkoxycarbonyl of C? _? 0, or arylalkoxycarbonyl; R10 is hydrogen; or R 10 and R 1 together are C 1 -C 3 alkylene substituted or unsubstituted by an oxo group; m and n are independently zero or one. Most preferably, the 8a-azalide has the formula I wherein n and m are zero; R1 is hydrogen, CMC alkyl, C2-10 alkenyl, C2-10 alkynyl or arylsulfonyl, wherein said alkyl and alkenyl are optionally substituted with halogen, hydroxy, cyano, CMO alkoxycarbonyl, amino, C? > di (C-MO alkylamino), aryl or aralkoxycarbonyl; R2, R3, R4, R5, R9 and R10 are each hydrogen;
one of R6 and R7 is hydrogen and the other is selected from hydroxyl, CMC alkylcarbonyloxy. aralkylcarbonyloxy, amino, amino substituted by CMO alkylcarbonyl, arylcarbonyl, C 1 O arylalkylcarbonyl, C 0 alkoxycarbonyl, C 1-10 arylalkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or arylsulfonyl; R8 is methyl. Still very preferred is the 8a-azalide of formula I wherein n and m are zero; R1 is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-fluoroethyl, -fluoroalyl, benzyl or oxiranylmethyl; R2, R3, R4, R5, R9 and R10 are hydrogen; one of R6 or R7 is hydrogen and the other is hydroxy or amino; R8 is methyl. The most preferred R1 groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl. In another preferred embodiment, the present invention provides a method for the treatment or prevention of bacterial respiratory infections of bovine or porcine wherein the causative organism is selected from the group consisting of Pasteurella spp., Actinobacillus spp., Haemophilus somnus and Mycoplasma spp. , which comprises administering to a bovine or porcine in need of such treatment or prevention a therapeutically or prophylactically effective amount of an 8a-azalide. Very
preferably, 8a-azalide is of formula I; and particularly preferred are the 8a-azalides of formula I wherein R1 is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl. , 2- (dimethylamino) ethyl, 2-fluoroethyl, 2-fluoroalyl, benzyl or oxiranylmethyl; R2, R3, R4, R5, R9 and R10 are hydrogen; one of R6 and R7 is hydrogen and the other is hydroxy or amino; R8 is methyl. Preferred R1 groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl. In another preferred embodiment, the present invention provides a method for the treatment or prevention of enteric bacterial infections of bovine or porcine wherein the causative organism is selected from
Escherichia coli, Treponema hyodysenteriae, and Salmonella spp., Comprising administering a therapeutically or prophylactically effective amount of an 8a-azalide to a porcine or bovine in need of such treatment or prevention. Most preferably, 8a-azalide is of formula I; and particularly preferred are 8a-azalides of formula I wherein R 1 is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-fluoroethyl, 2-fluoroalyl, benzyl or oxiranylmethyl; R2, R3,
R4, R5, R9 and R10 are hydrogen; one of R6 and R7 is hydrogen and the other is hydroxy or amino; R8 is methyl. The most preferred R1 groups are methyl, ethyl,
......... JB ..,, »...,. ...-, - - m r HMKffTÉMfy '? tríT i rffliiHBfí i i - ***** - ** ^ - * Jste ^ '- XT propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl. As used herein, "8a-azalide" means a compound having the following core structure wherein the asterisks indicate the sites for substitution:
The 8a-azalides are known herein as erythromycin A derivatives, primarily as derivatives of 9-deoxo-8a-aza-8a-15 homoerythromycin A. The term "therapeutically or prophylactically effective amount" means that the amount of an 8a- azalide that will provide a level of antibacterial activity at the target site of infection is sufficient to inhibit the bacterium in a manner that allows the host animal to counteract or
protect yourself from the infection. "Treatment or prevention" refers to the use of 8a-azalide before or after the manifestation of signs and symptoms suggestive of bacterial infection to allow the host animal to counteract or protect itself from
• ^ «. ¿S;; ^ * ^^ aa - ^ -... ^ - a. *. < . . . > - «^ -« ^ ~~ aim? Iíli- * ~ x-m? the infection. "Respiratory or enteric bacterial infections" refers to respiratory or digestive tract infections in which the causative organism or similar causative organism is susceptible to 8a-azalide. Such organisms include, but are not limited to, Pasteurella species (eg P. haemolytica, P. multocida), Haemophilus somnus, Actinobacillus pleuropneumoniae, Mycoplasma spp., E. coli, Treponema hyodysenteriae, and Salmonella spp. (for example, S. typhimurium, S. dublin). The terms that are used to define the variable groups of formula I (for example, alkyl, aryl, heterocyclyl, substituted, etc.) have the same meanings as those provided in EP 508,699. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particular preference is given to citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. The 8a-Azalides are known compounds, such as those described in European application 508,699, or can be prepared using known methods from readily available starting materials.
¿^ ^ The representative 8a-azalides are the following: 9-Deoxo-8a-aza-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-ethyl-8a-homoerythromycin A; 8a- (3-phenylpropyl) -8a-aza-9-deoxo-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-al-l-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (prop-1 -yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (prop-1-yloxy) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2-oxoet-1 -yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (2-hydroxyethyl-1 -yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - ((2,3-epoxy) prop-1-yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (11-azetidinyl) -2-et-1 -yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((1-pyrrole idinyl) -2-et-1 -yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((N-piperidinyl) -2-et-1-yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((4-morpholinyl) -2-et-1-yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((2-fluoroet-1 -yl) -2-aminoet-1 -yl) -8a-homoerythromycin A; 8a- (2-chloroalyl) -8a-aza-9-deoxo-8a-homoerythromycin A;
E »r? WTÍ mi + - ~ -» 8a- (2-fluoroalyl) -8a-aza-9-deoxo-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((2-cyano) et-1 -yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - ((3-amino) prop-1-yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - (((N, N-dimethyl) -3-amino) prop-1-yl) -8a-5 homoerythromycin A; 9-Desoxo-8a-aza-8a - ((2-cyanoethyl) -3-aminoprop-1-yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a - ((3,4-dihydroxybenzyl) -3-aminoprop-1-yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (3-acetoxyprop-1-yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (3-hydroxyprop-1 -yl) -8a-homoerythromycin A; (3-methoxy-3-oxopropyl) -8a-homoerythromycin A; 8a- (3-octyloxy-3-oxopropyl) -9-deoxo-8a-aza-8a-homoerythromycin A; 15 8a- (3- (2-methoxyethoxy) -3-oxopropyl) -9-deoxo-8a-aza-8a-homoerythromycin A; 8a- (3-isopropoxy-3-oxopropyl) -9-deoxo-8a-aza-8a-homoerythromycin A; 8a- (3-benzyloxy-3-oxopropyl) -9-deoxo-8a-aza-8a-20 homoerythromycin A; 8a- (2-carboxyethyl) -9-deoxo-8a-aza-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-cyanomethyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2-aminoethyl) -8a-homoerythromycin A;
9-Desoxo-8a-aza-8a- (2-dimethylamino ethyl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (N-L-leucyl-2-aminoethyl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-carboxymethyl-8a-homoerythromycin A; 5-Deoxo-8a-aza-8a-methoxycarbonylmethyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-3'-N-demyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2-fluoroet-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2-fluoroet-1-yl) -3'-N-demethyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2-fluoroet-1 -yl) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (3-fluoroprop-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (3-fluoroprop-1-yl) -3'-N-demethyl-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (3-fluoroprop-1 -yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - ((4,4,4-trifluoro) -but-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - ((4,4,4-trifluoro) but-1-yl) -3'-N-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a - ((4,4,4-trifluoro) but-1-yl) -8a-
What is it? ti mi tm ^^ ts homoerithromycin A; 9-Deoxo-8a-aza-8a- (benzyl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (benzyl) -3'-N-demethyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (benzyl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (4-methoxybenzyl) -3'N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (4-methoxybenzyl) -3'-N-demethyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (4-methoxybenzyl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2- (2-ethoxyethoxy) et-1-yl) 3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2- (2-ethoxyethoxy) et-1-yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2,2-difluoroet-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A; 9-Deoxo-8a-aza-8a- (2,2-difluoroet-1-yl) -3'-N-demethyl-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (2,2-difluoroet-1 -yl) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-hydroxy-8a-homoerythromycin A and 9-Deoxo-8a-aza-8a- (prop-il) -8a- (prop-il) -8a-homoerythromycin A; 9-Desoxo-8a-aza-8a-acetyl-8a-homoerythromycin A;
9-Deoxo-8a-aza-8a-glycyl-8a-homoerythromycin A; 9-Desoxo-8a-aza-8a- (Leu-Gli) -8a-homoerythromycin A; 9-Deoxo-8a-aza-8a-phenylsulfonyl-8a-homoerythromycin A; 2'-O-Acetyl-9-deoxo-8a-methyl-8a-aza-8a-homoerythromycin A; (11-0,12-O-Oxomethylene) -9-deoxo-8a-methyl-8a-aza-8a-homoerythromycin A; 4"-O-phenylacetyl-8a-aza-8a-methyl-9-deoxo-8a-homoerythromycin A of 8a-aza; 4" -O- (4-methoxyphenyl) -acetyl-8a-aza-8a-methyl-9 -deoxy-8a-homoerythromycin A; 2'-O-Acetyl-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-epi-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4" -Dioxy-4"-amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; "-Dosoxi-4" - (S) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Dosoxi-4" - (R) -amino-9-deoxo-8a- aza-8a-methyl-8a-homoerythromycin A; 4"-Desoxo-4" - (S) -acetylamino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Desoxo-4" - (R) -acetylamino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"- (4-methoxyphenylacetyl) amino-4" -deoxy-8a-aza-8a-methyl-8a-
^ j ^ i? ^^^ JßßBg ^ WW ^^^^^^^^^^^^ ß homoerithromycin A; 4"-Dosoxi-4" - (L-alanyl) amino-9-deoxo-8a-aza-8a-methyl-8a-methyl-8a-homoerythromycin A; 4"Deoxy-4" - (L-valyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"Deoxy-4" - (L-leucyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Dosoxi-4" - (L-phenylalanyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Dosoxi-4" - (O-tert-butyl-L-tyrosyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerytromycin A; 4"Deoxy-4" - (L-propyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"Deoxy-4" - (L-aspartyl-b-benzyl ester) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"Deoxy-4" - (L-aspartyl) amino-9a-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Dosoxi-4" - (L-pyroglutamyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 4"-Dosoxi-4" - (L-glutamyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A; 2"-O-Acetyl-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A; 4" -Dosoxy-4-amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A; '4"-Dioxy-4" -amino-9-deoxo-8a-aza-8a-propyl-8a-homoerythromycin A; 2"-0-Acetyl-9-deoxo-8a-aza-8a-methoxycarbonethyl-8a-5 homoerythromycin A; 4" -Dosoxy-4"-amino-9-deoxo-8a-aza-8a- (3-methoxy) 3-oxopropyl) -8a-homoerythromycin A; 2'-O-Acetyl-8a-aza-8a-homoerythromycin; and 4"-Dosoxi-4" -amino-8a-aza-8a-homoerythromycin A. 10 The 8a-Azalides can be administered to a host in need of treatment, or prevention of enteric or respiratory bacterial diseases similar to those used for other antibacterial agents, for example, 8a-azalides can be administered parenterally, orally, topically or rectally. administered will vary from
according to the compound used in particular, the infectious organism involved, the host in particular, the severity of the disease, the physical condition of the host, and the selected route of administration; the appropriate dose can be easily determined by one skilled in the art. For the treatment of bacterial diseases, the oral dose may be in
the scale from 1 mg / kg to 1000 mg / kg; and the parenteral dose on the scale from 0.01 mg / kg to 500 mg / kg. For prophylactic use in animals, the oral dose can be on a scale of 1 mg / kg to 1000 mg / kg; and the parenteral dose on the scale of
0. 01 mg / kg to 500 mg / kg. The 8a-azalides of the present invention are
preferably administered parenterally at a dose scale of from about 0.1 to about 10 mg / kg. The 8a-azalides are preferably used in a pharmaceutical composition comprising the active ingredient and an inert pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise an 8a-azalide as an active ingredient, and may also comprise a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The formulations include compositions suitable for oral, rectal, topical and parenteral administration (including subcutaneous, intramuscular and intravenous), although the most appropriate route in a given case will depend on the host in particular, and on the nature and severity of the conditions for which the active ingredient will be administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by one of the methods known in the pharmaceutical art. In practice, 8a-azalide can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The vehicle can take a wide variety of forms depending on the desired preparation form for administration, for example oral or parenteral (including intravenous, intramuscular and subcutaneous); parenteral administration is generally preferred. To prepare the compositions in oral dosage form, it is
possible to use any of the common pharmaceutical means. For example, in the case of oral liquid preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used; or in the case of solid oral preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be included. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form where solid pharmaceutical carriers are obviously used. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. In addition to the common dosage forms set forth above, the 8a-azalides can be administered by controlled release means and / or assortment devices. The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, lozenges or tablets each containing a predetermined amount of the active ingredient, such as a powder or granules or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. Said compositions can be prepared by any of the pharmacy methods, but all methods include the step of associating the active ingredient with the vehicle constituting one or more of the ingredients
necessary. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, form the product in the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compression, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, active surface or dispersing agent. The molded tablets can be made by molding in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent. Conveniently, each tablet contains about 1 mg to about 500 mg of the active ingredient and each tablet or capsule contains from about 1 to about 500 mg of the active ingredient. The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of these active compounds in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, the preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the degree that there is easy injection. They should be stable under manufacturing and storage conditions and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example glyc, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable topical formulations include transdermal devices, aols, creams, ointments, lotions, powders, and the like. These formulations can be prepared by conventional methods containing the active ingredient. To illustrate, a cream or ointment is prepared by mixing sufficient amounts of hydrophilic material and water, containing about 5-10% by weight of the compound, in sufficient amounts to produce a cream or ointment having the desired consistency. Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are preferably presented as unit dose suppositories. Suitable carriers include cocoa cream and other materials commonly known in the art, and suppositories can be conveniently formed by mixing the combination with the softened or molten vehicle followed by cooling and molding. It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, as appropriate, one or more additional ingredients such as diluents, pH regulators, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives ( including antioxidants) and the like, and substances included for the purpose of producing the isotonic formulation with the blood of the recipient in question. The compositions containing an 8a-azalide can also be prepared in concentrated liquid or powder form. In accordance with standard veterinary formulation practice, conventional water-soluble excipients, such as lactose or sucrose, can be incorporated into the powders to improve their physical properties. Therefore, particularly suitable powders of the invention comprise from 50 to 100% w / w, and preferably from 60 to 80% w / w of the combination and from 0 to 50% w / w and preferably from 20 to 40% w / w of conventional veterinary excipients. These powders can be added to the animal's food, for example by means of an intermediate premix or diluted in the water that will be drunk by the animals. The liquid concentrates of the invention suitably contain a water-soluble combination of compounds and may optionally include a veterinarily acceptable water-miscible solvent, by
example polyethylene glycol, propylene glycol, glyc, glyc formal or a solvent that is mixed with up to 30% v / v ethanol. The liquid concentrates can be administered to the water that will be drunk by the animals. The pharmaceutical composition containing 8a-azalide may optionally contain a second active ingredient, a biological component such as an antigen, or a food supplement such as minerals or vitamins. The active ingredients may include immunomodulators such as interf, interleukins and other chemokines, non-stdal anti-inflammatories such as propionic acid derivatives (eg, ibuprofen, ketoprofen, naproxen, benoxprofen, carprofen), acetic acid derivatives (eg acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclózico acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), phenamic acid derivatives (for example flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid (for example diflufenisal, flufenisal), and cyclooxygenase-2 (COX-2) inhibitors, and antiparasitic agents such as avermectin, ivermectins, milbemycins, levamisole, benzimidazoles, pirantel / morantel. Biologics can be vaccines commonly known in the cattle industry against infectious bovine rhinotracheitis, bovine diarrhea virus, respiratory syncytial virus, parainfluenza, transmissible gastroenteritis, porcine reproductive and respiratory syndrome, rotavirus and coronavirus. Food supplements can be vitamins, iron, selenium and the like.
* Umitt á *? The following examples are provided to illustrate the present invention in more detail, and are not in any way constructed as limiting factors within the scope of the claims.
In vitro activity of 8a-azalides
The antibacterial activity of representative 8a-azalides against a panel of veterinary pathogens was determined by the minimal inhibitory concentration (MIC) method well known in the art. This is done by preparing a series of culture tubes, each containing a medium with a different concentration of the antimicrobial agent, and inoculating all the tubes with the same organism. The lowest concentration of agent that completely avoids the appearance of turbidity is shown, and at this concentration it is called MIC. The scale of antibacterial activity of 4"-deoxy-4" -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A, 4"-deoxy-4" (R) -amino-9-deoxo- 8a-aza-8a-methyl-8a-homoerythromycin A, 4"-deoxy-4" (S) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A, and 4"-deoxy-4"-amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A against key organisms in veterinary medicine is summarized below: Organism MIC scale (uq / ml) P. haemolytica 0.125-0.5 P. multocida 0.125- 0.5 H. somnus 0.125-0.250 A. pleuropneumoniae 0.062-0.125 E. coli 0.5-2 Salmonella spp. 0.5-4"^ '• ^ ^^. ^^^ j ^ g ^ jH ^ t ^^ 3? | J ^ f¡ ^
Claims (19)
1. - The use of an effective amount of an 8a-azalide to prepare a medent for the treatment or prevention of respiratory or enteric bacterial infection in a livestock animal.
2. The use as claimed in claim 1, wherein the 8a-azalide has the formula I: or a pharmaceutly acceptable salt thereof, or pharmaceutly acceptable metal complexes thereof, and said metal complex is taken from the group consisting of copper, zinc, cobalt, nickel and cadmium; wherein R1 is hydrogen; hydroxy; C -? _ alkoxy; formyl; CMO alkylcarbonyl, G ^? l m .. ^ S »CMO alkoxycarbonyl. aryloxycarbonyl, CMC aralkoxycarbonyl, CMO alkylsulphonyl, O-arylsulphonyl wherein said CMO alkyl group is substituted by groups 1-3 halogen (F, Cl, Br), hydroxy, amino, C? - acylamino or C?; or CMO alkyl, C2-10 alkenyl or substituted or unsubstituted C2-10 alkynyl wherein said alkyl chain, if it has more than two carbons in length, may have 1 to 2 of oxa, thia or aza of the formula -NR-, wherein R is hydrogen or C-? -3 alkyl, and wherein said substituents are independently 1-3 of (a) aryl or heteroaryl optionally substituted by 1-3 halogen (F, Cl, Br, I), C-alkyl, C-? -3-amino alkoxy, C? -4 alkylamino, amino or hydroxy di (alkyl), (b) heterocyclyl substituted or unsubstituted by hydroxy, amino, C-alkylamino, di (CM alkyl) amino, C- or C5-alkylcarbonylaminocarbonylaxy, (c) halogen (F, Cl, Br or I), (d) hydroxy not acylated or acylated by a RaC (= O) or RbS group (O) 2 wherein Ra is hydrogen, C? .6alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and Rb is Ci-.beta.-O-aryl alkyl, (e) CMO-alkoxy, (f) aryloxy or substituted heteroaryloxy or not substituted by groups 1-3 halogen, hi droxy, amino or C? -4 alkyl, (g) amino or alkylamino of CO not acylated or acylated by a group RaC (= O), RaOC (= O), or RbS02, where Ra and Rb are as defined before; (h) di (CMO alkyl) amino, (i) arylamino, heteroarylamino, aralkylamino or heteroarylalkylamino wherein said aryl or heteroaryl group is unsubstituted or substituted by halogen, hydroxy, amino or alkyl groups of C -? - C, (j) mercapto, (k) CMC alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, aryisulfinyl or arylsulfonyl wherein said "^ -i-- - - - ^ aryl group is unsubstituted or substituted by groups 1-3 halogen, hydroxy, amino or C, (I) formyl alkyl, (m) CMO alkylcarbonyl, (n) arylcarbonyl, heteroarylcarbonyl , aralkylcarbonyl or heteroarylalkylcarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by halogen, 5-hydroxy, amino or alkyl groups of CM, (O) carboxy, (p) CMO alkoxycarbonyl, (q) aryloxycarbonyl, heteroaryloxycarbonyl , aralkoxycarbonyl or heteroarylalkoxycarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by groups 1-3 halogen, hydroxy, amino or C, (r) carbamoyl or sulfamoyl alkyl wherein the N atom is unsubstituted or substituted by 10 groups 1-2 Ci-β alkyl or an alkylene chain of C4-6, (s) cyano, (t) isonitrile, (u) nitro, (v) azido, (w) iminomethyl substituted or unsubstituted on nitrogen or carbon with CMO alkyl, (?) oxo (y) thiono; R2 and R3 are independently hydrogen, CMC alkyl, aryl; or R2 and R3 together are oxo or thiono; R4 and R5 are independently hydrogen or alkylcarbonyl; or R4 and R5 15 are carbonyl together; or R4 and R1 together are CrC3 alkylene substituted or unsubstituted by an oxo group; R6 and R7 are both hydrogen, or one of R6 and R7 is hydrogen and the other is hydroxy, an acyloxy derivative taken from the group consisting of formyloxy, CMO alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy, or -NHR12 wherein R12 is hydrogen, Arsenisulfonyl or 20 heteroarylsulfonyl substituted or unsubstituted by halogen 1-3 groups or C-? 3 alkyl, alkylsulfonyl or -C (= O) -XA-R13, wherein X is a linker, O or NH, A is a bond C1-C3 -alkylene or alkylene, R13 is hydrogen, C-Cio, aryl, aralkyl, heteroaryl, heterocyclyl, or C3-C-cycloalkyl, wherein any of the R13 groups other than hydrogen can be substituted by one or more of halogen, hydroxyl, C1-C3 alkoxy, cyano, isonitrile, nitro, amino, mono- or dialkylamino of (C1-C3), mercapto, C 1 -C 3 alkylthio, C 1 -C 3 alkylsulfinyl, C 1 -C 3 alkylsulfonyl, arylthio, arylsufinyl, sulfamoyl, aryisulfonyl, carboxy, carbamoyl, C 1 -C 3 alkylcarbonyl or C 1 -C 3 alkoxycarbonyl; or R6 and R7 are together oxo, hydroxyimino, alkoxyimino, aralkoxyimino or aminoimino; R8 is methyl, aralkoxycarbonyl, or arylsulfonyl; R9 is hydrogen, formyl, CMO alkylcarbonyl, CMO alkoxycarbonyl, or arylalkoxycarbonyl; R10 is hydrogen; or R10 and R1 together are C1-C3 alkylene 10 substituted or not substituted by an oxo group; m and n are independently zero or one.
3. The use as claimed in claim 2, wherein the 8a-azalide has the formula I in which n and m are zero; R1 is hydrogen, CMC alkyl, C2-10 alkenyl, C2-10 alkynyl or arylsulfonyl, Wherein said alkyl and alkenyl are optionally substituted with halogen, hydroxy, cyano, C 0 alkoxycarbonyl, amino, CMO alkylamino, di (CMO alkylamino), aryl or aralkoxycarbonyl; R2, R3, R4, R5, R9 and R10 are each hydrogen; one of R6 and R7 is hydrogen and the other is selected from hydroxyl, CMO alkylcarbonyloxy, aralkylcarbonyloxy, amino, substituted amino 20 for CMO alkylcarbonyl, arylcarbonyl, CMO arylalkylcarbonyl, CMO alkoxycarbonyl, CMO arylalkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryisulfonyl; R8 is methyl.
4. The use as claimed in claim 2, in ^ gb * where 8a-azalida has the formula I in which n and m are zero; R1 is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-fluoroethyl, -fluoroalyl, benzyl or oxiranylmethyl; R2, R3, R4, R5, R9 and R10 are hydrogen; one of R6 or R7 is hydrogen and the other is hydroxy or amino; R8 is methyl.
5. The use as claimed in claim 4, wherein R1 is methyl, ethyl, propyl, allyl, propargyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.
6. The use as claimed in claim 1, wherein said bacterial infection is respiratory infection of bovine or porcine.
7. The use as claimed in claim 6, wherein said respiratory infection is caused by a Pasteurella species, Actinobacillus spp., Haemophilus somnus or Mycoplasma spp.
8. The use as claimed in claim 2, wherein said bacterial infection is respiratory infection of bovine or porcine.
9. The use as claimed in claim 8, wherein said respiratory infection is caused by a Pasteurella species, Actinobacillus spp., Haemophilus somnus or Mycoplasma spp.
10. The use as claimed in claim 3, wherein said bacterial infection is respiratory infection of bovine or porcine.
11. The use as claimed in claim 10, wherein said respiratory infection is caused by a Pasteurella species, . , ^ i * - * ^. M ^. - ^. ~? > * ~? - * --- * - ~ - ~ Actinobacillus spp., Haemophilus somnus or Mycoplasma spp.
12. The use as claimed in claim 4, wherein said bacterial infection is respiratory infection of bovine or porcine.
13. The use as claimed in claim 12, wherein said respiratory infection is caused by a species Pasteurella, Actinobacillus spp., Haemophilus somnus or Mycoplasma spp.
14. The use as claimed in claim 5, wherein said bacterial infection is respiratory infection of bovine or porcine.
15. The use as claimed in claim 14, wherein said respiratory infection is caused by a species Pasteurella, Actinobacillus spp., Haemophilus somnus or Mycoplasma spp.
16. The use as claimed in claim 1, wherein said bacterial infection is enteric bovine or porcine infection.
17. The use as claimed in claim 16, wherein said enteric infection is caused by Escherichia coli, Treponema hyodysenteriae or Salmonella spp.
18. The use as claimed in claim 2, wherein said bacterial infection is enteric infection of bovine or porcine.
19. The use as claimed in claim 18, wherein said enteric infection is caused by Escherichia coli, Treponema hyodysenteriae or Salmonella spp. fek
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/058,329 | 1997-09-10 | ||
| GB9806029.6 | 1998-03-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00002432A true MXPA00002432A (en) | 2001-11-21 |
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