IE83796B1 - Antibacterial penem esters derivatives - Google Patents
Antibacterial penem esters derivatives Download PDFInfo
- Publication number
- IE83796B1 IE83796B1 IE2000/0929A IE20000929A IE83796B1 IE 83796 B1 IE83796 B1 IE 83796B1 IE 2000/0929 A IE2000/0929 A IE 2000/0929A IE 20000929 A IE20000929 A IE 20000929A IE 83796 B1 IE83796 B1 IE 83796B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- penem
- tetrahydrofuryl
- group
- following formula
- Prior art date
Links
- 150000002961 penems Chemical class 0.000 title description 7
- 230000000844 anti-bacterial Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 62
- -1 penem compound Chemical class 0.000 claims description 34
- 239000003242 anti bacterial agent Substances 0.000 claims description 13
- 230000003115 biocidal Effects 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 150000001340 alkali metals Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 206010060945 Bacterial infection Diseases 0.000 claims 1
- QMUWVIWDRVVTGE-IYSWYEEDSA-M O1[C@H](CCC1)C=1S[C@H]2N(C=1C(=O)[O-])C(C2)=O Chemical compound O1[C@H](CCC1)C=1S[C@H]2N(C=1C(=O)[O-])C(C2)=O QMUWVIWDRVVTGE-IYSWYEEDSA-M 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 239000011630 iodine Chemical group 0.000 claims 1
- 235000013350 formula milk Nutrition 0.000 description 11
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 10
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 10
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 10
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 10
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 10
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 10
- 229940079866 intestinal antibiotics Drugs 0.000 description 10
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 10
- 239000004615 ingredient Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000036912 Bioavailability Effects 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000035514 bioavailability Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 210000002700 Urine Anatomy 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical group I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 3
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 239000004606 Fillers/Extenders Substances 0.000 description 2
- CJCSPKMFHVPWAR-JTQLQIEISA-N Methyldopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 2
- 229960000615 Methyldopa Drugs 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940049954 Penicillin Drugs 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229960000626 benzylpenicillin Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940083181 centrally acting adntiadrenergic agents Methyldopa Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229940094025 potassium bicarbonate Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-M 2-iodoacetate Chemical compound [O-]C(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-M 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N Ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108060003095 GAS2 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- KRVDMABBKYMBHG-UHFFFAOYSA-N Isoguvacine Chemical compound OC(=O)C1=CCNCC1 KRVDMABBKYMBHG-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- UPIDXCYJXHFCOZ-UHFFFAOYSA-N N,N-dimethylformamide;sodium Chemical compound [Na].CN(C)C=O UPIDXCYJXHFCOZ-UHFFFAOYSA-N 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N Propadiene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 229940083599 Sodium Iodide Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- QXUAFCKBYYPTPQ-ZWKAXHIPSA-L [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O QXUAFCKBYYPTPQ-ZWKAXHIPSA-L 0.000 description 1
- VBDBHFZCFWQDNI-UHFFFAOYSA-M [Na+].[NH-]C=O Chemical compound [Na+].[NH-]C=O VBDBHFZCFWQDNI-UHFFFAOYSA-M 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001721 combination Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- RYPWQHONZWFXBN-UHFFFAOYSA-N dichloromethyl(methylidene)-$l^{3}-chlorane Chemical compound ClC(Cl)Cl=C RYPWQHONZWFXBN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N hydrogen atom Chemical group [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AOEKHRLNPVEHKG-WCCKRBBISA-M sodium;(2S)-oxolane-2-carboxylate Chemical compound [Na+].[O-]C(=O)[C@@H]1CCCO1 AOEKHRLNPVEHKG-WCCKRBBISA-M 0.000 description 1
- ICSAXRANXQSPQP-VUKDEKJYSA-M sodium;(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-oxolan-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound [Na+].S([C@@H]1[C@H](C(N1C=1C([O-])=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 ICSAXRANXQSPQP-VUKDEKJYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Description
Technical Field The present invention relates to penem compounds, and more specifically to penem compounds which are ex— pected to find clinical utility as promising antibiotics.
Background Art The present inventors previously found that a group of penem compounds represented by the following formula (IV); wherein R3 is a hydrogen atom or allyl group, —A— represents an oxygen or methylene group, and —B— represents a methylene, ethylene or carbonyl group, and their salts have excellent antibacterial activities on both gram—positive and gram—negative, aerobic or anaerobic bacteria (Japanese Patent Laid—Open No. /1986, corresponding to EP—A—Ol99446).
High safety of these compounds has been confirmed by a safety test in which laboratory animals were used.
Their development as medical drugs is now expected.
In the meantime, it has been found by the study on the correlation between structure and antibacterial activities of these compounds [J. Antibiotics, 41, 1685 (l988)] that, among 2—substituents of penem, lR)—2; tetrahydrofuryl group provides the highest antibac- terial activities while (S)—2—tetrahydrofuryl group, a diastereomer at its 2-side chain group, and (R) or (s)- 3—tetrahydrofuryl group, a position isomer, provide weaker activities particularly against gram-negative bacteria.
From these reasons, compounds represented by the (V): following formula wherein R4 represents a hydrogen atom or a group capable of forming a pharmaceutically—acceptable salt, have drawn interests as antibiotics. These compounds are also interested in that they do not require any special chemical modification for oral absorption and they themselves can be developed as both injections and oral drugs.
The bioavailability of the above- described compounds pane in laboratory animal (rats) has been found by no means inferior to commercial drugs which are used clinically.
However, from the viewpoint of safety and econo- my, further enhancement of their bioavailability upon oral administration is apparently more advantageous.
As far as the above compounds are concerned, there is yet room for further improvement in this regard.
Regarding improvements on the absorption upon oral administration, active studies have been conducted on penicillin and cephalosporin antibiotics so that many of these antibiotics are used as curative medi- only a few study reports of this type on penem and carbapenem antibiotics [J. Anti- biotics, 36, 938 (1983); Japanese Patent Laid-Open No. 67287/1990]. There has therefore been interest in cines. There are, however, determining whether or not the approaches used for penicillin and cephalosporin antibiotics are equally applicable to penem compounds.
GB-A-2206578 discloses the preparation of the penem compounds of formula (V) in which R4 is hydrogen (and salts thereof) by enzymic hydrolysis of a compound corresponding to formula (V) in which R4 is CHR’3OOCR’4, wherein R’3 is hydrogen or CH; alkyl and R’.«, is hydrogen or C148 alkyl, alkenyl, phenyl or phenylalkyl.
EP-A-0295100 discloses that certain esters of [5R,6S][(R) hydroxyethyl)methoxymethyl]-penemcarboxylic acid are prodrugs which are tract after subsequently hydrolysed in the bloodstream by aspecific serum esterases. Said absorbed from the gastro-intestinal oral administration and esters include the 2-oxo-1,3-dioxolanyl, (2-oxo—1,3-dioxolen—4—yl)methyl and 2- oxotetrahydrofuranyl esters in which said dioxolanyl or dioxolenyl ring can be substituted in the 5-position by C14 alkyl or phenyl and said tetrahydrofuryl ring can be substituted at the 4-position by C1-C4 alkyl. The only two exemplified esters tested were the acetoxymethyl and 5-rnethyloxo-1,3-di-oxolen yl)methyl esters and they are reported to have substantially the same oral bioavailability.
Hans Bundgaard in Chapter 2 of “Bioreversib|e Carriers in Drug Design, Theory and Application (Ed. E.B. Roche, Pergamon Press, 1987, 13-16) discusses the use of esters as prodrugs for drugs having carboxyl, hydroxyl or thiol groups. Reference is made to acyloxyalkyl esters of B—lactam antibiotics, cromoglycic acid, isoguvacine, methyldopa and tyrosine. Reference also is made to the 5-methyloxo-1,3-dioxolenyl)methyl esters of methyldopa and “a similar ester type of ampicillin”.
Disclosure of Invention The present inventors have carried out an ex- tensive investigation on the compounds (V) with a View toward making an improvement in their bioavailability.
As a result, it has been found that protection of their carboxyl group with a particular ester—forming group can significantly improve their bioavailability.
The present invention provides a penem compound represented by the following formula (I) wherein R represents a group of the general formula (II) -CH OCO—Y (II) in which Y represents a tetrahydrofuryl group.
Best Mode for Carrying Out the Invention The penem compound (I) of the present invention can be synthesized, for example, by reacting a halogenated alkyl compound (VI) with a penem compound (V') in accordance with the following formula: wherein X represents a halogen atom, R4 represents a hydrogen or alkali metal atom or an amino residuum, and R has the same meaning as defined above. when R4 in the compound (V') is an alkali metal atom or an amino residuum in this invention, the target compound can be obtained by stirring the compound (V') and the halogenated alkyl compound (VI) in an organic solvent. when R4 in the compound (V') is a hydrogen atom, on the other hand, it is first reacted with an alkali metal hydroxide, an alkali metal salt or an amine com- pound in an organic solvent to form a salt. The halogenated alkyl compound (VI) is then reacted with the reaction mixture, whereby the target compound is synthesized.
The halogenated alkyl compound represented by the formula (VI) serves to efficiently esterify the carboxyl group of the compound (V’) with the group R so that the target compound of the formula (l) is prepared. Compound (VI) includes those containing, as the group R, a tetrahydrofuryl-carbonyloxymethyl group, or its optically active isomer such as an (R)tetrahydrofuryl-carbonyloxymethyl group or an (S)tetrahydrofuryl—carbonyloxymethyi group and, as a halogen X, a chlorine, bromine or iodine atom. ’ ' ‘ No particular limitation is imposed on the alkali metal insofar as it forms a salt with the compound (V’). Examples of the alkali metal include lithium, sodium and potassium. Examples of their hydroxides and salts include sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carboxylate, potassium bicarbonate and potassium carbonate. Exemplary amine compounds include ammonia, triethylamine, and diisopropyl ethyl amine.
No particular limitation is imposed on the reac- tion solvent. Examples of the reaction solvent include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as pentane and hexane, halogenated alkyls such as methylene chloride and chloroform, halogenated aryls such as chlorobenzenes, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether and tetra- hydrofuran, and alcohols such as isopropanol and t- butanol. They can be used either singly or in combina- tion.
The reaction may be carried out at room tempera- ture or, when desired, under heating at a temperature below 80°C. The reaction time is generally 1-48 hours although it varies depending on the halogenated alkyl compound to be used.
As an alternative process for the preparation of the compound of this invention, the compound can also be synthesized by converting the compound of the for- mula (V) accordance with the process proposed by B. Balzer et al. [J. Antibiotics, 33, 1183 (l980)l it with a carboxylate salt represented by the following (VII):' into its chloromethyl or iodomethyl ester in and then reacting formula Y —COOM (VII) wherein Y is as defined above and M is an alkali metal or an amino residuum.
This reaction is carried out at a temperature in the range of from —40°C to room temperature, and is normally completed in 1-48 hours.
The penem compound (I) obtained as described above may be used as is but, in general, is purified, as needed, by a method such as column chromatography or recrystallization for use as a medicine.
For oral, parenteral or external administration, the compounds according to the present invention can be formulated as antibiotics in a manner known pwse in the art.
Although the dosage of each penem derivative of the present invention varies depending on many factors, the typical daily dosage ranges from 50 mg to 3 g for standard adults with the administration of 100 mg to 2 g in divided portions being preferred. In general, the above dosage will be administered in the form of a dosage unit which contains an appropriate amount of the active ingredient and a suitable, physiologically- acceptable carrier or extender.
For oral administration, tablets or capsules can be used. They may contain — together with the active ingredient — an extender, e g., lactose, glucose, sucrose, mannitol, sorbitol or cellulose, and a lubricant, e.g., talc, stearic acid or a stearate salt.
Tablets may additionally contain a binder, for example, hydroxypropyl cellulose or starch.
The compounds according to the present invention can be used not only for men but also for animals.
The present invention will hereinafter be de- scribed more specifically by the following examples.
Example 1 (Intermediate Compound Preparation) Chloromethyl (5R,6S)—6—[(R)—l—hydroxyethyl]- 2-[(R)~2-tetrahydrofuryl]penemcarboxylate (Compound 5) To the mixture of sodium (5R,6S)—6—[(R)—l- hydroxyethyl]—2—[(R)—2—tetrahydrofuryl]penem—3— carboxylate 2.5 hydrate (Compound 1, 24.7 g), tetrabutylammonium sulfate (2.38 g) and potassium bicarbonate (21.0 g), water (70 ml) and methylene (70 ml) were added. Into the resultant mix- (ll.5 g) diluted in methylene chloride (280 ml) was added drop- chloride ture, a solution of Chloromethyl chlorosulfate wise over about 10 minutes under ice cooling and stir— ring. After the reaction mixture was stirred for addi- tional 2.5 hours at room temperature, the organic layer was collected and washed with water. The organic layer was dried and then concentrated. The residue so ob- tained was purified by passing it through a silica gel column. The title compound was obtained in the amount of 9.92 g.
Example 2 (Intermediate Compound Preparation) iodomethyl (5R,6S)—6—[(R)—1—hydroxyethyl]— 2-[(R)—2—tetrahydrofuryl]penemcarboxylate (Compound 5) (5R,6S)-6—[(R)—1- hydroxyethyl][(R)—2—tetrahydrofuryl] penem—3— The mixture of chloromethyl (225 (2 ml) was stirred over night at room carboxylate (Compound 5, 334 mg), sodium iodide mg) and acetone temperature, and the reaction mixture was concentrated.
Ethyl acetate was added to the residue. The resultant solution was washed with water, dried, and then con- centrated, whereby 359 mg of the title compound were obtained.
Example 3 (Comparative Compound Preparation) (5R,65)-6—[(R)—1— hydroxyethyl]—2—[(R)tetrahydrofuryl]penem—3— [5- (Compound 2): carboxylate (SR,6S)~6—[(R)—1~ hydroxyethyl][(R)—2—tetrahydrofuryl]penem—3— The mixture of iodomethyl carboxylate (Compound 6, (3.83 g) was allowed to stand overnight at —20°C. .4 g), and N,N—dimethylformamide sodium monoallyl— glutarate (20 ml) The reaction mixture was then diluted with ethyl ether and washed with water. The organic layer was dried and then con- centrated. The residue was purified by passing it through a silica gel column, whereby 0.553 g of the title compound was obtained.
Example 4 (SR! '6‘ [(R)—l~hydroxyethyl][(R)—2—tetrahydrofuryl]- (R)-2~tetrahydrofurylcarbonyloxymethyl penem—3—carboxylate (Compound 3): The mixture of iodomethyl (SR,6S)~6—[(R)—l— hydroxyethyl]—2—[(R)-2—tetrahydrofuryl]penem—3— .4 g), (R)—tetrahydro—2— (1.38 g) and N,N—dimethyl— carboxylate (Compound 6, furoic acid sodium salt formamide (20 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl ether and then washed with water. The organic layer was dried and concentrated. The residue was purified by passing it through a silica gel column, whereby 0.72 g of the title compound was obtained.
Example 5 (S)-2—Tetrahydrofurylcarbonyloxymethyl (5R,6S)—6— [(R)—l—hydroxyethyl]a2-[(R)—2—tetrahydrofuryl]- penem—3—carboxylate (Compound 4): The mixture of iodomethyl (5R,6S)—6-[(R)—l— hydroXyethyl]~2—[(R)—2—tetrahydrofuryl]penem—3~ (S)—tetrahydro—2— furoic acid sodium salt (1.38 g) and N,N—dimethyl— carboxylate (Compound 6, 3.4 g), formamide (20 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl ether, followed by washing with water. The organic layer was dried and then concentrated. The residue was purified by passing it through a silica gel column, whereby 0.92 g of the title compound was ob- tained.
Physical properties of the compounds synthesized in Examplex 2-6 are summarized in Table 1. .~:n.._.~:m wnn.=u.:~_mm_n u.e_xxoL.cu.m,Eu:oa ..~:~,n.u.:_.on.m ..~=m.~na._.:_._n.a ..e.:_.¢n.. m~n_.m_~_ ..__..=_o.ux;~..o..~-.a._-~...»;.. .o... ._s.:._c~...n_.. ..e.:..go.«._n.m ..~:o.o en~_.m~am ..o :c._a» .».o.cx;._..x__.o._mu.xw. _»;.ue q .~:m._.a.:u.:___~.n ..s.:_.~m.~.mn.~ ..e.:_..n.~ m~m~.m¢.m .xxo_>:oa.~u_xu:.o.nxLe..u.-~.Am. .m..~ ..e.:o.¢_.~.~n._ ..~:m.wuw.u_:m.vn__ .n.:~.cm m .A~:n‘_ufi u.n_xxon.au.n.Eu:on .n.:_._m n ..~:m.~”w._.=_.~n.m ..s.:_.om.. n~m_.c_._ .—_».:_o~ux;n..u..~..m._-m.—_x:_o .~... ..a.:..c~...n_.. ..e_:..mo...~a A ..~:o.o oe~_.-m~ _.c :o._c» .».o_n»;._..¢__.o-.mm.¢m. _x;.oe m ..:n...n.:c_:_._~.n _.a.:_.mn ~.on.~ ._a.:_._n.~ m~c~.aoqn ‘x.e_»:o;..u_».:_o.n»;...u..~..¢. .: ~ ...__.__.::.~.3_ .?__o...I..:.__2:._ . _.a. . .v _. . e. _ . . ..~_ . w.~_.eo~_ _o :o__=, ,__x.:_o.ux;a..u.,~,.¢.__-~.._x;.u _ . . . . V . . . w~m~_mmqm ._».o__»_..=_a.»xo_»__...m__ mo ~.om _ .5 :_.wa ..~~ _ _~:m gas 2 :m_.n _ .m_uou. «:2 x. uc:c.ccaa< ucaoaeou .o= c.;eo. .uu: A: H mfifim _ 15 _ COHHCm>EH asp we mwczomaou uo: % .w.:N._o 9 ..~:m._ua.:.:_.~m m ..~:n.~ua...:_.mm.m ._e.:___m_.,m_.. ..s.=N. .o_v._c n ..~:m m. :.n._"n.:n..__.m~.n ..E.:_. _c.ux.u xc__o» m~u—xxon.¢u .m.Eu:ua~_>.:.o.nxcag.u. -~-~z__‘m‘~_xz.u>xo.u>L nnc om.~.mv.~ ..e.:m.~_.~.n~._ ..~:¢.oua.n.:n.am._ ._ _a._.o-.mm.mm..x;.~eono_ . ~ . . . _ . e. .~:a.m~_~:m.mm=.un.:~.oa m 0.”_»xog_.u.n.eu=~;_.»_=_ . =n _.a n :_.nn n . =_.~n n,c~ m . :_.on ..~_ . w=o;;.ose zo__c. ~_1; ,o.n»;e..~..~..m..,~,__>;-»;o.nx; Mam . e. . . . . N . .~ . N . . . . s. . :~..o V an m A :m 0 :9 N a nu :_.m~.m . :_. ._,.«._,o..m¢.¢m. _»;_ueo.o_;u mm.~-m._~ .2 =w.mo.~,mm._ .A~=o.o"n n.=m.wm _ A:oQoVm2z r:bva2m_ mo:N5maQ< c::oaEoO .oz.yqEoO .m. H mflnme Example 6 The bioavailability of Compounds 3 and 4 of the present invention was compared with that of Compound 2 and with sodium [5R,6S]—6—[(R)—1— hydroxyethyl][(R)tetrahydrofury|]penemcarboxylate (Compound 1) relying upon their recovery rates in urine.
Each test compound (30 umole/kg) was orally administered to SD strain rats (three male rats per group). Urine was collected over 6 hours from the administration, and the recovery rate of the corresponding compound present in the urine was determined by bioassay. The results are shown below.
Table 2 C°E::d R in the compound (I) re::3::;Y(%) Ratio 1 Na 4.38 1 (Con:rol)A 2* -CH2OCO(CH2) 3COOCH2Ci-{CH2 7.53 1 7 3 -CH2OCO:\O] lO.9O 2.5 H 4 -CH2OCOJ:OJ ll.57 2.5 H * not compound of the invention _ 18 _ As is apparent from the results, the compounds 3 and of the present invention showed the higher urinaly recovery rate, in other words, a higher bioavailability compared with the Compounds 1 and 2.
Preparation Examples Preparation 1 Capsules Ingredient No.
Ingredient Invention compound Lactose Magnesium stearate (Total) (Production procedures) mggcaosule I74 mg Ingredients 1 and 2 were combined together in a suitable mixer, to which Ingredient 3 was added, followed by further mixing. resultant mixture was filled by a capsule filling machine.
Preparation 2 Tablets Ingredient No. Ingredient mgftablet Invention compound 150 Crystalline cellulose 50 Calcium carboxymethylcellulose 10 Magnesium stearate 4 (Total) ' 214 mg (Production procedures) Ingredients 1-3 were combined together in a suitable mixer, to which Ingredient 4 was added, several minutes. followed by mixing for additional The resultant mixture was compressed into tablets of a predetermined size and weight by a tableting machine.
Claims (16)
1. -. A penem compound represented by the following formula wherein R represents a group of the general formula (II) —cH2oco-Y (II) in which Y represents a tetrahydrofuryl group.
2. A compound according to Claim 1, wherein Y represents an (R)—2-tetrahydrofuryl group.
3. A compound according to Claim 1, wherein Y represents a (S)—2—tetrahydrofuryl group.
4. A compound according to Claim 1, wherein R is an optically active group. U1
5. The compound of Claim 1, which is (R)-2—tetrahydrO_ furylcarbonyloxymethyl (ER,6S){(R)hydroXyethy1}_2_ [(R)tetrahydrofuryl]-penem—3—carboxylate.
6. The compound of Claim 1, which is (S)—2-tetrahydro— furylcarbonyloxymethyl (5R,6S}—6—[(R)-l—hydroxyethyl]~2- [(R)tetrahydrofuryl]—penem—3—carboxylate.
7. An antibiotic composition, comprising an effective amount of a compound of formula (I) as defined in Claim 1 and a pharmaceutically~acceptable carrier.
8. A composition according to Claim 7, wherein said compound is as defined in any one of Claims 2 to 6.
9. A composition according to Claim 7 or Claim 8 for oral administration.
10. A penem compound according to any one of Claims 1 to 6 for use in the treatment of bacterial infections in the human or animal body.
11. The use of a penem compound according to any one of Claims 1 to 6 in the manufacture of an antibiotic medicament.
12. A method of preparing a penem compound as defined in Claim 1 which comprises: (a) reacting a penem compound of the following formula (V’) HO wherein R4 represents an alkali metal atom or an amino residuum with an halogenated compound of the following formula (VI) RX (VI) wherein R is as defined in Claim 1 and X is halogen, OI (b) reacting a penem compound of the following formula (V”) HO s I7 I59’ COOR} (V") wherein R4’ represents ~CH2X’in which X’ is chloride or iodine L with a salt of the following formula (VII) Y - COOM (VII) wherein Y is as defined in Claim 1 and M is an alkali metal atom or an amino residuum.
13. A penem compound of the formula (I) of Claim 1, substantially as herein described.
14. An antibiotic composition according to Claim 7 9 substantially as herein described.
15. The use of a penem compound according to Claim 11, substantially as herein described.
16. A method of preparing a penem compound according to Claim 12, substantiaily as herein described. MACLACHLAN & DONALDSON, Applicants’ Agents, 47 Merrion Square, DUBLIN 2.
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