IE49407B1 - Antibacterial agents and beta-lactamase inhibitors - Google Patents
Antibacterial agents and beta-lactamase inhibitorsInfo
- Publication number
- IE49407B1 IE49407B1 IE338/80A IE33880A IE49407B1 IE 49407 B1 IE49407 B1 IE 49407B1 IE 338/80 A IE338/80 A IE 338/80A IE 33880 A IE33880 A IE 33880A IE 49407 B1 IE49407 B1 IE 49407B1
- Authority
- IE
- Ireland
- Prior art keywords
- group
- formula
- general formula
- penem
- compound
- Prior art date
Links
- 239000003242 anti bacterial agent Substances 0.000 title abstract 2
- 239000003781 beta lactamase inhibitor Substances 0.000 title abstract 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- -1 p.methoxybenzyl Chemical group 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 150000002148 esters Chemical class 0.000 claims abstract description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 239000000741 silica gel Substances 0.000 claims description 17
- 229910002027 silica gel Inorganic materials 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000005949 ozonolysis reaction Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 claims description 2
- 125000005633 phthalidyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000006000 trichloroethyl group Chemical group 0.000 claims 1
- 125000006502 nitrobenzyl group Chemical group 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 125000006501 nitrophenyl group Chemical group 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 abstract description 2
- 230000004913 activation Effects 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 230000002503 metabolic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 23
- 235000019256 formaldehyde Nutrition 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical group C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 18
- 101150041968 CDC13 gene Proteins 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 5
- DIOVBHTUHUUROP-UHFFFAOYSA-N acetyloxymethyl 2-oxoacetate Chemical compound CC(=O)OCOC(=O)C=O DIOVBHTUHUUROP-UHFFFAOYSA-N 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 238000005055 short column chromatography Methods 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 150000003952 β-lactams Chemical class 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- SGRDDXNVIPRUDM-OULFWDGXSA-N acetyloxymethyl (5r)-3-(acetyloxymethyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound S1C(COC(C)=O)=C(C(=O)OCOC(C)=O)N2C(=O)C(C(O)C)[C@H]21 SGRDDXNVIPRUDM-OULFWDGXSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- HVRMNEPIBIGCNZ-UHFFFAOYSA-N (4-nitrophenyl)methyl 2-oxoacetate Chemical compound [O-][N+](=O)C1=CC=C(COC(=O)C=O)C=C1 HVRMNEPIBIGCNZ-UHFFFAOYSA-N 0.000 description 1
- ARAIIFFPXFUMGY-AATRIKPKSA-N (E)-4-[(4-nitrophenyl)methoxy]-4-oxobut-2-enoic acid Chemical compound OC(=O)\C=C\C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 ARAIIFFPXFUMGY-AATRIKPKSA-N 0.000 description 1
- HKAVADYDPYUPRD-UHFFFAOYSA-N 1h-pyrazine-2-thione Chemical compound SC1=CN=CC=N1 HKAVADYDPYUPRD-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 101100048447 Caenorhabditis elegans unc-4 gene Proteins 0.000 description 1
- 101100260565 Dictyostelium discoideum thyA gene Proteins 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical group S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 description 1
- 101150052863 THY1 gene Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- VSZZHGWKOGMPOW-UHFFFAOYSA-N acetyloxymethyl 3-(acetyloxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound CC(=O)OCOC(=O)C1=C(COC(C)=O)SC2CC(=O)N12 VSZZHGWKOGMPOW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical group Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- DJANLSNABDFZLA-RQJHMYQMSA-N methyl (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound S1C(C)(C)[C@H](C(=O)OC)N2C(=O)C[C@H]21 DJANLSNABDFZLA-RQJHMYQMSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 101150068774 thyX gene Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
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- C07F9/02—Phosphorus compounds
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Abstract
There are provided penem- carboxylic acids and esters of the general formula In the formula, n=0 or 1; R''=H, lower alkyl, CCl3CH2-, p.nitrobenzyl, p.methoxybenzyl, phenyl, p.nitrophenyl or benzhydryl or a residue known to undergo metabolic activation in vivo and having favourable pharmacokinetic properties; Z=H, halogen, OH, NH2, NH2COO, SH or pyridinium or OR1, OCOR1, NHCOR1 or SR1 wherein R1=lower alkyl, aryl or a heterocyclic ring, each of which may be substituted or unsubstituted; R'=H, lower alkyl, lower alkoxy cycloalkyl or hydroxyalkyl (the hydroxy group of which is free or protected). Pharmaceutically acceptable salts of these compounds, which are antibacterial agents and beta -lactamase inhibitors, are included in the invention, as is a process for their preparation from penicillanic acid S-oxide esters.
Description
DESCRIPTION:
The invention relates to processes for the preparation cf ^-lactam ccntaining compounds, to certain of the ^-lactam containing compounds and to compositions containing them.
More particularly, the invention relates to penem-carboxylic acids and esters of the general formula (1)
jc, wher'.in n is 0 or 1, R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a 2,2,2-trichloroethyl, benzyl, acetonyl, £.nitrobenzyl, p.methoxybenzyl, phenyl, £.nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group
2r era group of the formula -CH (CH^) . OCOC^H^ or -CH2NHCOR2 v.herein represents an alkyl eroup having from 1 to 4 carbon atoms or a cycloalkvl or aryl group; Z represents a hydroxy, amino, carbamoyloxy, mercapto or pyridinium group, or a aro^p of the formula ORj, OCOR^ or SP.^
2= wherein R^ represents an alkyl group having from 1 tc 4 carbon atoms and R^ represents an alkvl group having
- 3 from 1 to 4 carbon atoms or a 5-methyl-l,3,4-thiadiazol-2-yl, 1-methyl-l H-tetrazol-5-yl, l,2,3-triazol-5-yl or pyrazinyl group; R' represents a hydrogen atom or an alkyl, alkoxy or hydroxyaikyl group, each of which has from 1 to 4 carbon atoms, the alcoholic function of the hydroxyaikyl group being free or protected by a p.nitrobenzyloxycarbonyl group. The 6-substituent may have the a- or β-configuration. 6a-substitution is preferred.
The invention provides a process for the preparation of compounds of the general formula CD in which n,
R' and R are as above defined and Z has any of the meanings ascribed to it above except a mercapto or pyridinium group of a group of the formula SR^.
The process is illustrated by the following reaction scheme, in which R', R, and n have the meanings ascribed to them above, R represents an alkyl group, X represents a group of the formula CHjZ* in which Z' has any of the meanings ascribed to Z above except a mercapto or pyridinium group or a group of the formula SR^, Y represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a cyano or alkoxycarbonyl group or a group of the formula Cf^Z’ 1° which Z' has the meaning
4-9 40 7 ascribed to it above, and Ph represents a phenyl group.
48407 'χΛ ^j=pph COOR
(14)
(15)
Y-
X
COOR
Ri
Sk /X
(ID
PPhCOOR” (1: n=O)
VPh3 COOR (11)
The process comprises condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) with an acetylenic compound of the general formula XCeCY, isomerising the resultant compound of the general formula (3) in basic conditions, converting the resultant azetidinone derivative of the general formula (4) into one of the general formula (11) by the steps of (a) ozonolysis of the 1-substituent of the formula
COOR in solution at reduced temperature, (b) removal of the 1-substituent of the formula r
COOR resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR by refluxing in a solvent, (d) chlorination of the 1-substituent of the formula r
COOR introduced in step (c) by the action of a chlorinating agent, (e) conversation of the 1-substituent of the formula
COOR introduced in step (d) into one of the formula
PPh3
COOR by reaction with triphenyl phosphine, (f) reduction of the 4β-(substituted vinylsulphinvl) group by the action of a reducing agent, and (g) ozonolysis of the double bond of the group of the formula in solution at reduced temperature,· the steps being carried out in the order (a),(b),(c),(d), (e),(f),(g) or (a), (f), (b), (c), (d), (e) , (g) or (f),(a) and (q) simultaneously, (b),(c),(d), (e), step (f) being carried out in acidic conditions if carried out after step (e), and cyclising the compound of the general formula (11) by heating it in an inert solvent at from 50°C to 140°C to obtain a compound of the general formula (1) in which n is 0, and optionally converting that compound to one of the general formula (1) in which n is 1 by oxidation.
The preparation of the remaining compounds of the general formula (1), that is those in which n, r> and R are as above defined and Z represents a mercapto or pyridini’um group or a group of the formula SR3 wherein R3 is as above defined, is carried out according to the above precess with the additional step
4-9407 of converting the substitutent X Into a substituent of the formula CH^Z wherein Z is as defined in this sentence. The additional step may be carried out at any stage in the above process after the condensation of the penicillanic acid S-oxide ester (2) with the acetylenic compound XC = CY, and is necessary because of the difficulty of condensing the penicillanic acid S-oxide ester (2) directly with an acetylenic compound HSCH2-C=qf, R3 SCH2~C=CY or PyCHgCSCY in which Py represents a pyridinium ion. This process is also within the scope of the invention.
The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)-6-aminopenicillanie acid following known procedures (see CIGNARELLA et al., Journal of Organic Chemistry, 27, 2668 and EVRARD et al.. Nature, 201, 1124).
When R' represents a C^-C^ alkyl or hydroxyalkyl group, it can be introduced according to the
2o procedure of Di Ninno et al., Journal of Organic
Chemistry 42, 2960 (1977). When R' represents a C^-C4 alkoxy group, it may be introduced
- 9 to the procedures of Hauser et al., Helv. Chem.
Acta, SO, 1327 (1967) and Giddings et al.. Tetrahedron Letters, 11, 995, (1978). Alternatively compounds of general formula (2) In which R’ represents a hydrogen atom can be converted to compounds of the general formula (2) in which R’ represents a C^-C^ alkyl or hydroxyalkyl group by introducing the substituent into the 6-position using a strong base, as illustrated in the following
Examples. Compounds of the general formula (2) in which R' represents a Cj-C^ alkyl or hydroxyalkyl group can also be prepared starting from a suitable ester of penicillanic acid
S-oxide, as Illustrated In the following Examples.
The substitution at the 6-position is stereospecifically directed to the 6a- derivatives.
The reaction sequence (a), (b), (c), (d), (e), (f) (g) is possible when Y is not a strong electron withdrawing group. Then the compound (6, n=l) is surprisingly stable.
The reduction step (f) may be carried out using phosphorus tribromide or sodium iodide in acetyl
4-»Λ07
- 10 chloride as reducing agent.
When R' represents a hydroxyalkyl group in the desired compound of the general formula (1), the reaction sequence is preferably carried out with the alcoholic function protected.
Compounds of the general fonnula (1) in which R represents a hydrogen atom can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds.
Compounds of the general formula (1) in which n is 1 are readily prepared starting from compounds of the general formula (1) in which n is 0 following known oxidation processes. Peracids can be advantageously used; m.chloroperbenzoic acid and peracetic acid are preferred
The compounds of the general formula (1) as above defined possess a wide spectrum of an antibacterial activity as well as a β-lactamase inhibiting activity. It should be pointed out that the stereochemistry at of the compounds of the general formula (1) as above defined, as well as that of all the intermediates of their preparation, is the same as in naturally occurring penicillins and cephalosporins.
4-3 4-0 7
- 11 Certain of the compounds of the general formula (1) as above defined themselves form part of the invention.
They are those in which n and R are as above defined,
Z represents a carbamoyloxy or pyridinium group or a group of the formula OCOR^ or SR3 wherein Rj and R3 are as above defined and R' represents a hydroxyalkyl group having from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a £-nitrobenzyloxycarbonyl group.
Preferably R' represents a 1-hydroxyethyl or 1-(d-nitrobenzyloxycarbonyloxy)-ethyl group.
Pharmaceutically acceptable salts of these penem-carboxylir acids, such as sodium,potassium, benzathin and procaine salts and salts of other bases conventionally used for salt formation with penicillins and cephalosporins are also included within the scope of the invention.
The compounds of the general formulae (3), (4), (9) and (14) are claimed in our Patent Applications Nos. 2.33 y/g 4^ 20 2.34-0/8¼ anJ 0.3-4//84 divided herefrom.
4-©4θ 7
-IZThe following Examples illustrate the invention.
EXAMPLE 1
4g-(1-acetoxymethyl-3-acetoxy-l-propenylsulphiny1)-1- (1-methoxycarbonyl—2-methyl-allyl) -azeti3in-'2-one (3): R=CH3; R'=H, X=Y=CH20.C0.CH3
A solution of 2.0 g of methyl penicillinate S-Oxide and 2.8 g of butyndiol diacetate in 40 ml Of toluene was refluxed for 24 hours. 1.4 g of the title compound was obtained after purification by column chromatography
on silica gel eluting with methane;ethy1 acetate. PMR (CDC13) : 2.03 δ (s, s, 2 CH3C0) 2.88 δ (dd, 15 C-3-Ηα) 9 3.38 δ (dd. C-3-Ηβ ) 9 3.83 δ (s, 1 4.88 δ (d, ,
ZO
I CH)
4.92 δ (broad s, CH2~^= ),
4.93-5.33 6 (m, =CH2 and
COO
.32 δ (dd, Jvic = 4 and 2Hz, C-4-H) ,
6.47 δ (t, Jvic = 6HZ, =C-C(H2)) .4
40 7
- 13 EXAMPLE 2
8- (1-a ce toxyme thy1-3-a ce toxy-l-propenyIs ulphiny1)-3- (l-methoxycarbcaiYl-2-methyl-l-propenyl)-a’ze'tidin-2-one (4) : R=CH3, R’ =H, X=Y=CH2O.CO.CH3
1.7 g of the compound prepared in Example 1 were dissolved in 80 ml of dichloromethane. 0.5 ml of triethylamine were added and the solution was left for a few hours at room temperature. After evaporating off the solvent, the title compound was obtained in pure form in quantitative yield.
PMR (CDC13) : 2.13 (9H) and 2.32 (3H) δ (two s, 2 CH3CO and 2 CH3-C=), 2.92 6 (dd, Jgem=15Hz,
Jvic cis = 5Hz, C-3-Ηα) , 3.38 δ (dd,
Jgem=15Hz, Jvic trans = 2.5 Hz, C-3-Ηβ),
3.82 δ (s, CH3O) 4.88 δ (d, Jvic=6.5 Hz,
CH_-C=), 4.92 δ (s, CH,-C=), 5.15 δ (dd, |
(H)
Jvic » 5 and 2.5Hz, C-4-H), 6.50 δ (t, Jvic 6.5Hz, =C-(H2))
H
EXAMPLE J
48-( l-acetoxymethyl-3-acetoxy-T-propenylBiilphlnyl) -1-methoxyoxalyl-azetldin-2-one (5) : R=CH3, R'=H, X=Y=CH2O.CO.CH3, n=l
2.0 g of the compound prepared in Example 2 were dissolved in 150 ml of dichloromethane and, after cooling to -78°C, a flow of ozone in oxygen was
PMR (CDC13)
IR (CH2C12)
- 14 bubbled through the solution until a slightly blue colour appeared. The solution was raised to room temperature, shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate.
The resulting organic phase gave, after· evaporation in vacuo of the solvent therefrom, 1.4 g of the title compound.
2.05 and 2.08 5 (two s, 2CH3C0) , 3.03 δ (dd, Jgem= 17H2, Jvic cis a 5.5Hz, C-3-Ηα),
3.50 δ (dd, Jgem a 17H?, Jvic trans =
3Hz, C-3-Ηβ), 3.90 δ (s, CBgO), 4,82 (d, Jvic = 6.5Hz, CH,-C= ), 4.90 δ (s, 2 I (H)
CH2~C=) , 5.32 δ (dd, Jvic = 5.5 and 3Hz, C-4-H), 6.47 δ (t, Jvic = 6.5Hz,. t=C-C(H,).
I 2
H
1830 on”l β-lactam C=0 1750 cm-! esters C=0 1715 cm-1 amide C=O
EXAMPLE 4
- (l—acetmcywethyl—J-'acetgxy-l-pr'c^eiaylthi'O) -l-methoxyoxalyl-azetldih-2—one (5)s R=CH3, R'=H, X=Y=CH2O.CO.CH3, n=0
A solution of 1.4 g of the compound prepared in Example 3 in 10 ml of anhydrous dimethylformamide was cooled to -25°C and 0.9 ml of phosphorus tribromide were added. After 10 minutes the mixture was diluted with ethyl acetate and washed twice with a saturated
4-9407
- 15 solution of sodium bicarbonate. After drying the solution over anhydrous sodium sulphate and evaporating the solvent therefrom, 0.9 g of the title compound were obtained.
PMR (CDC13) : 2.07 δ (a, 2CH3CO), 3.17 δ (dd, Jgem = 19Hz,
Jvic trans = 3.5Hz, C-3-H0), 3.65 δ (dd,
Jgem = 19Hz, Jvic cis = 5Hz, C-3-Hx),
3.90 δ (s, CH3O), 4,73 δ (d, Jvic = 6.5 Hz, CH2-C=), 4.88 δ (broad s, CH2~f=), (H)
.52 δ (dd, Jvic = 5 and 3.5Hz, C-4-H),
6.25 δ (t, Jvic = 6.5Hz, =C-C(H_).
I —
IR (CHC13) ·. 1815 an-1 8-lactam C=0 1745 can1 esters C=0 1710 cm1 amide C=0
EXAMPLE 5
- (l-aoetoxymethyl-3-a'oetoxy-l-propenyl thio) -azeti dln-2-one (6): R'=H, X=Y=CH2O.CO.CH3, n=0
1.5 g of the compound prepared in Example 4 were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the methanolic solution evaporated to give 0.8 g of the title compound.
PMR (CDC13) : 2.25 δ (8, 2CH3CO), 2.98 δ (dd, Jgem =
15Hz, Jvic trans = 2Hz, C-3-Ηβ), 3.486
- 16 (dd, Jgem = 15Hz, Jvic cis = 4.5Hz, C-3-Ηα)
4.78 δ (d, Jvic = 7Hz, CH2~C=), 4.87 (H) (s, CH2-C=), 5.03 δ (dd, Jvic = 4.5;and 2Hz, C-4-H), 6.02 δ (t, Jvic = 7Hz, =C-C(H2)), 7.13 δ (broad, N-H).
H
IR (CHC13) : 1770cm-1 β-lactam C=0
1740 cm 1 esters C=0.
EXAMPLE 6 β- (l-acetoxyTnethyl-l-acetOxy—l-propfenylSuTphihyl) -azetidin—2-one.
(6): R'=H, X=Y=CH2O.CO.CH3,· n=l
0.800 g of the compound prepared in Example 3 were dissolved in 80 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the solvent was evaporated off. 0.5 g of the title compound were obtained PMR (CDC13) ; 2.13 6 (s, 2CH3CO), 3.0-3.3 δ (m, 2 protons at C-3), 4.70 δ (m, C-4-H), 4.88 δ (d, Jvic = 6Hz, CH2-C=), 4.93 δ (s, (H) ch2-c=)
6.53 δ (t, Jvic = 6Hz, =C.-C(H2)), H
IR (CHC13)
7.23 δ (s, NH).
1790 cm-1 β-lactam C=0 1745 cm 1 esters C=0,
- 17 EXAMPLE 7
4B-acetylglycolloylthlo-i-acetoxymethoxyoxaly,l-azetidln-2-one.
(13) : R=X=CH2O.CO.CH3, R'=H
0.8 g of 48-(l-acetoxymethyl-3-acetoxy-l-propenylthio)-1- (l-acetoxymethoxycarbonyl-2-methyl-l-propenyl) -azetidin-2-one were dissolved in 80 ml of dichloromethane and cooled to -78°C. A flow of ozone in oxygen was bubbled through the solution until a blue colour appeared. The solution, after shaking with an aqueous solution of sodium pyrosulphite, was dried over anhydrous sodium sulphate.
The solvent was removed by evaporation to give 0.45 g of the title compound.
PMR (CDC13) : 2.10 ana 2.13 δ (two S, 2CH3CO), 3.2C δ (dd, Jgem = 17Hz, Jvic trans = 3.5Hz, C-3-H8), 3.77δ (dd, Jgem = 17Hz, Jvic cis = 5.5Hz, C-3-Ho), 4.73 δ (s, -CO-CH2~ -0C0-), 5.73 δ (dd, Jvlcs5.5 and 3.5Hz, C-4-H), 5.87 δ (s, COO-CH2-OCO).
EXAMPLE 8
4g-ao&tylglypollcyli±.lci-;azet-ldin-2-cine (14) : R’=H, X=CH2O.CO.CH3
0.6 g of 48-acetylglycollqylthio-l-methoxyoxalyl-azetidln-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the resulting solution gave, after evaporation of the solvent therefrom, 0.35 g of the title compound.
A- 9 4.0 7
- 13 PMR (CDC13) s 2.20 δ (s, CHjCO) , 3.03 δ · (dd, Jgem = 16Hz,
Jvic trans = 2.5Hz, C-3-H8), 3.50 δ (dd,
Jgem = 16Hz, Jvic cis = 4.5Hz, C-3-Ηα),
4.77 δ (s, -C0-CH2-0C0-),'5.32 δ (dd, Jvic =
4.5 and 2.5Hz, C-4-H) , 6.40 δ (broad s, NH) .
EXAMPLE 9 e~(1-acetoxymethyl—3^acetoxy-l-propenyl'tai'io)-1-(1- ace toxyme thoxycarbonyl-1—hydroxymethyl·) —a'zte tidin--2-one.
(7): R'=H, R=X=Y=CH2O.CO.CH3, n=0 10 0.7 g of ace toxyme thy 1 glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting solution was refluxed for 20 minutes through a Dean-Stark apparatus.
After cooling to 5O°-6O°C, 0.7 g of the compound prepared in Example 5 dissolved in 10 ml of benzene were added and the resulting solution was refluxed for 2 hours.
The title compound was obtained in almost quantitative yield and can be used as crude mixture for the next step.
A pure sample was obtained by preparative TLC, for analytical purposes.
PMR (CDC13) : 2.07 δ (s, 3CH3CO), 2.97 δ (dd, Jgem = 18Hz, Jvic trans = 2Hz, C-3-HB), 3.40 S (dd, Jgem = 18Hz, Jvic cis = 4Hz, C-3-Ηα), 4.70 δ (d, Jvic = 6Hz, CH2-C=), 4.77 δ (s, CH2~£=), 5.025
.4 δ (¢, C-4-H) and -N-CH-COO-), 5.77 δ 0(H) (s, -COO-CH2-OCO-), 6.12δ(t, Jvic = 6Hz, =C-C(H,)) .
I 2 H
-49407
- 19 EXAMPLE ΙΟ · β- (l-acetoxymethyl-3-aofetoxy-l-propenylthio) -1- (1-acetoxyme thoxycarbonyl-l-Chloriatiethyl-) -azetidin-2 -one.
(8) : R'=H, R=X=Y=CH2O.CO.CH3,· n=0
0.6 g of the compound prepared in Example 9 dissolved in ml of tetrahydrofuran were cooled to 0°c. 0.115 ml of pyridine and 0.104 ml of thionyl chloride were added and the mixture was left under stirring for 10 minutes, lhe insoluble material was filtered off and the solution was evaporated in vacuo at room temperature to give the title compound in high yield. A sample was purified on preparative TLC for analytical purposes, but the crude mixture can be used without purification for the next step.
PMR (CDClg) : 2.14 δ (s, JCHjCO) , 3.10 δ (dd, Jgem = 15.5
Hz, Jvic trans « 2Hz, C-3-Ηβ), 3.55 δ (dd, Jgem = 15.5 Hz, Jvic cis = 5Hz, C-3-Ha),
4.77 δ (d, Jvic=6.5Hz, CH2~C=), 4.83 δ {b, (H)
CH2-C=), 5.4-5.9 δ (jn, C-4-H) and -N-CHC1-C00-), 5.88 δ (s, -COO-CH2-OCO-), 6.13 δ (t, Jvic = 6.5Hz, =C-C(H_).
I 2 H
EXAMPLE 11
4 β- (l-acetoacymethyl-3-acetoxy-i-propenylthio) -1-(1-acetoxymethoxycarbonyi-l-trlphenylphosphoranyliden'emethyl) -azetidin-2-one (9) : R'=H, R=X=Y=CH2O.CO.CH3, n=0
- 20 A solution of 0.430 g of the confound prepared in Example 10 in 5 ml of tetrahydrofuran and 5 ml of dioxan containing 0.520 g of triphenylphosphine and 0.08 ml of pyridine was stirred overnight at 50°C. The resulting phosphorane was purified by column chromatog’raphy on silica gel eluting with 70:30 by volume dichloromethane: ethyl acetate. 0.400 g of the title compound was obtained. PMR (CDC13) : 2.05 6 (s, 3CH3CO), 4.70 5 (d, Jvic = 6.5Hz,
CH2-C=), 4.73 fi (s, ΟΗ2-ς=), 5.77 δ (ε, (Η)
-COO-CH2-OCO-), 5.90 δ (t, Jvic - 6.5Hz, =C-C(H2)), 7.1-8.0 6 (m, 3CgH5).
H
EXAMPLE 12 β-acetylglycolloylthio-l- (l-a'cetoxymethoxycarbonyl-'l-triphenylphosphoranylideneinethyl')-aze'ti'din-2-one.
(11): R'=H, R=X=CH2O.CO.CH3
0.7 g of the compound prepared in Exanple 11 were dissolved in 40 ml of dichloromethane and, after cooling to -20°C, 50 ml of a 10% solution of trifluoroacetlc acid in dichloromethane were added. After a few minutes, a flow of ozone in oxygen was bubbled through the solution at -20°C until a slightly blue colour appeared.
At this point, the reaction was stopped and few drops of trimethylphosphite were added. The organic solution was washed with a saturated solution of sodium bicarbonate and dried over anhydrous sodium sulphate. The solvent was
- 21 evaporated off to give 0.550 g of the title compound.
PMR (CDC13) : 2.10 and 2.15 δ (two d, 2CH3CO), 4.72 ί (s, -CO-CH2-OCO-), 5.64 δ (s, -C00-CH2-0C0), 7.1-8.0 6 (m, 3CgHs).
EXAMPLE 13 acetoxymethyl (SR) -2-acetoxymethyl-2-penem-3-carboxylate.
(1) R'=H, R-X=CH20.C0.CH3, h=0
0.7 g of the compound prepared in Example 12 were dissolved in 30 ml of dry toluene and refl uxed for 2 hours. The reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by a short column chromatography on silica gel, eluting with 97:3. by volume dichloromethane:ethyl acetate, to give 0.250 g of the title compound.
PMR (CDC13) : 2.11 and 2.13 δ (two s, 201/20), 3.49 δ (dd, Jgem = 16.5Hz, Jvic trans = 2Hz, C-6-H8), 3.86 δ (da, Jgem = 16.5Hz, Jvic cis = 3.8Hz, C-6-Ηα), 5.12 and 5.45 δ (two d, Jgem - 15.5Hz, =φ-ϋΗ2), 5.68 δ (dd,
Jvic = 3.8 and 2Hz, C-5-H), 5.87 δ (s, -COO-CHj-OCO-).
IR (CHCIJ : 1800 cm-1 8-lactam C=0
1750-1725 cm-1 esters C=0.
U.V. (EtOH): Xmax 325 nm.
MS : m/e 315.04108 (M+) calculated for C12H13N °7s 315.04127.
EXAMPLE 14 β- (l-acetoxymeth.yl-3-acetoxy-l-propenylthio)-1- (1-p.hltrcben zyloxycarbonyT-i-hyaroxymethyl)-azetidih-2-one.
(7) : R'=H, R=£.NO2.CgH4.CH2, X=Y=CH2O.CO.CH3, n=0
The title compound was obtained following the procedure described in Example 9, using'p-nitrobenzyl glyoxylate (freshly prepared by ozonolysis of p-nitrobenzyl fumarate) instead of acetoxymethyl glyoxylate. Quantitative yield. PMR (CDC13)5 : 2.1 (s, 6H); 2.8-3.7 (m, 2H); 4.7-4.9 (m,
5H); 5.1-5.6 (m, 2H); 5.2 (m, 1H); 6.1 (m, 1H); 7.5-8.3 (m, 4H).
EXAMPLE 15
4β - (1-ace toxyme thy 1-3-Acetoxy-l-propeny.lthio) -1- (1-p. nitrobenzyloxycarbc«iyl-l-chlorOme'thyI)-azetldih-2-ione.
(8) : R*=H, Rn=£,NO2.C6H4-CH2, X=Y=CH20.C0.CH3, n=0
The title compound was obtained following the procedure described in Example 10, but using the compound prepared in Example 14 instead of that prepared in Example 9.
PMR (CDC13) «5: 2.1 (s, 6H); 2.8-3.7 (m, 2H); 4.7-4.9 (m,
4H); 5.2-5.4 (Κι, 1H) ; 5.4 (m, 2H) ; 6.1-6.3 (m, 2H); 7.5-8.4 (m, 4H).
EXAMPLE 16
4β-{ 1-acetoxymethy 1-3-acetoxy-l-propenylthio) -1- (1-p.nitroben zyloxy carbonyl-1-triphenyiph'o'sphorany li cteneme thyi) -azetidin-2-one.
(9): R'=H, R=£.NO2.CgH4.CH2, X=Y=CH20.CO.CHj, h=0
4»4β7
- 23 The title compound was obtained following the procedure described in Example 11, but using the compound prepared in Example 15 instead of that prepared in Example 10.
EXAMPLE 17 β-acetylg lycolloylthiO-l-.( l-£.nitrobenzyloxycarbonyl-l-triphenylphosphorahylideneme'thyT)-azetidin-2-one.
(11): R’=H, R=£.NO2.CeH4.CH2, XeCHgO.CO.CHg
The title compound was obtained following theprocedure described in Example 12, but using the compound prepared in Example 16 in place of that prepared in Example 11.
EXAMPLE 18
£.nitrobenzyl (5R)-2-a.cetoxymetbyl-2-penem-3-carboxylate.
(1) R'=H, R=£.N02.C6H4.CH2, X=CH2O.CO.CH3, n=Q The title compound was obtained following the procedure described in Example 13, but using the compound prepared in Example 17 instead of that prepared in Example 12.
PMR (CDCl3)fi : 3.75 (1 H, dd, J = 2.3Hz, 16.8Hz, H-6a);
3.87 (1 H, dd, J = 3.6Hz, 16.8Hz, H-68);
.14 (1 H, d, J - 15.8, =C-CH2O-); 5.50 (1 H, d, J = 15.8Hz, =C-CH2O), 5.71 (1 H, dd, J = 2.3Hz, 3.6Hz, H-5).
L aJv + 87° ( c=l. 2 CHC13) .
R. (CHC13) : 1800 ι (8-lactam), 1750 and 1720 V. (EtOH) : 265 (e11000) and 322 fc 7000) nm S. : m/e 378 (M+) P· 122°-123 °C.
- 24 49 407
EXAMPLE 19 (5R ) - 2- ace toxyme thyl -2-pen ein-3-carb oxy 11 c acl d.
(1) R'=R=H, X=CH2O.CO.CH3, n=O
200 mg of the compound prepared In Example 18 were dissolved in 12 ml of ethyl acetate. 8 ml of 0.2 U sodium bicarbonate solution and 400 mg of 10 percent palladium-on-charcoal were added and the resulting two phase mixture was shaken under hydrogen for 60 minutes. After filtering off the catalyst, the aqueous phase was acidified with 20 ml of 5 .percent aqueous citric acid and extracted three times with dichloromethane, The organic layers were dried over anhydrous sodium sulphate and evaporated to give 60 mg of the title compound.
I.R. (CHC13) : I79o (βlactam), 1735 and 1700 cm-1.
U.V. (EtOH) : 300 nm
EXAMPLE 20
48-( l-hydroxymethyl-vinylsulphfnyl)-l-(lrtnethoxy carbonyl-2-methyl-allyl )-azetidin-2-o'n'e (3): R=CH3, R'=Y=H, X=CH20H g of methyl penicillanate S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol for 8 hours. After evaporating off the solvent in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane : ethyl acetate (1:1 by volume).
2.8 g of the title compound were obtained.
PMR (CDC13) 6: 1.96 (bs, 3 H, C-CHg); 2.91 and 3.35 (dd,
2H, J - 2Hz, 5Hz, 15Hz, CO-CHg-CH-S); 3.78 (s, 3 H, COOCHg); 4.36 (bs, 2 H, OHgOH); 4.90-5.25 (m, 3 H, CH-COOCHg,C-C=CH2); 5.35 (m, 1 H, CH2-CH-S); 5.88 (s, 2 H, VB^C-S).
EXAMPLE 21
6( l-hydroxymethyl-vinylsulphinyl)-l-( l->ne th'oxy carbonyl-2-tnethyl-l-propenyl)-azetidin-2-one.
(4): R=CHg, R'=Y=H, X’CHgOT
3.0 g of the compound prepared in Example 20 were dissolved in 100 ml of dichloromethane and left at room temperature for a few hours. After evaporating the solvent from the solution, the residue consisted of the title compound in pure form. Quantitative yield.
PMR (CDClg) δ : 2.08 (s, 3 H, = 0-¾); 2.18^, 3 H, =C-CH3) ;
2.7-3.6 (m, J 2Hz, 16Hz, CO-CHg-CH-S);
3.78 (s, 3 H, COOCHg); 4.35 (s, 2 H, CHgOH);
.32 (m, 1 H, CT-S); 5.90 (bs, 2 H, =¾).
EXAMPLE 22
46-( T-bromomethyl-vinyittiio)-l~A~methoxycarbohyl-2-inethylil-propenyl)-azetidin-2-one (12): R=CH3, R'=Y=H, X=CH2Br
1.8 g of the compound prepared in Example 21 were dissolved in 40 ml of dimethylformamide and cooled to -20°C. 0.7 ml of pyridine and 3.0 ml of phosphorus tribromide were added and the mixture was left for 15
- 26 4-9 4 0*7 minutes under stirring. Ethyl acetate was added and the organic layer was shaken with a saturated solution of sodium bicarbonate, washed with water and then dried over anhydrous sodium sulphate to give, after evaporating off
the solvent, 1 .6 g of the title compound. PMR (CDClg) δ : 2.04 (s, 3 H, =zCH3); 3.24 (dd, J = 2.9, 5, 2.24 (s, 3 fl =^ch3); 16Hz, 2 H, 0 1 C-CHg-CH); 3.75 (s, 3 H, OCHg); 4.02 (s, 2 H, CHgBr): 5.24 (bs, , 1 H,=CH); 5.37 (dd, J = 2.8Hz, 5 Hz, 1 H, CHg-CH-S); 5.60 (bs, 1 H, «CH). EXAMPLE 23
8-/1-(l-methyl-lH-tetrazol-5-yl-thiomethyl)-vinylthio/-I-(l-methoxycarbonyl-2-methyl-l'-propenyl)-aze'tidin-2-one
N—N
II 11 (12): R=CH3, R'=Y=H, x=ch2s-K n
1.4 g of the compound prepared in Example 22 were dissolved in 25 ml of tetrahydrofuran and cooled to 0°C.
0.8 g of l-methyl-5-mercapto-tetrazole sodium salt were added and the mixture was left under stirring for three hours at room temperature. After filtering off the insoluble matter, the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium qflifofe and evaporated to dryness. The residue consisted of 2.0 g
- 27 of the title compound in pure form.
PMR (CDClg) δ : 2.00 (s, 3 H, =C-GHg); 2.22 (s, 3 H,
-C-CHg); 2.70-3.80 (m, 2 H, J = 2Hz, 5Hz, 15Hz, CO-CH2-CH-S); 3.72 (s, 3 H, COOCHg); 3.95 (s, 3 H, N-CHg); 4.10 (s, 2 H, CT2~S); 5.18 (bs, 1 H, S-C-CH); 5.36 (», 1 H, CH2-CH-S); 5.57 (bs, 1 H, S-C=C-H).
EXAMPLE 24
46-/^1-me thy.l-.l-H-tetraZQl-5.-y.l-.th.io ) -acetylthio/-1-me thoxyoxalyl-azefi din-2-one.
N—N
K (13): R=CH3, R'=H, X=CH2S-4 N . I .CHg
1.8 g of the compound prepared in Example 23 were dissolved in 200 ml of dichloromethane and cooled to -78°C. A flow of ozonized oxygen was bubbled through the solution until a blue colour appeared. A few drops of trimethylphosphite were added and the mixture was raised to room temperature. Removal of the solvent by evaporation gave 1.3 g of the title compound.
PMR (CDClg) δ: 2.9-3.7 (m, 2 H, COCHgCH S); 3.85 (s, 3 H,
COOCHg); 3.98 (s, 3 H, H-CTg); 4,35 (s,
H, CHgS); 5.75 (m, 1 H, CHgCH S).
EXAMPLE 25
4g -ffd -me thy l-l-H-tetrazol-5-yl-thio) -acetylthio/-azetidin-2-one.
- 26 10 (14). χ,
1.2 g of the compound prepared in Example 24 were dissolved in a 1:1 by volume ethyl acetate:methanol mixture and a few grams of silica gel were added under vigorous stirring. After one hour the insoluble matter was filtered off and the solution was evaporated in vacuo. The title compound was crystallized from methanol:diethyl ether: 0.6 g were obtained.
EXAMPLE 26
8-2(’l-methyl-l-H-.tetrazo.l-5-y.l-.thi.o) -acehylthio/-1-( l-acetoxymethOxycarbon'yT-T-hy'drox'yMethyl)-azetidi'n-2-one.
(15)
R'=H, h=ch2o.co.ch3,
CH,
1.5 g of the compound prepared in Example 25 were refluxed in 50 ml of benzene with 1.2 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymetbyl fumarate). The reaction was complete after 3 hours. The crude oil obtained after evaporating off the solvent can be used for the next step without further purification. A sample was purified on TLC for spectroscopic data.
PMR (CDC13) δ; 2.05 (s, 3 H); 2.7-3.8 (m, 2 H); 3.95 (s, 3 H); 4.30 (s, 2 H); 5.40 (s, 1 H);
- 29 5.50 (ta, 1 H); 5.80 (β, 2 Η).
EXAMPLE 27 ¢5-/( l-methyl-l-H-tetrazol-5-.yl-thio) -acetylthio?
-1-( 1-acet oxymeth oxy carbonyl-l-ch lorolne thy1)-azeti di n-2-one (16): B'=H, B=CH2O.CO.CH3, X^CHgS
CH
The oil obtained from the last preceding Example was dissolved in anhydrous tetrahydrofuran (20 ml) and treated at 0°C with equimolar amounts of pyridine and thionyl chloride until all starting material had disappeared. After filtering off the insoluble matter, the filtrate was used immediately for the next step.
EXAMPLE 28
46-/(1-me thy.l-.l-B-tetrazol-5-yl-.thi4-acetylthio/
-1- (l-acetoxymethoxycarbonyT-T-triphenylphosphoranylideneffiethyl)-aze t i din-2-ohe.
N
CH
To the filtrate obtained in the last preceding Example were added 800 mg of triphenylphosphine and 0.4 ml of pyridine. The resulting mixture was heated to 60°-70°C and maintained at that temperature for a few hours. The
- 30 phosphorane was purified on silica gel eluting with dichloromethane:ethyl acetate (1:1 by volume).
EXAMPLE 29 acetoxymethyl (5R)-2-'(T-methyl-i'-B-tetrazol-5-yl-thioroe thy l)-2-penem-3-carbdxy late.
jy.,.
(1): R'=H, R=CH2O.CO.CH3, X=CH2S
Ν'
I ch3
0.500 g of the compound prepared in Example 23 were dissolved in 30 ml of toluene. The solution was heated to 100°C and maintained at that temperature for two hours.
The title compound was purified from triphenylphosphine oxide by short column chromatography on silica gel eluting with dichloromethanezethyl acetate (8:2 by volume).
PMR (CDClg)S : 2.15 (s, 3 H, COCHg); 3.30-4.03 (m, J =
4Hz, 2Hz, -CH2-(6); 3.97 (s, 3 H, -NCHg); 4.56 (d, J = 14Hz, 1 H,’HCH-S); 4.84 (d,
J = 14Hz, 1 H, HCH-S), 5.65 (dd, J = 4Hz
2Hz, 1 H, H-5a); 5.88 (s, 2 H, COOCHgO).
EXAMPLE 30 (5R)-2-(1-methyl-l-H-tetrazol-5-yl-thiomethyl) -2-penem-3-carboxylic acid.
N-N
D 11 (1): R'=R=H, X=CH2S_I( Ν , n=0
N
I
CH_
- 31 The title compound was prepared by catalytic reduction of £.nitrobenzyl (5R)-2-(l-methyl-l-H-tetrazol-:5-yl-thiomethyl)-2-penem-3-earboxylate, obtained by a process substantially as described in Examples 20 to 29 but using £.nitrobenzyl glyoxylate instead of acetoxymethyl glyoxylate. The catalytic reduction was effected following the method described in Example 19.
I.R. (CHC13) : 1800 ( 3 lactam), 1750 and 1720.
EXAMPLE 31 methyl 6a-(1'-hydroxyethyl)-penicillinate-S-oxide.
A solution of methyl, penicillinate S-oxide (2.3 g) in 50 ml of anhydrous tetrahydrofuran was cooled to -78°C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6 M solution of butyl lithium in hexane) dissolved in anhydrous tetrahydrofuran was added and the mixture left at -78°C for 10 minutes.
ml of acetaldehyde were then added and the mixture was stirred for 15 minutes. The reaction was then quenched with a saturated aqueous solution of ammonium chlorider extracted with ethyl acetate, washed twice with water and dried over anhydrous sodium sulphate.
After evaporating off the solvent the residue was
- 32 shortly purified by column chromatography on silica gel eluting with dichloromethanesethyl acetate (1:1 by volume). 1.5 g of the title compound were obtained consisting of a 2:3 mixture of epimers at the hydroxyl 5 bearing carbon based on the PMR, being the newOg-Cg bond only in the o position because of the stereospecificity of the reaction in the used conditions.
PMR (CDC13) δ : 1.27 (e, 3 H, 0-¾); 1.40 (d, 3 H, J c 5.7Hz, ch3-choh) major isomer? b48 (d, 10 ·3 H, J = 5,7Hz, CHg-CHOH) minor isomer?
1.70 (s, 3 Η, β-0Η3Η 3,4-3.8 (m, 18, H-6); 3.80 (S, 3 H, C0OCH,3)i 4.Ir4.7 (jn, 1 H, CHOH); 4.50 (s, 1 H, H-3)? 4.98 (d, J = 1.9Hz, 1 Η,' H-5) minor isomer; 5.05 (d, J = 1.9Hz, 1 Η,' H-5) major isomer.
- 33 49 4 07
EXAMPLE 32 methyl €-(l-hydroxyethyl)-3-penicillanate
To a solution of 2.2 g of methyl pencillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium diisopropylamide was added at -78°C under nitrogen. An excess of acetaldehyde was dropped in and the mixture was stirred for 5 minutes. The reaction was then quenched with a trace of acetic acid; the
IO mixture was poured into water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.8 g of the title compound,
EXAMPIE 33 methyl 6- Cl-p-nltrobenzyloxycarbonyloxyethyl) -3-penicillante.
1.2 g of methyl 6-(1-hydroxyethyl)-3-penicillanate, prepared as described in Example 32,were dissolved in 40 ml of tetrahydrofuran cooled to -78°C and treated with one equivalent of butyl lithium. 1.2 equivalents of g-nitrobenzyloxycarbonyl chloride were added to the mixture. After 30 minutes at -78°c, the reaction mixture was left at room temperature for 60 minutes, poured into water and extracted with dichloromethane. 1.4 g of the title compound were obtained after drying over anhydrous sodium sulphate and evaporating off the solvent.
- 34 EXAMPLE 34 me thyi 6- (l-p-nltrobenzyloxycarbonyloxyethyl-3-pen i cl 11 an a te -S - oxide (2): R=CH3, R'=CH3CH.O.C.OCH2 θ N02
1.8 g of methyl 6-/T-p-nitrobenzyloxycarbonyloxyethyl7-3-penicillanate, prepared as described in Example 33, were dissolved in 50 ml of dichloromethane and treated at 0°c with 1.5 equivalents of m-chlorcperbenzcfC acid. The organic phase was shaken with > saturated solution of sodium bicarbonate, extracted, dried over anhydrous sodium sulphate and evaporated: 1.4 g of the expected sulphoxide were obtained.
EXAMPLE 35 β- (1-ace t oxyme thy 1-3- ace toxy- 1-prop'enyis ttlphihyl) -315 - (l-p-nltrobenzyioXycarbonyiOxyethyl'l'-l-'Cl-methoxycarbonyl-2-methyl-allyl)-azetrdin-2-one • I
C3) : R=CH3, R' =CH3CH.0.C.0CH2 /o) N02, X=Y=CH20.C0.CH3 a solution of 2.0 g of the compound prepared in Example 34 and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography eluting with 9:1 by volume dichloromethanesethyl acetate
1.1 g of the title compound were obtained.
- 35 EXAMPLE 36
Β-(l-acetoxymethyl-3-acetoxy-l-propenylsulphlnyl)-3~ (l-p-nitrobenzyloxycartohyioxvethvl) -l-n-methnvyr-aH-^nu:-2-methyl-l-propenyl)-azetldlh-2-ohe !
(4) s R=CH3, R' =CH3CH.O.C.CXB2 N02, X=Y=CH2O.CO.CHg
1.3 g' of the conpound prepared in Example 35 were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture was left at room tenperature for 2 hours. The title conpound was obtained in pure form in quantitative yield by evaporating off the solvent.
EXAMPLE 37
- Cl-acetoxymethyl-3-acetoxy-l-propenylsulphiny 1) - 3- (1-p-ni troben zy loxycarbony loxye thyl) -T-mipthoxy ox aly 115 -aze tidin-2-ohe
Ϊ (5): R=CH3, R'j=CH3CH.O.C.OCH2^o^ NOj, X=Y=CH20. C0.CH3, n=l
A solution of 1.1 g of the conpound prepared in Example 36 in 100 ml of dichloromethane was cooled to -78°C. Ozone in oxygen was then bubbled through the solution until a blue colour appeared. The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. 0.5 g of the title conpound were obtained after evaporation off of the solvent, ί
- 36 EXAMPLE 38
8- (1-acetoxyme thy 1- 3-acetoxy-l-propeny lthl'o') -3-f 1-p-nitrobenzyloxycarbonyloxyethyl)-l-methoxy'Qxalyl-azetidln-2-one.
(5): R=CH3, R'=CH3CH.O.C.OCH2/o\ N02, X=Y=CH2O.CO.CH3,
-»=O
A solution of 0.8 g of the compound prepared in Example 37 in 15 ml of anhydrous dimethylformamide' was cooled to -20°C and 0.6 ml of phosphorus tribromide were added. The reaction mixture was diluted with ethyl acetate after 10 minutes and washed twice with a solution of sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate and the solvent was then evaporated off giving 0.4 g of the title compound.
EXAMPLE 39
48-( 1-ace toxymethy 1-3-acetoxy-T—propenylthio) -3- (1-p-ni troben zy 1 oxy carbony loxyethyl) - azeti dih-2-one
ΛΛ (6): R’=CH3CH.0.C.0CH2 (o) N02, X=Y=CH20C0.CH3, n=u
1.2 g of the compound prepared in Example 38 were dissolved in methanol and 2 g of silica gel were added to the solution. After 60 minutes the insoluble matter was filtered off and .the .organic phase was evaporated:, a short column chromatography afforded 0.4 g of the title compound.
- 37 EXAMPLE 40
48- (l-acetoxymethy 1-3-acetoxy-l-propenylthlo) -3-( 1-p-nltrobenzyloxycarbonyloxyethyl) -1- (1-acetoxyroethoxycarbonyl-l-hydroxymethvl)-azetldlh-2-one.
(7): R' =CH3CH.O.C.OCH2
°·€ g of the compound prepared in Example 39, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozcncfysis of diacetoxymethyl fumarate), were refluxed together. The reaction was completed after two hours. The condensation product can be used for the next step without further purification.
EXAMPLE 41
8- (l-acetoxymethyl-3-acetoxy-l-propenylthio) -3-(l-p-nltrobenzyloxycarbonyloxyethyl) -1-( 1-acetoxymeth oxycarbonyl-l-chloromethyl)-azetldln-2-one.
j (8): R’ =CH3CH.O.C.OCH2^ NOj, R =X=Y=CH20.CO.CH3, n=0 0.5 g of the compound prepared in Example 40 were dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to 0°C. 1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble matter was filtered off and the solvent was evaporated off at room temperature to give the title compound in nearly quantitative yield. The product can be used without further purification for the next step.
- 38 EXAMPLE 42
6-(l-acetoxyInethyl-3-acetoxy-l-propenylthio)-3-(l-p-nitroben^yloxycarbonyloxyethyl) -1- (acetoxymeth oxycarbonyl-1—trlphenylphosphoranyligenemethyl)-azetldin-25 one.
O ' I· (9)i.R' =CH3CH.O.C.OCH2 (o) N02, R =X=Y=CH2OCO.CH3, n=O A solution of 0.760 g of the compound prepared in Example 41 in 10 ml of tetrahydrofuran and 10 ml of dioxan was stirred overnight at 50°C with 2 equivalents of triphenylphosphine and 1.1 equivalents of'pyridine. The phosphorane was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane: ethyl acetate. 0.480 g of the title compound were obtained.
EXAMPLE 43
B-acetylglycoloylthlo-3-(1-p-nitrobenzyloxycarbonyloxyethyl) -1- (l-acetoxymethoxycarbonyl — l-tripheriylphosphoranylidenemethyl)-azetidin-2-one.
1 (11): R'=CH3CH.O.C.OCH2 (o> N02, R =X=CH2O.CO.CH3
0.45 g of the compound prepared in Example 42 were dissolved in 50 ml of dichloromethane and cooled to -20°C 30 ml of trifiuoroacetic acid dissolved in dichloromethane were added. After -a'few minutes ozone in oxygen was bubbled through the solution until a slightly blue colour appeared. The reaction was stopped and a few drops of trimethylphosphite were added. The organic
4®40T phase was washed with a saturated solution of sodiun bicarbonate and dried over anhydrous sodiun sulphate:
0.260 g of the title conpound were obtained.
EXAMPLE 44
4g- (l-acetoxymethyl-3-acetoxy-l-propenylthio)-3-(1-p-nltrobenzyloxycarbonyloxyethyl)-1-(methoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one.
s (12) . R=CH3, R'=CH3CH.O.C.OCH2^T> N02, X=Y=CH2O.CO.CH3
1.5 g of the compound prepared in Example 36 were dissolved in 10 ml of anhydrous dimethylformamide and cooled to -20°C.
0.8 ml of phosphorus tribromide were added, and the mixture was stirred for 10 minutes. It was then diluted with ethyl acetate and washed twice with a saturated solution of sodiun bicarbonate. The organic layer was dried oyer anhydrous sodiun sulphate and evaporation off of the solvent gave 1.1 g of the title compound.
EXAMPLE 45
B-acetylglycolloylthio-3-(1-p-nltrobenzyloxycarbonyloxyethyl)-1-methoxyoxalyl-azetidin-2-one.
• « ΛΑ (13) R=CH3, R'=CH3CH.O.C.OCH2 NOj, XCHjO. CO.CH3
1.4 g of the compound prepared in Example 44 in 120 ml of dichlorcmethane were cooled to -78°C. Ozone in oxygen was bubbled through the solution until a blue colour appeared. The solution was shaken with an aqueous
- 40 solution of sodinn pyrosulphite and dried over anhydrous sodium sulphate. Evaporation off of the solvent gave 0.8 g of the title compound.
EXAMPLE 46
4 8-^cetylglycolloylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one.
Ϊ r\ (14) : R'=CH3CH.O.C.OCH2 ςο) N02, X=CH2O.CO.CH3 0.800 g of the compound prepared in Example 45 were dissolved in 50 ml of methanol and a few grams of silica
1q gel were added. The mixture was left at room temperature for 60 minutes, and then the insoluble material was filtered off. The filtrate, after the solvent had been removed by evaporation, gave 0.300 g of the title compound.
EXAMPLE 47 g-acetylglycolloylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(l-aoetoxymethoxycarbonyl.—l-hydroxymethyl)-azetidin-2-one.
(15) : R'=CH3CH.O.C.OCH2 (0/ N02, 8 =X=CH2O.CO.CH3
0.5 g of the compound prepared in Example 46 and 0.5 g of acetoxymethyl glyoxylate in 30 ml of benzene were refluxed until the reaction was complete (two hours)-.
The title compound was obtained and can be used for the next step without further purification.
- 41 EXAMPLE ,48 <8-acety lglycolloylthio-3-(l-p-mtrobenzyloxycarbony loxyethyl) -1- (1-acetoxyroethoxycarbonyl —1-chloromethyl)-azetidin-2-one.
(16): R'=CH3CH.0.C.0CH2 N02, R =X=CH20. CO.CH3
0.35 g of the compound prepared in Example 47 were dissolved in 10 ml of anhydrous tetrahydrofuran at 0°C. 1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was stirred for 10 minutes. .The precipitate was filtered off and the filtrate, after evaporation off of the solvent, gave the title compound in quantitative yield. The crude product was used as such for the next step.
EXAMPLE 49
-a cetylglycQlloylthio-3- (1-p-nitrobenzyloxycarbony loxyethyl) -1- (1-ace toxymethoxy carbonyl *—l-trlphenylphosphoranylidenemethyl)-azetidln-2-one.
(11): R'=CH3CH.0.C.0CH2 ^o> N02, R =X=CH2O£O.CH3
0.400 g of the compound prepared in Example 48 were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and dioxan; 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture was efeirred overnight at 50°C. The title compound was obtained and was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.280 g of the
- 42 phosphorane were obtained.
EXAMPLE 50 acetoxymethyl (5R)-6- (1-p-nltrobenzyloxycarbonyloXyethyl)-2-acetoxymethyl-2-penem-3-carboxylate..
(1): R' =CH3CH.0.1.0CH2 NOj, R =X=CH20C0.CH3
0.210 g of the compound· prepared in Example 43or Example 49 were dissolved in 7 ml of toluene and the solution was refluxed for two hours. Purification by short column chromatography, eluting -with 95:5 by volume dichloro10 methane:ethyl acetate, afforded 0.050 g of the title compound.
EXAMPLE 51 acetoxymethyl (5R) -6- (1-hydroXyethyl) -2-acetoxymethyl-2-penem-3-carboxylate.
(1): R'=CH3CH.OH, R =X=Cfi20.C0.CH3
0.060 g of the compound prepared in Example 50 were poured into a water:ethanol:dipotassium monohydrogen orthophosphate mixture and hydrogenolysed with 10% palladiun-on-carbon. A quick purification by silica gel column chromatography gave 0.015 g of the title compound.
4940
- 43 EXAMPLE 52
Operating as described in the previous Examples, but employing 5-methyl-2-raercapto-l,3,4-thiadiazole, 5-mercapto-l,2,3-triazole or mercaptopyrazine instead of l-methyl-lH-5-mercapto-tetraaole, (5R)-2-(5’-methy1-1’,3’,4’
-thiadiazol-2 ’ -y 1-thiomethyl) -2-penem-3-carboxylic acid, (5R)-2-(l' ,2' ,3,-triazol-5-yl-thiomethyl)-2-penem-3-carboxylic acid, (5R)-2-(pyra2inyl-thiomethyl)-2-penem-3-carboxylic acid, (5R)-6-(1*-hydroxyethyl)-2-(5-methyΙΙΟ -1, 3, 4’,-thiadiazol-2-yl-thiomethyl) -2-penem-3-.
-carboxylic acid >(5R)-6-(l’-hydroxyethyl)-2-(l,2,3-triazol-5-yl-thiomethyl)-2-penem-3-carboxylic acid, (5R)-6-(1*-hydroxyethyl)-2-(pyrazinyl-thiomethyl)-2-penem-3-carboxylic acid were prepared.
Operating as previously described, but reducing the methyl 6-(1*-hydroxyethyl)-3-penicillinate following the widely known pr ocedure, the corresponding 6-ethyl-derivatives were obtained.
Claims (10)
1. A process for the preparation of a penem-carboxylic acid or ester of the general formula (1) (fi). S. CH 2 Z COOR wherein n is 0 or 1, R represents a hydrogen atoip, ah 1q alkyl group having from 1 tp 4 carbon atoms f 3 2,2(27 trichloroethyl, benzyl, acetpnyl, o-nit^pbepzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula - CH(CHg).OCOOCgHg or 15 CHgNHCORg wherein Rg represents an alkyl group having from 1 to 4 carbon atoms or a cycloalkyl or aryl group, Z represents a hydroxy, amino or carbamoyloxy group, or a group of the formula OR^ or OCOR^ wherein R^ represents an alkyl group having from 1 to 4 carbon 2. O atoms, and R' represents a hydrogen atom or an alkyl, alkoxy or hydroxyalkyl group, each of which has from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a p-nitrobenzyloxycarbonyl group, the process comprising 25 condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as herein defined with an acetylenic compound of the general formula XC=CY as herein defined, isomerising the resultant compound of the general formula 13) in basic conditions, converting the resultant azetidinone derivative of the general formula (4) into one of the general formula (11) by the steps of (a) ozonolysis of the 1-substituent of the formula CH COOR in solution at reduced temperature, (b) removal of the 1-substituent of the formula COOR resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR as herein defined by refluxing in a solvent, .(d) chlorination of the 1-substituent of the formula OH COOR introduced in step (c) by the action of a chlorinating agent, (e) conversion of the l-substituent of the formula \ pf C1 introduced in step (d) COOT _00R into one of the formula COOR by reaction with triphenylphosphine, (f) reduction of the 4g-(substituted vinylsulphinyl) group by the action of a reducing agent, and (g) ozonolysis of the double bond pf the group of the formula in solution at reduced temperature, the steps being carried out in the order (a),(b),(c),(d), 15 (e),(f),(g) or (a), (f), (b), (c), (d), (e), (g) or (f), (a) and (g) simultaneously, (b), (c), (d), (e), step (f) being carried out in acidic conditions if carried out after step (e), and cyclising the compound of the general formula (11) by heating it in an inert solvent at from 20 50°C to 140°C to obtain a compound of the general formula (1) in which n is 0, and optionally converting that-compound to one of the general formula (1) in which n is 1 by oxidation.
2. A process for the preparation of a penem-carboxylic 25 acid or ester of the general formula .(1) in which n, R' and R are as defined in claim 1 and Z represents - 47 a mercapto or pyridinium group or a group of the formula SR^ wherein R 3 represents an alkyl group having from 1 to 4 carbon atoms or a 5-methyl-l,3,4-thiadiazol-2-yl, 1-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl group, the process being according to claim 1 and further comprising converting the substituent X into a substituent of the formula wherein Z is as defined in this claim by a substitution reaction carried out at any stage in the process according to claim 1 after the condensation of the penicillanic acid E-oxide ester of the general formula (2) with the acetylenic compound of the general formula XC=CY.
3. A penem-carboxyl ic acid or ester of the general formula (1) in which n and R are as defined in claim 1, Z represents a carbamoyloxy or pyridinium group or a group of the formula OCOR^ or SR 3 wherein R^ is as defined in claim 1 and Rj is as defined in claim 2, and R‘ represents a hydroxyalkyl group having from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a p-nitrobenzyl4-94-07 - 48 oxycarbonyl group; or a pharmaceutically acceptable salt thereof.
4. A penem-carboxylic acid or ester according to claim 3 wherein R' represents a 1-hydroxyethyl or l-{p5 -nitrobenzyloxycarbonyloxy)-ethyl group,
5. (5R)-2-Acetoxymethy1-6-(1'^hydroxyethyli-S-penem-3-carboxylic acid.
6. (5R)-6-(1'-Hydroxyethyl-2-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-2-penem-3-carboxylic acid. 10
7. (5R)-6-(1'-Hydroxyethyl)-2-(5-methyl-l,3,4''-thiadiazol-2-yl-thiomethyl)-2-penem-3-carboxylic acid
8. (5R)-6-(1 *-Hydroxyethyl )-2-(1,2,3-triazol-5-yl -thiomethyl )-2-penem-3-carboxylic acid.
9. (5R)-6-{l'-Hydroxyethyl)-2-pyrazinylthiomethyl-215 -penem-3-carboxylic acid.
10. A pharmaceutical composition comprising a penem-carboxylic acid or ester according to any of claims 3 to 9, or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable 20 diluent or carrier.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE2339/84A IE49408B1 (en) | 1979-02-24 | 1980-02-20 | Azetidinone derivatives |
IE2340/84A IE49409B1 (en) | 1979-02-24 | 1980-02-20 | Azetidinone derivatives |
IE234184A IE49410B1 (en) | 1979-02-24 | 1980-02-20 | Azetidinone derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7906634 | 1979-02-24 | ||
GB7932591 | 1979-09-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE800338L IE800338L (en) | 1980-08-24 |
IE49407B1 true IE49407B1 (en) | 1985-10-02 |
Family
ID=26270697
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE338/80A IE49407B1 (en) | 1979-02-24 | 1980-02-20 | Antibacterial agents and beta-lactamase inhibitors |
Country Status (24)
Country | Link |
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AT (1) | AT368506B (en) |
AU (1) | AU535080B2 (en) |
CA (2) | CA1154010A (en) |
CH (2) | CH654831A5 (en) |
CS (1) | CS226010B2 (en) |
DE (1) | DE3006273A1 (en) |
DK (1) | DK159448C (en) |
ES (2) | ES488886A0 (en) |
FI (1) | FI75163C (en) |
FR (1) | FR2449690B1 (en) |
GB (1) | GB2043639B (en) |
GR (1) | GR73623B (en) |
HK (1) | HK74487A (en) |
HU (1) | HU182664B (en) |
IE (1) | IE49407B1 (en) |
IT (1) | IT1193922B (en) |
LU (1) | LU82192A1 (en) |
NL (1) | NL192265C (en) |
NO (1) | NO161000C (en) |
NZ (1) | NZ192949A (en) |
PT (1) | PT70849A (en) |
SE (1) | SE449489B (en) |
UA (1) | UA6041A1 (en) |
YU (1) | YU42964B (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5625110A (en) * | 1978-12-18 | 1981-03-10 | Bristol Myers Co | Antibacterial |
DE3121510A1 (en) * | 1980-07-04 | 1982-06-16 | Farmitalia Carlo Erba S.p.A., 20159 Milano | 6-Alkyl-2-subst. penems and process for their preparation |
JPS588084A (en) * | 1981-07-08 | 1983-01-18 | Takeda Chem Ind Ltd | (6r)-substituted-(5r)-penem-3-carboxylic acid derivative and its preparation |
EP0180252B1 (en) * | 1981-07-15 | 1989-04-26 | Sumitomo Pharmaceuticals Company, Limited | Process of preparing azetidinone compounds |
NL8204720A (en) * | 1981-12-11 | 1983-07-01 | Erba Farmitalia | METHOD FOR PREPARING OPTICALLY ACTIVE PENEM COMPOUNDS |
NO831160L (en) * | 1982-04-08 | 1983-10-10 | Erba Farmitalia | PREPARATION OF SUBSTITUTED PENEM DERIVATIVES |
PH21930A (en) * | 1982-11-16 | 1988-04-08 | Ciba Geigy Ag | 6-hydroxy-lower alkylpenem compounds,pharmaceutical composition containing same and method of use thereof |
DE3372968D1 (en) * | 1982-11-16 | 1987-09-17 | Ciba Geigy Ag | Heterocyclyl-thio compounds, process for their preparation, pharmaceutical compositions containing them and their use |
GB8300295D0 (en) * | 1983-01-06 | 1983-02-09 | Erba Farmitalia | Penem esters |
JPS59152387A (en) * | 1983-02-10 | 1984-08-31 | Shionogi & Co Ltd | Novel penem compound |
GB8321677D0 (en) * | 1983-08-11 | 1983-09-14 | Erba Farmitalia | Preparation of penems |
US4656165A (en) * | 1983-09-02 | 1987-04-07 | Ciba-Geigy Corporation | Aminomethyl penem compounds |
US4711886A (en) * | 1984-07-02 | 1987-12-08 | Merck & Co., Inc. | β-lactam derivatives as anti-inflammatory and antidegenerative agents |
US4761408A (en) * | 1984-11-02 | 1988-08-02 | Ciba-Geigy Corporation | Crystalline aminomethyl compound |
ES2058328T3 (en) * | 1987-02-11 | 1994-11-01 | Ciba Geigy Ag | BETA-LACTAM ACIDS BICYCLE CARBOXYLICS. |
US5364768A (en) * | 1987-07-07 | 1994-11-15 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of penems |
GB2206578B (en) * | 1987-07-07 | 1991-07-03 | Erba Carlo Spa | Process for the preparation of penems |
IT1286558B1 (en) * | 1996-02-27 | 1998-07-15 | Menarini Farma Ind | PROCESS FOR THE PREPARATION OF 2-HALOGENOMETHYL-PENEMS AND THEIR USE FOR THE PREPARATION OF ANTIBACTERIAL PENEMS |
JP3866298B2 (en) | 1997-12-29 | 2007-01-10 | リサーチ コーポレイション テクノロジーズ,インコーポレイティド | 2β-Substituted-6-alkylidenepenicillanic acid derivatives as β-lactamase inhibitors |
US6407091B1 (en) | 1999-04-15 | 2002-06-18 | Research Corporation Technologies, Inc. | β-lactamase inhibiting compounds |
US6720445B2 (en) | 2000-12-21 | 2004-04-13 | Beacon Laboratories, Inc. | Acetyloxymethyl esters and methods for using the same |
CA2454413A1 (en) | 2001-07-24 | 2003-03-13 | Alamx, L.L.C. | 7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors |
JP2005525399A (en) | 2002-04-04 | 2005-08-25 | アラムクス エルエルシー | Inhibitors of serine and metallo-β-lactamases |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LU77306A1 (en) * | 1977-05-09 | 1979-01-18 | ||
AU3796278A (en) * | 1977-07-13 | 1980-01-17 | Glaxo Group Ltd | Penams and azetidinones |
US4168314A (en) * | 1977-11-17 | 1979-09-18 | Merck & Co., Inc. | 6-(1'-Hydroxyethyl)-2-aminoethylthio-pen-2-em-3-carboxylic acid |
US4155912A (en) * | 1977-12-14 | 1979-05-22 | Bristol-Myers Company | 2-Methylpenem-3-carboxylic acid antibiotics |
JPS54117459A (en) * | 1978-01-20 | 1979-09-12 | Glaxo Group Ltd | Novel lactam compound |
EP0042026B1 (en) * | 1978-02-02 | 1986-01-08 | Ciba-Geigy Ag | 3,4-disubstituted azetidin-2-on compounds and process for their preparation |
EP0010358A1 (en) * | 1978-09-20 | 1980-04-30 | Glaxo Group Limited | Beta-lactam compounds, processes for their preparation, compositions containing them, intermediates of use in their preparation and methods for the production thereof |
JPS5625110A (en) * | 1978-12-18 | 1981-03-10 | Bristol Myers Co | Antibacterial |
EP0013067A1 (en) * | 1978-12-22 | 1980-07-09 | Beecham Group Plc | Bicyclic beta-lactam antibacterial agents, their use in pharmaceutical compositions, processes for their preparation and intermediates for use in such processes |
-
1980
- 1980-02-19 AT AT0091980A patent/AT368506B/en not_active IP Right Cessation
- 1980-02-19 AU AU55670/80A patent/AU535080B2/en not_active Ceased
- 1980-02-19 GR GR61228A patent/GR73623B/el unknown
- 1980-02-19 GB GB8005476A patent/GB2043639B/en not_active Expired
- 1980-02-19 NL NL8001012A patent/NL192265C/en not_active IP Right Cessation
- 1980-02-19 IT IT20021/80A patent/IT1193922B/en active
- 1980-02-19 FI FI800493A patent/FI75163C/en not_active IP Right Cessation
- 1980-02-20 DE DE19803006273 patent/DE3006273A1/en active Granted
- 1980-02-20 YU YU461/80A patent/YU42964B/en unknown
- 1980-02-20 IE IE338/80A patent/IE49407B1/en not_active IP Right Cessation
- 1980-02-20 PT PT70849A patent/PT70849A/en not_active IP Right Cessation
- 1980-02-20 CA CA000346011A patent/CA1154010A/en not_active Expired
- 1980-02-21 CH CH2794/84A patent/CH654831A5/en not_active IP Right Cessation
- 1980-02-21 CH CH1400/80A patent/CH651570A5/en not_active IP Right Cessation
- 1980-02-22 DK DK077580A patent/DK159448C/en not_active IP Right Cessation
- 1980-02-22 HU HU80420A patent/HU182664B/en not_active IP Right Cessation
- 1980-02-22 UA UA2886007A patent/UA6041A1/en unknown
- 1980-02-22 SE SE8001424A patent/SE449489B/en not_active IP Right Cessation
- 1980-02-22 NZ NZ192949A patent/NZ192949A/en unknown
- 1980-02-22 LU LU82192A patent/LU82192A1/en unknown
- 1980-02-22 NO NO800501A patent/NO161000C/en unknown
- 1980-02-22 FR FR8003938A patent/FR2449690B1/en not_active Expired
- 1980-02-22 CS CS801241A patent/CS226010B2/en unknown
- 1980-02-23 ES ES488886A patent/ES488886A0/en active Granted
- 1980-10-16 ES ES495977A patent/ES495977A0/en active Granted
-
1986
- 1986-01-14 CA CA000499579A patent/CA1212665B/en not_active Expired
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1987
- 1987-10-15 HK HK744/87A patent/HK74487A/en not_active IP Right Cessation
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