DK166387B - Penemestere, en fremgangsmaade til fremstilling heraf samt et farmaceutisk praeparat indeholdende disse - Google Patents
Penemestere, en fremgangsmaade til fremstilling heraf samt et farmaceutisk praeparat indeholdende disse Download PDFInfo
- Publication number
- DK166387B DK166387B DK005284A DK5284A DK166387B DK 166387 B DK166387 B DK 166387B DK 005284 A DK005284 A DK 005284A DK 5284 A DK5284 A DK 5284A DK 166387 B DK166387 B DK 166387B
- Authority
- DK
- Denmark
- Prior art keywords
- formula
- penem
- compound
- carboxylic acid
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- -1 Penem carboxylic acid esters Chemical class 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000012430 organic reaction media Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- YJRHGJZKRWGUTB-VFWDIBGWSA-N 2,2-dimethylpropanoyloxymethyl (5R,6S)-3-(carbamoyloxymethyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical group C(N)(=O)OCC=1S[C@H]2N(C=1C(=O)OCOC(C(C)(C)C)=O)C([C@@H]2[C@@H](C)O)=O YJRHGJZKRWGUTB-VFWDIBGWSA-N 0.000 claims description 2
- FZKGLCPKPZBGLX-ROXVQFJHSA-N acetyloxymethyl (5r,6s)-3-(carbamoyloxymethyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical group S1C(COC(N)=O)=C(C(=O)OCOC(C)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 FZKGLCPKPZBGLX-ROXVQFJHSA-N 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 231100000331 toxic Toxicity 0.000 claims 1
- 230000002588 toxic effect Effects 0.000 claims 1
- IKQNRQOUOZJHTR-UHFFFAOYSA-N 3-(carbamoyloxymethyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1C(COC(N)=O)=C(C(O)=O)N2C(=O)C(C(O)C)C21 IKQNRQOUOZJHTR-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000022362 bacterial infectious disease Diseases 0.000 description 4
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 4
- 125000005633 phthalidyl group Chemical group 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- IKQNRQOUOZJHTR-UWBRJAPDSA-N ritipenem Chemical compound S1C(COC(N)=O)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 IKQNRQOUOZJHTR-UWBRJAPDSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 208000015181 infectious disease Diseases 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
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- OOUSUFKQKJONBC-UHFFFAOYSA-N n-(chloromethyl)acetamide Chemical compound CC(=O)NCCl OOUSUFKQKJONBC-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- DUNKKIRUWZSMPT-RXMQYKEDSA-N (5r)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CS[C@@H]2CC(=O)N12 DUNKKIRUWZSMPT-RXMQYKEDSA-N 0.000 description 1
- 125000005869 (methoxyethoxy)methanyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-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
- CLMSHAWYULIVFQ-UHFFFAOYSA-N 3-bromo-3h-2-benzofuran-1-one Chemical compound C1=CC=C2C(Br)OC(=O)C2=C1 CLMSHAWYULIVFQ-UHFFFAOYSA-N 0.000 description 1
- 206010056519 Abdominal infection Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- YKPQQNQROSEMFQ-ROXVQFJHSA-N C(C)(=O)NCOC(=O)C1=C(S[C@H]2N1C([C@@H]2[C@@H](C)O)=O)COC(N)=O Chemical compound C(C)(=O)NCOC(=O)C1=C(S[C@H]2N1C([C@@H]2[C@@H](C)O)=O)COC(N)=O YKPQQNQROSEMFQ-ROXVQFJHSA-N 0.000 description 1
- PIWJFCFHQLEBSJ-VFWDIBGWSA-N C(N)(=O)OCC=1S[C@H]2N(C1C(=O)OCOCCOC)C([C@@H]2[C@@H](C)O)=O Chemical compound C(N)(=O)OCC=1S[C@H]2N(C1C(=O)OCOCCOC)C([C@@H]2[C@@H](C)O)=O PIWJFCFHQLEBSJ-VFWDIBGWSA-N 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- 206010056523 Hepatobiliary infection Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010053636 Obstetric infection Diseases 0.000 description 1
- 241000972349 Ocoa Species 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 101150093411 ZNF143 gene Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- TYOQLJHWYCTPCB-RCAYSMOQSA-N benzamidomethyl (5R,6S)-3-(carbamoyloxymethyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound C(C1=CC=CC=C1)(=O)NCOC(=O)C1=C(S[C@H]2N1C([C@@H]2[C@@H](C)O)=O)COC(N)=O TYOQLJHWYCTPCB-RCAYSMOQSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012455 bioassay technique Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZYZWOSIRFVIBRH-UHFFFAOYSA-N chloroform;cyclohexane Chemical compound ClC(Cl)Cl.C1CCCCC1 ZYZWOSIRFVIBRH-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- ZPOHKOVSRSGLAD-NJUACVTBSA-N methoxymethyl (5R,6S)-3-(carbamoyloxymethyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound C(N)(=O)OCC=1S[C@H]2N(C=1C(=O)OCOC)C([C@@H]2[C@@H](C)O)=O ZPOHKOVSRSGLAD-NJUACVTBSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- CIUJQWLLGXKZQD-UHFFFAOYSA-N n-(chloromethyl)benzamide Chemical compound ClCNC(=O)C1=CC=CC=C1 CIUJQWLLGXKZQD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 150000002961 penems Chemical class 0.000 description 1
- 229930189471 penicacid Natural products 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- C07D499/86—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 with only atoms other than nitrogen atoms directly attached in position 6 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
i
DK 166387 B
Den foreliggende opfindelse angår hidtil ukendte penemcarboxylsyreestere med den i det følgende angivne almene formel (II), hvilke estere er aktive over for gram-positive, gram-negative, /3-lactamaseproducerende og anaerobe bakterier, 5 hvilket gør disse forbindelser anvendelige som terapeutiske og profylaktiske midler mod bakterieinfektioner hos pattedyr, herunder mennesker, og fjerkræ.
I GB patentskrift nr. 2.043.639A er der beskrevet penemderivater med den almene formel 10 i 0)
II
R'v /S v/CH,Z
—I 11 (I)
1—N
15 Q/ COOR" hvori n er 0 eller 1, R" er et hydrogenatom, en lavere alkylgruppe, en 2,2,2-trichlorethyl-, benzyl-, acetonyl-, p-nitrobenzyl-, 20 p-methoxybenzyl-, phenyl-, p-nitrophenyl- eller benzhydrylgruppe eller en rest, der aktiveres metabolisk in vivo, og som har gunstige farmakokinetiske egenskaber, Z er et hydrogen- eller halogenatom, en hydroxy-, 25 amino-, carbamoyloxy-, mercapto- eller pyridinium- gruppe eller en gruppe med formlen 0Rlf OCOR!, NHCORi eller SRlf hvor Rj er en lavere alkylgruppe, en arylgruppe eller en heterocyclisk ring, og hver af Rj-grupperne even-30 tuelt er substitueret, og R' er et hydrogenatom eller en lavere alkyl-, lavere alkoxy-, cycloalkyl- eller hydroxya1kylgruppe, idet hydroxyalkylgruppens alkoholfunktion er fri eller beskyttet.
35 6-Substituenten kan have a- eller β-konfiguration, idet 6-a-substitution foretrækkes.
2
DK 166387 B
I kampen mod infektionssygdomme er det meget vigtigt, at man råder over nye antibiotiske forbindelser, der adsor-beres godt ved oral indgivelse og således tillader en ufarlig og egnet behandling af bakterieinfektioner. Den foreliggende 5 opfindelse er baseret på den opdagelse, at visse estere af (5R,6S)-2-carbamoyloxymethyl-6-[l(R)-hydroxyethyl]-2-penem- 3-carboxylsyre (med formlen (I), hvor Z er OCONH2, R' er CH3-CH(OH)-, og n er 0) udviser betydelig biotilgængelighed efter oral indgivelse til mus og rotter, medens den tilsva-10 rende penemcarboxylsyre og dens natriumsalt kun adsorberes, når de indgives parenteralt. Denne drastiske forskel kunne ikke forudses ud fra kendskabet til de kendte derivater, f.eks. som beskrevet i GB patentskrift nr. 2.043.639A.
Opfindelsen angår således penemcarboxylsyreestere, 15 der er ejendommelige ved, at de har den almene formel
OH
oconh 1Γ (11) 2 0 J N -
0 * \ C00R
i hvilken R er en acetoxymethyl-, pivaloyloxymethyl-, meth-oxymethyl-, methoxyethoxymethyl-, phthalidyl-, 25 α-ethoxycarbonyloxyethyl-, acetamidomethyl- eller benzamidomethylgruppe.
Forbindelserne med formlen (II) ovenfor kan ifølge opfindelsen fremstilles ved en fremgangsmåde, der er ejendommelig ved, at en forbindelse med formlen
30 OH
" ^COOH
(III) 35 0 3
DK 166387 B
eller et salt eller et reaktionsdygtigt esterificerende derivat deraf esterificeres med en forbindelse med formlen RX, hvori R er som anført ovenfor, og X er et halogenatom, en hydroxygruppe eller en gruppe med formlen 0S02R2» hvori 5 R2 er en lavere alkyl- eller en substitueret eller usubsti-tueret arylgruppe. Egnede halogenatomer, som X kan repræsentere, er chlor, brom og iod, og foretrukne R2-grupper er methyl- og p-tolylgrupper.
Esterificeringen kan f.eks. ske ved at omsætte den 10 frie syre med en passende forbindelse med formlen RX i nærværelse af en base eller ved omsætning af et salt af den frie syre, eventuelt dannet in situ, med en passende forbindelse med formlen RX. Alternativt kan der i stedet for den frie syre anvendes et passende salt såsom et hvilket som 15 helst, af lithium-, natrium-, kalium- eller magnesiumsaltene, eller salte med en organisk base, fortrinsvis en aromatisk base eller en aliphatisk tertiær amin, mest hensigtsmæssigt triethylamin, dimethylaminopyridin eller pyridin. Andre reaktionsdygtige esterificerende derivater af syren (III) 20 omfatter de reaktionsdygtige mellemprodukter, der dannes ved reaktion in situ med et kondensationsmiddel såsom et carbodiimid, f.eks. Ν,Ν-diethyl- eller N,N-dicyclohexylcar-bodimid, eller en passende carbonylforbindelse, f.eks. N,N'-carbonyldiimidazol.
25 Reaktionen udføres fortrinsvis i et organisk reak tionsmedium, f.eks. methylendichlorid, dimethylformamid, acetonitril, en alkohol, benzen, dioxan eller tetrahydrofuran, ved en temperatur fra 0 til 70°C. Udgangsforbindelsen med formlen (III) findes beskrevet i engelsk patentskrift nr.
30 2.097.786A.
En anden fremgangsmåde, der kan anvendes til fremstilling af forbindelser med formlen (II), er den, der er beskrevet alment i GB patentskrift nr. 2.111.496A.
Den foreliggende opfindelse angår endvidere et far-35 maceutisk præparat, der er ejendommeligt ved, at det indeholder en penemcarboxylsyreester med den almene formel 4
DK 166387 B
OH
IH
5 -l^'Y^-OCONHj (I1)
. i IL
O ^ COOR
i hvilken R er en acetoxymethyl-, piva1oy1oxymethy1-, meth-10 oxymethyl-, methoxyethoxymethyl-, phthalidyl-, a-ethoxycar-bonyloxyethyl-, acetamidomethyl- eller benzamidomethylgruppe sammen med et farmaceutisk acceptabelt bærestof eller ex-cipiens.
Det er blevet konstateret, at penemcarboxylsyreesterne 15 med formlen (II), selv om de generisk er omfattet af kravene i GB patentskrift nr. 2.043.639A, er stærkt og overraskende overlegne i forhold til de øvrige derivater, der er omfattet af kravene i dette patentskrift, eftersom de kan indgives per os. Til støtte for denne angivelse viser tabel I plas-20 maniveauerne og det areal under kurven, der fremkommer, når acetoxymethyl- og pivaloyloxymethylesterne af (5R,6S)-2-carbamoyloxymethyl-6- [ 1 (R) -hydroxyethyl ] -2-penem-3-carboxylsyre (herefter omtalt som FCE 22101) indgives oralt til mus og rotter.
25 Til opnåelse af de i tabel I viste resultater indgives hver af de to estere af FCE 22101 oralt i opløsning til mus og rotter i en mængde, der svarer til 40 mg FCE 22101 pr. kg legemsvægt efter den forventede in vivo-hydrolyse.
Der tages med mellemrum blodprøver fra dyrene, og 30 alle prøver analyseres for FCE 22101-indhold ved hjælp af standard-bioanalyseteknik.
35
5 DK 166387 B
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Den terapeutiske virkning hos mus ved afprøvning efter oral indgivelse bekræfter antibiotikummets biotilgængelighed ad oral indgivelsesvej med ED50, der er sammenlignelig med FCE 22101 indgivet subcutant, således som anført 5 i tabel II.
Tabel II
Ingivelses- Infektion 10 Forbindelse måde i.p. ED50 mg/kg FCE 22101 s.c. Staf. aureus 1
Smith
Acetoxymethylester 15 af FCE 22101 per os do. 3,2
Piva1oy1oxymethy1- ester af FCE 22101 per os do. 1,7 20 På grund af deres høje antibakterielle aktivitet hos pattedyr eller mennesker over for såvel gram-positive som gram-negative bakterier er forbindelserne ifølge opfindelsen anvendelige til behandling af infektioner, der forårsages af de nævnte mikroorganismer, såsom i luftvejene, f.eks.
25 bronchitis, bronchopneumoni og lungehindebetændelse, hepato-biliære og abdominale infektioner, f.eks. sepsis, urinvejsinfektioner, f.eks. pyelonephritis og cystitis, obstetriske og gynækologiske infektioner, f.eks. cervicitis og endometritis, øre-, næse og halsinfektioner, f.eks. otitis, sinui-30 tis og parotitis. Toksiciteten af forbindelserne ifølge opfindelsen er ganske ubetydelig, og de kan derfor uden risiko anvendes til terapi.
35 7
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Resultater af sammenlianinasforsøcr
Forbindelser ifølge opfindelsen sammenlignes ved et forsøg med den ester ifølge SE fremlæggelsesskrift nr.
449.489 (svarende til DK fremlæggelsesskrift nr. 159.448), 5 der kommer forbindelserne ifølge opfindelsen nærmest.
Ved forsøget bestemmes den orale absorption af forbindelserne, idet de indgives oralt i opløsning til mus i en mængde ækvivalent med tilstedeværelsen af 20 g penemsyre pr. kg kropsvægt efter den forventede in vivo-hydrolyse.
10 Biotilgængeligheden af de penemestere, som sammenlig nes, afprøves ved en standardmetode, og resultaterne fremgår af den følgende tabel:
Tabel
15 OH
>S-y Sc«2OCOm2 N ^COOR
20 --—-- R Ifølge: Farmakokinetiske parametre
Område under % Ab- 25 kurve sorp- mcg. min./ml) tion
Acetonyl SE 449.489 7 2,2 30 eks. 51
Acetoxymethyl Eks. 2 iflg. opf. 171 56 o-Ethoxycar- Eks. 6 iflg. opf. 204,6 66,6 35 bonyloxyethyl
Pivaloyloxymethyl Eks. l iflg. opf. 97 32
Phthalidyl Eks. 5 iflg. opf. 104,5 34 40 --—-- ifi 8
DK 166387 B
Som det tydeligt fremgår af de angivne værdier, har kun forbindelserne ifølge den foreliggende opfindelse en hastighed for oral absorption, som giver en sikker og hensigtsmæssig oral behandling af bakterieinfektioner. Dette 5 indebærer, at penemcarboxylsyreesterne ifølge den foreliggende opfindelse er væsentligt og overraskende bedre end de i det ovennævnte SE fremlæggelsesskrift beskrevne forbindelser, eftersom de kan indgives per os.
Forbindelerne ifølge opfindelsen er anvendelige til 10 behandling af bakterieinfektioner hos pattedyr, herunder mennesker. De indgives oralt og kan foreligge i form af kapsler, tabletter, pulvere, flydende opløsninger, suspensioner, eliksirer og lignende. Forbindelserne kan anvendes alene eller kombineret med andre aktive stoffer. De kan 15 anvendes i sammensætninger, der omfatter et eller flere farmaceutisk acceptable bærestoffer eller fortyndingsmidler og andre bestanddele såsom stabilisatorer, bindemidler, antioxidanter, konserveringsmidler, smøremidler, suspenderingsmidler, viskositetsmidler og/eller smagsstoffer.
20 Acceptable bærestoffer og fortyndingsmidler er f.eks.
vand, gelatine, lactose, stivelser, magnesiumstearat, talkum, vegetabilske olier og cellulose.
Daglige doser mellem ca. 1 og ca. 100 mg pr. kg legemsvægt kan anvendes til flere forskellige dyrearter, idet 25 den nøjagtige dosering afhænger af alder, vægt og tilstand for det dyr eller menneske, der behandles, og af indgivelseshyppigheden. Forbindelserne kan f.eks. indgives til voksne mennesker i en mængde fra ca. 100 til ca. 300 mg pr. dosis, fortrinsvis ca. 200 mg pr. dosis 1-4 gange daglig. De er 30 også anvendelige som tilsætningsmidler i dyrefoder.
Opfindelsen illustreres nærmere i de følgende eksempler.
35 9
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O
Eksempel 1
Pivaloyloxvmethyl-(5R,6S)-2-carbamoyloxymethyl-6-[1(R)hydroxy-ethyl]-2-penem-3-carboxylat Formel II: R = -CH2O.COC(CH3)3 5 OH u OH '
AI
I 0C01vH2 i-1 oca®2 10 /*~\χχχ* </ * ^-cooch2ococ(ch3)3 775 mg natrium-(5R,6S)-2-carbamoyloxymethyl-6-[1(R)-hydroxyethvl]-2-penem-3-carboxylat opløses i 15 ml dimethylformamid og behandles med 50 mg dimethylaminopyridin og 1,15 ml piva-15 loyloxymethylchlorid ved 40°C i 4 timer. Reaktionsblandingen fortyndes med ethvlacetat, vaskes med vand, tørres over Na2S0^, og opløsningsmidlet afdampes.
Remanensen består af 480 mg ren forbindelse som nævnt i overskriften.
20 UV (EtOH 95%) : λ-max 325 nm (£ 7000).
IR (CH-CI0) 9 : 3600, 1795, 1725 cm”1.
PMR (200 MHz, CDCI3), £ (ppm): 1,21 (s, 9H, (CH3)3, 1,33 (d, J = 6,3 Hz, 3H, CHCH3), or 3.75 (dd, J = 1,5, 6,4 Hz, IH, H-6), 4,23 (m, IH, CHOH), 4.76 (bs, 2H, CONH2), 5,08, 5,42 (to d, J = 15,8 Hz, CH2OCONH2), 5,62 (d, J = 1,5 Hz, IH, H-5), 30 5,81, 5,91 (to d, J = 5,5 Hz, OCH2OCOO(CH3)3).
35 10
DK 166387 B
o
Eksempel 2
Acetoxymethyl-(5R,6S)-2-carbamoyloxymethvl-6-[1(R)-hvdroxvethyl]" -2-penem-3-carboxylat Formel II: Rs -CH2O.COCH3·
5 OH OH
i ,* ^ i; f οαα®2 [ ocoa,i2 ff-N -ff— K-^ ,0 V COONa </ OOOCHjCCOCHj 1,3 g natrium-(5R,6S)-2-carbamovloxymethy1-6-[1(R)--hydroxvethyl]-2-penem-3-carboxylat opløses i 30 ml vandfrit dime thylformamid og behandles med 0,65 g acetoxvmethylbromid ved 15 stuetemperatur i 3 timer.
Reaktionsblandingen fortyndes derpå med ethylacetat, vaskes med vand, tørres over natriumsulfat og inddampes.
Den opnåede rå forbindelse krystalliseres ud fra chlo-roform-cyclohexan og derpå ud fra varm chlorofom.
20 Smeltepunkt 127°C (ud fra CHCI^).
[a]2D° = +137°C (1% i acetone).
IR (KBr) : >) 3500-3300, 1800, 1760, 1720 og 1590 cm"1, max 3 UV: A. (EtOH 95%) 327 nm (B 7800). max PMR (200 MHz, acetone dg), S (ppm): 25 1,26 (d, J = 6,0 Hz, 3H, CH-jCH) , 2,06 (s, 3H, -C-CH-.)
II J
o 3,78 (s, IH, OH), 3,80 (dd, J = 1,7 og 6,4 Hz, IH, H-6), 30 4,14 (m, IH, CH3CH), 5,08, 5,34 (to d, J = 16,0 Hz, 2H, CH2OCONH2), 5,69 (d, J = 1,7 Hz, IH, H-5), 5,80, 5,86 (to d, J = 5,8 Hz, 2H, COOCH2OCO) og 6,10 (bs, 2H, NH ).
35 Å 11
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o
Eksempel 3
Methoxymethyl- (5R,6S) -2-carbamoyloxvmethyl-6- [1 (R) -hydroxy-ethyl] - -2-penem-3-carboxylat Formel II: R = -CH2OCH3.
5 Man går frem som beskrevet i eksempel 2, men anvender methoxvmethylbromid i stedet for acetoxymethvlbromid, hvorved fås den i overskriften nævnte forbindelse i et udbytte på 65%.
IR (CH~C10) ^ = 3610, 1795, 1720 cm"1.
2 2 max 10 Eksempel 4
Methoxyethoxymethyl-(5R,6S)-2-carbamovloxvmethyl-6-[1(R)-hydro-xvethvl]-2-penem-3-carboxylat Formel II: R -CH2OCH2CH2OCH3.
Man går frem som beskrevet i eksempel 1, men anvender 15 methoxyethoxymethylchlorid i stedet for pivaloyloxvmethylchlo-rid, hvorved fås den i overskriften nævnte forbindelse i et udbytte på 58%.
IR (CH0Clo) : ^ = 3590,' 1795, 1720 cm"1.
i i max 20 Eksempel 5
Phthalidyl-'5R,6S)-2-carbamoyloxymethvl-6-[1(R)-hydroxyethyl3 - -2-penem-3-carboxvlat Formel II: R = phthalidyl
Man går frem som beskrevet i eksempel 2, men anvender 25 3-bromphthalid i stedet for acetoxymethvlbromid, hvorved fås den i overskriften nævnte forbindelse i et udbytte på 62%.
IR (CH0C10): ^ = 3600, 1795, 1750, 1720 cm"1.
& & max 30 35 12
DK 166387 B
O
Eksempel 6 g-Ethoxycarbonyloxyethyl- (5R, 6S) -2-carbamovloxymethvl-6- [1 (R) -hy-droxvethy1]-2-penem-3-carboxylat Formel II: R * CH (CH3)O.CO.OC^.
5 Man går frem som beskrevet i eksempel 1, men anvender chlordiethylcarbonat i stedet for pivaloyloxymethylchlorid, hvorved fås den i overskriften nævnte forbindelse i et udbytte på 40%.
IR (CH-Cl,): ί = 3600, 1795, 1720, 1420 cm"1.
2 2 max 10
Eksempel 7
Acetamidomethyl- (5R,6S)-2-carbamoyloxymethyl-6- [1 (R) -hvdroxye-thyl] -2-penem-3-carboxylat Formel II: R = -CH2NHCOCH3.
15 Man går frem som beskrevet i eksempel 1, men anvender acetamidomethylchlorid i stedet for pivaloyloxymethylchlorid, hvor ved fås den i overskriften nævnte forbindelse i et udbytte på 45%.
IR (CH0C10): ^ = 3600, 1795, 1720, 1690 cm"1.
Z Z ΙΏαΧ 20
Eksempel 8
Benzamidomethyl- (5R, 6S) -2-carbamovloxymethyl-6- [1 (R) -hydroxyethyl] -2-penem-3-carboxvlat Formel II: R = -CH2-NH-COC6H5.
25 Man går frem som beskrevet i eksempel 7, men anvender benzamidomethylchlorid i stedet for acetamidomethylchlorid, hvorved fås den i overskriften nævnte forbindelse i et udbytte på 43%.
IR (CH0C10): ^ = 3600, 1795, 1715, 1690 cm"1.
& £ max 30 35
Claims (8)
1. Penemcarboxylsyreestere, kendetegnet ved, at de har den almene formel OH Al f ^OCONH, I 2 (II) CT ^ COOR 10 i hvilken R er en acetoxymethyl-, pivaloyloxymethyl-, meth-oxymethyl-, methoxyethoxymethyl-, phthalidyl-, a-ethoxycar-bonyloxyethyl-, acetamidomethyl- eller benzamidomethylgruppe.
2. Penemcarboxylsyreester ifølge krav 1, kende-15 tegnet ved, at den er acetoxymethyl-(5R,6S)-2-carb- amoyloxymethyl-6- [ 1- (R) -hydroxyethyl ] -2-penem-3-carboxylat.
3. Penemcarboxylsyreester ifølge krav 1, kendetegnet ved, at den er pivaloyloxymethyl-(5R,6S)-2-carbamoyloxymethyl-6 [ 1 (R) -hydroxyethyl ] -2-penem-3-carboxylat.
4. Farmaceutisk præparat, kendetegnet ved, at det indeholder en penemcarboxylsyreester med den almene formel OH 25 -^NAAoconh 2 (ID er ^ COOR 30. hvilken R er en acetoxymethyl-, pivaloyloxymethyl-, meth-oxymethyl-, methoxyethoxymethyl-, phthalidyl-, a-ethoxycar-bonyloxyethyl-, acetamidomethyl- eller benzamidomethylgruppe sammen med et farmaceutisk acceptabelt bærestof eller ex-cipiens.
5. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1-3, kendeteg- DK 166387 B net ved, at en forbindelse med formlen OH 5 (XII) _N -H-COOH eller et salt eller et reaktionsdygtigt esterificerende 10 derivat deraf esterificeres med en forbindelse med formlen RX, hvori R har den i krav 1 anførte betydning, og X er et halogenatom, en hydroxygruppe eller en gruppe med formlen 0S02R2/ hvori R2 er en lavere alkyl- eller en substitueret eller usubstitueret arylgruppe.
6. Fremgangsmåde ifølge krav 5, kendeteg net ved, at den fri syre med formlen (III) omsættes med en forbindelse med formlen RX som defineret i krav 5 i nærværelse af en base i et organisk reaktionsmedium ved en temperatur fra 0 til 70°C.
7. Fremgangsmåde ifølge krav 6, kendeteg net ved, at det organiske reaktionsmedium er methylen-dichlorid, dimethylformamid, acetonitril, lavere alkohol, benzen, dioxan eller tetrahydrofuran.
8. Præparat ifølge krav 4,kendetegnet 25 ved, at det er en oral antibakteriel doseringsenhed, der omfatter en forbindelse ifølge krav 1-3 i en mængde, der er tilstrækkelig til at være oralt effektiv som et bredspektret antibakterielt middel, og et ikke-toksisk farmaceutisk acceptabelt bærestof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8300295 | 1983-01-06 | ||
| GB838300295A GB8300295D0 (en) | 1983-01-06 | 1983-01-06 | Penem esters |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK5284D0 DK5284D0 (da) | 1984-01-05 |
| DK5284A DK5284A (da) | 1984-07-07 |
| DK166387B true DK166387B (da) | 1993-05-10 |
| DK166387C DK166387C (da) | 1993-09-27 |
Family
ID=10535987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK005284A DK166387C (da) | 1983-01-06 | 1984-01-05 | Penemestere, en fremgangsmaade til fremstilling heraf samt et farmaceutisk praeparat indeholdende disse |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US5051416A (da) |
| JP (1) | JPS59134795A (da) |
| KR (1) | KR900004418B1 (da) |
| AT (1) | AT382622B (da) |
| AU (1) | AU557178B2 (da) |
| BE (1) | BE898603A (da) |
| CA (1) | CA1215042A (da) |
| CH (1) | CH659073A5 (da) |
| CS (2) | CS235996B2 (da) |
| DE (1) | DE3400090A1 (da) |
| DK (1) | DK166387C (da) |
| ES (1) | ES8505372A1 (da) |
| FI (1) | FI81103C (da) |
| FR (1) | FR2539130B1 (da) |
| GB (2) | GB8300295D0 (da) |
| GR (1) | GR81730B (da) |
| HK (1) | HK74987A (da) |
| HU (1) | HU191243B (da) |
| IE (1) | IE56903B1 (da) |
| IL (1) | IL70606A (da) |
| IT (1) | IT1209490B (da) |
| NL (1) | NL8400015A (da) |
| NO (1) | NO160446C (da) |
| NZ (1) | NZ206743A (da) |
| PH (1) | PH18881A (da) |
| PT (1) | PT77922B (da) |
| SE (1) | SE458117B (da) |
| SG (1) | SG34387G (da) |
| SU (1) | SU1209031A3 (da) |
| UA (1) | UA6039A1 (da) |
| ZA (1) | ZA8457B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2206578B (en) * | 1987-07-07 | 1991-07-03 | Erba Carlo Spa | Process for the preparation of penems |
| US5364768A (en) * | 1987-07-07 | 1994-11-15 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of penems |
| EP0567949B1 (en) | 1992-04-28 | 2001-02-21 | Tanabe Seiyaku Co., Ltd. | Method for removing silyl protecting groups for hydroxy group |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7401782A (da) * | 1973-02-14 | 1974-08-16 | ||
| ZA80993B (en) * | 1979-02-24 | 1981-02-25 | Erba Farmitalia | -lactam-containing antibacterial agents and -lactamase inhibitors and preparation thereof |
| GB2043639B (en) * | 1979-02-24 | 1983-07-20 | Erba Farmitalia | 3-optionally substituted methyl-2-penem derivatives |
| GB2043699B (en) * | 1979-03-03 | 1983-05-11 | Park Chem Co | Cyanide-free carburizing process and composition |
| US4482565A (en) * | 1980-02-22 | 1984-11-13 | Farmitalia Carlo Erba S.P.A. | β-Lactam-containing antibacterial agents and β-lactamase inhibitors |
| US4508649A (en) * | 1981-12-11 | 1985-04-02 | Farmitalia Carlo Erba | Process for preparing optically active penems |
-
1983
- 1983-01-06 GB GB838300295A patent/GB8300295D0/en active Pending
- 1983-12-29 ES ES528546A patent/ES8505372A1/es not_active Expired
-
1984
- 1984-01-02 FI FI840003A patent/FI81103C/fi not_active IP Right Cessation
- 1984-01-03 DE DE19843400090 patent/DE3400090A1/de not_active Ceased
- 1984-01-03 GB GB08400043A patent/GB2133010B/en not_active Expired
- 1984-01-03 IL IL70606A patent/IL70606A/xx not_active IP Right Cessation
- 1984-01-03 AT AT0001584A patent/AT382622B/de not_active IP Right Cessation
- 1984-01-03 CS CS8480A patent/CS235996B2/cs unknown
- 1984-01-03 FR FR8400040A patent/FR2539130B1/fr not_active Expired
- 1984-01-03 NL NL8400015A patent/NL8400015A/nl not_active Application Discontinuation
- 1984-01-03 GR GR73420A patent/GR81730B/el unknown
- 1984-01-03 AU AU23047/84A patent/AU557178B2/en not_active Ceased
- 1984-01-03 IT IT8419007A patent/IT1209490B/it active
- 1984-01-04 BE BE0/212151A patent/BE898603A/fr not_active IP Right Cessation
- 1984-01-04 IE IE6/84A patent/IE56903B1/en not_active IP Right Cessation
- 1984-01-04 CA CA000444654A patent/CA1215042A/en not_active Expired
- 1984-01-04 PH PH30064A patent/PH18881A/en unknown
- 1984-01-04 PT PT77922A patent/PT77922B/pt not_active IP Right Cessation
- 1984-01-04 ZA ZA8457A patent/ZA8457B/xx unknown
- 1984-01-04 SE SE8400040A patent/SE458117B/sv not_active IP Right Cessation
- 1984-01-05 DK DK005284A patent/DK166387C/da active
- 1984-01-05 UA UA3688716A patent/UA6039A1/uk unknown
- 1984-01-05 JP JP59000110A patent/JPS59134795A/ja active Granted
- 1984-01-05 CH CH42/84A patent/CH659073A5/de not_active IP Right Cessation
- 1984-01-05 HU HU8437A patent/HU191243B/hu not_active IP Right Cessation
- 1984-01-05 NO NO840035A patent/NO160446C/no unknown
- 1984-01-05 NZ NZ206743A patent/NZ206743A/en unknown
- 1984-01-05 SU SU843688716A patent/SU1209031A3/ru active
- 1984-01-05 KR KR1019840000014A patent/KR900004418B1/ko not_active IP Right Cessation
-
1987
- 1987-04-14 SG SG34387A patent/SG34387G/en unknown
- 1987-10-15 HK HK749/87A patent/HK74987A/xx not_active IP Right Cessation
-
1989
- 1989-04-03 US US07/331,853 patent/US5051416A/en not_active Expired - Fee Related
-
1991
- 1991-12-20 CS CS914150A patent/CS415091A3/cs unknown
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