CH646703A5 - Process for the preparation of 1,3-dihydro-3-oxo-1-isobenzofuranyl (2S)-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyc lo[3.2.0]heptane-2-carboxylate - Google Patents
Process for the preparation of 1,3-dihydro-3-oxo-1-isobenzofuranyl (2S)-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyc lo[3.2.0]heptane-2-carboxylate Download PDFInfo
- Publication number
- CH646703A5 CH646703A5 CH745980A CH745980A CH646703A5 CH 646703 A5 CH646703 A5 CH 646703A5 CH 745980 A CH745980 A CH 745980A CH 745980 A CH745980 A CH 745980A CH 646703 A5 CH646703 A5 CH 646703A5
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- dihydro
- water
- isobenzofuranyl
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- -1 1,3-dihydro-3-oxo-1-isobenzofuranyl Chemical group 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LJGFJCOLMZZTBJ-UHFFFAOYSA-N 4-phenyl-1,3-thiazolidine-2,5-dione Chemical compound O=C1SC(=O)NC1C1=CC=CC=C1 LJGFJCOLMZZTBJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- AVKUERGKIZMTKX-DGVZPSOQSA-N (2s)-6-[(2-amino-2-phenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound CC([C@@H](N1C2=O)C(O)=O)(C)SC1C2NC(=O)C(N)C1=CC=CC=C1 AVKUERGKIZMTKX-DGVZPSOQSA-N 0.000 claims 1
- 101100440643 Rhodospirillum rubrum cooC gene Proteins 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229960002780 talampicillin Drugs 0.000 description 5
- SOROUYSPFADXSN-SUWVAFIASA-N talampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OC2C3=CC=CC=C3C(=O)O2)(C)C)=CC=CC=C1 SOROUYSPFADXSN-SUWVAFIASA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000002906 microbiologic effect Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- WNZQDUSMALZDQF-UHFFFAOYSA-N isobenzofuranone Natural products C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002904 solvent 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung des (2S)-6-[(AminophenylacetyI)-amino]--3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptan-2-car-bonsäure-l,3-dihydro-3-oxo-l-isobenzofuranylesters der Formel I The present invention relates to a new process for the preparation of (2S) -6 - [(aminophenylacetyI) amino] - 3,3-dimethyl-7-oxo-4-thia-l-azabicyclo [3.2.0] heptane-2 -car-bonic acid-l, 3-dihydro-3-oxo-l-isobenzofuranyl ester of the formula I.
<OV GH-COHH—] <OV GH-COHH—]
— NH- oJ N - NH- oJ N
CH, OH CH, OH
-cooC® -cooC®
h2n- h2n-
CH, CH' CH, CH '
■C00 ■ C00
(II) (II)
(I) (I)
, mit dem 4-Phenylthiazolidin-2,5-dion der Formel III , with the 4-phenylthiazolidine-2,5-dione of the formula III
-C=0 -C = 0
NH NH
(HD (HD
(i) (i)
und dessen) pharmazeutisch annehmbarer Salze. and its) pharmaceutically acceptable salts.
Die Verbindung der Formel I wird erfindungsgemäss derart hergestellt, dass man den 6-Aminopenicillansäure-l,3-di-hydro-3-oxo-l-isobenzofuranylester der Formel II The compound of formula I is prepared according to the invention in such a way that 1,3-di-hydro-3-oxo-l-isobenzofuranyl ester of formula II is 6-aminopenicillanoic acid
II II
0 0
20 20th
kondensiert. condensed.
Die Kondensation wird vorzugsweise in einem Gemisch aus einem wassermischbaren Lösungsmittel und Wasser, vorzugsweise in Aceton/Wasser in volumetrischem Verhältnis 25 von 7:2 bis 7:3, bei einem pH-Wert von 6,2 bis 8,0 unter Kühlen, vorzugsweise bei einer Temperatur von —5 bis 10°C, ausgeführt. Das erhaltene Produkt wird in Form von pharmazeutisch verwendbaren Salzen nach schon bekannten Verfahren gereinigt und isoliert. The condensation is preferably carried out in a mixture of a water-miscible solvent and water, preferably in acetone / water in a volumetric ratio 25 of 7: 2 to 7: 3, at a pH of 6.2 to 8.0 with cooling, preferably with a temperature of -5 to 10 ° C. The product obtained is purified and isolated in the form of pharmaceutically usable salts by known processes.
30 Die Verbindung der allgemeinen Formel I ist ein bekanntes halbsynthetisches Antibiotikum mit einem breiten antibakteriellen Wirkungsspektrum (Talampicillin), welches sich im Organismus in das Ampicillin hydrolysiert. Es wird peroral verabreicht und wird als solches zweimal schneller 35 absorbiert und erzielt eine zweimal höhere Konzentration im Blut als eine äquivalente Dosis von Ampicillin. Die Verbindung ist in J. Med. Chem. 19,1385 (1976) und J. Anti-biot. 27, 665 (1974) beschrieben. 30 The compound of general formula I is a known semi-synthetic antibiotic with a broad spectrum of antibacterial activity (talampicillin), which hydrolyzes into the ampicillin in the organism. It is administered orally and as such is absorbed twice as quickly and achieves a concentration in the blood which is twice as high as an equivalent dose of ampicillin. The compound is described in J. Med. Chem. 19, 1385 (1976) and J. Anti-biot. 27, 665 (1974).
Gemäss den bisher bekannten Verfahren wird Talampi-40 cillin mittels Kondensation der reaktiven Form des N-ge-schützten D-Phenylglycins und des 6-Aminopenicillansäure--l,3-dihydro-3-oxo-l-isobenzofuranylesters gewonnen. Diese Verfahren sind zeitraubend, da man in der letzten Phase der Synthese die N-geschützten Gruppen vor der endgültigen 45 Isolierung des Talampicillins chemisch beseitigen muss. Der Vorteil unseres Verfahrens besteht insbesondere in der chemischen und technologischen Einfachkeit, da beim Verfahren zur Synthese von Talampicillin gemäss der vorliegenden Erfindung das 4-Phenylthiazolidin-2,5-dion verwen-50 det wird, ini welchem die funktionellen Carboxy- und Ami-nogruppen gleichzeitig geschützt und für die Reaktion der Kondensation mit dem 6-Aminopenicillansäure-phthalidyl-ester entsprechend aktiviert sind. Nach beendeter Kondensation wird das Endprodukt Talampicillin ohne chemische 55 Nachbehandlungen, die bei bisher bekannten Verfahren unumgänglich waren, gewonnen. According to the previously known processes, Talampi-40 cillin is obtained by condensing the reactive form of the N-protected D-phenylglycine and the 6-aminopenicillanic acid - 1,3-dihydro-3-oxo-l-isobenzofuranyl ester. These procedures are time consuming since the N-protected groups have to be chemically removed in the last phase of the synthesis before the talampicillin is finally isolated. The advantage of our process is, in particular, its chemical and technological simplicity, since 4-phenylthiazolidine-2,5-dione, in which the functional carboxy and amino groups are used, is used in the process for the synthesis of talampicillin according to the present invention at the same time protected and appropriately activated for the reaction of the condensation with the 6-aminopenicillanic acid phthalide ester. After the condensation has ended, the end product talampicillin is obtained without chemical aftertreatments, which were inevitable in previously known processes.
Das Verfahren wird durch die folgenden Ausführungsbeispiele näher erläutert, jedoch keineswegs eingeschränkt. The method is explained in more detail by the following exemplary embodiments, but is in no way restricted.
» Beispiel 1 " Example 1
0,385 g (0,001 Mol) 6-Aminopenicillansäure-l,3-dihy-dro-3-oxo-l-isobenzofuranylester. Hydrochlorid werden in einem Gemisch aus 5 ml Aceton und 2 ml Wasser bei einer Temperatur von 2 bis 3°C gelöst. Die derart erhaltene Lö-65 sung wird unter Rühren mit einer Lösung von 0,193 g (0,001 Mol) 4-Phenyl-thiazolidin-2,5-dion in 2,5 ml wässerigem Aceton (5%iger Wassergehalt) versetzt. Das Reaktionsgemisch wird bei derselben Temperatur 40 Minuten bei 0.385 g (0.001 mol) 6-aminopenicillanoic acid 1,3-dihydro-3-oxo-l-isobenzofuranyl ester. Hydrochloride are dissolved in a mixture of 5 ml acetone and 2 ml water at a temperature of 2 to 3 ° C. A solution of 0.193 g (0.001 mol) of 4-phenyl-thiazolidine-2,5-dione in 2.5 ml of aqueous acetone (5% water content) is added to the solution thus obtained with stirring. The reaction mixture is at the same temperature for 40 minutes
3 3rd
646703 646703
einem pH-Wert von 7,2 bis 7,6 weitergerührt, der pH-Wert wird mittels 4 N HCl auf 6,2 eingestellt und bei derselben Temperatur noch 1 Stunde weitergerührt. Nach beendeter Reaktion wird mit 10 ml Wasser versetzt und mittels 4 N HCl auf einen pH-Wert von 2 angesäuert. Die wässerige Lösung wird mehrmals mit Äthylacetat gewaschen und mit 4 g NaCl versetzt, so dass sich das Öl abscheidet, welches zweimal mit 10 ml Methylenchlorid extrahiert wird. Die vereinigten organischen Schichten werden mit einer 15%igen wässerigen NaCl-Lösung gewaschen, mit Na^C^ getrocknet und filtriert. Es wird mit 8 ml Isopropanol versetzt und in Vakuum abdestilliert. Nach Entfernung der überwiegenden Menge des CH2C12 beginnt sich das Produkt abzuscheiden. Das abgeschiedene Produkt wird über Nacht im Kühlschrank gelassen und anschliessend filtriert. Nach Trocknen im Vakuum (200 mbar) werden 2,33 g des Ampi-cillin-l,3-dihydro-3-oxo-l-benzofuranylester. Hydrochlorids erhalten (45%ige Ausbeute). a pH of 7.2 to 7.6, the pH is adjusted to 6.2 by means of 4N HCl and stirring is continued for 1 hour at the same temperature. When the reaction is complete, 10 ml of water are added and the mixture is acidified to pH 2 using 4N HCl. The aqueous solution is washed several times with ethyl acetate and 4 g of NaCl are added, so that the oil separates, which is extracted twice with 10 ml of methylene chloride. The combined organic layers are washed with a 15% aqueous NaCl solution, dried with Na ^ C ^ and filtered. It is mixed with 8 ml of isopropanol and distilled off in vacuo. After the majority of the CH2C12 has been removed, the product begins to separate. The separated product is left in the refrigerator overnight and then filtered. After drying in vacuo (200 mbar), 2.33 g of the ampi-cillin-l, 3-dihydro-3-oxo-l-benzofuranyl ester. Hydrochloride obtained (45% yield).
Schmp. (Zers.) = 154 bis 158 °C. Mp (decomp.) = 154 to 158 ° C.
[a]B20 = +157° (1 Vol./Vol., MeOH). [a] B20 = + 157 ° (1 v / v, MeOH).
Jodometrisch ermittelter Gehalt 96,5% Argentometrisch ermittelter Gehalt 97% Mikrobiologisch ermittelter Gehalt 98% Iodometric content 96.5% Argentometric content 97% Microbiological content 98%
Die IR und NMR Spektren entsprechen dem Standard Talmapicillin. HCl. The IR and NMR spectra correspond to the standard talmapicillin. HCl.
Beispiel 2 Example 2
0,385 g (0,001 Mol) 6-Aminopenicillansäure-l,3-dihy-dro-3-oxo-l-isobenzofuranyl-ester-Hydrochlorid werden in 7 ml eines Gemisches aus Aceton : Wasser (5:2) bei einer 5 Temperatur von 0°C gelöst. Die derart hergestellte Lösung wird mit einer vorbereiteten Lösung von 4-Phenylthiazolidin--2,5-dion ini 2 ml Aceton tropfenweise versetzt. Die Lösung wird 1,5 Stunden bei derselben Temperatur und bei einem pH-Wert von 7 bis 8 gerührt. Es wird mit 10 ml Wasser io versetzt und das Aceton wird abdestilliert. Anschliessend wird mit 20 ml Äthylacetat versetzt und unter Rühren wird der pH-Wert mittels 2 n HCl auf 2 eingestellt. Die wässerige Schicht wird noch zweimal mit 20 ml Äthylacetat gewaschen. Es wird mit 4 g NaCl versetzt, um ein Öl abzu-15 scheiden, welches zweimal mit 10 ml Methylenchlorid extrahiert wird. Die vereinigten organischen Schichten werden mit einer 15%igen wässerigen NaCl-Lösung gewaschen und mittels MgS04 getrocknet. Das Trocknungsmittel wird abfiltriert und es wird mit 20 ml Äther versetzt. Der erhaltene 20 Niederschlag wird filtriert und in Vakuum getrocknet (200 mbar). Es werden 2,08 g erhalten (40%ige Ausbeute). 0.385 g (0.001 mol) of 6-aminopenicillanoic acid 1,3-dihydro-3-oxo-1-isobenzofuranyl ester hydrochloride are dissolved in 7 ml of a mixture of acetone: water (5: 2) at a temperature of 0 ° C solved. A prepared solution of 4-phenylthiazolidine-2,5-dione ini 2 ml of acetone is added dropwise to the solution prepared in this way. The solution is stirred for 1.5 hours at the same temperature and at a pH of 7-8. 10 ml of water are added and the acetone is distilled off. Then 20 ml of ethyl acetate are added and the pH is adjusted to 2 using 2N HCl while stirring. The aqueous layer is washed twice more with 20 ml of ethyl acetate. 4 g of NaCl are added to separate an oil, which is extracted twice with 10 ml of methylene chloride. The combined organic layers are washed with a 15% aqueous NaCl solution and dried using MgSO4. The drying agent is filtered off and 20 ml of ether are added. The precipitate obtained is filtered and dried in vacuo (200 mbar). 2.08 g are obtained (40% yield).
Schmp. (Zers.) = 153 bis 157°C. Mp (decomp.) = 153 to 157 ° C.
[a]Dz0 = +158° (1 Vol./Vol., MeOH). [a] Dz0 = + 158 ° (1 v / v, MeOH).
Jodometrisch ermittelter Gehalt 95,5% 25 Argentometrisch ermittelter Gehalt 98% Mikrobiologisch ermittelter Gehalt 95% Iodometric content 95.5% 25 Argentometric content 98% Microbiological content 95%
Die IR und NMR Spektren entsprechen dem Standard Talampicillin. HCl. The IR and NMR spectra correspond to the standard talampicillin. HCl.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU251679A YU41185B (en) | 1979-10-16 | 1979-10-16 | Process for preparing the 1,3-dimydro-3-oxo-1-isobenzofuranyl-ester of (2s)-6(amino-phenylacetyl)-amino)-3,3-dimethy-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH646703A5 true CH646703A5 (en) | 1984-12-14 |
Family
ID=25558180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH745980A CH646703A5 (en) | 1979-10-16 | 1980-10-06 | Process for the preparation of 1,3-dihydro-3-oxo-1-isobenzofuranyl (2S)-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyc lo[3.2.0]heptane-2-carboxylate |
Country Status (4)
| Country | Link |
|---|---|
| CH (1) | CH646703A5 (en) |
| DE (1) | DE3038950A1 (en) |
| FR (1) | FR2467853A1 (en) |
| YU (1) | YU41185B (en) |
-
1979
- 1979-10-16 YU YU251679A patent/YU41185B/en unknown
-
1980
- 1980-10-06 CH CH745980A patent/CH646703A5/en not_active IP Right Cessation
- 1980-10-10 FR FR8021660A patent/FR2467853A1/en not_active Withdrawn
- 1980-10-15 DE DE19803038950 patent/DE3038950A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| YU41185B (en) | 1986-12-31 |
| YU251679A (en) | 1982-10-31 |
| DE3038950A1 (en) | 1981-05-07 |
| FR2467853A1 (en) | 1981-04-30 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased | ||
| PL | Patent ceased |