DE1795476C - Mitomycin C derivatives and a process for their preparation. Eliminated from: 1445979 - Google Patents
Mitomycin C derivatives and a process for their preparation. Eliminated from: 1445979Info
- Publication number
- DE1795476C DE1795476C DE1795476C DE 1795476 C DE1795476 C DE 1795476C DE 1795476 C DE1795476 C DE 1795476C
- Authority
- DE
- Germany
- Prior art keywords
- mitomycin
- preparation
- derivatives
- eliminated
- och
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical class C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 title claims description 12
- 238000000034 method Methods 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229960004857 Mitomycin Drugs 0.000 description 7
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000005662 Paraffin oil Substances 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 229930016911 cinnamic acid Natural products 0.000 description 2
- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940075615 Bacillus subtilis Drugs 0.000 description 1
- 240000008371 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241001646716 Escherichia coli K-12 Species 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N Ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229940045505 Klebsiella pneumoniae Drugs 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241001677568 Leutea Species 0.000 description 1
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 229940055023 Pseudomonas aeruginosa Drugs 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000192023 Sarcina Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 229940076185 Staphylococcus aureus Drugs 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- IWTYTFSSTWXZFU-QPJJXVBHSA-N [(E)-3-chloroprop-1-enyl]benzene Chemical compound ClC\C=C\C1=CC=CC=C1 IWTYTFSSTWXZFU-QPJJXVBHSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000009632 agar plate Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
in der R die /3-Phenylvinyl- oder Äthoxygruppe bedeutet.in which R is the / 3-phenylvinyl or ethoxy group.
2. Verfahren zur Herstellung der Verbindungen gemäß Ansprach 1, dadurch gekennzeichnet, daß man Mitomycin C der Formel2. Process for the preparation of the compounds according spoke 1, characterized in that one Mitomycin C of the formula
CH2-O-CO-NH2
OCH3 CH 2 -O-CO-NH 2
OCH 3
NHNH
H1CH 1 C
mit einem Halogenkohlensäureäthylester oder einem Säurehalogenid oder dem Anhydrid der Zimtsäure umsetzt.with an ethyl halocarbonate or an acid halide or the anhydride of cinnamic acid implements.
Gegenstand der Erfindung sind Mitomycin C-Derivate der allgemeinen FormelThe invention relates to mitomycin C derivatives of the general formula
O
H2N [j CH2 — O — CO — NH2 O
H 2 N [j CH 2 - O - CO - NH 2
OCH3 OCH 3
N —CO —RN —CO —R
in der R die /S-Phenylvinyl- oder Äthoxygruppe bedeutet, und ein Verfahren zur Herstellung dieser Verbindungen.
Die erfindungsgemäßen Mitomycin C-Derivate werden dadurch hergestellt, daß man Mitomycin C der Formelin which R is the / S-phenylvinyl or ethoxy group, and a process for the preparation of these compounds.
The mitomycin C derivatives according to the invention are prepared by using mitomycin C of the formula
O
H2N Il CH2-O-CO-NH2 O
H 2 N II CH 2 -O-CO-NH 2
H1CH 1 C
mit einem Halogenkohlensäureäthylester oder einem Säurehalogenid oder dem Anhydrid der Zimtsäure umsetzt.with an ethyl halocarbonate or an acid halide or the anhydride of cinnamic acid implements.
Die Acylierung wird in einem geeigneten Lösungsmittel für das Mitomycin C, beispielsweise in Wasser, Methanol, Aceton, Pyridin, Tetrahydrofuran oder Dimethylformamid, in Gegenwart einer anorganischen Base, beispielsweise einem Alkalicarbonat, oder einer organischen Base, beispielsweise Pyridin oder Triäthylainin, durchgeführt, um die entstehende Säure NHThe acylation is carried out in a suitable solvent for the mitomycin C, for example in water, Methanol, acetone, pyridine, tetrahydrofuran or dimethylformamide, in the presence of an inorganic one Base, for example an alkali carbonate, or a organic base, for example pyridine or triethylainin, carried out to the resulting acid NH
zu neutralisieren, die sonst das Mitomycin C zersetzen und die Ausbeule verringern würde.to neutralize, which would otherwise decompose the mitomycin C and reduce the bulge.
Die erfindungsgemäßen Mitomycin C-Derivate wurden auf ihre antibaktericlle Wirksamkeit geprüft. Die nach der Agarplattenmcthode bestimmten Werte für die Mindesthcmmkonzentrationen und die Toxizitätswerle sind mit den entsprechenden Werten für das Mitomycin C in der folgenden Tabelle zusammengestellt. Die Verbindungen zeigen eine starke anlibaklcriclle Wirksamkeit. *The mitomycin C derivatives according to the invention were tested for their antibacterial effectiveness. The values for the minimum concentration and toxicity values determined by the agar plate method are compiled with the corresponding values for mitomycin C in the following table. The connections show a strong anlibaklcriclle Effectiveness. *
Antibakterielle Wirksamkeit (Mindesthemmkonzentration in μΒ/ und Toxizität (LD50 in mg/kg Maus bei intravenöser Verabreichung)Antibacterial effectiveness (minimum inhibitory concentration in μΒ / and toxicity (LD 50 in mg / kg mouse with intravenous administration)
H2NH 2 N
CH2-O-CO-NH2
OCH3 CH 2 -O-CO-NH 2
OCH 3
N — CO — RN - CO - R
-CH = CH -\_J> -CH = CH - \ _ J>
Staphylococcus aureus 209 P ...Staphylococcus aureus 209 P ...
Sarcina leutea Pci 1001 Sarcina leutea Pci 1001
Bacillus subtilis ATCC 6633 Bacillus subtilis ATCC 6633
Salmonella typhi 379 Salmonella typhi 379
Shigella flexneri Za 3196 Shigella flexneri Za 3196
Klebsiella pneumoniae 0/10 ....Klebsiella pneumoniae 0/10 ....
Proteus X 19 Proteus X 19
Escherichia coli K 12 Escherichia coli K 12
Pseudomonas aeruginosa 35 ....Pseudomonas aeruginosa 35 ....
Vibrio comma 62 Vibrio comma 62
Mycobacterium tuberculosis 607 Streptococcus haemolyticus 68 ..Mycobacterium tuberculosis 607 Streptococcus haemolyticus 68 ..
Streptococcus faecalis 5 Streptococcus faecalis 5
Diplococcus pneumoniae 1-19 Corynebacterium diphtheriae 92Diplococcus pneumoniae 1-19 Corynebacterium diphtheriae 92
Toxizität toxicity
4040
Die Herstellung der erfindungsgemäßen Verbindungen ist in den folgenden Beispielen beschrieben.The preparation of the compounds according to the invention is described in the following examples.
1 g Mitomycin C wurde in 50 ml wasserfreiem Tetrahydrofuran gelöst und die erhaltene Lösung mit 2 ml Triäthylamin versetzt. 500 mg Cinnamylchlorid, gelöst in 5 ml wasserfreiem Benzo!, wurden bei Raumtemperatur tropfenweise unter Rühren zugegeben. Nach 15minutigem Rühren fiel allmählich Triäthylamin-hydrochlorid aus. Das Reaktionsgemisch ι wurde zur Entfernung von Triäthylamin-hydrochlorid filtriert und das Filtrat unter vermindertem Druck zur Trockne eingedampft. Der Rückstand wurde in 10 ml Äthylacetat gelöst und an Kieselgel Chromatographien (Säule 2 x40 cm). Die Entwicklung mit Äthylacetat ergab zwei blaue Zonen. Die erste, größere Zone war das Reaktionsprodukt, während die zweite, kleinere Zone eine geringe Menge des Ausgangsproduktes enthielt.1 g of mitomycin C was dissolved in 50 ml of anhydrous tetrahydrofuran and the resulting solution mixed with 2 ml of triethylamine. 500 mg of cinnamyl chloride dissolved in 5 ml of anhydrous benzo !, were added dropwise at room temperature with stirring. After stirring for 15 minutes, it gradually fell Triethylamine hydrochloride from. The reaction mixture was used to remove triethylamine hydrochloride filtered and the filtrate evaporated to dryness under reduced pressure. The residue was in 10 ml of ethyl acetate dissolved and chromatographed on silica gel (column 2 × 40 cm). The development with Ethyl acetate gave two blue zones. The first, larger zone was the reaction product, while the second, smaller zone a small amount of the starting product contained.
Die erste Zone wurde mit Äthylacetat eluiert, das Eluat eingedampft und der Rückstand au.; Metha-0,78 1,56 0,78 25 12,5 12,5 6,25 6,25 6,25 0,195 0,39 0,78 1,56 0,024 0,195The first zone was eluted with ethyl acetate, the eluate was evaporated and the residue was removed; Metha-0.78 1.56 0.78 25 12.5 12.5 6.25 6.25 6.25 0.195 0.39 0.78 1.56 0.024 0.195
2626th
nol kristallisiert. Es wurden etwa 1000 mg la-Cinnamyl-mitomycin
C in blauen Nadeln erhalten. Schmelzpunkt: über 300° C.
Elementaranalyse für C2^H24O6N4:nol crystallizes. About 1000 mg of la-cinnamyl-mitomycin C were obtained in blue needles. Melting point: over 300 ° C.
Elemental analysis for C 2 ^ H 24 O 6 N 4 :
Berechnet ... C 62,06, H 5,21, N 12,06%; gefunden ... C 61,86, H 5,05, N 12,30%.Calculated ... C 62.06, H 5.21, N 12.06%; found ... C 61.86, H 5.05, N 12.30%.
Das IR-Spektrum in Paraffinöl ist in F i g. 1 wiedergegeben. The IR spectrum in paraffin oil is shown in FIG. 1 reproduced.
B e i.s ρ i e 1 2B e i.s ρ i e 1 2
Die Arbeitsweise vom Beispiel 1 wurde wiederholt unter Verwendung von 500 mg Chlorkohlensäureäthylester. Es wurden 850 mg la-Äthoxycarbonylmitomycin C in purpurnen nadelfömiigen Kristallen erhalten. Schmelzpunkt: 185°C.The procedure of Example 1 was repeated using 500 mg of ethyl chlorocarbonate. There were 850 mg of la-ethoxycarbonylmitomycin C in purple needle-shaped crystals receive. Melting point: 185 ° C.
Elementaranalyse für C8H22O7N4:Elemental analysis for C 8 H 22 O 7 N 4 :
Berechnet ... C 53,20, H 5,46, N 13,76%; gefunden ... C 53,05, H 5,61, N 13,65%.Calculated ... C 53.20, H 5.46, N 13.76%; Found ... C 53.05, H 5.61, N 13.65%.
Das IR-Spektrum in Paraffinöl is:t in F i g. 2 wiedergegeben. The IR spectrum in paraffin oil is: t in FIG. 2 reproduced.
Hierzu 1 Blatt Zeichnungen1 sheet of drawings
Claims (1)
Family
ID=
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