DE1593961C - - Google Patents
Info
- Publication number
- DE1593961C DE1593961C DE1593961C DE 1593961 C DE1593961 C DE 1593961C DE 1593961 C DE1593961 C DE 1593961C
- Authority
- DE
- Germany
- Prior art keywords
- erythromycin
- desosaminyl
- pentadecan
- hexamethyl
- trihydroxy
- 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.)
- Active
Links
- KYTWXIARANQMCA-ZTILBQITSA-N (3R,4S,5S,6R,7R,9R,10E,11S,12R,13S,14R)-6-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-ZTILBQITSA-N 0.000 claims description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229960003276 erythromycin Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 240000005855 Dictamnus albus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 1
- FETSNIOLRHZWCD-UHFFFAOYSA-N CCC1OC(=O)C(C)CC(C)CC(C)(O)CC(C)CC(C)C(O)C1(C)O Chemical compound CCC1OC(=O)C(C)CC(C)CC(C)(O)CC(C)CC(C)C(O)C1(C)O FETSNIOLRHZWCD-UHFFFAOYSA-N 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 206010040550 Shigella infection Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229940076185 Staphylococcus aureus Drugs 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 244000052616 bacterial pathogens Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- PRUSTPADOGZAML-LMXGZOGMSA-N erythromycin E Chemical compound C([C@H]1C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@@H](C)[C@@H]1O1)(C)O)CC)O[C@]21C[C@@](C)(OC)[C@@H](O)[C@H](C)O2 PRUSTPADOGZAML-LMXGZOGMSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003638 reducing agent 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
Die Erfindung betrifft das ^Amino-S-O-cladinosyl-S-O-desosaminyl-ö, 11,12-trihydroxy-2,4,6,8,10,12-hexamethyl-pentadecan-13-olid der Formel A :"The invention relates to the ^ amino-S-O-cladinosyl-S-O-desosaminyl-ö, 11,12-trihydroxy-2,4,6,8,10,12-hexamethyl-pentadecan-13-olide of the formula A: "
H,C H CH, H OH CH OHH, C H CH, H OH CH OH
HOHO
HOHO
H,CH, C
OHOH
sowie ein Verfahren zu dessen Herstellung.and a method for its production.
Es wurde gefunden, daß diese Verbindung antibiotische Aktivität aufweist und hierin dem Erythromycin überlegen ist. Es wurden Versuche mit einigen pathogenen Mikroorganismen durchgeführt, wobei die minimale inhibitorische Konzentration der zu prüfenden Substanzen in der Weise ermittelt wurde, daß nach der Dilutionsmethode nach Ramellk a m p, »Brain Heart Infusion«, bei einem pH-Wert von 7,2 gearbeitet und das Ergebnis in mcg/ml ausgedrückt wurde. Die erhaltenen Ergebnisse sind in der folgenden Tabelle I zusammengestellt.This compound was found to have antibiotic activity, and herein erythromycin is superior. Experiments have been carried out with some pathogenic microorganisms, with the minimum inhibitory concentration of the substances to be tested was determined in such a way that according to the Ramellk a m p dilution method, "Brain Heart Infusion", at a pH value of 7.2 worked and the result expressed in mcg / ml would. The results obtained are summarized in Table I below.
MikroorganismusMicroorganism
A.aerogenes A. aerogenes
Escher, coli B Escher, coli B.
Escher, coli C Escher, coli C.
Salmonella typhi L-T 2Salmonella typhi L-T 2
Shigella YGR Shigella YGR
Staphylococcus aureusStaphylococcus aureus
ErythromycinErythromycin
128,0
128,0
128,0
128,0
128,0
16,0 bis 32,0128.0
128.0
128.0
128.0
128.0
16.0 to 32.0
Verbindung AConnection A
64,0
32,0
32,0
64,064.0
32.0
32.0
64.0
32,0 bis 64,0 8,032.0 to 64.0 8.0
Aus den gefundenen Werten ist ersichtlich, daß die neue Verbindung A im Gegensatz zu dem bekannten Erythromycin eine bessere Wirkung aufweist.From the values found it can be seen that the new compound A, in contrast to the known Erythromycin has a better effect.
Ein weiterer bedeutender Vorteil der Verbindung A im Vergleich zu dem Erythromycin ist seine Stabilität in einem sauren Medium vom pH-Wert 2. In der folgenden Tabelle II sind die Aktivitätswerte der geprüften Verbindungen angegeben, die bei den Stabilitätsversuchen bei einem pH-Wert von 2 nach der in »British Pharmacopoeia«, 1968, S. 1313 bis 1318, angegebenen Methode erhalten wurden.Another important advantage of compound A compared to erythromycin is its stability in an acidic medium of pH 2. In the following Table II the activity values are those tested Compounds indicated that were found in the stability tests at a pH value of 2 according to the in "British Pharmacopoeia", 1968, pp. 1313 to 1318, given method were obtained.
3535
4040
Erythromycin E/mg..Erythromycin E / mg ..
9 - Amino - 3 - O - cladinosyl-5-O-desosaminyl-6,ll,12-trihydroxy-2,4,6,8,10,12-hexamethyl - pentadecan- 13-olid E/mg9 - Amino - 3 - O - cladinosyl-5-0-desosaminyl-6, ll, 12-trihydroxy-2,4,6,8,10,12-hexamethyl - pentadecan-13-olide U / mg
Aktivität nach StundenActivity after hours
875875
460460
Spurensense
370370
330330
292292
Durch den Ausdruck E/mg wird die Aktivität des Antibiotikums pro Milligramm der Substanz ausgedrückt, wobei der Buchstabe »E« nach dem deutschen Wort »Einheit« verwendet worden ist.The expression U / mg expresses the activity of the antibiotic per milligram of the substance, where the letter "E" was used after the German word "Einheit".
Das 9 -Amino - 3 - O - cladino sy 1 - 5 - O - desosaminyl-'The 9-amino - 3 - O - cladino sy 1 - 5 - O - desosaminyl- '
6,11,12 -trihydroxy-2,4,6,8,10,12 -hexamethyl - pentadecan-13-olid wird dadurch hergestellt, daß man Erythromycinoxim in an sich bekannter Weise redu-6,11,12 -trihydroxy-2,4,6,8,10,12 -hexamethyl-pentadecan-13-olide is produced by reducing erythromycin oxime in a manner known per se
. ziert.. adorns.
Für die Reduktion eignet sich als Reduktionsmittel z. B. Natriumborhydrid.A suitable reducing agent for the reduction is e.g. B. sodium borohydride.
Das als Ausgangsmaterial zu verwendende Erythromycinoxim kann in üblicher Weise aus Erythromycin hergestellt werden.The erythromycin oxime to be used as the starting material can be prepared from erythromycin in the usual manner getting produced.
Zu einer Lösung von 10,0 g Erythromycinoxim in 100 ml Methanol wird in geringen Mengen 3,0 g rohes Natriumborhydrid im Verlauf von 4 Stunden zugesetzt, wobei die Temperatur des Reaktionsgemisches 100C nicht überschreiten darf. Das Reak- tionsgemisch wird anschließend 2 Stunden bei Zimmertemperatur stehen gelassen und hierauf trockenes, gasförmiges Kohlendioxyd eingeleitet. Der entstandene Niederschlag wird abfiltriert und das Filtrat beiTo a solution of 10.0 g of erythromycin oxime in 100 ml of methanol, 3.0 g of crude sodium borohydride is added in small amounts over the course of 4 hours, the temperature of the reaction mixture not being allowed to exceed 10 ° C. The reaction mixture is then left to stand for 2 hours at room temperature and dry, gaseous carbon dioxide is then passed in. The resulting precipitate is filtered off and the filtrate is added
Zimmertemperatur im Vakuum zur Trockne eingedampft. Der erhaltene Niederschlag wird in 100 ml Chloroform gelöst und die Lösung 3mal mit je 25 ml 10%iger wäßriger Natriumbikarbonatlösung und 2mal mit je 25 ml Wasser gewaschen. Der Chloroformextrakt wird danach über Natriumsulfat getrocknet, filtriert und im Vakuum zur Trockne eingedampft. Aus dem als Rückstand erhaltenen rohen 9-Amino-3-O-cladinosyl-5-O-desosaminyl-6,ll,12-trihydroxy-2,4,6,8,10,12-hexamethyl-pentadecan-13-olid wird die gereinigte Verbindung vom F. 124 bis 127° C, [n]f = -52,25° (Konz. = 1% in Methanol) in üblicher Weise auf chromatogiaphischem Weg unter Verwendung von Silicagel und eines Gemisches aus Butanol-Essigsäure-Wasser (3:1:1) und/oder durch Umkristallisation aus Äther—Petroläther erhalten.Evaporated to dryness in vacuo at room temperature. The resulting precipitate is dissolved in 100 ml of chloroform and the solution is washed 3 times with 25 ml of 10% aqueous sodium bicarbonate solution each time and 2 times with 25 ml of water each time. The chloroform extract is then dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude 9-amino-3-O-cladinosyl-5-O-desosaminyl-6, ll, 12-trihydroxy-2,4,6,8,10,12-hexamethyl-pentadecan-13-olide obtained as residue becomes the purified compound from mp 124 to 127 ° C, [n] f = -52.25 ° (conc. = 1% in methanol) in the usual way by chromatography using silica gel and a mixture of butanol-acetic acid-water (3: 1: 1) and / or obtained by recrystallization from ether-petroleum ether.
Claims (2)
Family
ID=
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