DE1668624C - Process for the preparation of 3 Oxo 17 beta hexahydrobenzyloxy carbonyloxy ostra 4,9,11 triene - Google Patents
Process for the preparation of 3 Oxo 17 beta hexahydrobenzyloxy carbonyloxy ostra 4,9,11 trieneInfo
- Publication number
- DE1668624C DE1668624C DE1668624C DE 1668624 C DE1668624 C DE 1668624C DE 1668624 C DE1668624 C DE 1668624C
- Authority
- DE
- Germany
- Prior art keywords
- triene
- oxo
- preparation
- hexahydrobenzyloxy
- ostra
- 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
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000005671 trienes Chemical class 0.000 title description 2
- 241000237519 Bivalvia Species 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 230000001548 androgenic Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000001195 anabolic Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AOQONNCNKUWWRI-UHFFFAOYSA-N cyclohexylmethyl carbonochloridate Chemical compound ClC(=O)OCC1CCCCC1 AOQONNCNKUWWRI-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 206010003549 Asthenia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010061428 Decreased appetite Diseases 0.000 description 1
- 208000008466 Metabolic Disease Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229960003604 Testosterone Drugs 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 208000000558 Varicose Ulcer Diseases 0.000 description 1
- GPTIZNPODRMHFN-UHFFFAOYSA-M [O-]C(=O)OCC1CCCCC1 Chemical compound [O-]C(=O)OCC1CCCCC1 GPTIZNPODRMHFN-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- -1 hexahydrobenzyl Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Description
O=O =
in der R den Hexahydrobenzylrest bedeutet, dadurch gekennzeichnet, daß man Hexahydrobenzylchlorrormiat aur das 3-Oxo-17/9-hydroxy-östra-4,9,11-trien in Gegenwart einer tertiären Base einwirken läßt.in which R denotes the hexahydrobenzyl radical, characterized in that one hexahydrobenzyl chloromate aur 3-oxo-17/9-hydroxy-estra-4,9,11-triene allowed to act in the presence of a tertiary base.
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von ß-Oxo-n/i-hexahydrobenzyloxycarbonyloxy-östra-4,9,11-trien der allgemeinen FormelThe present invention relates to a process for the preparation of ß-oxo-n / i-hexahydrobenzyloxycarbonyloxy-estra-4,9,11-triene the general formula
3535
in der R den Hexahydrobenzylrest bedeutet, das dadurch gekennzeichnet ist, daß man Hexahydrobenzylchlorformiat auf das 3-Oxo-17/i-hydroxy-östra-4,9,l 1-trien in Gegenwart einer tertiären Base einwirken läßt.in which R denotes the hexahydrobenzyl radical, which is characterized in that one hexahydrobenzyl chloroformate to the 3-oxo-17 / i-hydroxy-estra-4,9, l 1-triene allowed to act in the presence of a tertiary base.
Dieses Produkt besitzt interessante therapeutische Eigenschaften. Es besitzt insbesondere eine bedeutende und verlängerte anabolischc Wirkung.This product has interesting therapeutic properties. In particular, it has a significant and prolonged anabolic effects.
Die Wirkung des in 17-Stellung Sauerstoff enthaltenden 3-Oxogona-4,9,l 1-triens ist bereits bekannt. Diese Verbindungen besitzen eine androgene und eine intensive anabolische Wirkung. Die Aktivitäten dieser Verbindungen besitzen jedoch im allgemeinen eine kurze Wirkungsdauer, und deshalb ist eine wiederholte Verabreichung notwendig.The effect of containing oxygen in the 17-position 3-Oxogona-4,9,11-triens is already known. These compounds have one androgenic and one intense anabolic effect. However, the activities of these compounds generally have one short duration of action and therefore repeated administration is necessary.
Es wurde nun gefunden, daß die nach dem beanspruchten Verfahren herstellbare Verbindung sich durch eine bedeutende anabolische Wirksamkeit auszeichnet, deren Wirksamkeit nicht nur bemerkenswert verlängert ist, sondern außerdem auch sofort eintritt. Darüber hinaus wurde festgestellt, daß diese Verbindung keine androgene Wirkung auf den Menschen besitzt, während die Trienausgangsverbindung oder gleichartige Ester, wie beispielsweise das Testosteronhexahydrobenzylcarbonat, sehr intensive androgene Wirkungen zeigen.It has now been found that the connection which can be produced by the claimed method is possible characterized by a significant anabolic effectiveness, the effectiveness of which is not only remarkable is extended, but also occurs immediately. It was also found that this compound has no androgenic effect on humans, while the triene parent compound or similar esters, such as testosterone hexahydrobenzyl carbonate, show very intense androgenic effects.
Ohne daß dies vorauszusehen war, zeigt sich also, daß die Veresterung mit Hexahydrobenzoyloxychloramcisensäureester die therapeutische Aktivität der <>5 Ausgangsverbindung tiefgehend verändert, indem sie gleichzeitig einen Einfluß auf die Wirkungsdauer, auf die Art der Wirkung und auf die Eigenschaften der Wirkung ausübt (vgl. hierzu auch französisches Brevet special de medicament No. 5979 M).Without this being foreseen, it turns out that that the esterification with Hexahydrobenzoyloxychloramcisensäureester the therapeutic activity of the <> 5 parent compound profoundly changed by at the same time an influence on the duration of action, on the type of effect and on the properties of the Has an effect (see also French Brevet special de medicament No. 5979 M).
Darüber hinaus scheint es bemerkenswert, daß bei der klinischen Untersuchung selbst bei erhöhter Dosierung bei Kranken weiblichen Geschlechtes, bei denen das Produkt verabreicht wurde, kein Anzeichen Tür eine androgene Wirkung entdeckt wurde.In addition, it seems noteworthy that on clinical examination even at elevated levels Dosage in female patients to whom the product has been administered, no indication Door an androgenic effect was discovered.
Das 3 - Oxo - 17/i - hexahydrobenzoyloxycarbonyloxy-östra-4,9,11-trien kann zur Behandlung der Störungen des Proteinanabolismus, der Asthenie und Magersucht, Seneszenz, der Osteoporose, der Störungen des Stoffwechsels bei längerer Corticotherapie, der Fibrome und bei der ergänzenden Behandlung des Mamma-Carzinomes und als Mittel zur Vernarbung bei der Behandlung variköser UIcera verwendet werden, wobei es transcutan oder rectal verabreicht wird.The 3 - oxo - 17 / i - hexahydrobenzoyloxycarbonyloxy-estra-4,9,11-triene can be used to treat disorders of protein anabolism, asthenia and Anorexia, senescence, osteoporosis, metabolic disorders with prolonged corticotherapy, the fibroids and in the complementary treatment of the mammary carcinoma and as a means of scarring used in the treatment of varicose ulcers, either transcutaneously or rectally is administered.
Die verwendete Dosierung liegt beim Erwachsenen in Abhängigkeit von der Art der Verabreichung zwischen 25 und 250 mg (in freiem Alkohol ausgedrückt) pro Einnahme.The dosage used in the adult depends on the route of administration between 25 and 250 mg (expressed in free alcohol) per intake.
3-Oxo-17/i-hexahydrobenzoyloxycarbonyloxyöstra-4,9,11-trien 3-Oxo-17 / i-hexahydrobenzoyloxycarbonyloxyestra-4,9,11-triene
Man löst bei 0°C unter Rühren und in einer Stickstoffatmosphäre 3 g des S-Oxo-H/i-hydroxy-östra-4,9,11-triens in 15 cm3 Pyridin und fügt langsam 6 cm3 Hexahydrobenzylchloroformiat hinzu, wobei die Temperatur zwischen 0 und + 100C gehalten wird. Man bringt aur Raumtemperatur, rührt 2'/2 Stunden, kühlt auf O0C ab, fügt 0,9 cm3 Triäthylamin hinzu, läßt die Temperatur unter 30minutigem Rühren auf Raumtemperatur zurückkommen und schüttet die Reaktionsmischung in eine Wasser-Eis-Mischung. Man extrahiert mit Methylenchlorid, wäscht die organischen Phasen bis zur Neutralität mit Wasser, trocknet sie über Natriumsulfat und verdampft unter Vakuum zur Trockne. Der Rückstand wird an Kieselgel chromatographiert, mit einer Mischung Benzol/Essigsäureäthylester (4:1) eluiert und in der Mischung Isopropyläther/Hexan umkristallisiert. Man chromatographiert noch einmal an Kieselgel, eluiert mit einer Mischung Benzol/Essigsäureäthylester und kristallisiert in Cyclohexan und Petroläther um. Es werden 1,60 g 3-Oxo-17/Miexahydrobenzyloxycarbonyloxy - östra - 4,9,11 - trien erhalten. Dissolve at 0 ° C with stirring and in a nitrogen atmosphere 3 g of S-oxo-H / i-hydroxy-estra-4,9,11-triene in 15 cm 3 of pyridine and slowly adds 6 cm 3 of hexahydrobenzyl chloroformate, the Temperature between 0 and + 10 0 C is kept. Bringing aur room temperature, stirred for 2 '/ 2 hours and cooled to 0 ° C., added 0.9 cm 3 of triethylamine, the temperature below 30minutigem stirring allowed to return to room temperature and pour the reaction mixture into a water-ice mixture. It is extracted with methylene chloride, the organic phases are washed until neutral with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel, eluted with a benzene / ethyl acetate mixture (4: 1) and recrystallized from the isopropyl ether / hexane mixture. It is chromatographed once more on silica gel, eluted with a benzene / ethyl acetate mixture and recrystallized from cyclohexane and petroleum ether. 1.60 g of 3-oxo-17 / miexahydrobenzyloxycarbonyloxy-estra-4,9,11-triene are obtained.
F. = 90 bis 95°C (Koflerblock), [Vp' = + 41,6° (c = 0,5%, Äthanol).F. = 90 to 95 ° C (Kofler block), [Vp '= + 41.6 ° (c = 0.5%, ethanol).
Das Produkt liegt in Form von in Alkohol, Äther, Benzol, Aceton und Chloroform löslicher und in Wasser, mit Wasser verdünnten Säuren und Alkalien unlöslichen Prismen vor.The product lies in the form of and is soluble in alcohol, ether, benzene, acetone and chloroform Water, acids and alkalis diluted with water present insoluble prisms.
Analyse: C2nH14O4 = 410,53.Analysis: C 2n H 14 O 4 = 410.53.
Berechnet ... C 76.06. H 8,34%;
gerunden .... C 76,4, H 8,4%.Calculated ... C 76.06. H 8.34%;
rounded .... C 76.4, H 8.4%.
IR-Spektrum:.IR spectrum:
Anwesenheit von Carbonat C = O bei 1738 cm ', C — O bei 1270 cm"'.Presence of carbonate C = O at 1738 cm ', C - O at 1270 cm "'.
Trienon C = O komplexe Bande um 1650 cm^1, C = C bei 1576cm-1.Trienone C = O complex band around 1650 cm ^ 1 , C = C at 1576 cm -1 .
UV-Spektrum (Äthanol):
/.muv bei 237 ηΐμ, /·■ = 6 240,
hifi. ιιηι270ιημ,
<■■ = 3 570,
W bei 339 mμ, , = 29 600.UV spectrum (ethanol):
/. muv at 237 ηΐμ, / ■ = 6 240,
Hi-Fi. ιιηι270ιη μ , <■■ = 3 570,
W at 339 m.mu., = 29 600th
Claims (1)
Family
ID=
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