CH536296A - Oestratriene-3-cyclopentyl ethers oestrogeni - regulators - Google Patents
Oestratriene-3-cyclopentyl ethers oestrogeni - regulatorsInfo
- Publication number
- CH536296A CH536296A CH1870472A CH1870472A CH536296A CH 536296 A CH536296 A CH 536296A CH 1870472 A CH1870472 A CH 1870472A CH 1870472 A CH1870472 A CH 1870472A CH 536296 A CH536296 A CH 536296A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- tetrahydrofuran
- estratriene
- cyclopentyloxy
- acetoxy
- Prior art date
Links
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 14
- -1 3-cyclo pentyloxy Chemical group 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 9
- HLCRYAZDZCJZFG-BDXSIMOUSA-N (8s,9s,13s,14s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene Chemical compound C1CC2=CC=CC=C2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 HLCRYAZDZCJZFG-BDXSIMOUSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- BOTLEXFFFSMRLQ-UHFFFAOYSA-N cyclopentyloxycyclopentane Chemical compound C1CCCC1OC1CCCC1 BOTLEXFFFSMRLQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 150000002085 enols Chemical class 0.000 claims description 4
- 238000006735 epoxidation reaction Methods 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- OVMHABLOXWFPMV-UHFFFAOYSA-N acetyloxycarbonyl acetate Chemical compound CC(=O)OC(=O)OC(C)=O OVMHABLOXWFPMV-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 229960003399 estrone Drugs 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 230000001076 estrogenic effect Effects 0.000 abstract description 4
- 230000001836 utereotrophic effect Effects 0.000 abstract description 4
- 238000002513 implantation Methods 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 210000001109 blastomere Anatomy 0.000 abstract description 2
- 238000003776 cleavage reaction Methods 0.000 abstract description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 abstract description 2
- 230000035558 fertility Effects 0.000 abstract description 2
- 230000007017 scission Effects 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000027326 copulation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000624 ovulatory effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/168—Steroids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/184—Hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Animal Husbandry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
Substd. oestratriene-3-cyclopentyl ethers, oestrogenic uterotropic, fertility regulators. 7-Alpha-methyl-3-16alpha, 17-trihydroxy-DELTA 1,3,5,(10)-oestratriene-3-cyclopentyl ethers are of formula in which the 17-OH grp. may be alpha or beta, and R is H or acetyl. They may be prepared by etherifying the corres. 3-OH cpd. with cyclopentanol, by reduction of 3-cyclopentyloxy-7alpha-methyl-16alpha-acyloxy-17-keto-DELTA 1,3,5,(10)-oestratriene or by reaction of 3-cyclopentyloxy-7alpha-methyl-DELTA 1,3,5,(10e,16-oestratraene with OsO4 and cleavage of the osmiate. The 16, 17-dihydroxy cpd. may be acetylated if desired. The cpds. have oestrogenic, uterotropic and blastocyte implantation inhibiting activities.
Description
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung des 3-Cyclopentyläthers des 70c- -Methyl- 3rlG9csl7B¯ trihydroxy A1s3s5(10)¯ östratriens der Formel
EMI1.1
Diese Verbindung besitzt wertvolle pharmakologische Eigenschaften. So wirkt sie vor allem östrogen, uterotrop und / oder Blasto cyten-impiantationshemmend. Sie zeigt z.B. eine östrogene Wirkung bei einmaliger oraler Applikation im Vaginalkeratinisiernngstest an der weiblichen Ratte bei Dosen von 0,1 bis 10 mg/kg. Die uterotrope Wirksamkeit kann an der weiblichen Ratte bereits nach einmaliger peroraler Applikation von Dosen von 1 bis 10 mg/kg nachgewiesen werden.
Die Blastacytenimplantationshemmende Eigenschaft lässt sich an normalen Ratten nach Kopulation mit einer einmaligen peroral gegebenen Dosis von 0,1 bis 0,3 mg/kg demonstrieren und die Störung der vaginalen und ovulatorischen Zyklen der weiblichen Ratte mit einmaliger peroraler Applikation von 1 mg/kg beheben. Die neue Verbindung kann somit als östrogenes Mittel und zur Steuerung der Fertilität verwendet werden.
Die neue Verbindung der Formel I wird erhalten, wenn man erfindungsgemäss eine Verbindung der Formel
EMI1.2
bzw. der Formel
EMI1.3
worin entweder R1 eine Oxogruppe und R2 eine a-ständige veresterte Hydroxygruppe zusammen mit einem Wasserstoffatom, oder R1 eine S-ständige freie oder veresterte Hydroxygruppe zusammen mit einem Wasserstoffatom und R2 eine Oxogruppe und R eine B-ständige veresterte Hydroxylgruppe darstellen, reduziert, aus dem Reaktionsgemisch das Umsetzungsprodukt isoliert und falls in der erhaltenen Verbindung in 16- und/oder 17 Stellung veresterte Hydroxygruppen vorhanden sind, diese in an sich bekannter Weise zu freien Hydroxygruppen spaltet.
Die vorgenannte Reduktion erfolgt zweckmässig in an sich bekannter Weise. So kann man eine 16a-Acyl- oxy- 1 7-oxo-Verbindung oder eine 1i,17cc-Epaxy-17F- -acyloxy-verbindung mit einem Bileichtmetallhydrid, vorzugsweise Lithiumaluminiumhydrid oder Natriuntborhy- drid reduzieren. Man kann diese Reduktion aber auch katalytisch, z.B. mit Wasserstoff in Gegenwart eines Platinkatalysators vornehmen. Die 16-Oxo-17,-hydroxy- verbindung, deren Hydroxylgruppe auch verestert sein kann, wird vorzugsweise mit nascierendem Wasserstoff, wie er z.B. durch Natrium in einem Alkohol erzeugt wird, oder auch katalytisch, in Gegenwart z.B. eines Platinkatalysators reduziert.
Gegebenenfalls vorhandene veresterte Hydroxygruppen werden in üblicher Weise zur freien Hydroxygruppe gespalten.
Die Abtrennung der gewünschten Verbindung aus den gegebenenfalls isomere Verbindungen erhaltenden Reaktionsgemisch erfolgt in an sich bekannter Weise z.B. durch fraktionierte Kristallisation oder Chromatographie.
Die Spaltung der veresterten Hydroxylgruppen erfolgt in an sich bekannter Weise, in erster Linie basisch oder hydrogenolytisch, z.B. mit Lithiumaluminiumhydrid.
Die Ausgangsstoffe der Formel IIa bzw. IIb lassen sich in an sich bekannter Weise z.B. durch Verätherung der entsprechenden 3-Hydroxyverbindungen mit Cyclopentanol erhalten lassen.
Das neue Verfahrensprodukt kann als Heilmittel in Form von pharmazeutischen Präparaten verwendet werden, welche diese Verbindung zusammen mit pharmazeutischen organischen oder anorganischen, festen oder flüssigen Trägerstoffen, die für enterale, insbesondere orale oder parenterale Gabe geeignet sind, enthalten.
Für die Bildung derselben 'kommen solche Stoffe in Frage. die mit den neuen Verbindungen nicht reagieren.
Die pharmazeutischen Präparate können in fester oder in flüssiger Form vorliegen. Gegebenenfalls enthalten sie Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz: oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer. Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten. Die pharmazeutischen Präparate werden nach an sich üblichen Methoden gewonnen.
Die neue Verbindung der Formel I kann auch in der Tiermedizin z.B. in einer der obgenannten Formen, oder in Form von Futtermitteln oder von Zusätzen für Tierfutter verwendet werden. Dabei lassen sich z.B. die üblichen Streck- und Verdünnungsmittel bzw. Futtermittel anwenden.
In den folgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben.
Beispiel I
2,0 g 3-Cyclopentyloxy-7-methyl-16x,170c-epoxy-173- -acetoxy-9135fl0)-östratrien werden in 100ml Tetrahy drofuran gelöst und zu einer gerührten Suspension von
2,0 g Lithiumaluminiumhydrid in 150 mg Tetrahydrofuran zugetropft. Das Reaktionsgemisch rührt man wei tere 50 Minuten bei ca. 400, kühlt dann ab, setzt trop fenweise 10 ml Essigester in 40 ml Tetrahydrofuran und anschliessend 5 ml Wasser in 30 ml Tetrahydrofuran zu, filtriert das ausgefallene Aluminiumhydroxyd ab und dampft das Filtrat im Wasserstrahlvakuum ein.
Durch Chromatographie des Rohproduktes am Silicagel und anschliessende Kristallisation wird das reine 3-Cyclo pentyloxy - 7α - methyl-16α,17ss-dihydroxy-#1,3,5(10)-östra- trien von Smp. 107 - 114 ; [α]D20 = +47 (in Chloroform) gewonnen.
Der als Ausgangsstoff verwendete Cyclopentyläther wird aus 7a-Methyl-östron durch Verätherung z.B. mit
Cyclopentylbromid, anschliessende Enolacetylierung mittels Acetanhydrid/Pyridin, und Epoxydierung des ge bildeten 3 - Cyclopentyloxy - 7cc - methyl- 17-acetoxy - 5 < '5 > 16-östratetraens mit einer Persäure, z.B. mit m-Chlor- perbenzoesäure in Methylenchlorid, herstellt.
Beispiel 2
Man tropft 1,50 g 3-Cyclopentyloxy-7α-methyl-16α- -acetoxy-17-oxo-#1,3,5(10)-östratrien in 70 ml absolutem Tetrahydrofuran bei ca. 5-10 C zu einer Suspension von 600 mg Lithiumaluminiumhydrid in 30 ml absoluten Tetrahydrofuran, spült mit 50 ml Tetrahydrofuran nach und kocht die Reaktionsmischung 4 Stunden am Rückflusskühler.
Das auf ca. 50 abgekühlte Gemisch wird nacheinander tropfenweise mit 5 ml Essigester in 10 ml Tetrahydrofuran und 4,5 ml Wasser in 10 ml Tetrahydrofuran versetzt, von ausgefallenen anorganischen Anteilen abgenutscht und im Wasserstrahlvakuum eingedampft. Durch Kristallisation des anfallenden amorphen Rohproduktes aus Toluol wird das bei 106- 1120 schmelzende 3-Cyclopentyloxy - 7α - methyl-16α,17ss-dihydroxy - #1,3,5(10)-östra- trien erhalten.
Das als Ausgangsstoff verwendete Acetoxyketon wird aus 7,oc-Methylöstron durch Verätherung z.B. mit Cyclopentylbromid, anschliessende Enolacetylierung durch Erwärmen einer Pyridinlösung des Cyclopentyläthers mit Acetanhydrid, Epoxydierung des gebildeten A16-Enol- acetats mit m-Chlorperbenzoesäure und milde saure Hydrolyse des Epoxyds gewonnen.
PATENTANSPRUCiI
Verfahren zur Herstellung des östrogen hochwirksamen 3 -Cyclopentyläthers des 7α-Methyl-3,16α, 17ss-trihy- droxy-Al 35(l0)-östratriens der Formel
EMI2.1
dadurch gekennzeichnet, dass man eine Verbindung der Formel
EMI2.2
oder der Formel
EMI2.3
worin entweder R1 eine Oxogruppe und R3 eine oc-stän- dige veresterte Hydroxygruppe zusammen mit einem Wasserstoffatom, oder R, eine 0-ständige freie oder veresterte Hydroxygruppe zusammen mit einem Wasserstoffatom und R5 eine Oxogruppe und R eine ,8-ständige veresterte Hydroxylgruppe darstellen, reduziert,
aus dem Reaktionsgemisch das Umsetzungsprodukt isoliert und falls in der erhaltenen Verbindung veresterte Hydroxygruppen vorhanden sind diese zur freien Hydroxygruppe spaltet.
UbITERANSPRÜCHE
1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man das 3-Cyclopentyloxy-7-methyl-160c- -acetoxy- 17-oxo-1,5,5 (10) -östratrien mit Lithiumaluminiumhydrid reduziert.
2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man das 3-Cyclopentyloxy-70Ç-methyl- - 16c ,170c-epoxy- 17ss-acetoxy-#1,3,5(10)-östratrien mit Lithiumaluminiumhydrid reduziert.
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The present invention relates to a process for the preparation of the 3-cyclopentyl ether of 70c- -Methyl- 3rlG9csl7B¯ trihydroxy A1s3s5 (10) ¯ oestratriene of the formula
EMI1.1
This compound has valuable pharmacological properties. It has a particularly estrogenic, uterotropic and / or blastocyte implantation inhibiting effect. It shows e.g. an estrogenic effect after a single oral application in the vaginal keratinization test on the female rat at doses of 0.1 to 10 mg / kg. The uterotropic efficacy can already be demonstrated in the female rat after a single oral application of doses of 1 to 10 mg / kg.
The blastacyte implantation-inhibiting property can be demonstrated in normal rats after copulation with a single oral dose of 0.1 to 0.3 mg / kg and the disturbance of the vaginal and ovulatory cycles of the female rat can be remedied with a single oral administration of 1 mg / kg. The new compound can thus be used as an estrogenic agent and for controlling fertility.
The new compound of the formula I is obtained when, according to the invention, a compound of the formula
EMI1.2
or the formula
EMI1.3
wherein either R1 is an oxo group and R2 is an a-position esterified hydroxyl group together with a hydrogen atom, or R1 is an S-position free or esterified hydroxyl group together with a hydrogen atom and R2 is an oxo group and R is a B-position esterified hydroxyl group, reduced from the Reaction mixture isolates the reaction product and, if esterified hydroxyl groups are present in the compound obtained in the 16- and / or 17-position, this cleaves in a manner known per se to give free hydroxyl groups.
The aforementioned reduction is expediently carried out in a manner known per se. For example, a 16a-acyl-oxy-17-oxo compound or a 1i, 17cc-epaxy-17F-ayloxy compound can be reduced with a light metal hydride, preferably lithium aluminum hydride or sodium borohydride. However, this reduction can also be carried out catalytically, e.g. with hydrogen in the presence of a platinum catalyst. The 16-oxo-17, -hydroxy compound, the hydroxyl group of which can also be esterified, is preferably treated with nascent hydrogen, as e.g. generated by sodium in an alcohol, or else catalytically, in the presence of e.g. a platinum catalyst reduced.
Any esterified hydroxyl groups present are cleaved in the customary manner to give the free hydroxyl group.
The desired compound is separated off from the reaction mixture, which may contain isomeric compounds, in a manner known per se, e.g. by fractional crystallization or chromatography.
The cleavage of the esterified hydroxyl groups takes place in a manner known per se, primarily basic or hydrogenolytic, e.g. with lithium aluminum hydride.
The starting materials of the formula IIa or IIb can be used in a manner known per se, e.g. can be obtained by etherifying the corresponding 3-hydroxy compounds with cyclopentanol.
The new process product can be used as a remedy in the form of pharmaceutical preparations which contain this compound together with pharmaceutical organic or inorganic, solid or liquid carriers which are suitable for enteral, in particular oral or parenteral administration.
Such substances come into question for the formation of the same. which do not react with the new connections.
The pharmaceutical preparations can be in solid or liquid form. They may contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The pharmaceutical preparations are obtained according to conventional methods.
The new compound of formula I can also be used in veterinary medicine e.g. in one of the forms mentioned above, or in the form of feed or additives for animal feed. For example, use the usual extenders and thinners or feed.
In the following examples the temperatures are given in degrees Celsius.
Example I.
2.0 g of 3-cyclopentyloxy-7-methyl-16x, 170c-epoxy-173-acetoxy-9135fl0) oestratriene are dissolved in 100 ml of tetrahydrofuran and added to a stirred suspension of
2.0 g of lithium aluminum hydride in 150 mg of tetrahydrofuran were added dropwise. The reaction mixture is stirred for a further 50 minutes at about 400, then cooled, 10 ml of ethyl acetate in 40 ml of tetrahydrofuran and then 5 ml of water in 30 ml of tetrahydrofuran are added dropwise, the precipitated aluminum hydroxide is filtered off and the filtrate is evaporated in a water jet vacuum .
By chromatography of the crude product on silica gel and subsequent crystallization, the pure 3-cyclo pentyloxy - 7? methyl-16α, 17ss-dihydroxy- # 1,3,5 (10) -estratriene of m.p. 107-114; [α] 20 D = +47 (in chloroform) recovered.
The cyclopentyl ether used as the starting material is obtained from 7a-methyl-estrone by etherification e.g. With
Cyclopentyl bromide, subsequent enol acetylation using acetic anhydride / pyridine, and epoxidation of the 3-cyclopentyloxy-7cc-methyl-17-acetoxy-5 <'5> 16-oestratetraene with a peracid, e.g. with m-chloroperbenzoic acid in methylene chloride.
Example 2
1.50 g of 3-cyclopentyloxy-7α-methyl-16α-acetoxy-17-oxo- # 1,3,5 (10) -estratriene in 70 ml of absolute tetrahydrofuran are added dropwise at about 5-10 ° C Suspension of 600 mg of lithium aluminum hydride in 30 ml of absolute tetrahydrofuran, rinsed with 50 ml of tetrahydrofuran and the reaction mixture is boiled for 4 hours on the reflux condenser.
The mixture, which has cooled to approx. 50, is successively added dropwise with 5 ml of ethyl acetate in 10 ml of tetrahydrofuran and 4.5 ml of water in 10 ml of tetrahydrofuran, the inorganic components which have precipitated out are filtered off with suction and evaporated in a water jet vacuum. By crystallization of the amorphous crude product obtained from toluene, the 3-cyclopentyloxy-7α, which melts at 106-1120, is obtained. methyl-16α, 17ss-dihydroxy - # 1,3,5 (10) -estratriene obtained.
The acetoxyketone used as the starting material is obtained from 7, oc-methylestrone by etherification e.g. obtained with cyclopentyl bromide, subsequent enol acetylation by heating a pyridine solution of cyclopentyl ether with acetic anhydride, epoxidation of the A16 enol acetate formed with m-chloroperbenzoic acid and mild acidic hydrolysis of the epoxide.
PATENT CLAIMS
Process for the preparation of the highly estrogenically active 3-cyclopentyl ether of 7α-methyl-3,16α, 17ss-trihydroxy-Al 35 (10) -estratriene of the formula
EMI2.1
characterized in that a compound of the formula
EMI2.2
or the formula
EMI2.3
wherein either R1 is an oxo group and R3 is an oc-esterified hydroxyl group together with a hydrogen atom, or R, a 0-position free or esterified hydroxyl group together with a hydrogen atom and R5 is an oxo group and R is an 8-position esterified hydroxyl group, reduced,
the reaction product is isolated from the reaction mixture and, if esterified hydroxyl groups are present in the compound obtained, these are cleaved to form the free hydroxyl group.
UBITER CLAIMS
1. The method according to claim, characterized in that the 3-cyclopentyloxy-7-methyl-160c-acetoxy-17-oxo-1,5,5 (10) -estratriene is reduced with lithium aluminum hydride.
2. The method according to claim, characterized in that the 3-cyclopentyloxy-70Ç-methyl- - 16c, 170c-epoxy- 17ss-acetoxy- # 1,3,5 (10) -estratriene is reduced with lithium aluminum hydride.
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1870472A CH536296A (en) | 1970-04-24 | 1970-04-24 | Oestratriene-3-cyclopentyl ethers oestrogeni - regulators |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1870472A CH536296A (en) | 1970-04-24 | 1970-04-24 | Oestratriene-3-cyclopentyl ethers oestrogeni - regulators |
| CH622070A CH540243A (en) | 1970-04-24 | 1970-04-24 | Process for the production of a new, highly estrogenic steroid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH536296A true CH536296A (en) | 1973-04-30 |
Family
ID=4306174
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1870472A CH536296A (en) | 1970-04-24 | 1970-04-24 | Oestratriene-3-cyclopentyl ethers oestrogeni - regulators |
| CH622070A CH540243A (en) | 1970-04-24 | 1970-04-24 | Process for the production of a new, highly estrogenic steroid |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH622070A CH540243A (en) | 1970-04-24 | 1970-04-24 | Process for the production of a new, highly estrogenic steroid |
Country Status (4)
| Country | Link |
|---|---|
| AT (1) | AT312827B (en) |
| CH (2) | CH536296A (en) |
| CS (1) | CS157121B2 (en) |
| GB (1) | GB1333332A (en) |
-
1970
- 1970-04-24 CH CH1870472A patent/CH536296A/en not_active IP Right Cessation
- 1970-04-24 CH CH622070A patent/CH540243A/en not_active IP Right Cessation
-
1971
- 1971-04-21 GB GB1042971*[A patent/GB1333332A/en not_active Expired
- 1971-04-23 AT AT273272A patent/AT312827B/en not_active IP Right Cessation
- 1971-04-23 CS CS174073*1A patent/CS157121B2/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SU437279A3 (en) | 1974-07-25 |
| CH540243A (en) | 1973-08-15 |
| GB1333332A (en) | 1973-10-10 |
| CS157121B2 (en) | 1974-08-23 |
| AT312827B (en) | 1974-01-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |