DE1205095B - Process for the preparation of the hexahydrobenzoate of 2alpha-fluoro-testosterone - Google Patents
Process for the preparation of the hexahydrobenzoate of 2alpha-fluoro-testosteroneInfo
- Publication number
- DE1205095B DE1205095B DEL37597A DEL0037597A DE1205095B DE 1205095 B DE1205095 B DE 1205095B DE L37597 A DEL37597 A DE L37597A DE L0037597 A DEL0037597 A DE L0037597A DE 1205095 B DE1205095 B DE 1205095B
- Authority
- DE
- Germany
- Prior art keywords
- testosterone
- hexahydrobenzoate
- fluoro
- preparation
- fluorine
- 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.)
- Pending
Links
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 4
- QRNFMYYNRYGOQD-JIEICEMKSA-N 2alpha-fluoro-17beta-hydroxyandrost-4-en-3-one Chemical compound O=C1[C@H](F)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 QRNFMYYNRYGOQD-JIEICEMKSA-N 0.000 title description 2
- 229960003604 testosterone Drugs 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 241001465754 Metazoa Species 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000001456 gonadotroph Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000001548 androgenic effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 230000001817 pituitary effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000006877 Pituitary Hormones Human genes 0.000 description 2
- 108010047386 Pituitary Hormones Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000960 hypophysis hormone Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- QRNFMYYNRYGOQD-NIFJOCIDSA-N (8r,9s,10r,13s,14s,17s)-2-fluoro-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound O=C1C(F)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 QRNFMYYNRYGOQD-NIFJOCIDSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102000004451 Pituitary Gonadotropins Human genes 0.000 description 1
- 108010081865 Pituitary Gonadotropins Proteins 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- JOHUAELJNSBTGS-UHFFFAOYSA-N cyclohexanecarbonyl cyclohexanecarboxylate Chemical compound C1CCCCC1C(=O)OC(=O)C1CCCCC1 JOHUAELJNSBTGS-UHFFFAOYSA-N 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 231100000508 hormonal effect Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung des Hexahydrobenzoats von 2a-Fluor-testosteron Die Erfindung betrifft ein Verfahren zur Herstellung des Hexahydrobenzoats von 2 x-Fluor-testosteron.Process for the preparation of the hexahydrobenzoate of 2a-fluoro-testosterone The invention relates to a process for preparing the hexahydrobenzoate of FIG x-fluorine-testosterone.
Es ist bekannt, daß 2 a-Fluor-testosteron auf die Hypophyse hemmend wirkt und daß die androgene Wirksamkeit dieser Verbindung vermindert ist (Journ. Am. Chem. Soc., Bd. 81, 1959, S. 5262), nach eigenen Untersuchungen auf etwa 1/2s der Androgenwirkung des Testosterons.It is known that 2 a-fluoro-testosterone is inhibitory on the pituitary gland acts and that the androgenic effectiveness of this compound is reduced (Journ. At the. Chem. Soc., Vol. 81, 1959, p. 5262), according to our own investigations to about 1 / 2s the androgenic effects of testosterone.
Es wurde nun gefunden, daß das nach dem erfindungsgemäßen Verfahren erhaltene Hexahydrobenzoat von 2 a-Fluor-testosteron überraschende physiologische Eigenschaften aufweist. Diese Verbindung wirkt insbesondere länger hemmend auf die Hypophyse als der freie Alkohol und weist dabei überhaupt keine androgene Sekundärwirkungen auf; auch ist die anabolische Wirkung des Verfahrensprodukts bereits merklich geringer als die von 2-Fluortestosteron.It has now been found that the process according to the invention obtained hexahydrobenzoate from 2 a-fluoro-testosterone surprising physiological Has properties. This compound has a particularly long-term inhibitory effect Pituitary than the free alcohol and has no androgenic secondary effects at all on; the anabolic effect of the process product is also noticeably lower than that of 2-fluorotestosterone.
Das Hexahydrobenzoat von 2 a-Fluor-testosteron kann nach bekannten Methoden hergestellt werden, indem man Hexahydrobenzoesäure oder ein reaktionsfähiges funktionelles Derivat derselben, z. B. Hexahydrobenzoesäureanhydrid oder Hexahydrobenzoylchlorid, auf eine Lösung von 2 ec-Fluor-testosteron einwirken läßt.The hexahydrobenzoate of 2 a-fluoro-testosterone can according to known Methods are made by adding hexahydrobenzoic acid or a reactive one functional derivative thereof, e.g. B. hexahydrobenzoic anhydride or hexahydrobenzoyl chloride, lets act on a solution of 2 ec-fluorine testosterone.
Nach beendeter Umsetzung extrahiert man, wäscht auf übliche Art und isoliert das Hexahydrobenzoat von 2 a-Fluor-testosteron auf bekannte Weise, indem man zur Trockne eindampft oder die Verbindung ausfällt, zentrifugiert und filtriert.When the reaction has ended, the mixture is extracted, washed in the usual way and isolates the hexahydrobenzoate of 2 a-fluoro-testosterone in a known manner by it is evaporated to dryness or the compound is precipitated, centrifuged and filtered.
Das folgende Beispiel erläutert das erfindungsgemäße Verfahren.The following example explains the method according to the invention.
Beispiel Herstellung des Hexahydrobenzoats von 2 x-Fluor-testosteron Man löst 180 mg 2 «-Fluor-testosteron, das nach dem in Journ. Am. Chem. Soc., Bd. 81, 1959, S. 5262 beschriebenen Verfahren erhalten wurde, in 2 ccm wasserfreiem Benzol. Man versetzt mit 0,5 ccm Pyridin, kühlt auf +5°C ab und versetzt tropfenweise unter Stickstoff und unter Rühren mit 104 mg Hexahydrobenzoylchlorid. Es bildet sich beinahe sofort ein weißer Niederschlag. Nach 45minütigem Rühren bei ; 5°C säuert man mit Chlorwasserstoffsäure an, versetzt mit 10 ccm Benzol, dekantiert und extrahiert die wäßrige Phase mit dem gleichen Lösungsmittel. Die vereinigten benzolischen Lösungen werden mit Wasser, Natronlauge und wieder mit Wasser gewaschen und dann im Vakuum zur Trockne eingedampft. Der Rückstand kristallisiert aus Alkohol und ergibt 166 mg Hexahydrobenzoat von 2 a-Fluor-testosteron vom F. = 169°C (Kofler-Block) und [,c] ö = + 113,5°C ± 2 (c = 1 °/o in Chloroform). Die Verbindung ist löslich in Aceton, Benzol und Chloroform, schlecht löslich in Alkohol, sehr schlecht löslich in Äther und unlöslich in Wasser und verdünnten wäßrigen Säuren und Alkalien.Example Preparation of the hexahydrobenzoate of 2 x -fluoro-testosterone Dissolve 180 mg of 2 ″ -fluoro-testosterone, which according to the in Journ. At the. Chem. Soc., Vol. 81, 1959, p. 5262 was obtained in 2 cc anhydrous Benzene. 0.5 ccm of pyridine is added, the mixture is cooled to + 5 ° C. and added dropwise under nitrogen and with stirring with 104 mg of hexahydrobenzoyl chloride. It educates a white precipitate appeared almost immediately. After stirring for 45 minutes at; Acidifies 5 ° C it is mixed with hydrochloric acid, mixed with 10 cc of benzene, decanted and extracted the aqueous phase with the same solvent. The combined benzene solutions are washed with water, sodium hydroxide solution and again with water and then in vacuo evaporated to dryness. The residue crystallizes from alcohol and gives 166 mg of hexahydrobenzoate of 2 a-fluoro-testosterone with a temperature of 169 ° C (Kofler block) and [, c] δ = + 113.5 ° C ± 2 (c = 1 ° / o in chloroform). The compound is soluble in Acetone, benzene and chloroform, poorly soluble in alcohol, very poorly soluble in ether and insoluble in water and dilute aqueous acids and alkalis.
Analyse: C28Ha,03F = 416,56.Analysis: C28Ha, 03F = 416.56.
Berechnet: ... C 74,96, H 8,95; F 4,56 °/o; gefunden: ... C 74,9, H 8,8, F 4,7°/o. UV-Spektrum in Äthanol: @maz = 242 mu, E = 14900.Calculated: ... C 74.96, H 8.95; F 4.56%; Found: ... C 74.9, H 8.8, F 4.7%. UV spectrum in ethanol: @maz = 242 mu, E = 14900.
Die Verbindung ist bisher nicht in der Literatur beschrieben.The compound has not yet been described in the literature.
Versuchsbericht Zum Nachweis der überlegenen Hypophysenhemmwirkung des Verfahrensprodukts wurde die gonadotrope Wirkung auf kastrierte Ratten, die mit unversehrten Ratten parabiotisch vereinigt sind, bestimmt.Test report To demonstrate the superior pituitary inhibiting effect of the product of the process was found to have gonadotropic effects on castrated rats which are parabiotically associated with intact rats.
Der Parabiosetest gestattet, die quantitative Erhöhung der gonadotropen Hypohpysenaktivität des kastrierten Tieres durch Messung des Gewichts der Ovarien des unversehrten Partners zu bestimmen. Diese Hypertrophie der Gonaden nach Kastration kann durch androgene und östrogene Sexualhormone inhibiert werden, jedoch nur mit allen Nachteilen, die deren hormonale Wirkung mit sich bringt.The parabiosis test allowed the quantitative increase in the gonadotropic Pituitary activity of the castrated animal by measuring the weight of the ovaries of the intact partner. This hypertrophy of the gonads after castration can through androgenic and estrogenic sex hormones be inhibited, but only with all the disadvantages that their hormonal effects bring with them.
Die Arbeitstechnik ist die folgende: Ratten von 30 Tagen vom gleichen Wurf werden parabiotisch nach der Methode von B u n s t e r und M e y e r (Änat. Rec., 57, 1933, 339) vereinigt. Eines der Tiere wird kastriert und am gleichen Tag mit 25,2 mg 2 x-Fluor-testosteron-hexahydrobenzoat bzw. 18,5 mg 2 ix-Fluor-testosteron (diese Menge ist 25,2 mg Hexahydrobenzoat äquimolekular) auf subkutanem Wege behandelt.The working technique is as follows: rats of 30 days of the same Litter are parabiotic according to the method of B u n s t e r and M e y e r (Änat. Rec., 57, 1933, 339). One of the animals is neutered and on the same day with 25.2 mg 2x-fluorine-testosterone-hexahydrobenzoate or 18.5 mg 2x-fluorine-testosterone (this amount is 25.2 mg hexahydrobenzoate equimolecular) treated by subcutaneous route.
Die Tiere werden nach der in Spalte 3 der nachfolgenden Tabelle (Dauer
der Einwirkung in Tagen) angegebenen Anzahl von Tagen nach ihrer parabiotischen
Vereinigung getötet. Dabei erhielt man folgende Ergebnisse:
Dagegen ergibt sich aus den Werten für 2 rx-Fluortestosteron, daB dieses zwar 10 Tage eine hemmende Wirkung auf die gonadotropen Hypohysenhormone ausübt, jedoch verschwindet diese Wirkung sehr schnell, da die Stimulierung der Ovarien des unversehrten Partners durch die gonadotropen Hormone des kastrierten Tieres schon am 19. Tag wieder deutlich zu erscheinen beginnt.In contrast, the values for 2 rx-fluorotestosterone show that this 10 days an inhibitory effect on the gonadotropic pituitary hormones exerts, however, this effect disappears very quickly as the stimulation of the Ovaries of the intact partner by the gonadotropic hormones of the castrated Animal begins to appear clearly again on the 19th day.
Der Vergleich der Ergebnisse zeigt, daB 2 a-Fluortestosteron-hexahydrobenzoat eine deutliche Retardwirkung hat, da seine inhibierende Wirkung auf die Hypophysengonadotropine noch 18 Tage nach einer einmaligen Injektion auf dem Maximum liegt und nicht vor 24 Tagen abzunehmen beginnt, während der freie Alkohol keine Retardwirkung zeigt.A comparison of the results shows that 2α-fluorotestosterone hexahydrobenzoate has a clear sustained release effect, since its inhibiting effect on the pituitary gonadotropins is still at its maximum 18 days after a single injection and is not present 24 days begins to decrease, while the free alcohol shows no sustained release effect.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1205095X | 1959-12-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1205095B true DE1205095B (en) | 1965-11-18 |
Family
ID=9673132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEL37597A Pending DE1205095B (en) | 1959-12-10 | 1960-11-22 | Process for the preparation of the hexahydrobenzoate of 2alpha-fluoro-testosterone |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1205095B (en) |
-
1960
- 1960-11-22 DE DEL37597A patent/DE1205095B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
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