DE2007415B - 7alpha-methyl-estratriol - Google Patents

Description

This compound has valuable pharmacological properties. So it works mainly estrogen, antigonadotropic, ovulation-inhibiting and / or blastocyte implantation-inhibiting.

The estrogenic effectiveness can e.g. B. in the well-known Allen-Doisy test on the female rat with cans from 0.003 to 0.3 mg / kg s. c. and 0.01 to 3 mg / kg p.o. and in the well-known Bülbring burn test as well of the female rat at doses of 0.0003 to 0.3 mg / kg s.c. and 0.003 to 1 mg / kg p.o. shown will. In the parabiosis test on rats, doses of 0.0003 to 0.03 mg / kg s.c. and 0.01 to 0.3 mg / kg p.o. show the antigonadotropic effect. On normal female rats in the cycle can be with doses from 0.0001 to 0.003 mg / kg s.c. and 0.003 to 0.1 mg / kg p.o. the ovulation-inhibiting effectiveness to demonstrate. The anti-blastocyte inhibitory efficacy can be observed in normal rats after copulation with doses of 0.001 to 0.003 mg / kg s.c. and 0.01 to 0.03 mg / kg p.o. to be shown. the new compound can thus be used as an estrogenic agent Inhibition of gonadotropic function, ovulation and generally used to control fertility will.

The new compound can be obtained by using a compound of the formula

where RO is a free, esterified or etherified hydroxy group, R _{1 is} an oxo group and R _{2 is} an α-esterified hydroxyl group together with a hydrogen atom, R _{1 is} a 9-position free esterified hydroxyl group together with a hydrogen atom and R _{2 is} an oxo group or R ₁ represent an esterified hydroxyl group in the jö position and together with R ₂ a Λ, α-epoxy group, reduced, the 16%, 17 /? - dihydroxy compound isolated from the reaction mixture and, if esterified or etherified hydroxyl groups are present in the compound obtained, these cleaves to free hydroxyl groups in a manner known per se.

The aforementioned reduction takes place in a manner known per se. So you can create a 16 "acyloxy-17-oxo compound or a 16 ", 17" -epoxy-17/3-acyloxy compound with a light metal hydride, preferably

xo wise lithium aluminum hydride or sodium borohydride, to reduce. However, this reduction can also be carried out catalytically, e.g. B. with hydrogen in the presence a platinum catalyst. The 16-oxo-17 /? - hydroxy compound, whose hydroxyl group can also be esterified, is preferably with nascent Hydrogen, such as B. is generated by sodium in an alcohol, or catalytically in the presence z. B. reduced a platinum catalyst. Any esterified or etherified ones that may be present Hydroxy groups are cleaved to the free hydroxy group in the usual way.

An esterified hydroxyl group in the starting materials is preferably one with a lower aliphatic one Carboxylic acid, e.g. B. hydroxyl group esterified with acetic acid.

The separation of the desired compound from the optionally containing isomeric compounds The reaction mixture is carried out in a manner known per se, for. B. by fractional crystallization or Chromatography.

The starting materials are known or can be derived from known compounds in a manner known per se receive. So you can get the 16,17-epoxy-17-acyloxy compound by converting the known 7 <x -methyl-oestrone into its 17-enol acylate and reacting with a peracid win. The 16 * acyloxy-17-oxo compound can be passed through from this Implement with z. B. perchloric acid and from it by rearrangement with a base z. B. potassium carbonate the 16-oxo-17jS-hydroxy compound obtained.

The new compound can be used as a remedy in the form of pharmaceutical preparations which this compound together with pharmaceutical, organic or inorganic, solid or liquid carriers used for enteral, e.g. B. oral or parenteral administration are suitable. for the formation of the same are those substances that do not react with the new compound, such as z. B. water, gelatin, lactose, starch, magne-

sium stearate, talc, vegetable oils, benzyl alcohol, Gum, polyalkylene glycols, cholesterol, or other known excipients. The pharmaceutical Preparations can e.g. B. as tablets, coated tablets, capsules or in liquid form as solutions, suspensions or emulsions are present. If necessary, they are sterilized and / or contain auxiliary materials, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic Pressure or buffer. They can also contain other therapeutically valuable substances.

The invention is described in more detail in the following examples. The temperatures are in Degrees Celsius.

example 1

3.0 g of 3,16a-diacetoxy-7'-methyl-17-oxoji.s, 6 (io) are added dropwise. _oestratr j _en j _n 100 ml of absolute tetrahydrofuran, at about 5 to 10 ° to a suspension of 1 g

3 4

Lithium aluminum hydride in 50 ml of absolute tetrahydrate over sodium sulfate and steam it in the water

drofuran, rinsed to dryness with 100ml absolute tetrahydrofuran jet vacuum. The residue

after and the reaction mixture is boiled for 14 hours and acetylated overnight with 15 ml of pyridine and

on the reflux condenser. First 5 ml of acetic acid 15 ml of acetic anhydride are added at 5 °. It is then poured onto ice

ester in 10 ml of tetrahydrofuran and then 5 ml of water 5 and water, let stand at room temperature,

drop by drop, warmed up briefly to about 40 °, sucks off, extracted twice with ether and washes the organ-

and washes well with chloroform. The niche phase is stirred with dilute sulfuric acid, water,

Filter residue for 1 hour with 300 ml of 2N hydrochloric acid with saturated sodium hydrogen carbonate solution and again

Room temperature, filtered and washed with water or with water. The extract is dried over

after. The residue is suspended in water using sodium sulfate and evaporated using a water jet

and four times with 300 ml each of a chloroform-methane vacuum. This gives the 3,1.6 * -diacetoxy-

ol (4: 1) mixture extracted. The combined orga- 7 «-methyl-17-oxo- / J ¹ - ³ ' ⁶ < ¹⁰ >) - oestratrien, which after conversion

niche phases are dried with sodium sulfate dissolve from ether-petroleum ether melts at 138 to 139 °,

and evaporated in a water jet vacuum. One obtains [cc] f ° = + 135 ° ± 2 ° (c = 0.550).

so the 3.16 «, 17j5 - trihydroxy - 7« - methyl - Λ ¹ · * · 15.

⁵ < ¹⁰ > -oestratriene (7a-methyl-oestriol), which according to Um- Example 2

dissolve from methylene chloride-methanol-ether at 235 To a suspension of 2.85 g of lithium aluminum

melts up to 236 °. [oi \ f ° = + 55 ° ± 1 ° (c = 0.912 in hydride in 285 ml of tetrahydrofuran is added at approx

Ethanol). 10 to 15 ° a solution of 7.14 g 3.17 /? - Diacetoxy-

The starting 20 7 «-methyl-16«, 17o> oxido-zl ¹ " ^s ' ^e < ¹⁰ > -oestratriene in

material can be z. B. obtained as follows: 285 ml of tetrahydrofuran to. After rinsing with

A solution of 30 g of 7 "-Me- 140 ml of tetrahydrofuran is distilled, it is boiled for 2 hours in a thylestrone, 300 ml of isopropenyl acetate and 19.2 ml of a reflux condenser. about 10 ° first with 30 ml of ethyl acetate and then centered sulfuric acid at normal pressure about »5 with 550 ml of 2N hydrochloric acid and add 11% of chloroform. 100 ml. After further addition of 300 ml of ISO, the mixture is stirred for 10 minutes at room temperature, propenyl acetate and 19.2 ml of a 40 ml solution are separated from the organic components, washed with water, isopropenyl acetate and 1.3 ml of concentrated sulfur, dried over sodium sulfate and evaporate them in the acid are in the course of a further 3 hours in a water jet vacuum to dryness. The residue normal pressure about 400 ml is distilled off, whereupon after 30, 50 times the amount of silica gel is adsorbed and a solution of 42 ml of pyridine acid with a 7: 3 mixture of toluene and vinegar 300 ml of ether is added to cooling to 5 °. After the esterification and then eluted with ethyl acetate. The evaporation thin with ice and water, the dark of the eluate obtained with ethyl acetate is the 3.16λ, mixture twice with an ether-methylene chloride- 17/3 - tribydroxy - 7 "- methyl - J". "." U "> - oestratrien, (4: 1) mixture, washes the organic components with 35 dais after dissolving from methylene chloride / methanol / water, ice-cold dilute sulfuric acid, water, ether melts at 235 to 236 °. [<x] $ ^a = + 55 ° ± 1 ° saturated sodium hydrogen carbonate solution and how- (c = 0.912 in ethanol),
neutral with water. One dries over sodium.
sulfate and evaporates in a water jet vacuum, for example 3
Dry up. The resulting 40,600 mg of 3.17 "- dihydroxy - 7" - methyl - 16 - oxo - brown foam is chromatographed on 50 times the amount of silica gel. J ¹ ' ³ ' * < ¹⁰ > -oestratriene are boiled in 50 ml of isopropanol by eluting with a toluene-ethyl acetate (95: 5) reflux condenser. Within 20 minutes mixture obtained crude 3,17-diacetoxy-7 "-me · are added in portions 2.0 g of sodium, and, after thyl- ^ ^{l !! l '6 (10>' ie} -oestratetraen that after a single All sodium is dissolved, you pour the cooled solution from ether / petroleum ether at 110 to 111 ° 45 solution on ice / water and acidify with dilute melts. [<%]? ° = + 77 ° ± 2 ° (c = 0.639). Hydrochloric acid. The precipitated substance is filtered off

To a solution of 3.38 g of the compound obtained and after dissolving in methylene chloride / methanol,

manure in 70 ml of methylene chloride is added at about 18 °, drying over sodium sulfate and evaporation

2.3 g of approximately 88% m-chloroperbenzoic acid and water jet vacuum on 30 times the amount of silica gel stirs for 30 minutes at room temperature. 50 chromatographies are used. By elution with a toluene

thinning the reaction solution with ether, washing with ethyl acetate (30:70) mixture, 365 mg of crude

Potassium iodide solution, sodium thiosulfate solution, water, 7 <x -methyl-oestriol obtained, which after dissolving from

saturated sodium hydrogen carbonate solution and like methylene chloride / methanol / ether at 235 to 236 °

the one with water neutral, pulls the wash water with melts. The starting ether used in this example from and dries the combined organic material can be z. B. produce as follows:

Phases over sodium sulfate. After evaporation to a briefly boiled suspension of 5.0 g

and dissolving the residue of methylene chloride-potassium carbonate in 100 ml of methyl alcohol

Ether-petroleum ether gives the 3.17 / 5-diacetoxy- 4.0 g 3.16λ - diacetoxy - Toc - methyl - 17 - oxo-

7α - methyl - 16 ", Γ7α - oxido · / J ^{li8i6 <10)} - oestratrien J ^ - 'H ^ -oestratrien added in solid form. Those with a melting point of 156 to 157 °. [λ]! ⁵⁰ = + 51 ° ± 2 ° 60 reaction mixture is then 45 minutes

(c = 0.635). Boiled under reflux and nitrogen, on ice / water

3.22 g of this compound are poured into 32 ml of a, acidified with dilute hydrochloric acid and

Acetic acid-perchloric acid solution obtained from 49 ml filtered. The filter cake is dried for the purpose of

96 ° / o acetic acid and 1 ml of 70 ° / ₀ perchloric acid, Ge separation of a polar impurity stirred in methylene Dissolves and 10 minutes at room temperature. 65 chloride dissolved and 50 g aluminum oxide (Akt.-

The reaction solution is mixed with ice and water, stage II, neutral) and filtered, whereby 2.50 g of pure, not

extracted twice with ether-methylene chloride, washes crystallizing 3,17 / 3-dihydroxy-7 «-methyl-16-oxo-

the organic extracts twice with water, dries Δ ^χ · ³ - ⁶ < ¹⁰ > -oestratrien are obtained.

Claims (1)

Claim: 7λ - methyl - 3,16κ, Πβ - trihydroxy oestratriene of the formula HO The present invention relates to the 7 <x - methyl - 3.16 <x, 17/5 - trihydroxy - Δ i - ». Ss (n>) - oestratriene of the formula