DE3018903A1 - OESTRENO- SQUARE CLAMP ON 2,3-D SQUARE CLAMP ON -DIHYDROISOXAZOLEDOLS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

ÖBtreno- [2,3-d] -dlhydroisoxazoldiol, method for their manufacture position and medicinal products containing them

The invention relates to estreno- [2,3-d] -dihydroisoxazole diols and Process for their manufacture.

In US-PS 3,135,743 steroido- [2,3-d] -isoxazoles are with metallic, hormonal and anti-hormonal properties, in particular described with anabolic properties. The US-PS 3,145,200 describes steroido- [3 »2-c] -isoxazoles with endocrinological Properties including myotropic, anabolic pituitary inhibiting and steroid synthesis inhibiting Properties. The US-PS 3,100,171 describes androstano- [3,2-c] -

5'-hydroxy-A -isoxazolines with metabolic and hormonal properties, especially pituitary-inhibiting anabolic and myotropic properties. Eaneko, Nakamura, Yamato and Kurokawa (Chem. Pharm. Bull. Vol. 17, No. 1, pp. 11-22, 1969) describe the production of the compound with the structural formula

CH.

i y

1..CIU

Formula E.

OK H

from the corresponding P.-hydroxymethylene-3-ketone and hydroxylamine and dehydrating the compound of Formula E with an acid to form the corresponding [2,3-d] isoxazole (loc.cit. pages 15-16). A myotropic-androgenic index of 0.9 is shown for the compound of Formula E.

The invention produces 17a-Q-10β-R-5cc-estr-2-eno- [2,3 ~ d] -4 ', 5 ^l -dihydroisoxazole-3 ^ -17β-diols with the structural formula

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CH. OH

OH H

provided wherein Q is hydrogen, methyl, ethyl, vinyl or

Ethynyl is and

R is hydrogen or methyl.

The compounds of formula I are suitable as pituitary gonadotropin inhibitors. or as an anabolic agent. The compounds of formula I in which Q is vinyl or ethynyl are preferred. The compounds of formula I in which Q is ethynyl are particularly preferred. Particularly preferred embodiments are Compounds of the formula I in which Q is vinyl or ethynyl and R is methyl.

The compounds according to the invention can be used to inhibit the pituitary-gonadal (or sex gland) axis in a teat utilize gonadal function by administering to the mammal an amount of a compound of formula I which is sufficient or to reduce sex gland function.

The compounds are known in a pharmaceutical composition in solid or liquid dosage form for oral, parenteral or intravaginal administration with a pharmaceutical useful vehicle or carrier.

A process feature of the invention lies in the process for the preparation of a compound of the formula I, which consists in the corresponding 17α-Q-10β-R-2-hydroxymethylene-17β-hydroxy-5aestran-3-one with the structural formula

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II

with hydroxylamine or with a hydroxylamine salt in an aqueous Mixtures of solvents under neutral or slightly acidic To condense conditions at room temperature or under cooling.

The compounds of the formula II are known and are generally used prepared by condensing the corresponding 17a-Q-10β-R-17β-hydroxy-5a-estran-3-ones with ethyl formate under alkaline Conditions. Hydroxylamine or any salt thereof can be used in practicing the process feature of the invention will. The easily accessible salts, for example, hydroxylamine hydrochloride and hydroxylamine sulfate are preferred and particularly Hydroxylamine hydrochloride is preferred.

The non-aqueous portion of the solvent mixture can be anything Be a solvent that is suitable to dissolve the compound of formula II in a sufficient manner to cause condensation with the hydroxylamine or the hydroxylamine salt without interfering with the condensation. Solvents miscible with water are preferred, especially the alkaline solvents. tert-Butyl alcohol and ethanol have been used successfully .

Any acid or base suitable for achieving the neutral or slightly acidic conditions desired can be used without interfering with the condensation. The compounds of formula I become more than slightly acidic even under Conditions formed, for example, in the presence of acetic acid or p-toluenesulfonic acid. Using aqueous Ethanol as a mixed solvent, approximately equimolar amounts of one Compound of formula II and of hydroxylamine hydrochloride, for example

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a half molar amount of sodium carbonate and about a two-fold, molar amount of sodium bicarbonate, giving a pH in the range 6.5 "to 6.8, gave good yields the corresponding compound of formula I achieved.

A temperature range from about -4O ° C to about + 4-O ⁰ C can be used.

The compounds of formula I in which Q is ethyl or vinyl are also prepared by catalytic hydrogenation or partially catalytic hydrogenation of the corresponding compounds of the formula I in which Q is ethynyl. Effective catalyst-solvent combinations for the preparation of the compounds of the formula I, in which Q is ethyl, are palladium on carbon and ethanol, Ethyl acetate or tetrahydrofuran. An effective catalyst-solvent combination for the preparation of the compounds of formula I in which Q is vinyl is palladium on strontium carbonate and pyridine.

. The following examples serve to illustrate the invention. The structures of the products are derived from the known structures the starting materials and the expected course of the manufacturing reactions and are confirmed by the melting point range (Fp.), Elemental analysis, infrared spectral analysis, nuclear magnetic spectral analysis, mass spectroscopic Analysis and / or thin layer chromatography, which is also used to determine the purity of the starting materials and evaluate the products.

example 1

A. A solution of 0.84 g of hydroxylamine hydrochloride in 10 ml Water was stirred into a solution of 3.42 g of 17α-ethynyl-10β-methyl-2-hydroxymethylene-17β-hydroxy-5α-estran-3one added in 40 ml of tert-butyl alcohol. It was continued at room temperature stirred for 1 hour. A solution of 1.63 g of sodium acetate trihydrate in 10 ml of water was then added and stirring was continued for a further 30 minutes. 250 ml of water was added and the mixture was mixed with 2 portions (50 ml each) of chloroform

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Methanol (9: 1) extracted. The extracts were dried, filtered and the solvents evaporated. By. Crystallization of the residue from 30 ml of acetonitrile at room temperature gave 1.4-0 g of 17α-ethynyl-10β-methyl-5α-estr-2-eno [2,3-d] -4 », 5′-dihydroisoxazole-3 ^ -17ß-diol (Pp. 198-200 ⁰ C), the compound of formula I wherein Q is ethynyl and R is methyl.

Thin layer chromatography showed that the crude product of the above reaction was primarily the compound of formula I wherein Q is ethynyl and R is methyl and secondarily the compound of formula D wherein R ^{1 is} ethynyl and R and R "" are both

Mean hydrogen. The ratio of the two products was not changed by the addition of acetic acid or p-toluenesulfcic acid to the reaction mixture.

B. A solution of 50 g of sodium bicarbonate in 500 ml of water was stirred at room temperature to a solution of 100 g of 17α-ethynyl-1 Oβ-methyl-2-hydroxymethylene-17β-hydroxy-5α-estran-3-one in 2 1 ethanol added. A small amount of the steroid failed. It was stirred for a further 10 minutes. A solution of 24.6 g of hydroxylamine hydrochloride in 50 ml of water was then added over 25 minutes and stirring was continued for 3 hours. Finally, 20 ml of acetic acid was added dropwise and stirring was continued for an additional hour. The mixture was cooled in an ice bath ⁽⁰ to 5 O). The resulting solid was collected, washed first water and then sit with methanol and dried under vacuum at 60 ⁰ C to give 59 g of 17a-ethynyl-17-methyl-5a-estr-2-eno [2,3-d ] -4 ', ^5-t -dihydroisoxazol 3 * -17ß-diol (mp. 216-218 ⁰ C).

A solution of 166 g of the combined products of various such preparations of 17a-ethynyl-10ß-methyl-5a-estr-2-eno- [2,3-d] -4 ^l , 5'-dihydroisoxazole-3f-17ß-diol in hot dimethylformamide was filtered to remove cloudiness. Warm water was added to the filtrate until just the onset of crystallization, and the mixture was cooled in ice water. The solid was collected, ^{washed with cold (5 °} C.) methanol and dried (in vacuo at 65 ^° C.) with the formation of

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142 g 17a-Äthiny1-1Oß-methyl-5a-estr-2-eno [2,3-a} ~ 4 ', 5 x -dihydroisoxazol-3 $ -17ß-diol (Pp. 212-214 ⁰ C). For removal of a pale yellow discoloration of the product in acetone was slurried again recovered and dried (136 g, Pp. 212-214 ⁰ C).

Example 2

A sufficient amount of a solution of 3.35 g sodium artonate in about 30 ml v / ater was stirred into a slurry of 25 g 17α-methyl 1-1 Oβ-methyl-2-hydroxymethyleji-17β-hydroxy-5-x-estran -'3-one added to 300 ml of ethanol to achieve a pH of 6.5 to 6.8. The solution was cooled (to -2O ⁰ C) and a solution of 5.7 g of hydroxylamine hydrochloride, 13.7 g Batriumbicarbonat and about 125 ml of water was added dropwise with stirring. The temperature was then allowed to rise to room temperature by over fold, with continued stirring. The mixture was quenched in water to give a coarse gel which was collected, washed with dimethylformamide-water ($ 50) and dried (17.3 g). Water was added to a filtered solution of the gel in 200 ml of dimethylformamide until the solution became cloudy. The resulting fine crystals were collected, slurried with ether, washed with ether and acetone, and dried (7.37 g). A second crop was obtained from the ether-acetone washes (1.47 g). The two crops and the corresponding product (1.97 g) from a previous smaller scale preparation were combined, slurried with ether, recovered and dried to give 17α-methyl-10β-methyl-5α-estr-2-eno- [2 (Pp. 197-198 ⁰ C), 3-d] -4 ^f, 5 ^l -dihydroisoxazol-3f-17.beta.-diol, the compound of formula I, wherein Q and R are both methyl.

Example 3

A. A solution of 14.08 g of 17oc-ethynyl 1-1 Oβ-methyl-5oc-oestr-2-eno [2,3-d] -4 ', 5'-dihydroisoxazole-3 ^ -17β-diol in 300 ml of pyridine, 2.0 g of 2 $ palladium hydroxide was added to strontium carbonate hydrogenated in a Parr apparatus. From the colloidal mixture the pyridine was withdrawn. Ethyl acetate was added and the mixture was again drawn off. A mixture of the residue

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with hot ethyl acetate was filtered through infusor earth (Super-Cel) and the filter cake was washed with hot ethyl acetate. (Mp 175.5 to 176 ⁰ C 7.20 g.) Of the filtrate, the ethyl acetate was stripped and the residue (12.5 g, mp 160-165 ⁰ C.) Was recrystallized from acetonitrile. The product was combined with the product (3.20 g) from a previous smaller scale preparation and the combined products were recrystallized from acetonitrile to give 8.07 g of 17a-vinyl-10ß-methyl-5a-estr-2-eno- [2,3-d] -4 - ', 5 ^l -dihydroisoxazol-3f 17ßdiol (Fp.180-182 ⁰ C), the compound of formula I wherein Q is vinyl, and R is methyl, has received.

B. The condensation of 17cc-vinyl-10ß-methyl-2-hydroxymethylene-17ß-thiydroxy-5a-oestra-3-one with hydroxylamine or hydroxylamine salt under neutral or slightly acidic conditions at room temperature or with cooling also gives 17a-vinyl-10ß methyl-5a-estr-2-eno [2,3-d] -4 ^l, 5 ^l -dihydroisoxazol-3 $ -17ß-diol.

Example 4

In the same manner as in Example 2 and keeping the pH at 6.0 to 6.5, 25 g of IOβ-methyl-2-hydroxymethylene-17β-hydroxy-5oc-oestran-3-one with 5.7 g of hydroxylamine hydrochloride were added condensed. The crude product (15.82 g, mp. 181-, 3-183 ⁰ C), using the product (4.85 g, mp. 178-179 ⁰ C) combines a previous preparation in the lower scale and the combined products were prepared from Dimethylformamide-water recrystallizes to give 14.95 g of 1Oß-methyl-5a-estr-2-eno [2,3-d] -4 ', 5'-dihydroisoxazol-3 ^ -17ß-diol (m.p. 179- 181 ⁰ C), the compound of the formula I in which Q is hydrogen and R is methyl.

Example 5

In the same way as in Examples 2 and 4, 20 g of 17a-ethynyl-2-hydroxymethylene-17β-hydroxy-5a-estran-3-one were added 4.9 g of hydroxylamine hydrochloride condensed. The resinous crude product was extracted with ether and methylene chloride. The extracts were washed with dilute aqueous sodium hydroxide, dried over potassium carbonate, treated with activated charcoal, filtered

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riert and the solvents were removed to give a solid in three! fractions obtained (12.73 g, 1.48 g, 2.73 g). The first two fractions were combined and recrystallized from dimethylformamide-water and the product was dried under vacuum and heat (initially at 50-6O ⁰ C and then at 85-100 ⁰ C) and dried to yield 8.40 g 17a-ethynyl-5a -estr-2-eno [2,3-d] -4 ^I, 5 ^l -dihydroisoxazol-3 ^ -17ß-diol (mp. 182-185 ⁰ C) received the compound of formula I wherein Q is ethynyl and R is hydrogen.

Example 6

A. The condensation of 17α-ethyl-17β-methyl-2-hydroxyniethylen-17β-hydroxy-5α-estran-3-one with hydroxylamine or a hydroxyI-amine salt under neutral or slightly acidic conditions at room temperature or with cooling gives 17α-ethyl -1Oβ-methyl-5aestr-2-eno- [2,3-d] -4 ', 5 ^! -dihydroisoxazol-3 $ -17ß-diol, the compound of the formula I in which Q is ethyl and R is methyl.

B. The hydrogenation of 17ß-ethynyl-10ß-methyl-5a-estr-2-eno- [2,3-d] -4 ', 5 ^l -dihydroisoxazol-3 ^ -17ß-diol under pressure over palladium on carbon in Ethanol also gives 17a-ethyl-10ßmethyl-5a-ö3tr-2-eno [2,3-d] -4 ^! , 5 ^! -dihydroisoxazole-3i-17ß-diol.

Biological properties of the compounds :

As mentioned above, the compounds of formula I are suitable as inhibitors of pituitary gonadutropin as well as anabolic agents. These uses have been made through Tests in rats and monkeys have shown comparable uses in the treatment of humans. The properties of the compounds of the formula I which reduce the function of the gonads and gonads were determined by the following investigations shown on the rat.

Investigations into altered endocrine balance .

Sexually mature male rats each weighing about 200 g were given orally or subcutaneously with an aqueous tragacanth gum tint (1 ^) / suspension or an ethanol (lO ^) cotton

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seed oil (905Q solution / suspension of the compound to be investigated treated twice a day for 14 consecutive days. Control rats received the vehicle only. On the day that Following the final administration, the rats were weighed and then sacrificed. The testicles, the ventral prostate, the seminal vesicles, the thymus, adrenals, and pituitary were removed, marked, and weighed. The pituitary gonadotropin effectiveness is calculated from the relative weights of the testes of the ventral prostate glands and the seminal pollen of the treated Rats and control animals were assessed.

In a similar test on sexually mature female rats, the testes were replaced by the ventral prostate and seminal vesicles the uterus and ovaries removed.

Study of androgen / anabolic efficacy ;

Immature castrated male rats each weighing about 70 g were administered orally or subcutaneously with an aqueous Tragacanth gum ($ 1) solution / suspension or an ethanol (10 ^) cottonseed oil (90 ^) - solution / suspension of test compound treated once a day for 10 consecutive days. Control rats received the vehicle only. Testosterone propionate was used as a reference standard and administered subcutaneously. The day after the last medication, the rats were weighed and then killed. The levator ani, the ventral one Prostate and seminal vesicles from each rat were removed, marked, and weighed. The androgenic and anti-androgenic effectiveness were obtained from the weights of the ventral prostate and seminal vesicles of treated control animals and reference standard rats determined. The myotropic and antimyotropic effectiveness were evaluated from the weight of the levator ani of treated rats, control rats and reference standard rats. the Myotropic potency is viewed as an indicator of anabolic potency.

Investigation: the uterotropic / anti-estrogenic effectiveness ; Immature female rats, each weighing approximately

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40 g were taken orally or subcutaneously with an aqueous tragacanth gum (1 #) - solution / suspension or an ethanol ($ 10) - cottonseed oil (90 #) - solution / suspension of the compound under investigation once treated daily for three consecutive days. Zone control rats only received the vehicle. Estradiol was used as a reference standard and administered subcutaneously. On days after the last medication, the rats were weighed and then sacrificed. The uterus of each rat was removed, marked and weighed. The uterotropic and anti-estrogenic effectiveness were determined from the uterine weights of treated rats, control rats and reference standard rats.

The results of the above studies for the compounds Examples 1 to 5 are listed in Table I.

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Connected changed endocirculation d. Equilibrium in ge-ex. poorly mature male rats

CO O O • P-OO

decreased increase in body weight, ventral prostate, seminal vesicles and thymus gland at 30, 15, 40 po

inactive at 45 po

50, 15,

Decreased body weight gain as well as weight v. ventral prostate and seminal vesicles "at 50 sc and 100 po Also testicular and thymus weights at 50 sc

Table I Examination (dosages in mg / kg)

Androgenic / myotropic changed endocrine- uterotropic- efficacy in case of imbalance in anti-estrogenic male rats, poorly mature female efficacy

Rats in immature

female rats

but not androgenic
myotropic at 25,
and 400 po

androgenic and myotropic with low od.
no antiandrogenic
or antimyotropic agents
Effect at 100 po

Reduction of the uterotropic
Increased body and thymus weights at 0.16, 2.5 po, increase in pituitary weight marginally
50 sc Decreased
Increase in body weight and thymus weight and number of

vaginal estrous'

Days at 200, 800 po

uterotropisoh at 8, 32 po

uterotropisoh at 5, 20, 80 po but not estrogenic.

CJO CO O CO

Continuation of Table I - Examination (dosages in mg / kg)

Associated- Altered Endocrine Androgen / Myotropic Altered Endocrine- Uterotropic Dung d. Equilibrium in ge Efficacy with imbalance in equilibrium with anti-oestrogens E.g. poorly mature male rats poorly mature female efficacy Rats in immature rats

v / eibl. Rats

CD
CO
O
O
4> OO

Reduced body weight and weights v. ventral prostate, testes and adrenal glands at 100 s.c.

Decrease in body weight and weights of the ventral prostate, seminal vesicles, testes and thymus gland at 50 sc and 100 po and increase in adrenal weights at 50 sc, increasing weights v. decreased uterotrophic thymus
Levator ani, ventral weight and increase at 50 sc
Prostate and seminal vesicles - weights of ovaries
chen at 100 pou pituitary gland at 100 sc

decreased body weight and weight of
Levator ani as well as increased weight of the

Seminal vesicles at 100 po uterotropic

at 1.6, 6.25,
25, 100 po and estrogen at 6.25 _f 25 and 100

OO CO O CO

Monkey study - compound of Example 1

Female rhesus monkeys whose last three menstrual cycles were regular, were orally treated with the test compound for 90 consecutive days and the Effects on the menstrual cycle have been observed. In this investigation, the compound of Example 1 caused which is the compound of formula I wherein Q is ethynyl and R is methyl and which is as above mentioned in order to elucidate a preferred embodiment of the invention is amenorrhea at 6.25 mg / monkey / day.

Comparative experiments - compound of example 1

The compound of Example 1 was compared in the investigation of the changed endocrine balance in male rats and the investigation of the androgen / myotropic activity in immature male rats with corresponding compounds of the prior art of the aforementioned formula B ^1. The results of the two comparative tests are shown in Table II and Table III.

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TABLE II - Altered Endocrine Gleiohgewioht in Legged Tires male rats

treatment
Dose mg / kg / day χ 14 Vehicle control 195
311 link the 45 link
"Re I pm Is»! I from Number of rats: i.g. ° ± 0.2 ^a 15th 8th · 10 30th Body weight (g) 8th 8th 8th 8th ° originally
°° at the end 276.6
± 11.8 · · 195
260 ο change
* · "G / advice / day
Often 254.3
± 10.4 195
296 4.6
± 0.3 ** 195
276 195
254 KJtJ
***. Organ weights 2.80
± 0.1 7.2
± 0.2 * 5.8
± 0.2 * ± 5.4 * CD
oo ventral
ro prostate (mg) 676.3
± 48.2 119.9
± 14.3 ** Seminal vesicles
(mg) 48.6
± 1.8 187.5
± 11.7 ** 122.3
± 13.0 ** 191.7
± 14.8 ** 132.3
± 9.5 Testicles
(G) 11.0
± 0.5 212.7
± 17.0 2.37
• ± o, i 224.2
± 6.1 162.0
± 12.2 ** Thymus
(mg) 2.73
± 0.06 531.7
± 35.4 2.67
± 0.1 2.60
± 0.1 Adrenal glands
(mg) 625.9
± 43.0 48.9
± 3.1 519.2
± 34.6 513.8
± 32.0 Pituitary gland
(mg) 43.9
± 1.2 9.5
± 0.4 48.7
± 2.2 52.4
± 1.9 10.8
± 0.7 10.7
± 0.4 * 10.3
± 1.2

a - mean - se

* - considerably from the mean of the control group P <0.01
** - Considerably relative to the control group P <0.001

The table above shows that "both compounds gave a dose-related reduction in the weights of the ventral prostate and seminal vesicles and a significant reduction in body weight at all dosages. The compound of Formula B ¹ but not the compound of Formula 1 of Example 1 caused one considerable reduction in testis weight at the higher dose Although the compound of Example 1 showed a relative potency of 2.1 (95% statistical pair of numbers from 0.8 to 3.6) based on the comparison of the ventral prostate weights, the two lie Compounds within the experimental error range of the same potency.

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TABLE III- »Androgen / Myotropic Efficacy Free Immature TnBTT in Flea Rats

treatment

Dose mg / kg / day r 10 ig number of rats body weight (g)

; g originally ϊ ° at the end

J ^ change oo g / rat / day

ο Organ weights S ventral -J Prostate (mg)

Seminal vesicles (mg)

Levator ani (mg)

Vehicle control
(1% GT) 75 Connection of
Formula B ¹ 100 400 C. 2 link
example 1 100 from 400 1** 00
I. 0 150 25th 10 • 9 9
8th** 25th 9 10 3
3 ** 1.0 7.5
± 0.3 10 75 75 0
0 ** 9 75 75 7th
3 ** 6.2
± 0.7 75 146 141 3
3 ** 75 132 125 8th
3 10.9
± 0.4 142 7.0
± 0.3 6.6
± 0, 3e. pi 135 5.7
± 0, 5.0
± 0, CO
O 2 6, '9
± 1.6 6.7
± 0.3 11.6
± 1.2 * 23,
± 0, 6.0
± 0.3 ä: 4 * 19
± 2, 9.9
± 1.0 24.4
± 2.2 ** 40,
± 2, 11.3
± 1.1 * 27 6th
4 ** 32,
± 2, 16.7
± 1.1 32.0
± 1.5 42,
± 2, 22.8
± 0.8 ** 23,
± 1, 8th
6 ** 30,
± 1, 26.5
± 1.6 [ontrolle: rutile 25.8
± 3.4 8th
7th peaceful by the means of the E C Π-Ω1

a - mean ± s.e.

* - considerably below pp,,

** - considerably different from the mean of the control group, P <0.001

The table above shows that both compounds gave dose-dependent increases in the weights of the ventral prostate and seminal vesicles. The compound of Example 1, but not the compound of Formula B ¹ , caused a significant reduction in body weight gain at all dosages. The compound of formula B ¹ caused a significant increase in the weight of the levator ani at the highest dose. Although the compound of Example 1 showed a relative potency of 0.8 (95% static number pair from 0.4 to 1.6) based on the comparison of the weight of the ventral prostate, the two compounds are within the experimental margin of error of the same effectiveness.

The compound of Example 1 and the compound of the formula B ¹ were approximately equivalent in the studies on the rat, but the compound of Example 1 was at least 15 times more effective than the compound of the formula B ¹ in causing amenorrhea or oligomenorrhea in monkeys . The minimum oral dose of the compound of Example 1 to induce amenorrhea in the regular cycle of female rhesus monkeys was 6.25 mg / monkey / lay for 90 days, whereas the comparable dose of the compound of formula B ^{1 was} 100 mg / monkey / day.

The compound of Example 1 was at least 400 times more effective in inducing amenorrhea or oligomenorrhea in monkeys than danazol (prior art ^{compound of formula B 1).}

The compounds of formula I are suitable for oral, parenteral and intravaginal administration, with oral administration being preferred. For these routes of administration you can the usual pharmaceutical vehicles or carriers and additives or auxiliaries are used for the production of liquid and solid dosage forms such as solutions, suspensions, emulsions, capsules, tablets, injectable forms and suppositories. The preferred dosage form is tablets or capsules.

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Claims (7)

800O Munich 2 ■ BräuhausstraQe 4 ■ Telephone collective number 22 5341 - Telegrams Zumpat · Telex 529979 Case 1-4601-A
12/10 / bs 17a-Q-10β-R-5a-oestr-2-eno- [2,3-d] -4 ', 5'-dihydroxyisoxazole- -17ß-diol with the formula I. CH, OH OH H wherein Q is hydrogen, methyl, ethyl, vinyl or ethynyl " and R is hydrogen or methyl. 2. A compound according to claim 1, in which Q "vinyl or ethinyi is. 3. A compound of Claim 2 wherein R is methyl. 4. A process for the preparation of a compound according to claim 1, characterized in that a corresponding 17oc-Q-1 Oß-R-2-hydroxymethylene-17ß-hydroxy-5oc-oestran-3-one with hydroxylamine or a hydroxylamine salt in an aqueous solvent or solvent mixture under neutral or slightly acidic Conditions "condensed at room temperature or with cooling and optionally a compound of the formula I obtained, wherein Q ethynyl i3t to obtain a corresponding compound in which Q is ethyl or vinyl is catalytically hydrogenated or partially catalytically hydrogenated. 030048/0827 5. TerfaTaren after. Claim. 4 for the production of 17 oc-ethynyl diol, characterized in that 17α-ethynyl-1 Oβ-methyl-2-hydroxymethylene-17β-hydroxy-5α-estran-3-one Reacts with hydroxylamine. 6. The method according to claim. 5 for the preparation of 17a-vinyl-5a-1Oßmethyl ~ estr-2-eno [2,3-d] -4 ^l, 5 ^l ~ dihydroisoxazol-3 | -17ß-diol, characterized, in that 17a-ethynyl -1Oß-methyl-5a-estr ~ 2-eno [2,3-d] -4- ^I, 5'-dihydro-3 ^ -17ß-diol, which was obtained iiher palladium hydroxide is hydrogenated. 7. Pharmaceutical composition, in solid or liquid dosage form for oral, parenteral or intravaginal administration, Containing a compound according to any one of claims 1 "to 3 and a pharmaceutically acceptable carrier. 030048/0827