DE2023917A1 - Steroids - Google Patents

Description

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BDH PHABMACEUTICALS LIMITED, -Edinburgh-11, England

Steroids

The present invention is concerned with improvements in Steroids that have sex hormone activity. It was found that new compounds can be made that exhibit different sex hormone properties if one further examines the structure of steroids with sex hormone activity modified below. Such compounds show "for example estrogens or pregnancy-influencing Effects and they "have in human and veterinary medicine Value for handling and limiting a wide variety of reproductive system conditions and defects or increasing fertility.

According to the invention, new compounds are provided, the sex hormone activity and which are steroid compounds which have a '17β oxygen function and which are in the 17α-position by a group of the formula

OH

- (C s C) ₀ - C - R <- ι

R ²

009847/1984

_BATH

are substituted, wherein

Έ a carboxylic aryl group, an aralkyl group, a
heterocyclic group, an alicyclic group; an alkenyl group having 2 to 5 carbon atoms or an alkyl group
means having 1 to 5 carbon atoms;

E is hydrogen, a carbocyclic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having 2 to 5 carbon atoms or a
Represents an alkyl group having 1 to 5 carbon atoms; or

12th

E and E along with the carbon atom to which they are attached form an alicyclic ring.

The term "steroids" as used herein means compounds which have a backbone which is derived from perhydro-1,2-cyclopenter..ophenanthrene. Since the compounds according to the invention are structurally related to compounds which have sex hormone activity, they generally contain an oxygen puncture, for example hydroxy, methoxy or oxo, in the 3-position; they generally contain unsaturation of olefinic or aromatic character in the A input, but they can also be present in the A ring
to be saturated; they generally have a lower alkyl group on the C ^ and they may or may not contain a methyl group on the CLq. These functional groups are generally found in a variety of sex hormones to a greater or lesser extent, although it is known that there are sex hormones, for example without
Oxygen puncture in the 5 position, there.

The compounds according to the invention have a 17β acid

substance-functional group, ie a ^/ l7ß - hydroxyl

group or an ester or ether group thereof, for example a lower alkoxy group or a lower alkanoyloxy group.

009 8 47/19 84

_ 3 -

The expression "sex hormone activity" is intended to mean activity estrogenic, gestagenic or androgenic in nature and it includes the activity caused by natural occurring steroids, as well as steroids that are not believed to occur naturally. Sex hormone activity can be in the compounds be present directly or it can be manifested in vivo by biological transformation of the compound. Of the The term is also intended to encompass the activity that acts as anti-hormone activity although some of the compounds in question have the usual hormonal activity, e.g. a compound that shows residual estrogenic activity may act as an anti-oestrogen.

1 2

According to the definitions, B and R can be identical or different be.

If E or E is a carbocyclic aryl group, then it can be mono- or bicyclic and, if bicyclic.

Λ 2

is, the rings may be condensed. R or R can; so represent phenyl, 1- or 2-naphthyl or o- or % -biphenylyl. You can use a carbocyclic aryl group in unsubstituted form or such a group can be substituted, for example, with one or more fluorine, chlorine or bromine atoms, hydroxyl groups, alkyl groups containing 1 to 5 carbon atoms, alkoxy groups containing 1 to 5 carbon atoms. Contain material atoms or trifluoromethyl groups. Examples of such substituted carbocyclic aryl groups include p-tolyl, o-chlorophenyl, o- and p-methoxyphenyl.

12th
If R or R is an aralkyl group, the aryl part or so the aryl parts can be mono- or bicyclic carboxyl groups, substituted or unsubstituted, as indicated above, and the alkyl part can contain 1 to 5 carbon atoms. Examples of such aralkyl groups include benzyl, phenethyl and ^v cyl.

Ί 2

If R or R is a heterocyclic ring, this can be a

009847/198 4

5- or 6-membered ring containing 1 or more heteroatoms, selected from O, N and S. It can be aromatic or non-aromatic. Examples of such heterocycle " Shear groups include 2- or 3-pyridyl or 2- or 3-thienyl.

1 2
When R or R is an alicyclic group, it can be, for example, a cyclohexyl or adamantyl group, while when r ' ¹ or R ^{2 is} alkenyl, it can be, for example, vinyl »propenyl or isopropenyl.

1 Ρ

If R or R is an alkyl group, this can, for example be a methyl, ethyl, propyl, isopropyl, n- or sec-butyl or n-pentyl group.

When R is hydrogen, R is preferably carboxylic Aryl group, a heterocyclic group, an alicyclic group, or an alkenyl group.

The compounds according to the invention can be derived from anyone Steroid compound that exhibits sex hormone activity and contains a 17-keto or 17β-oxygen function. Generally, but not exclusively, such compounds contain unsaturation and / or substituents in the rings A and B.

Thus, the compounds according to the invention can contain one or more unsaturations, such as ^, Α, Δ, Δ, Δ. » Δ 5 (10) ^ ^ 6 ^ ^ 7 ^ 8 _and ^ 9 _β For example, ring A can be aromatic or it can be Δ or Δ. Contain unsaturation. Again, the unsaturation may be in one ring, or it may be divided among rings A and B, for example like Δ or &; \ Or ring A can be aromatic and ring B can contain one or two double bonds.

The rings A and B can contain one or more substituents, which are selected from acyloxy, alkoxy, alkyl and

009847/1984

Alkenyl (each containing up to 5 carbon atoms), halogen, Hydroxy and oxo. One or more of these substituents can be chosen to form in vivo metabolized by unsaturation.

Ring C may be free of substituents or it may, for example an oxygen or halogen (for example chlorine or Bromine) puncture on G .. included.

The compounds of the invention include 19-nor compounds, as well as 10-Methy! compounds. They also close a 13-methyl, ethyl and propyl connection. The inventive Compounds can, for example, to the androstan-, 19-norandrostan- (or estran-), 18 ~ methyl estran- or 18-Ethyl oil belong to the series.

Compounds according to the invention which are of particular interest are those that have estrogenic and / or pregnancy activity exhibit. Such compounds can be used to control the Fertility can be used.

An important compound according to the ^{invention is / l7 c} * ^k - (5-hydroxy-5-methyl-1,3-hexadiynyl) -2-methoxy-1,3,5 (10) -estratriene-17βol, which is a potent estrogen, many times more active than ethinyl estradiol as shown by vaginotropic experiments. This compound can be in a daily dose of 1 to 10 ug mg together with a schwangerschaftsbeeinflußeSSen ⁿ §eiii> _w ielsweise with megestrol acetate at a daily dose of 2 to 5 at 21 days women are administered to prevent Pertilität during each menstrual cycle. At the rate of experimentation, the compounds according to the invention show an unusual separation of estrogenic and anti-fertility activity in comparison with ithinyl estradiol. It was found that the estrogenic activity determined in the usual way with the uterine experiment was smaller in relation to the anti-fertility activity. If the estrogenic efficacy is determined in the vagina experiment, it is »higher than in the uterine experiment and corresponds more to the anti-fertility activity. A separation of efficacy between

0098 47/198 4

the uterotrophic and vaginal atrophic experiments with ethinylestradiol is completely unexpected. _w

A compound that has greater anti-fertility activity in humans shows as corresponds to their total hormone activity, offers in terms of reduced side effects and increased safety of oral contraception preparations

Advantages compared to ethynyl

estradiol, which is currently widely used in such preparations.

Important compounds according to the invention with regard to the separation their estrogenic and anti-fertility properties. sen a:

(a) 17c <- §- Hydroxy-5-phenyl-1,3-pentadiynyl) -3-methoxy-1,3,5- (10) -estratrien-17β-ol;

(b) 17O ¹ V- (5-hydroxy-5-p-tolyl-1,3-pentadiynyl) -3-methoxy-1,3,5- (10) -estratrien-17β-ol;

(c) 17d ~ / 5-hydroxy-5- (2-naphthyl) -1,3-pentadiynyl / -3-methoxy-1,3,5 (10) -estratrien-17β-ol ;.

(d) Λ7 <λ- (5-hydroxy-5-o-chlorophenyl-1,2-pentadiynyl) -3-methoxy- ^/ 1 »3» 5 ("10) -estratrien-17β-ol;

(e) 17 <λ- (5-Hydroxy-5-cyclohexyl-1,3-pentadiynyl) -3-methoxy-1,3V " 5 (10) -estratrien-17β-ol;

(f) 17 (λ- (5-Hydroxy-p-biphenylyl-1,3-pentadiynyl) -3-methoxy-1,3,5 (10) -estratrien-17β-ol; and

(g) 17c <- (5-Hydroxy-5-diethyl-1,3-hexadiynyl) -3-methoxy-1,3,5 (10) -e stratrien-17ß-ol

of which compounds (b), (d) and (f) show pronounced separations with respect to the activities. Compounds of the present invention which have remarkable anti-fertility activity include
17 $ - (5-Hydroxy-1,3- & exadiinyl) -4-androstene-17β-ol-5-Qne and

»1» 3-hex & (liinyl) -4-oestren-17β-ol - 3-one 009847/1984

The compounds of the invention can be prepared by any suitable Process are produced. A method of manufacture however, the compounds are a further subject of the present invention. The procedure is characterized by that one is a mixture of an ithynyl compound

R ⁵ - C 5 CH
and a haloethinyl compound

R ^ - C a - CBr

converts, in which one of R, R represents a steroid residue which the xthinyl or haloäthinylgruppe in el configuration in

17-position 'and the other of R ^ and R the group

OH
- C - R ¹

R ²

means in which R and R have the definition given above and where the reaction is carried out in the presence of a copper-I salt carried out, while the copper I salt remains in a reduced state.

It is advantageous to use a catalytic amount of the copper (I) salt to use, which is preferably a copper-CO-halide, for example " wise copper (I) chloride, although other copper (I) salts, for example the acetate can be used. The two ethynyl reactants may be used in approximately equivalent parts or one may be present in slight excess be. It is desirable to carry out the reaction in the presence of a base in order to promote the desired reaction and so that the hydrogen bromide is absorbed. Is the base a relatively strong organic base, for example a lower alkyl / like ethylamine or triethylamine, it can fulfill both functions. If it is a relatively weak organic base, it should be used together with an inorganic base, for example powdery Sodium hydroxide or powdered calcium carbonate is used

009847/1984

will.

In order to obtain the copper (I) salt in the reduced state, a reducing agent is advantageously present in the reaction mixture. A preferred reducing agent is hydroxylamine or a salt of it. It is advantageous to carry out the reaction in an inert atmosphere, for example nitrogen.

Suitable temperatures for the conversion range are between -10 and 30 ⁰ C, preferably -5 to +5 ⁰ C.

The reaction is generally carried out in a suitable reaction medium which should be sufficiently polar to dissolve at least a small portion of the copper (I) salt of the ethynyl compound RC s CH. It is not necessary that the reactants be completely in solution, but the reaction is believed to take place in solution. It is very desirable that the reaction medium contain water. Suitable reaction media include lower alcohols (e.g. methanol or ethanol) or their mixtures with dimethylformamide, dimethylacetamide or dimethylsulfoxide with some water present.

Once the reaction has ended, a reagent, for example potassium cyanide, can be added to "copper (I]] compounds "to react and the steroid can be isolated by conventional work-up procedures. For example, the The reaction mixture can be diluted with water and filtered or extracted with a solvent such as Ither. The last Purification can be achieved, for example, by chromatography and / or recrystallization.

If the steroid used as the starting material contains an oxo group, it may be necessary to place such a group in front of the reducing agent which is present in the reaction mixture is to protect. This can be achieved by using the Oxo group, for example in an enol ether, .. enamine, ketal, thioketal or oxime transferred. Appropriately, one can

009847/1984

then use hydroxylamine as a reducing agent, the oxo group being converted into an oxime. After that, the oxo group if desired, can be regenerated. However, it can be found that an oxo group is not attacked to a large extent and it is unnecessary to protect it.

Compounds according to the invention which contain a 17β-hydroxy group, can by reacting a 17-oxosteroid with a Compound of the general formula

OH

M - (0 = C) ₂ - 0 - E ¹

E ²

where R and R are as defined above and M represents Li, Na, K or Mg Hai (wherein Shark = Cl ,. Br or J- means) and by subsequently using the desired derivative regenerated from the resulting complex. If M is Ka, K or MgHaI, the OH group can be protected the acetylene compound, for example by converting it into a tetrahydropyranyl ether beforehand, be advantageous. The desired derivative is regenerated from the resulting Complex obtained by the usual method. Another one Process for the preparation of the compounds according to the invention consists in that a metal derivative (for example a Grignard reagent) of a 17cN- (buta-1,3-diynyl.) -steroid with

1 ? an aldehyde or ketone of the general formula R R CO treated

1 2
delt, where R and R are as defined above.

When the compound obtained according to the present invention is a 17β-hydroxy compound the latter can be esterified or etherified. This can lead to simultaneous esterification or etherification lead to the OH group in the 17e * chain.

The invention is also concerned with pharmaceuticals Compositions which one or more compounds of the invention together with a pharmaceutical carrier or diluent contain. Such compositions can also

009847/1984

also one or more other active compounds, with- ' e.g. contain other gender norms. For example, compounds that exhibit pregnancy activity, advantageously be formulated together with one or more hormones exhibiting estrogenic activity.

The compositions according to the invention can be used for administration to serve people and animals. The term "pharmaceutical" as used herein includes compositions and carriers that can be used in both human and veterinary medicine. The compositions lie preferably in dosage unit form and they can for daily administration can be formulated in such forms as tablets, capsules, sachets, etc., either that you take them directly or in the form of drops. Suppositories for rectal use can also be used will. Injection preparations can be formulated, preferably with a prolonged effect. Furthermore, implantation pellets can be formulated, which have the advantage of that they require less frequent administration. "

Usual pharmaceutical diluents for solid preparations can include, for example, sugar alcohols, sugars, starch, magnesium stearate gelatin, polyethylene glycols and suitable coloring agents. The tablets may be coated to protect by color discrimination or better appearance by conventional methods such as _v with a film coating or sugar or an ordinary pill coating. The suppositories can be made by using common raw materials such as glycogelatine, coconut butter or water-dispersible raw materials with a melting point above body temperature, such as polyglycols »

For injection purposes, preparations for intramuscular or subcutaneous administration in conventional sterile oily aqueous or emulsion bases in solution and / or in suspension are produced »Carriers preferably include a physiologically compatible vegetable oil, both

for example peanut oil, fractionated coconut oil, oily esters, for example isopropyl myristate, non-aqueous solvents, for example propylene glycol, aqueous carriers ₄ such as sterile water or physiological saline solution, together with suitable formulation agents such as suspending agents, for example aluminum stearate for oily materials, carboxymethyl cellulose for aqueous preparations, physiologically acceptable emulsifying agents, for example "Tween" 81, buffering agents for pH control, antioxidants, stabilizers and solubilizing agents. The injections can be formulated for direct use or as a dry powder for constitution with a separate carrier prior to use. Unit injections which are required for extended periods, for example periods of one month, will of course receive an increased amount of the active material.

Each dose is in unit form for daily administration Humans preferably contain 1 g to 5 mg of the invention active material, depending on the circumstances to be treated and the effectiveness of the compound.

Implant pellets should generally be a higher dose included to give longer effect for preferably several months. The implants can be aseptically made of sterile material, for example by fusing or pressing under Print, preferably produced without the addition of other substances will.

For use in veterinary medicine in particular, long-acting vaginal eyelets, such as tampoons and pessaries, are more common Way to be made. The dose required to treat the animals depends of course on the size of the animal. ·

The pregnancy compounds according to the invention can be used as oral contraceptives can be used, preferably either in daily doses of 0.1 mg to 5 mg at approximately 21 days in, each menstrual cycle alone or together

009847/1984

BATH ORIGINAL

men with an estrogen, for example ethinyl estradiol 0.05 or 0.1 mg. Regardless of their use as oral contraceptives, the progestogens can clinically be used in the following Conditions to be used: dysmenorrhea, functional Uterine bleeding, pre-menstrual tension, pregnancy diagnosis and endometriosis.

The following examples illustrate the invention, but without it to restrict.

example 1

17ος- (5-hydroxy-5-phenyl-1,3-pentadiynyl) -3-methoxy-1,3,5 (10) -ö stratrien-17-ß-ol

A solution of ethynyl-phenyl-carbinol (3.4 ml) in N, N-dimethyl-formamide (4-0 ml) was added to a stirred mixture of copper (I) chloride (0.38 g), hydroxylamine hydrochloride (0.86 g), methanol (4-7 ml), N, N-dimethylformamide (80 ml) and 70% aqueous ethylamine (9.7 ml) and the mixture was stirred under nitrogen at room temperature for one hour. It was then ^{cooled to 0} ° C. and 17 * -Brom.äthinyl-3-methoxy-1,3,5 (10) -estratrien-17β-ol in Ν, Ν-dimethylformamide (87 ml) was added over the course of one hour. The mixture was allowed to warm to room temperature, then stirred for 2 hours, treated with potassium cyanide (1.0 g) in water (11 ml) and poured into water (67 ml). The precipitate Wurd collected and recrystallized from a mixture of ether and light boiling petroleum ether - crystallized, yielding 1 c * ~ {5-hydroxy-5-phenyl-1,3-pentadiynyl) -3 (Sp 60 8O ⁰ O.)? -methoxy-1,3 »5 (1O) -8stra-

° fikffi 46 °

trien-17β-ol, m.p. 134 ° fikffi -46 ° (C-1.2 in dioxane), λ ' 287.5 nm (£, 2000), 278 nm (ε, 2100), 24.6.5 nm (E. , 1100).

Example 2

17cX- (5-Hydroxy-5-P-tolyl-1,3-pentadiynyl) -3-methoxy-1 _l 3 * 5 (iO) - oestratrJGn-17β-ol.

Sodium (23 g) was added to liquid ammonia (1 liter),

009847/1984

BATH ORIGINAL

while a stream of acetylene was passed through to form the monosodium derivative of acetylene. p-Tolualdehyde (120 g) in tetrahydrofuran (500 ml) was added and the mixture was heated at reflux with stirring for 3 hours with a continuous stream of acetylene ^{1 being passed} through the reaction mixture. The ammonia was then able to distill off and the residue was treated with water, acidified and extracted with ether. The distillation of the ether layer yielded ethynyl-p-tolyl-carbinol. Sp. 78 ° / 0.3 mm.

A solution of ethynyl-p-tolyl-carbiriol (3.89 g) in N, N-dimethylformamide (53 ml) was added to a stirred mixture of copper (I) chloride (0.4-7 g), hydroxylamine hydrochloride (1.03 g), methanol (57 ml), N, N-dimethylformamide (96 ml) and 70% aqueous ethylamine (12 ml) and the mixture was stirred under nitrogen at room temperature for one hour. It was then ^{cooled to 0} ° C. and a solution of 1 ^ -bromoethinyl-3-methoxy-1,3) 5 (10) -estratrien-17β-ol (8.0 g) in NN-dimethylformamide (104 ml) became added over 30 minutes. After a further 10 minutes at 0 ^° C., the mixture was able to warm to room temperature within 30 minutes. Potassium cyanide (1.32 g) in water (14.5 ml) was added and the mixture poured into ice / water. The precipitate was collected and recrystallized from a mixture of benzene and low-boiling petroleum ether (sp. 60 80 ⁰ C), the 17ov- (5-hydroxy-5-p-tolyl-1,3-pentadiinyl) -3-methoxy -1,3,5 (iO) -estratrien-17β-ol received.

154 °, A-ZJp -43.6 ° (C-0.3 in dioxane), Λ _max 277.5 nm (£, 2173), 286.5 mn (£, 1968).

Example 3

a) Production of ethynyl (2-naphthyl) carbinol

Ethylmagnesiurabromide, made from ethyl bromide (30.0g) and Magnesium (6.8 g) in tetrahydrofuran (175 ml) was during 2 Added to a saturated solution of acetylene in tetrahydrofuran (150 ml) for hours. The mixture was left for 2 hours stirred while continuously passing acetylene through. 2-

009847/1984

Naphthaldehyde (25.0 g) was added and the mixture was refluxed for one hour and then allowed to cool. Thereafter saturated aqueous ammonium chloride solution (50 ml) was added added to the mixture, which was then extracted with ether. Distillation of the ether layer gave ethynyl-2-naphthyl-car ~ binol, Sp. 148 - 150 ° C / O, 75 mm, recrystallized from benzene, . 61 °.

b) 17 c * - / "5-hydroxy-5 - (2-na phthyl) - ^<1.3 ~ pentadiinyl7-3-methoxy- 1, 3, 5 (10) -o-17.beta. stratrien ~ _ql

A solution of ethynyl- (2-naphthyl) -carbinol (5.0 g) in N, N-dimethylformamide (53 ml) was added to a stirred mixture of copper (I) chloride (0.47 g), hydroxylamine hydrochloride ( 1.03 g), methanol (57 ml), N, N ~ dimethylformamide (96 ml) and 70% aqueous ethylamine (12 ml) and the mixture was stirred under nitrogen at room temperature for one hour. The mixture was then ^{cooled to 0 0} G and a solution of 17c ^ -Bromäthinyl-3 ~ methoxy-1,3,5 (1Q) »ö stratrien-17ß-ol (8.0 g) in Ν, Ν-dimethylformamide ( 104 ml) was then added over 20 minutes. After a further 10 minutes at ⁰ ° C., the mixture was allowed to warm to room temperature over 30 minutes. A solution of potassium cyanide (1.32 g) in water (14.5 ml) was then added and the mixture poured into ice / water. The precipitate was collected and recrystallized from a mixture of benzene and low-boiling petroleum ether (bp. 60 80 ⁰ C), the 17o ( -Γ 5-hydroxy-5- (2-naphthyl) -1,3-pentadiynyl "7 ™ 3-methoxy ~ 1,3,5 (10) -estratrien-17β-ol. Mp. 114 ° C / "o (7p ³ -39.8 ⁰ (G-0.3 in dioxane) A _max 267, 5 nm (£, 7850), 247.75 nm (t, 4900), 275.5 nm (€., 6650), 285.5 nm (£, 4850).

Example 4

17 (A- (5- hydroxy-5-o-chlorophenyl-1,3-PQntadiinyl) -3-roethoxy- 1 »3i!? (10) -estratrien-17β-ol

A solution of o-Ohlorphenyl-ethynyl-carbinol (4 ₉ 75 s) i- ⁿ H, N-Diraethylformamid was (aal 65) au a stirred mixture

Ί984 -

BATH ORIGINAL

of copper (I) chloride (0.47 g), hydroxylamine hydrochloride (1 * 03 g), methanol (57 ml), Ii, N-dimethyl formamide (96 ml) and 70% aqueous ethylamine (12 ml) given under nitrogen at room temperature. The mixture was then ^{cooled to 0} ° C. and a solution of 1 'fa.-bromoethinyl-3-methoxy-1 »3.5 (10) -estratrien-17β-ol (8.0 g) in Ν, Ν-dimethylformamide (104 ml) was added over 25 minutes. After a further 10 minutes at ⁰ ° C., the mixture was allowed to warm to room temperature over 45 minutes, then a solution of potassium cyanide (t> 32 g) in water (15 ml) was added and the Mixture poured onto ice / water. The precipitate was collected and from cyclo-

hexane crystallizes. Remove the adhering solvent in vacuo at 68 ⁰ C afforded amorphous 1 ^l M- (5-hydroxy-5-o-chlorophenyl-1,3-p-entadiiny) i-3-Eiethoxy-1,3,5 (10) -östratrien- 17β-ol f <* Jp - 36 ° (C, 0.3 in dioxane) λ _{m & x} 247.5 nm (£, 1400) 263.5 nm (£, 1600), 278 nm (£, 2205, 287.5 nm (£, 2000).

- (5-Hydroxy-5,5-diphenyl-1,3-pentadiinyl) -3-methoxy-1, 3 ^ - 5 (10) -estratrien-17β-ol

A solution from. 1 TU-ethynyl-3-methoxy-1,3,5 (10) -estratrien-17ß-ol (9 »2 g) in N, N-dimethylformamide (50 ml) was added to a stirred mixture of copper (I) Chloride (0.43 g), hydroxylamine hydrochloride (1.01 g), methanol (52 ml), Ν, Ν-dimethylformamide (84 ml) and 70% aqueous ethylamine (13.6 ml) and the mixture was added stirred under nitrogen for one hour at room temperature. A solution of 1-bromo-3) 3-diphenyl-1-propyn-3-ol (5 »4 g) £ W. Chodkiewicz, Annales de Chimie, 2, 819 1957) in N, N-dimethylformamide (50 ml) was added over one hour. The mixture was stirred for 11/2 hours, treated with a solution of potassium cyanide (1.2 g) in water (50 ml) and poured onto water. The precipitate was collected and purified by chromatography on silica gel using toluene / ethyl acetate as the eluent. Crystallization from cyclohexane gave 1'M- (5-hydroxy-5,5-diphenyl-1,3-pentadiinyl) -3-methoxy-1,3,5 (10) -östratrien-17ß-ol _f the crystal

009847/1984

Lization cyclohexane contained m.p. 96-97 ° C, / "<* J ^ - 55.7 ° (C - 0.47 in dioxane), λ _rooY 287 nm (€., 1782),. 277 nm (£., 1927 ), 261.5 nm (£, 1544), 247.5 nm (£, 1452).

Example 6

a) Preparation of 17 (X-bromoäthinyl-6ß-methyl-5o (-androstane-3ß, 5,17ß-triol

Silver nitrate (15.0 g) was added to a solution of 17 & -ethynyl-6ß-methyl- ^ -androstane-3ß, 5.17ß-triol (15.0 g) in ethanol (700 ml) and water, (210 g) given. The mixture was stirred for 45 minutes. Then N-bromosuccinimide (15.0 g) was added, the mixture was stirred for an additional 5 minutes and poured into 5% aqueous bicarbonate solution (3 liters). The precipitate was collected and recrystallized from methylene chloride and acetone / low boiling petroleum ether (bp. 60 - 80 ⁰ C) to give it the 17 & -Bromäthinyl-6ss-methyl-5c-androstan-3.beta. ^ »5,17ß-triol received. Mp. 201 C ⁰ / oC / ^ ^8-52.3 ° (C 0.25 in ethanol).

b) 17 <* - (5-Hydroxy-5-phenyl-1,3-pentadiinyl) -6ß-methyl-5 ⁽ ^ .- androstane-3ß, 5,17ß-triol

A solution of ethynyl-phenyl-carbinol (4.0 ml) in N, N-dimethylformamide (40 inl) was added to a stirred mixture of copper (I) chloride (0.45 g) hydroxylamine hydrochloride (1.00 g), Methanol (55 ml), N, N-dimethylformamide (95 ml) and 70% aqueous ethylamine (10.7 ml) were added and the mixture was stirred under nitrogen at room temperature for one hour. The mixture was ^{cooled to 0} ° C. and a solution of I7c <-Bromäthinyl-6ß-methyl-5 ^ -androstah-3ß, 5,17ß-trioi (8.0 g) in N, N-dimethylformamide (110 ml) was added over an hour. The mixture was allowed to warm to room temperature. It was stirred for 2 hours, treated with a solution of potassium cyanide (1.2 g) in water (70 ml) and poured into water (700 ml). The precipitate was collected and crystallized from ether / low-boiling petroleum ether and aqueous methanol, the 17c ^ - (5-hydroxy-5-phenyl-1,3-pentadiynyl) -6ß-methyl-5ck-androstane-3ß, 5 , 17ß ~ triol received. M.p. 175 ^° C

009847/1984

d ^{0 to} 54.3 ° (C 0.5 in ethanol); λ _max 299.5 nm (£, 331.7) 283 nm (£, 41.3,7), 259 nm (ζ, 867.5), .247 nm (£., 1039).

Example 7 _;

17 <A- / 5-Hydroxy-5- (1-naphthyl) -1, 3-pentadiynyl7-3-methoxy-1,3,5 (10) -estratrien-17β-ol ■

A solution of itynyl (1-naphthyl) carbinol (0.49 g) in N, N-dimethylformamide (5.0 ml) was added to a stirred mixture of copper (I) chloride (0.047 g), hydroxylamine hydrochloride (0.103 g), methanol (5.7 ml), ₁ N-dimethylformamide (9.6 ml) and aqueous Ithylamin (1.2, where N ml 70%) and the mixture was stirred for one hour under nitrogen at room temperature. The mixture was ^{cooled to 0} ° C. and a solution of 1 ^ -bromoethinyl-3-methoxy-1,3,5- (10) -estratrien-17β-ol (0.80 g) in N, N-dimethylformamide (10 , 0 ml) was added over the course of 10 minutes and stirring was continued at ⁰ ° C. for a further 10 minutes. A solution of potassium cyanide (0.13 g) in water (2.0 ml) was added and the mixture was poured into water. Precipitate ¹ was collected and crystallized from cyclohexane, using 17 # - / 5-hydroxy-5- (1-naphthyl) -1,3-pentadiynyl / -3-methoxy-1,3,5 (10) -estratriene -17ß-ol obtained containing crystallization cyclohexane. Fp. Difficult to determine, / Co ^ Jf, - 33 ° (CJ- · 0.25 in dioxane)? \ _Max 272 nm (£, 9700), 281.5 nm (£, 11900), Ainf ²⁶² » ^{5 1} ^ Cl '6200), 286.5 nm (£, 9100), 292 nm (£, 7150). .

Example 8

17 ^ - (5-Hydroxy-5-cyclohexyl-1,3-pentadiiny ^; l) -3-methoxy-1,3 »- 5 (10) -estratrien-17β-ol

A solution of ithynyl-cyclohexyl-carbinol (2.65 g) in N, N- ' Dimethylformaride (30 ml) was added to a stirred mixture of copper (I) chloride (0.28 g), hydroxylamine hydrochloride (0.64g) Methanol (35 ml), N, N-dimethylformamide (60 ml) and 70% Added to aqueous ethylamine (7.2 ml) and the mixture was

009847/1984

stirred under nitrogen for one hour at room temperature. The mixture was ^{cooled to 0} ° C. and a solution of 17 ^ -Bromäthinyl-3-methoxy-1,5,5 (10) -estratrien-17ß-ol (5.0g) in Ν, Ν-dimethylformamide (70 ml) was added over 80 minutes. Stirring was then continued at ⁰ ° C. for a further 1 3/4 hours. A solution of potassium cyanide (0.74 g) in water (9 ml) was added and the mixture poured into water. The precipitate was collected and crystallized from cyclohexane, yielding 17 * - (5-hydroxy-5-cyclohexyl-1,3-pentadiynyl) -3-methoxy-1,3,5 (10) -estratrien-17β-ol containing crystallization cyclohexane. Fp. Difficult to determine, / Wjp- 36.3 ° (£, 0.4 in dioxane), ^ _max 261 mn (£, 831), 278 nm (£, 1911), 287.5 nm (£ ·, 1804) .

Example 9

t- (5-hydroxy-5-o-niethoxyphenyl-1,3-pentadiynyl) -3-methoxy -1,3,5 (10-estatrien-17β-ol

A solution of ethynyl-o-methoxyphenyl-carbinol (3.37 s) in N, N ~ dimethylformamide (40 ml) was added to a stirred mixture of copper (I) chloride (0.35 g), hydroxylamine hydrochloride (0, 78 g), methanol (43 ml), N, N-dimethylformamide (73 ml) and 70% aqueous ethylamine (8.8 ml) were added and the mixture was stirred for one hour at room temperature under nitrogen. The mixture was then ^{cooled to 0} ° C. and a solution of 17 <^ - bromoethinyl-3-methoxy-1,3,5 (1O) -estratriene-17β- j oil (6.08 g) in N, N-dimethylformamide ( 79 nil) was added over 80 minutes. The mixture was stirred for 2 hours at 0 ^° C. and for one hour at room temperature. A solution of potassium cyanide (1.0 g) in water (11 ml) was added and the mixture poured into water. The precipitate was collected and purified by crystallization from ether / cyclohexane, the i7bK5-hydroxy-5-o-ynethoxyphenyl-1,3-pentadiynyl-3-methoxy-1,3,5 (10) -estratrien-17β-ol received, the crystallization cyclohexane contained "melting point poorly defined, loiJT

22.5 ° (0-0.4 in dioxane), λ _rav 220 nm (£, 20500), 246.2 nm '(£, 1950), 277 nm (£, 51-00).

009847/1984 "

Example 10

a) Production of iJ-biphenyl-äthinyl-carbinol

Ethyl magnesium bromide prepared from ethyl bromide (12.0 g) and magnesium (2.7 g) in tetrahydrofuran (50 ml) was added to a saturated solution of acetylene in tetrahydrofuran (60 ml) over 30 minutes. The mixture was stirred for one hour, during which acetylene was continuously passed through. A solution of p-phenylbenzaldehyde (8.5 g) in tetrahydrofuran (40 ml) was then added and the mixture was refluxed for one hour and then allowed to cool. Saturated aqueous ammonium chloride solution (25 nil) was then added and the mixture extracted with ether. The ether layer was washed, dried (Na ^ SO ^) and freed from the solvent under reduced pressure. Crystallization of the residue from benzene / low-boiling petroleum ether (bp 60-80 ° C.) yielded p-biphenylyl-ethinylcarbinol, melting point 11? - 118 ⁰ ^ _11181x 253.5 nm (£, 21517).

b) 17ο * .- (5-Hydroxy-5-p-biphenylyl-1,5 ~ pentadiinyl) -3-methoxy - 1 ^ 3,5 (10) -estratriene-17β-o1

A solution of 'p-biphenylyl-ethinyl-carbinol (5.8 g) in N, N-dimethylformamide (65 ml) was added to a stirred mixture of copper (I) chloride (0.47 g) and hydroxylamine hydrochloride (1 , 03 g), methanol (57 ml), ^^ - dimethylformamide (96 ml) and aqueous ethylamine (12 ml; 70%) and the mixture was stirred for one hour under nitrogen at room temperature. The mixture was then ^{cooled to 0} ° C. and treated with a solution of 1 'fo-bromoethinyl-3-methoxy-1,3,5 (10) -estratrien-17β-ol (8.0 g) in Ν, Ν-dimethylformamide ( 104 ml), which was added over 25 minutes. The mixture was ^{stirred at 0} ° C. for 10 minutes and then for one hour while it was allowed to warm to room temperature. It was then treated with a solution of potassium cyanide (1.2 g) in water (10 ml) and poured into water (2 1/2 liters). The precipitate was collected and crystallized from methylene chloride / low-boiling petroleum ether (sp. 60-80 ⁰ O), the 1? ^ - (5-hydroxy-5-p-biphenyl- -1,3-pentad.iinyl) -3-methoxy-1,3,5 (10) -estratrien-17β-ol

009847/1984

received. Mp. 119 °, / ol / jp- 39.8 ° (C, 0.53 in dioxane), Λ _max 220 nm (£, 18800), 232.5 nm, (έ, 14435), 255 mn (β, 24410).

Example 11

--1, 3-peiitadiynyl) -3-methoxy

1,3,5 (10) -ÖGtratrien- 17β-ol

A solution of lthiiiyl ~ p-methoxyphenyl ~ carbinol (0.443 g) in! 0.103 g), methanol (5, x 7 ml), N, N-dimethylformamide (6 DiI) and 70% aqueous ethylamine (1.2 ml) and the mixture was stirred for "one hour" at room temperature under nitrogen. the mixture was cooled to -20 ⁰ C and a solution of 17ci _v -Bromäthinyl-3-methoxy-1,3,5 (1O) -estratriene-17.beta. ~ ~ oil (0.80 g) in Ν, Ν-dimethylformamide ( 10 ml) was added during 5 minutes. The mixture was stirred for one hour at -15 to -2O ⁰ C and poured into V / ater. The precipitate was collected and purified by chromatography on alumina with a cyclohexane / ethyl acetate mixture as eluent. Crystallization from cyclohexane gave the 17c * - (5-hydroxy-5 "P-methoxyphe3ryl-1,3-pentadiynyl)" 3-rciethoxy ~ 1,3,5 (10) -estratrien-17β-ol, which contained crystallization cyclohexane. " Mp 106 ° C , / öi / jp-30.5 ° (C, 0.15 in dioxane); i \ _{m & x} 230 nm (£, 227OO), 276 nm (£, 4600), 281 im (£, 4200); λ _inf 286.5 nm (£, 3100).

Example 12

~ 1, 3-hGxad iinyl) ~ 3 "in6thoxy-1, 3, 5 (10) -

ö ntr atria-1? ß-iol

A solution of 2-methyl-3-butyn-2-ol (3.00 g) in N, N-dimethylformamide (50 ml) was added to a stirred mixture of copper (I) chloride (0.43 g), Hydroxylamine hydrochloride (1.01 g), methanol (52 ml), ^! ^ Dimethylformamide (84 ml) and 70% aqueous ethylamine (13.6 ml) were added and the mixture was stirred under nitrogen at room temperature for one hour. 1 ^r M-Bromoäthinyl-3-Metlioxy-1,3 _i 5 (10) -estratrien-17ß-ol (8.00 g)

009847/19 8 4

BATH

in N, N ~ diraethylformamide was added over the course of one hour. After a further 10 minutes, potassium cyanide (1.2 g) in water (15 ml) was added and the mixture poured into water. The precipitate was collected and purified by crystallization from a mixture of diisopropyl ether and light-boiling petroleum ether (60-80 ⁰ G) and purified from aqueous methanol to give the 17ol- (5-hydroxy-5-iaethyl-1 _{3-hexadiynyl?} ) -3-methoxy-1,3i5 (10) -estratrien-17β-ol, which contained water of crystallization. Pp. 104 ⁰ C, / "ex / ^ - 53-6 ° (C, 0.41 in dioxane), λ _max 287.7 µm (£, 2000), χ _max 278.5 '(£, 2200).

Example 13

-1,3- p entadiinyl) -1, 3, 5 (10) -estra -

'"Silver nitrate (2.00 g) were added to a stirred solution of 3- ~ _{acetoxy-17ö>} -äthinyl-1,3,5 (10) ~ östratrien-17-ol (2.00 g) in a mixture of ethanol (100 ml) and water (30 ml) were added, and the mixture was stirred at room temperature for 35 minutes. N-bromosucciniinide (2.00 g) was added and the mixture was stirred for 5 minutes and then poured into an aqueous sodium bicarbonate solution. The precipitate was collected and recrystallized from aqueous methanol, giving the 3-acetoxy-17-c ^ bromoethinyl-1,3,5 (10) -stratrien-T7ß-ol. Mp. 176 ° C, / ouf ⁵ ~ 13.5 ° (£, 0.68 in dioxane).

Ethynyl-phenyl-carbinol (5 O ₅ ml) was added to a stirred mixture of copper (I) chloride (0.60 g), hydroxylamine hydrochloride (1.40 g), methanol (70 ml), Ν, Ν-dimethylformamide (120 ml) and 70% aqueous ethylamine. (14.6 ml) and the mixture was stirred for one hour under nitrogen at room temperature. It was then ^{cooled to 0} ° C. and 5-Ac; etoxy-1 ^r / ni-bromoethinyl-1,3,5 (10) -öεtratrieii-17ß-ol (10.00 g) in Ιϊ, ΐί-D.iinüthylformamid ( 130 ml) were added for about an hour. The mixture was allowed to warm to room temperature and was then stirred for 2 1/2 hours with Er-ni-gsliuro (20

0 0 9 8 4 7 / I 9 8 4 ^BA D ORIGINAL

ml) treated in water (150 ml) and poured into water (2 l). The precipitate was collected and purified by chromatography on an aluminum oryde column using a mixture of toluene and ether as the eluent. To give the 17 ^ - ^ - hydroxy-5-phenyl-1,3-pentadiynyl) -1, 3,5O0) -östi \ atria-3,17ß ~ cLio.l, Pp 174 -. 177 ⁰ C, / ^ 7 ^ - ^ - 9.8 ° (C, 0.41 in dioxane), λ _inf 286 mn (ε, 2150), A _max 281 nm (£, 2400).

Example 14

'-1,3-hexad iinyl) -1, 3, 5 (10) -estratriene -

3,17β-diol

2-methyl-3-butyn-2-ol (0.60 g) in Ν, Ν-dimethylformamide (13 ml) were added to a stirred mixture of copper (I) chloride (0.116 g), hydroxylamine hydrochloride (0, 26 g), methanol (14 ml), N, H-dimethylformamide (24 x ml) and 70% aqueous ethylamine (30 ml) and the mixture was stirred at room temperature for 45 minutes and then cooled to ^{0 ° G.} 3-Acetoxy-17o <.- bromoethinyl-1,3,5 (10) -octratrien-17ß-ol (2.40 g) in N, N-dimethylformamide (25 ml) was for 6 to 8 minutes at ^{0 0} C added b. After an additional 5 minutes, potassium cyanide (0.33 g) in waccer (5 ml) was added and the mixture poured into water. The precipitate was collected and washed with potassium hydroxide (2.0 g). treated in ethanol (50 ml) and water (20 ml) at room temperature for 15 minutes "The solution was poured into water containing a slight excess of hydrochloric acid and the precipitate was collected and dried" Purification by crystallization from methylene chloride / cyclohexane provided 1to ^ - (5-Hydroxy-5-methyl-1,3-hexadiynyl) -1,3,5 (10) -estratriene-3,17ß-diol, melting point 140-145 ° C. (difficult to determine) _s Λ _{m v} 280 nm (£, 2100) Z "(X7 ^ - 50.7 ° (£, 0.37 in dioxane), λ _inf 258 nm (£, 790), 285.3 mn (£, 1950).

At »ρi eI 15

Ivrt.yo ·;:., / · - '! , 3- hexadiiriyl) - ^ -methoxy-1, ~? < , ^ (LO) -östratr-i en-

'.. »5% -i [re.'jw.r.r. 1-BuIin-3-oil (1.30 ml) vmrde to a

0 0 9 8 4 7/1984

BATH ORIGINAL

stirred mixture of copper (I) sulfite (0.10 g), hydroxylarain hydrochloride (0.15 g) r methanol (12 ml), v / water (4 ml) and 70% aqueous ethylamine (J, 4. ml) and the mixture was stirred at room temperature under nitrogen for 45 minutes and then cooled to ^{0 ° C.} 170-Bromoäthinyl-3-methoxy-1,3,5 (10) -estratrien-17β-ol (1.95 g) in methanol (50 ml) was added over 45 minutes. After a further 15 minutes, potassium cyanide (0.1 g) in water (ml) was added and the mixture was poured into water. The steroid product A was isolated by extraction with ether and purified by crystallization from methylene chloride / cyclohexane, the 17CÄ- (5-hydroxy-1, J-hexadiynyl) -J-methoxy-1, J, 5 (10) -östra ~ trien-17ß-ol received. Mp 129 -. 134 ⁰ C, £ ^ ΐψ- 40.8 ° (C, 0.37 in dioxane) Λ _{w v} in 277 (fc, 2215), 286.5 nm (£ 1860).

Max

Example 1 6

J-Oy cl-oOentylqx y-17d-5- ^ cIrOXy- (5-i nethyl - 1, 3-hoxadynyl ) -1, -3 , 5 (10) -ÖBtratr ie n-i7ß ~ o l

-1,3,5 (iO) -estratrien-17β-ol (3? 50 g) in N, N ~ dimethylforreamide (75 ml) was added to a stirred clay mixture of copper (I) chloride (0.25 g ) 5 Hydroxylamine hydrochloride (0.50 g), methanol (31 ml), Ν, Η-dimethylformamiä '(50 ml) and 70% aqueous iS-thylaniine (7.5 ml) were added and the mixture was stirred under nitrogen and cooling stirred at ⁰ ° C. for one hour. 1-Bromo-3-methyl-1-butyn-3-ol (1.50 g) in Ν, Ι'Τ-dimethylforiQamide (30 ml) was added over the course of one hour. The mixture was allowed to warm to room temperature over an hour and potassium cyanide (1.5 g) in water (20 ml) was added. The mixture was added to water (1 liter) and the steroid product collected by filtration, dried and purified by crystallization from aqueous methanol to give the 3-cyclopentyloxy-17tA- (5-hydroxy-5-methyl-1,3-hexadiynyl ) -1,3,5 (10) ~ oestratrien ~ 17β-ol. M.p. 142-145 ° C, / ^ 7Jp- 35.8 ° (C, 0.40 in Ohloroform), λ _{m & x} 223-WL (6 »9 ^ 00), 280 nm (£, ^ 7t>), h _{± ηΐ} 259 nm ce »^ 81) .-

009847/1984 _BAD OR.GIHAU

Example 1 7

17 ^ - (5-Hydroxy-5-methyl-1,3-hexadiynyl) -4-androsten-17β-ol-3-one

The 3-oxime des 17 ^ -ethynyl-4-androsten-17ß-ol-3-one (17.0 g) in N, N-dimethylformamide (350 ml) was added to a stirred mixture of copper (1) chloride ( 1.25 s) »Hydroxyl aiaine hydrochloride (2.50 g), methanol (156 ml), N, N-dimethylformide (250 ml) and 70% aqueous ethylamine (37> 5 nil) and the mixture was added under nitrogen Stirred for one hour and cooling to O ^{0 C.} 1-Bromo-3-methyl-1-butyn-3-ol (7.5Og) in N, N-dimebhylformamide (150ml) was added over one hour. The mixture was allowed to warm to room temperature over an hour and potassium cyanide (0.75 g) in water (10 ml) was added. The mixture was poured into water (4 liters) and the steroid collected by filtration. Crystallization from aqueous methanol afforded the oxime, m.p. 240 -. 241 ⁰ G.

A mixture of the Ox.inxs (8.00 g) glacial acetic acid (40 ml), pyruvic acid (6.24 g), sodium acetate (3.04 g) and water (16 ml) was refluxed for 4 hours and then dissolved in V / water (650 ml) poured. The steroid product was collected by filtration and purified by crystallization from aqueous methanol to give the 17oi- (5-hydroxy-5-methyl-1,3-hexadiynyl> 4-androsten-17β-ol-3-one, mp 237 ° C, / dj ^ ⁶ ~ 34 ° (C, 0.41 in dioxane), λ 240 nm (£, 15728).

Example 18

17r /. ~ (5-Hy dj ^ ox y-5-m ethyl- 1,3-h oxadiinyl) -4 ~ 6'stren-17β-ol ~ 3 - one

17C4-ethynyl-3-methoxy ~ 3.5 - estradiene-17-ol (13.6 g) in N ₁ N-dimethylformamide (340 ml) were added to a stirred mixture of copper (I) chloride (1 13 g) »Hydroxylamine hydrochloride (3.40 g), methanol (142 ml), N, N-dimethylformamide (226.5 ml) and 70% aqueous ethylamine (34 ml) and the mi

009847/1984

The mixture was stirred for 5 minutes at room temperature under nitrogen and then ^{cooled to 0} ° C. 1-Bromo-3-methyl-i-butyn-3-ol (6.80 g) in ^^ - dimethylformamide (136 ml) was added The mixture was allowed to warm to room temperature, stirred for 75 minutes, and poured into water (4.5 liters). The steroid product was isolated by extraction with ether and poured into refluxing methanol (800 ml) with p-'ioluenesulphonic acid (2.08 g) and water (5.5 ml) for 10 minutes "treated. The methanolic solution was poured into water and the steroid product was collected by filtration, dried and purified by chromatography on aluminum oxide with toluene / ether as the eluent and by crystallization from cyclohexane ether, the 17c (- (5-hydroxy-5-diethyl-1, 3-hexaoinyl) -4 »oestren-17 [beta] -ol-3-ones. Mp. 131-143 ° C, / Wip-. 80.5 ° (C, 0.58 in Dioxins), ) \ 239.5 m (£, 14800).

Beis piel 19

17 ^ - (5-H7 / dro x; y-5-met h7 / l-1 , 3-hexa diinyl) -5 ~ a ndrost en- 3ß _T i7ß- diol

17rj.-Ät} iinyl ~ 5-androßten-3ß, 17ß-diol (7.00 g) in K, N-dimethylformamide (150 ml) is added to a stirred mixture of copper (I) chloride (0, 50 g), hydroxylamine hydrochloride (1.00 g), methanol (6.25 ml), N, W-dimeth7 / lformamide (100 ml) and 70% v / aq ethylamine (15 ml) and the mixture was added Nitrogen and cooling to ^{0 0} G, stirred for 30 minutes. 1-Bromo-3-methyl-1-butyn-3-ol (3.00 g) in II, II-diethylformamide (60 ml) was added over the course of one hour. The mixture was allowed to warm to room temperature over an hour and potassium cyanide (3.00 g) in v / water (40 ml) was added. The mixture was poured into water (2 liters) and the steroid product was collected by filtration, dried and purified by crystallization from aqueous "methanol" and from ether / low boiling petroleum ether to give the 1 * / U- (5-hydroxy -5-methyl-1,3-hexadirnyl ") -5-anaesthetic-3β, 17β-diol. Mp. 209 ° C, / c * 7Jp- W ⁰ (C ₁₀₅₄ in dioxane).

009847/1086 ORIGINAL BATHROOM

Claims (1)

Claims (Λ . 'Compounds with sex hormone activity, the steroxdverbindungen contain, which have a 17ß - oxygen function and in the 1 ^ -position by a group of the structure OH - (C ξ C) ₂ - C - R ¹ are substituted, wherein R is a carboxylic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having 2 to 5 carbon atoms or an alkyl group with 1 to 5 carbon atoms means $ ρ
1ΐ ~ denotes hydrogen, a carboxylic aryl group, ea.ne aralkyl group, a heterocyclic group, an alicyclic group, an alkonyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms; or i 2 L and R together with the carbon atom to which they are attached form an alicyclic ring. 2. Compounds according to claim 1 having an oxygen function in the 3 position. 3. Compounds according to claim 1 or 2 with an olefinic or aromatic unsaturation in ring A. ^ l ·. Compounds according to one of the preceding claims, in which the IVβ oxygen function is a hydroxyl group means. H. Preliminary bindings according to one of the preceding claims 0098 4 7/198 / » BATH ORIGINAL the, -wherein R or E is a phenyl, 1- or 2-haphthyl or mean o- or p-biphenylyl group. 6. Compounds according to claim 5, wherein the group R or E by one or more fluorine, chlorine or bromine atoms, Hydroxy groups, alkyl or alkoxy groups with 1 to 5 carbon atoms or trifluoromethyl groups are substituted. 7. Compounds according to claim 6, wherein the group E ρ
or R is p-tolyl or o-chlorophenyl or o- or p-methoxyphenyl. 8. Compounds according to any one of claims 1 to 4, wor- 1 P
in R or R denotes an aralkyl group, the aryl part having a definition according to the LruTprücben 5 to 7, and the alkyl part containing 1 to 5 carbon atoms. 12th 9 »Compounds according to claim 8, wherein R or R is benzyl or phenethyl means. . 10. Compounds according to any one of claims 1 to 4, wor- 1 p
in R or R is a 5- or 6-membered heterocyclic group which contains one or more heteroatoms, such as 0, N and S. Ί P 11., compounds according to claim 10, wherein R or R 2- or 3-pyridyl or 2- or 3-thienyl. 12. Compounds according to any one of claims 1 to -4, wor- 1 2
in R or R is cyclohexyl, adamantyl, vinyl, propenyl or isopropenyl. 13. Compounds according to any one of claims 1 to 4, wherein R ¹ or R ^{2 is} methyl, ethyl, Mean butyl or n-pentyl. 1 ?
in R or R methyl, ethyl, propyl, isopropyl, n- or sec.- 14. Compounds according to any one of claims 1 to 12, wor- 2 1 m R is hydrogen and R is a carboxylic aryl group, a 00 98 47/198 4 BATH ORIGINAL heterocyclic group, an alicyclic group or a Mean alkenyl group. 15 · Compounds according to one of the preceding claims, which have one or more Δ ^, Δ ² , C ?, & \ & - \ Ä ^ ¹⁰ ', Ä ⁶ ,' / V \ PQ j ^ or Δ contained unsaturations. 16. Compounds according to one of the preceding claims before, in which the rings A and B of the steroid compounds have one or contain several substituents, such as acyloxy, alkoxy, alkyl and alkenyl (each group containing up to 5 carbon atoms) , Halogen, hydroxy and oxo. 17 · Compounds according to any one of the preceding claims, wherein the ring C of the steroid compound exi an oxygen or contains halogen function on CL ^. 18. Compounds according to any one of the preceding claims, wherein the »steroid compounds 19-Kor-," 10-methyl- or 15 ~ are methyl, ethyl 'or propyl compounds. 19 connections according to one of the preceding claims, where the steroid compounds to the Androstanν 19-Norandrostan-, 18-methyl-estran or 18-ethyl-estran series belong to. 20. Compounds according to any one of the preceding claims with estrogenic and / or pregnancy-influencing Effect. 21. 17a- (3-hydroxy-5-methyl-1,3-hexadiynyl) -3-methoxy-1,3,5 (iO) -äßtratrien-17β-ol. 22. 17o (- (i? -Hydroxy-5-phenyl-1,3-pentadiynyl) -3-methoxy-1,3 »5 (10) -estratrien-17β-ol. 23. 17 (A- (5-Hydroxy-5-p-tolyl-1,3-pentadiynyl) -3-methoxy-1,3,5 (10) -estratrien-17β-ol. 009847/1984 ORIGINAL BATHROOM 24. 17 ^ - / ~ 5-Hydroxy-5- (2-naphthiyl) -1,3-pentadiynyl7-3 methoxy-1 ·, 3,5 (10) -ö stratrien-i 7β-ol. 25. 17o (- (5 ~ Hydroxy-5-o-cblorpiienyl-1,3-pentadiinyl) ~ 3 ■ - 26th
oxy-1 _i 3,5 (10) -estratrien-17β-ol. 27 17o (- (5-Hydroxy-5-phenyl-1,3-pentadiynyl) -6ß-methylyl-- 5 ~ androsteii-3ß> 5 ₎ 17ß-'triol. 28. 17 ^ - / "5-Hydroxy-5- (1-naphttLyl) -1.3" pentadiynyl I-3- methoxy-1,3-5 (10) -estratriene-17β-ol. 29 · i7ol- (5-hydroxy-5-cyclobexyl- ^/ 1,3-pentadiynyl) -3-meth oxj ^r -1,3,5 (10) -estratrien-17β-ol. 30. 17c <- (5-Hydroxy-5-o-methoxyphenyl-1,3-pentadinyl) -3 methoxy-1,3ί5 31. 17o ( _l - (5-IIydroxy-5-p-biplienylyl-1,3-pentadiynyl) -3-methoxy ~ 1 _i 3, i? (10) -ostT ^> atrien-17β-ol. 32. '^ 7d ;- (5-Hydroxy ~ 5 ~ p-metl·loxypheIlyl-1,3-pentadiynyl) -5-methoxy-1,3, i? (10) -estratrien-17β-ol. 33. 17ol- (5-hydroxy-5-phenyl- ^/ 1,3-pentadiynyl-1,3,5 (10) -esbratriene-3 _T 17β-diol. 34. 17ot- (5-Hydroxy-5-methyl-1,3-hexadiynyl) -1,3,5 (iO) -estratx-ien-3 > 17β-diol. 35. 5-Cyclopentyloxy-17 ^ - (5-hydroxy-5-methyl-1,3-hexa-: diinyl) -1,3,5 (10) -osstratrien-17β-ol. 36.17o (-C5-hydroxy-5-methyl-1 _t 3-hexadiynyl) -4-androsten- 1? Ss-ol-3-one. 009847 / 198A 37-17c (- (5-Hydroxy-5-methyl-1,5-liexadiinyl) - 'i {-östren-. 17β-ol-3-ones. . J58. 17c ^ - (5-Hydroxy-5-methyl-1,3-hexadiynyl) -5-androstene-3 [beta], 17 [beta] -diol. 39. 17cA- (5-Hydroxy-1,3-hexadiynyl) -3-methoxy-1,3,5 (1O) -estratrien-17β-ol. 40. Process for the preparation of compounds according to claim 1, characterized in that one ™ (A) a mixture of an ethynyl compound R ⁵ - C Ξ CH and a haloethinyl compound R ⁴ - C ξ CBr wherein one of r3, R is a> steroid radical to which the ethynyl or
/ Haloäthinylgruppe in, ^ - configuration are bonded in 17-position and the other of R · 'and R the group OH - C - E ¹ 1 2 denotes in which R and R have the meanings given in claim 1 own, in the presence of a copper (I) -salzeε converts, while the copper (I) -salζ is obtained in a reduced state, or (B) a 17-oxo-steroid with a compound of the general formula OH M - (G s C) ₂ - C - E ¹ E ² 1 2
wherein R and R have the meaning given in claim 1, 009847/198 4 .and ΓΙ Li ', Na, K or KgHaI means (viorin Hai = Cl,. Br or J) dax ', converts and then the desired derivative regenerated from the resulting complex to give a product containing a 17β-hydroxy group, or (C) by reacting a metal derivative of a 17e ^ ~ (buta ~ 1,3-diinyl) steroid compound with an aldehyde or ketone of the general formula R ^ ¹ R ² CO, τ
has given definition. NEN formula R R CO converts, wherein R and R are those in claim 1 41. The method according to claim 40 (A), characterized in that that the copper (I) salt is copper (I) chloride. 42 "Method" according to claim 40 (A) or 41, characterized in that that at least one base is present in the reaction mixture to aid the reaction and to hydrogen bromide to record. 43 · Method according to one of claims 40 (A), 41 or 42, characterized in that in the reaction mixture a Reducing agent is present. 44. The method according to claim 45, characterized in that that the reducing agent is hydroxylamine or a salt thereof. 45. The method according to any one of claims 40 (A) or 41 to 44, characterized in that the reaction is carried out in an inert atmosphere. 46. The method according to claim 40 (A) or 41 to 45, characterized characterized in that the reaction temperature is between -10 and t30 ° C. 47. The method according to claim 43, characterized in that that the reaction temperature is between -5 and 5 ° C. 48. The method according to any one of claims 40 (A) or 41 to 47, characterized in that the reaction takes place in a reaction 009847/1984 BATH ORIGINAL medium is carried out that is sufficiently polar to at least to dissolve a small part of the copper (I) salt of the ethynyl compound R ^ - C s CH. 49. The method according to claim 48, characterized in that that the reaction medium contains water. 50. The method according to claim 49, characterized in that the reaction medium is a lower alcohol or a mixture of which with dimethylformamide, dimethylacetamide or dimethyl sulphoxide contains. φ 51 «Method according to claim 50, characterized in that that the lower alcohol is methanol or ethanol. 52. Verfaliren according to claim 40 (B), characterized in that that M represents Na, K or MgHaI, and wherein the OH group the acetylene compound through a suitable protecting group is protected. 53 · Method according to claim 40 (C), characterized in that the metal derivative is a Grignard reagent. 54. The method according to any one of claims 40 to 53 »thereby characterized in that the product has a 17β-hydroxy group W contains and that the latter is subsequently esterified or etherified will. 55 Pharmaceutical composition, characterized that they claimed one or more of the claims 1 to 38 Compounds contained in association with a pharmaceutical carrier or diluent. 56. A pharmaceutical composition according to claim 55 in the form of dosage unit form. 57 · Pharmaceutical composition according to claim 55 or 56, characterized in that it has one or more additional 009847/1984 BATH ORIGINAL contains pharmaceutical active compounds. 58. Pharmaceutical composition according to claim 571
in the form of daily dosage unit forms, characterized in that they contain 1 to 10 ng of 17o (- (5-H5 ^r droxy-5-methyl-1,3-hexadiynyl) -3-methoxy-1,3r5 ( ^/ IO) - Estratrien-17ß-ol together with a sex-influencing compound. 009847/1984