DE2119327A1 - New steroids as well as methods of making steroids - Google Patents

Description

New steroids as well as methods of making steroids

The present invention relates to a method for introducing a propadienyl group in the 17a or position equivalent positions of steroids. The method according to the invention is already in our older 'however not previously known, patent application no. (Case 600-6248) for the preparation of compounds of the Formula XX

_ _ CH = C = CH,

XX

described, where * in R _{1 is} an alkyl group with 1-3 carbon atoms and Rjh is hydrogen, a. Hydroxy group or an alkanoyloxy group with 2-4 carbon atoms, and represents the radical of a steroid of the formula XXI

XXI

109845/1863

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in which Zuenten

the Riugü A and B and the so bound Substiumfaisst. and by the following Forrnelbi.ldor.

^R i6

R-,

7Λ

Z7

ZlO

Z5

H i H Sn

R.

Z8

Target

z6

Z9

Z12

CH ,.

Z15

1098 ^ 5/1953

-3- ⁶ TfIIf2 7

is reproduced. In these formulas Z1-Z15 there are R ,, for hydrogen, an alkyl group with 1-5 carbon atoms, a cycloalkyl group having 5-7 carbon atoms, an alkanoyl group with 2-4 carbon atoms or a Tetrahydrcpyranylgruppe, Rp. For hydrogen, a 6a-methyl group or a 7 «-methyl group, R ^ for hydrogen or a methyl group, R "for hydrogen, fluorine, chlorine or a methyl group and R, ο for an alkanoyl group with 2-4 carbon atoms or an alkyl group.

According to the invention, compounds of the formula I

OH

wherein R, has the above meaning, the ring D is a 5- or 6-membered ring and p ~ * ~ q, the rest of steroids, with the restriction that these are not defined by the group x "*" ^ radicals of steroids can be, in the case of the ring D and the substituents on it, the structure XXII,

GH

'"■" ■ "■ a mi

in which R ₁ and R ^ have the above meaning, arrive by connecting long compounds of the formula II,

R.

, 2 I®

/ ι ^D I ^h

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wherein R ₁ , the ring D and ρ q have the above meaning and either Rp and R ^. are identical or different and each stand for an alkyl group with 1-3 carbon atoms or Rp and R, together with the nitrogen atom, form a pyrrolidino, piperidino or homopiperidino ring, R ^, an alkyl

.: r> group with 1- ^ carbon atoms and X ^ for the anionic residue of a mineral acid with the exception of the fluoride ion, the anionic radical of an alkyl sulfonic acid or the anionic radical of an aromatic sulfonic acid is with a hydride ion source consisting of compounds of the formula X.

Y® W-M-H

¹ I.

where Y "is an alkali metal or alkaline earth metal ion, for example a lithium, sodium, potassium, calcium or magnesium ion, M is aluminum, gallium or boron and W ,, W ₀ and W_. are identical or different and are each hydrogen, an alkyl - .. alkoxy / alkoxyalkoxy group, in which the alkyl or alkylene radicals each have up to 6 carbon atoms, mean and compounds of the formula XI,

W _c -MH XI

wherein M has the above meaning and W ^ and W_ are identical or different and each represent hydrogen or an alkyl group having 1-6 carbon atoms, treated in an organic medium which is not detrimental to the reaction.

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Preferably used hydride ion sources are lithium aluminum hydride, Lithium borohydride, sodium dihydro ~ bis (2-methoxyethoxy) -aluminate, lithium gallium hydride, magnesium aluminum hydride, Lithium diisobutyl methyl aluminum hydride, lithium tri methoxy aluminum hydride, diethyl aluminum hydride and diborane.

The compounds of the formula II can contain, as an anionic radical Cs X , for example a chloride, bromide, iodide, methanesulphonate or p-toluenesulphonate ion, preferably an iodide ion. R 1, Rp and R ~ preferably each represent a methyl group.

Medium The (inert) organic / (solvent) used in this process is preferably aprotic. Suitable solvents are cyclic and acyclic ethers, for example Diethyl ether, tetrahydrofuran or dioxane and aromatic solvents, for example benzene, toluene or pyridine. However, mixtures of these solvents can also be used. The implementation is expediently carried out at temperatures between -4o ° and + 120 ° C for example, at the boiling point of aes reaction mixture. However, it is useful to have a Select a temperature between -10 ° and + 50 ° C. Although the reaction is faster at higher temperatures, it is favorable to work at lower temperatures, since purer end products are obtained. It is also cheap to carry out the reaction in an inert atmosphere, for example in a nitrogen atmosphere, and "~ preferably to protect from any moisture.

The compounds of the formula I thus obtained can be isolated in a manner known per se and in a manner known per se getting cleaned.

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ff? J327

When using the method according to the invention one arrives at to compounds of the formula I with a high degree of purity and essentially without contamination by acetylene derivatives.

"Those used as starting compounds according to the invention Quaternary ammonium compounds of the formula II are obtained by adding compounds of the formula III

wherein R ₁ , Rp, R ^, p ~ ^ ~ h and the ring D have the above meanings, by reaction with compounds of the formula XII,

R ^ -X XlI.

wherein R ₁ and X have the above meanings, quaternized.

The Qtuaternisierung of compounds of formula III is conveniently effected in an inert organic solvent, for example acetone h at temperatures between -20 ° and + 50 ° C, wherein neither the solvent used or the reaction temperature are critical. Methyl iodide is preferably used here as the compound of the formula XII.

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600-624 ^

9327

The compounds of the formula III can be obtained by man

a) compounds of the formula IV,

OK

ι JL- c'-cn

IV

where FL,

and the ring D have the above meanings with compounds of the formula XIII,

R ₂ -N-CH ₂ -OH R-.

XIII

wherein Rp and R have the above meaning or with one Mixture consisting of formaldehyde and compounds of the formula XIV,

R ₂ - NH R-,

XIV

wherein R ₂ and R_ ^ have the above meaning, converts or

b) by adding compounds of the formula V

where-R, rp qV and the ring D have the above meaning, with organometallic compounds of the formula XV,

1098-5 / 1953

- 8 - βθΟ-6248 / Β

P - C Ξ C-CH ₂ -NR ₂ XV

wherein R and R have the above meanings and P is an active metal or the halide of an active metal, for example an alkali metal such as lithium, Sodium or potassium, aluminum, zinc or the group -MgBr or -MgI is converted and the reaction product hy- · drolyzed.

The process described in section a) can be carried out under the conditions known for carrying out a Mannich reaction take place. The process is preferably carried out in the presence of copper ions and small amounts of a weak acid, for example acetic acid. The copper ions are obtained by adding, for example, copper chloride. Suitable reaction temperatures are between 10 ° and 80 ° C, preferably between 0 ° and 70 ° C. The reaction is preferred carried out in an inert organic solvent, for example dioxane or tetrahydrofuran.

The process listed under b) is expediently carried out under the conditions known for the reaction of acetylidene with ketones. The reaction is preferably carried out in an anhydrous organic solvent at temperatures between -JO ⁰ and + 100 ° C, preferably -20 ° and + 50 ° C, with subsequent hydrolysis of the reaction product, for example with water or with a highly concentrated aqueous salt solution, for example a saturated one Ammonium chloride or sodium chloride solution.

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The preferred compound of the formula XV is N, N-dimethylamino-2-propynyl lithium used, which is conveniently in situ, for example by dissolving lithium in ethylenediamine and adding N, N-dimethylamino-2-propyne to the resulting solution.

The organic solvent required for carrying out the process listed under b) depends on the type of compounds of the formula XV used here. For example, if P stands for -MgBr, -MgI or Li, as a solvent a cyclic or acyclic ether, for example diethyl ether or tetrahydrofuran, and, if P stands for sodium, as organic medium, for example, dioxane or pyridine or a mixture of liquid ammonia and diethyl ether, a mixture of ethylenediamine and tetrahydrofuran or a mixture of dioxane and pyridine. If N, N-dirnethylamino ~ 2 ~ propynyl lithium is the starting compound is used, which is produced in situ in ethylenediamine, ethylenediamine can also be used as a further solvent of the ' Reaction can be used.

The compounds of the formulas IV and V are either known or can be prepared in a manner known per se from known starting materials getting produced.

The compounds of formula I can, for example, A-homosteroidal, 3-homosteroidal, C-homosteroidal, D-homosteroidal, A-nor-steroidal, A-nor-B-homosteroidal, B-nor-steroidal, C-norsteroidal or azasteroidal, but especially 8-azasteroidal.

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21,9327

In the compounds of the formula I, the ring system, for example contain up to 5 double bonds. Based on the ring system with a cyclopentanophenanthrene or a Equivalent structure are the double bonds in certain Combinations, for example in the positions 1.3 »5 (10); 4; 5 (10); 3.5; or 4.9 (10) or 4.9 (10), 11 arranged. the Carbon atoms in the ring system can be substituted or unsubstituted be. For example, the ring system can contain the following substituents (where the designation is refers to a cyclopentanophenanthrene system);

a) up to 4 alkyl groups with 1-4 carbon atoms and cycloalkyl groups with 3-7 carbon atoms, these groups preferably being arranged in the positions 1,6,7,8,9,10,11 and 12 are, where 2 cycloalkyl groups are preferably not on the same or adjacent carbon atoms are bound;

b) up to 2 alkylidene groups with a maximum of 4 carbon atoms, which are in positions 1,6,7.11 and 12;

c) up to 2 hydroxyl groups, alkoxy groups with 1-4 carbon atoms, Cycloalkoxy groups with 3-7 carbon atoms, tetrahydrofuran-2-yloxy groups, Tetrahydropyran-2-yloxy groups, Acyioxy groups with 2-4 carbon atoms and trimethylsilyloxy groups, which are preferably in positions 3 and / or 11;

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d) up to 2 keto, ethyl end! oxy-,; Ethylenedithio and Oximnogruppen, which are preferably in the ^ and / or 11 positions can;

e) up to 2 Ilalogensubstituenten , consisting of fluorine, chlorine and bromine, these substituents are preferably in the positions 6, 7 and 11, if the carbon atoms are ethylenically or aromatically substituted or in the 8 and / or 9 positions, if as Halogen fluorine is used;

f) up to 2 substituents which connect ring carbon atoms located next to one another or next to one another, for example epoxy , methylene polymethylene with 2 carbon atoms, methylenedioxy and dihalomethylene groups.

In the preparation of compounds of the formula I and their intermediates, if the process products or their starting compounds contain substituents or bonds which can be changed during the reaction, such Substituents are protected by certain protective groups. The introduction of protecting groups is known, for example it is described in "Steroid Reactions, An outline for Organic Chemists", by Carl Djerasse, chap. 1, Holder-Day Inc., San Francisco (1963).

The protected compounds of the formula I and processes for their preparation are accordingly also included in the present invention Invention included.

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The compounds of the formula I can also be used in others Compounds of the formula I and in compounds which are similar to the compounds of the formula I, for example be converted into compounds of the formula XX. This conversion can be carried out, for example, by acylation, tetrahydropyranyl ie tion, oxidation, for example Cbinonoxidation of the existing hydroxyl group, hydrolysis of the ketals or enol ethers, dehydrogenation of the quinones, reduction of the keto groups or etherification.

W den. Such conversions are preferably carried out if certain substituents could be changed in an undesirable way during the reaction. For example, a keto group present in the compounds of the formula II can at least partially be converted into a hydroxyl group during the reduction of the compound. Accordingly, if compounds of the formula I are to be prepared which contain a keto group, the formation of the keto group will be carried out as the last stage, for example by oxidation of a hydroxyl group. The conversion of compounds of the formula I, being

. certain groups are subjected to a further reaction, forms part of the present invention.

In this way, for example, compounds of the formula XX ^{1 are obtained}

OH

__ PH = Tr = T ¹ T,

XX '

wherein Rj is methyl, ethyl or n-propyl, by reducing compounds of the formula II ',

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₂ -N-

• ~ r. »■ - ■

II ¹

where Β? ,, Rp, R- ,, R ₂ ^ and X have the above meaning and the wavy line indicates that the hydroxyl group is either in the α- or ß-position, with the aid of a hydride ion source consisting of compounds of the formulas X and XI , org. Medium and subsequent oxidation of the jü-hydroxyl group of the compounds of formula I 'obtained

OH

--CH = C = CPr _{2 jf}

wherein R ^f , and the wavy line have the above meaning, to a keto group.

The reaction conditions for the reduction are already discussed above in the discussion of the preparation of compounds of Formula I described from compounds of formula II.

The oxidation of the 3-hydroxy group of the compounds of the formula I ¹ to a keto group can conveniently be carried out using oxidizing agents which are customary

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wise to the oxidation of allyl-like secondary hydroxyl groups to be used to keto groups. Such suitable oxidizing agents are, for example, quinones such as p-benzoquinone, Chloranyl or 2,3-dicyano-5,6-> dichlorobenzochi-. non and activated manganese dioxide. The oxidation is preferably at temperatures between 10 ° and 50 ° C, in particular between 20 ° and 30 ° C, in an inert organic Solvent, for example a cyclic ether such as dioxane or a tert. Alcohol, such as tert. Butanol, carried out.

The compounds of the formula XX 'obtained in this way can have isolated and purified methods known per se.

The compounds of the formula II ¹ are obtained by quaternizing corresponding compounds of the formula III by the process described above. The compounds of the formula III are obtained from the corresponding compounds of the formula IV using the process given under a),

The compounds of the formula I 'are valuable intermediate compounds for the preparation of compounds of the formula XX '. the However, compounds of the formula I 'are also exceptional favorable pharmacodynamic, but especially progestational properties.

The compounds of the formula I 'and the process for their preparation also form part of the present invention Invention.

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The compounds of the formula XX 'are extremely favorable pharmacodynamic properties which, according to the results of the well-known Clauberg test, are found in a progestational Express the effect. The compounds of the formula XX 'can therefore be used in fertility control and for regulating the Menstruation as well as the menstrual cycle can be used.

The amount of compounds of the formula XX ¹ to be administered daily should be between 0.01 mg and 10 mg. This dose is preferably administered in sustained-release form in smaller doses between 0.005 and 5 mg twice a day. The amount of active substance to be administered daily is, as is known to any person skilled in the art, independent of body weight.

For the above use, the compounds of the formula XX ^{1 can be administered} alone or together with suitable estrogenic active ingredients. The estrogenic active ingredients can be used, for example, in a daily amount of 0.1 mg. The estrogenic active ingredients can be mixed with the compounds of the formula XX 'or the estrogenic active ingredients can be administered alone in the first part of the menstrual cycle and then together with compounds of the formula XX ¹ in the later days of the cycle.

For the above use, the compounds of the formula XX ^{1 can be} mixed together with pharmaceutically acceptable carriers and other additives and administered either orally in the form of tablets, capsules, elixirs, suspensions or solutions or parenterally in the form of injection solutions, suspensions or emulsions.

A formulation suitable for oral administration Is a tablet obtained in a known way by mixing the following ingredients:

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Bestan dteile

17α-Propadienylöstra-4 _i 17β-ol-> one

Tragacanth

Lactose

Cornstarch

Talk

Magnesium stearate

Parts by weight 0.05

89.45 5

0.5

The inventive method can be used to for example to produce the following compounds of formula I:

.a) compounds of the formula Ia,

CH = C = CH,

Yes

wherein R, has the above meaning, R. for hydrogen χ al

or methyl and R _? denotes a cycloalkyl group with 3-7, preferably with 5-7 carbon atoms,

b) compounds of the formula Ib,

CH-C = CH ,.

Ib

10984S / 19

600-6248 / B

wherein R, has the above meaning and R,, denotes an alkyl group having 1-4 carbon atoms

c) compounds of the formula Ic,

- CH = C = CH,

Ic

where R has the above meaning and the ring Q together with the substituents attached to it, the structure

or

(Ql)

(Q2)

(05)

(QH)

wherein R, represents hydrogen, an alkyl group with 1-4 carbon atoms or an acyl group with 2-4 carbon atoms stands, owns;

d) compounds of the formula Id,

- CH = C = CH,

Id

wherein R ^{1 has the} above meaning;

10984S / 19S3

600-62.KQ / B

e) compounds of the formula Ie,

CH = C = CH

Ie

wherein R ¹ -, has the above meaning,

f.) compounds of the formula Ig,

CH

wherein R, has the above meaning.

To prepare the compounds of the formulas Ia to Ie and Ig, the corresponding compounds are used as starting compounds of the formulas IV or V, III and II are used.

The preparation of compounds of formula Ie by treatment of compounds of the formula He,

lie

'1098457 19

- 19 - 600-6248 / B

wherein R ', Rp, R ,, R ^ and X ^x - ^{V have the} above meaning, with a hydride ion source consisting of compounds of the formula X and XI in an aprotic solvent, also forms part of the present invention.

The compounds of the formula Ia, Ib, Ic have pharmacodynamic properties Properties. In particular, the compounds of formula Ia have according to the results of the known Clauberg tests show a progestational effect. The compounds of the formulas Ib and Ic have a estrogenic effects. The compounds of the formulas Ia, Ib and Ie can therefore be used to control fearfulness will.

The amount of compounds to be administered daily Formula Ia is between 0.1 and 30 mg of compounds of the formula Ib between 0.02 and 10 mg and of compounds of the formula Ic between 0.01 and 40 mg. The connections are preferably administered in evenly divided doses twice a day or in sustained-release form. The amount however, the compounds to be administered daily are independent of body weight.

The compounds of the formulas Ia, Ib and Ic can be administered in the same form and composition as the compounds of formula XX '.

The compounds of the formula Id can be used as intermediate compounds for the preparation of the pharmacodynamically "active compounds of the formula Ih,

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, OH
11 ..-- CH = C = CH,

where R 'has the above meaning and the ring R in the structures

(Rl).

can occur. The compounds of the formula Ih can be obtained by adding compounds of the Formula Id by the action of aqueous-acidic conditions subjected to a hydrolytic rearrangement.

The hydrolytic rearrangement can expediently sigerweise at a temperature * between 0 ° and 100 ° C, preferably between 20 ° and 70 ° C in an inert organic solvent which is miscible with water, for example a lower alcohol such as methanol. If the formation of acidic conditions is a water-soluble organic Acid is used, the excess of which can replace the solvent. Additional solvents can be used however, can also be used.

If compounds of the formula Ih are to be produced, wherein the ring R has the structure (Rl), takes place

109845/1953

hydrolytic rearrangement expediently by action; a strongly acidic medium, that is to say with a pH value of less than 3 »or, on the other hand, a weaker acidic medium, that is to say with a pH value of, for example, up to 1 hour, for a comparatively longer period of time, for example more than 1 hour. If, however, compounds of the formula Ih are to be prepared in which the ring R has the structure (R2), the hydrolytic rearrangement, preferably in a weaker acidic medium, should take place over a comparatively shorter period of time, for example less than 3 hours, a strongly acidic medium obtained with the help of strong inorganic or organic acids, for example sulfuric acid, hydrochloric acid, p-toluene, valphonic acid or oxalic acid. A weakly acidic kediun is obtained

org. ,
one with the help of water-soluble / acids, for example oxalic acid or acetic acid.

The compounds of the formula Ie can be used as intermediate compounds for the preparation of pharmacodynamically active compounds of the formula Ii, ..... '

Ii

wherein FL, 'has the above meaning, are used. Di ^ connections of the formula Ie, however, also have pharmakodynamtsche, especially progestational, properties. 2u the connections of the formula Ii can be obtained by adding compounds of the formula Ie by the action of an aqueous acid Subjects to cleavage reaction.

- 22 - 600-62WB

The cleavage reaction can, for example, under mil-r the or strongly acidic conditions. For this purpose the acids hydrochloric acid, Sulfuric acid, acetic acid and oxalic acid as well as aromatic and lower aliphatic acids Sulphonic acids, such as p-toluenesulphonic acids, proved to be suitable. The reaction can, for example, at a pH of above 2, preferably between 5 and 5 * using oxalic acid or acetic acid, expediently for a period of less than 5 hours. The reaction temperature is expediently chosen between and 100 ° C, preferably between 20 ° and 70 ° C. Besides the water necessary for the reaction can be added to the reaction mixture still contain an inert organic solvent, for example a lower alkanol such as methanol. However, if the acid used is liquid under the reaction conditions, an excess of the same can be used used as a solvent

1098-5 / 1953

The compounds of the formula Ig can be used as intermediate compounds for the preparation of pharmacodynamically useful Compounds of the formula Ik,

CH

R ^0H
1 I CH = C = CH _r

Ik

in which R _{1 has the} above meaning, can be used. Compounds of the formula Ik can be obtained by subjecting compounds of the formula Ig to a cleavage and rearrangement reaction by the action of aqueous acid.

The cleavage and rearrangement reaction can expediently under strongly acidic conditions, for example at a pH of 2 or below, for example between 1 and 2, using, for example, oxalic acid, p-toluenesulfonic acid or a mineral acid such as chlorine water st off acid to be carried out. The action of the Acid should occur for a relatively short period of time, for example less than 3 hours. The reaction can also under weaker acidic conditions, for example

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carried out at a pH of above 2, for example between 3 and 5j. Here you leave organic Acids such as oxalic acid or acetic acid for a comparatively longer period of time, for example more a.ls Act on compounds of the formula Ig for 3 hours. The reaction temperature is, for example, a temperature selected between 0 ° and 50 ° C. The response may be when using a mineral acid / a water-miscible solvent, for example a lower one Alcohol such as methanol can be carried out. However, if the acid is liquid under the reaction conditions, for example acetic acid, an excess of it can serve as a solvent. However, additional solvents can be used can also be used.

According to the results of the Clauberg test, the compounds of the formulas Ih, Ii and Ik have a progestational effect. The compounds can therefore be used in fertility

f3 pd ° n control and regulation of the menstrual cycle application "

The amount of compounds of the formula to be administered daily Ih should be between 0.01 and 30 mg, of compounds of the Formula Ii between 0.1 and 30. rng and on compounds of Formula Ik can be between 0.05 and 50 mg. The connections are preferably administered in equal doses twice a day or in sustained-release form. The connections of the Forrre In Ih, Ii and Ik can be used in the same form and in the same composition as the compounds of Formula XX '.

The invention is described in the following examples. In these examples, all temperatures are given in 0 ^° C .; A temperature between 20 ° and J0 ° is regarded as room temperature, unless otherwise stated.

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Example 1:

a) mixture of 17a-Aethinylöstra-4 ₁ 9-dien-3a 17ß_und_30 _{1 1} 17-diol

225 S 17a-ethynylestra-4,9 ~ - dien-17ß-ol-5-one and 4500 ml of dry methanol entered and the resulting mixture at room temperature with stirring in small portions for 3 hours 60 g of sodium borohydride added. Stirring is continued for a further hour. Thereafter, the reaction mixture 500 ml Water was carefully added and the mixture was evaporated in vacuo at 40 ° to a volume of 2000 ml. The evaporation residue is in a mixture consisting of 4000 ml of a saturated aqueous sodium chloride solution and 4000 ml of water, registered. An OeI is deposited here. After multiple extraction with methylene chloride, the methylene chloride extracts are combined, washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered off and evaporated to dryness. This gives an oil which is a mixture of 17α-ethynylestra-4,9-diene-3a, 17β-diol and 17α-ethynylestra-4,9-diene-3β, 173-diol represents.

b) 17a-Dimethylaminopropinylöstra-4 ₁ 9 ~ dien-3 ₁ 17-and ~ 33 ₁ 17-diol

236 g of a mixture consisting of 17oc-ethynylöstra-4,9-diene-3a, 17ß-and-3ß, 17ß-dlol, 2250 ml of p-dioxane, 225 ml of dimethylaminomethanol, 5.75 g of copper chloride and 135 ml

109U5 / 19S3

- 26 - 600-6248 / 3

Glacial acetic acid are added to a vessel and the mixture stirred at 50 ° for 1 1/2 hours. Then I 300 ml are grounded p-Dioxane distilled off under vacuum at 50 °. The residue is in a mixture consisting of -6000 ml of a saturated aqueous sodium chloride solution and 2000 ml V / water entered. The mixture thus obtained is with a solution of 165 g of anhydrous potassium carbonate are added to 1000 ml of water. It is then extracted repeatedly with methylene chloride. The methylene chloride extracts are, combined, washed 2 times with a saturated aqueous sodium chloride solution, over anhydrous sodium sulfate-dried and in vacuo to approx. 3000 ml evaporated. The evaporation residue is covered with wooden bowls treated and filtered off. The piltrat is evaporated to a syrup. The remaining p-dioxane is in a boiling vacuum removed. What remains is an oil that is a mixture of 17a-dimethylaminopropinylestra-4,9-diene-3a, 17β- and -33,17β- ole represents.

c) Methiodide von_17oc-DimethylaminoproOinylostra24 _i 9-diene- and -2ß, 17ß-diol

265 g of a mixture of 17cc-Dimethylaminopropinylöstra-4,9-diene-3a, 17ß- and -j5ß, 17ß-diol and 2050 ml of acetone are in brought a vessel and the resulting mixture v / ground over half an hour with stirring 265 ml of methyl iodide dropwise admitted. The crystals of the methiodide salt are formed during this process. After the addition of methyl iodide is complete is stirred for another hour. The crystals formed are then filtered off and washed with ice-cold acetone and dried in vacuo to remove the acetone. This gives the methiodides of 17a-dimethylaminopropinylestra-4,9-diene-3a, 17ß- and -j $ ß, 17ß-diol.

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d) l7a-Propadienylöstra-4,9-diene-5a, l "3-and-3 [beta], 17 [beta] -diol

220 g of the methiodide salts obtained in section c) and 66OO ml of dry pyridine are placed in a vessel. The mixture thus obtained is stirred and in portions added 49 g of lithium aluminum hydride, taking care that the temperature of the mixture does not exceed 50 °. After completing the addition, is cooled to room temperature and with 49 ml of water, 49 ml of a 15 fig aqueous sodium hydroxide solution and then carefully mixed with 150 ml of water. Here Care must be taken that the temperature of the mixture does not exceed 50 °. The precipitate formed is filtered off and washed with pyridine. That The piltrate and wash liquid are combined and evaporated in vacuo to a syrup. This is in 15OO ml

Toluene added. The toluene is distilled off in vacuo and the residue taken up in methylene chloride. The methylene chloride solution is with water and then washed with a saturated aqueous sodium chloride solution. Then the methylene chloride solution dried over anhydrous sodium sulfate, filtered off and evaporated to a syrup. The syrup is taken up in 2000 ml of acetone (after the undissolved material has been filtered off). The acetone is then removed in vacuo. The residue obtained is an oil which consists of a mixture of 17oc-Propadienylöstra-4,9-diene-3a, 17β and 5β, 17β-diol.

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Ij58, j5 g of a mixture consisting of 17α-propadienylÖstra-4,9-diene-3a, 17β- and * .3β, 17β-diol (obtained in section d)) and 150 ml of p-dioxane are introduced into a vessel. To the mixture is added a solution of 125 g of 2, j5-dicyano ~ 5, o- d! Chlorobenzoquinone in 69O ml of p-dioxane was slowly added, keeping the temperature of the mixture to ca, JO is held ^0th The mixture is then stirred for 1 hour at room temperature and a solution of 105.5 g of anhydrous potassium carbonate and 44 g of sodium dithionide in 1000 ml of water is added, the temperature being kept at or below J> 0 ° . The reaction mixture is then poured into 800 ml of a saturated aqueous sodium chloride solution. After extracting several times with diethyl ether and combining the ether extracts, they are washed with a saturated aqueous sodium chloride solution and stored in a high vacuum. The residue is taken up in diethyl ether and the ether solution is filtered through an aluminum oxide column. In this case after evaporation of the solvent, the obtained 17a-Propadienylöstra-4,9-dien-17.beta.-ol-3-one, mp. III-II3 ^0th

Example 2: ^ -Cyclopentyloxy- ^ a-propadienylostra- jli, 5ji dien-173-ol

a) 3-Cyclopentyloxy-17a-dimethylaminopn3pynylöstra-3> 5-dien-17β-ol

To a Grignard mixture, made from 1.5 6 magnesium shavings, 4.68 ethyl bromide in 70 ml of tetrahydrofuran

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«29 -

5 * 3 g of diethylaminopropine dissolved in 10 ml of tetrahydrofuran were added dropwise. After the evolution of ethane has ended, a solution of 1.716 g of 3-cyclopentyloxyöstra-3,5-dien-17-one in 30 ml of tetrahydrofuran is added dropwise, the temperature during the addition being between 0 ° and 5 ° and after the addition for a further 4 Hours between 20 ° and 25 ° is held. 100 ml of a 2 N aqueous sodium hydroxide solution are then added and the mixture is evaporated to a volume of 100 ml in vacuo at a temperature not exceeding 30 °. The evaporated mixture is extracted 5 times with 25 ml of diethyl ether each time, centrifuging to facilitate separation from the salt-containing aqueous phase. The combined ethereal extracts are evaporated and the excess of dimethylaminopropine is removed. This gives the 3 ~ CycΙο-pen tyloxy- ^ ct-dimethylaminopropiny dissolves ra-3j5-diene ~ 17ß "oil.

t>) 3 ~ Cyclopentyloxy-17oc-dimethylaminopropinylestra-3,5-diene-17β ~ ol-met3niodide

2 g of 3-cyclopentyloxy-17α-dimethylaminopropinylestra-3,5-dien-17β-ol are dissolved in 30 ml of acetone. To the resulting solution, 3.5 g of methyl iodide are added and the mixture held at 8 ° for 18 hours. The 3-cyclopentyloxy-17a-dimethylaminopropinylestra-3,5-dien-17ß-ol-methiodide crystallizes here from which is filtered off and viaschen with anhydrous diethyl ether.

109845/1953

^c ) 3-Cyclopentyloxy-17a-propad jenylöstra-3, 5-dien-17 _t > ~ ol

To a suspension of 2.5 g of 3-cyclopentyloxy-17'a-di "methylaminopropinylestra-3,5-dieri-17P" ol-metriiodide in 50 ml of tetrahydrofuran was added at - '(o 9.3 ^ri! L a 0 5 molar lithium aluminum hydride solution in tetrahydrofuran is added After the addition is complete, the Ge! Nir.f; i. Is warmed to -10 ° and stirred at this temperature for about 90 minutes until a clear solution is disfigured. The mixture is then left to stand at room temperature for 12 hours. After adding 100 ml of a 2N aqueous sodium hydroxide solution which still contains 50 mg of di-tert-butylcresol, the mixture is reduced to ΐ-xS in vacuo volume of IOC ml evaporated This Einda / rip / '^ i'U kstand iSnml is extracted with 20 ml of diethyl ether, whereby, as described above, also centrifuged \.:. Vierden lr ^ The combined -Aetnerlösungen about Kaliu.noarboi ^ l dried and then evaporated. A3.s RUokstf.no er'nhlx,: τ: αη

the J-cyclopentyloxy-lYa-propadienylöotra- ^, 5-difcn-17ß-cl. Example 3;

Using the information in sections a), b) and c) of Process described in Example 2, but replacing the J-cycloperityloxyöstra-5,5 "dien-17-one used there as the starting compound by equivalent shares of the in KoI. A of the compounds listed below in Table 1, the end connections obtained are those in KoI. B of the compounds listed in Table 1:

109845 / 19S3

BATH ORIGINAL

600-62 ^ 8 /

TABLE 1

A) Universal connections B) End connections

^a ) jS-Cyclopentyloxy-lj-äthylgona- a) 3-Cyclopsntyl oxy-IjJ - j5,5-dien-l'f-one ethyl-17a-propadiene; / l--

gona-5 »5-dien-17ß-oi

b) jS-Cyclohexyloxy-lJ-äthylgona- b) j5-CyclohexyloxY-lj3-

5,3-dien-17-one ethyl-17a ~ propadienyl ~

gona-3,5-diene-17ß-cl

c) J-Cyclopentyloxy-ö-methylöstra- c) J-Cyclopentyloxy-ö-

5,5-dien-17-one inethyl-17a - prcpadiciiyl-

östra-3,5-diene - 17ß-ol

Example 4: 3-methoxy-17a-prcpadienylestra -1, p_, β (IQ ) -triene-llg, 173-diol

a) ii

To a mixture consisting of 10 g of a lithium acetylide / ethylenediamine complex and 80 ml of dimethyl sulfoxide, a solution of 5 g of 11β-hydroxy-oestrone methyl ether in 100 ml of dimethyl sulfoxide is added at room temperature. The reaction mixture is stirred at room temperature for 2 hours and then further J g of the lithium acetylide reagent is added. The mixture is then stirred for a further 2 hours and poured into 1500 ml of ice water. The mixture is rendered neutral by adding 2N hydrochloric acid and the brown precipitate formed is filtered off. This is dried in vacuo at 60 ° and then dissolved in acetone. The acetone solution is decolorized by treatment with animal charcoal. It is then filtered off and hexane is added to the piltrate, as a result of which the 3-methoxy-17α-ethynylestra-1 / 15.5 (10) -triene-11β, 17β-diol with a melting point of 178-179 ^{0 is} precipitated.

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b) 3-Methoxy-17a-N, N ~ dimethylaminopropinylestra-1,3,

3 ml of N, N-dimethylaminomethanol and 100 mg copper chloride added. ' The reaction mixture is kept with stirring for 1 1/2 hours at a temperature between 60 ° and 70 °. The solvents are then removed under reduced pressure and the residue is partitioned between equal parts by volume of diethyl ether and an aqueous sodium hydroxide solution which contains enough sodium hydroxide to keep the solution alkaline. After separation, the aqueous phase is extracted twice with diethyl ether and the combined diethyl ether phases are washed with water and dried. Thereafter, the diethyl ether is evaporated under vacuum, to yield the 3-M ^e thoxy-17-N, N-dimethylaminopropinylöstra-l, 3 »5 (lO) -triene-LLSs, I7ß-diol as a crude foam"

c) N ₁ N, N-trimethyl-N- ^[3'-t il - (3-methoxy-17a-estra-l, 3,5 (lO) -triene-LLSs, 17beta-diol)} propynyl] ammonium iodide

To a solution of 3 g of crude 3-methoxy-17a-N, N-dimethylaminopropinylestra-1,3,5 (10) -triene-11ß, 17ß-diol (obtained by the method of section b)) in J> 0 ml Acetone is added to 20 ml of methyl iodide. The solution is left to stand at a temperature of 5 ° for 18 hours and then the solvent is removed in vacuo. The residue is recrystallized from acetone. The Ν, Ν, Ν-trimethyl-N- [3'-il ^l - (3-methoxy-17a-estra-1,3,5 (10) -trienllß, 17ß-diol) propynyl] ammonium iodide melts at 180 ° (with decomposition).

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d) 3-methoxy-17a-propadienylöstra-1,3,5 (10) _ -triene-11ß, 17ß ₌ diol

To a suspension of 2.76 g Ν, Ν, Ν-trimethyl-N- [3 * - {l ¹ - (3-methoxy-17a-östra-1,3,5 (10) -triene-llß, 17ß- diol)} propiriyl] ammonium j od id (prepared according to the process of section c)) in 20 ml of anhydrous tetrahydrofuran, a solution of 455 mg of lithium aluminum hydride in 40 ml of tetrahydrofuran is added in 4 portions while cooling with ice. The mixture is then stirred for 11/2 hours, the reaction components completely dissolving. After careful addition of 5 ml of water, the solution is rendered neutral by adding a 2N chlorine or hydrochloric acid and the tetranydrofuran is removed in vacuo. The aqueous residue is extracted twice with methylene chloride and the combined methylene chloride extracts are dried over anhydrous sodium sulfate. Then these are evaporated to a volume of approx. 5-10 ml and diluted with the 5-fold amount of their volume of diethyl ether. The 3-Mefchoxy-17a-propadienylöstra-1,3 _J 5 (10) -triene-11ß, 17ß-diol with a melting point of 155-156 ° precipitates out.

Example 5: 3-Methoxy-8a-methyl-17a-propadienylöstra-1,3, 5 (10) -trien-17β-ol

a) 3-methoxy-8α-methγl-17a-dimethylamonoprΌpinylöstra-l, 3-

To a solution of 2 g of metallic lithium in 36 ml Ethylenediamine are added dropwise 15 ml of 3-Dimethylaminc.propin added. To this reagent obtained in this way is added dropwise

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wise a solution of 3.2 g of 3-methoxy-6a-methylostra-1, 3,5 (10) ~ trien ~ 17-one added in 20 ml of tetrahydrofuran. After about 3 hours of standing at room temperature the mixture is introduced into ice water, extracted with chloroform, the chloroform solution is evaporated and obtained so the 3-methoxy-8α-methyl-17α-dimethylaminopropίnylöstra-1,3,5 (1.0) ~ trien-17β-ol.

b) ^ -Meth ^ xy-Sa-methyl- ^ a-dirne ^ hylarninopropinylestral, 3,5 (10) -tricn-17ß-ol-methiodide

The crude 3-methoxy-8a-methyl-17oc-dirnethylaminopropinylestra-1,3j 5 (10) -trien-17β-ol obtained in the process of section a) is dissolved in 40 ml of acetone and 6 ml of methyl iodide are added to the solution. After standing at 5 ° for 18 hours, a precipitate separates out and is filtered off. This precipitate consists of 3-kethoxy- 8a-methyl-17a-dimethylaminopropinylestra-1,3jb (10) -trien-17ß-ol-methyodide.

c) 3 ~ Methox3 ^r -8a-methyl-17oc-propadienylöstra-1,5,5 (10) -trien-17β-ol

To a solution of 4.2 g of 3-M ^e thoxy ~ 8a-methyl-17a-dxmethylaminopropinylöstra-1,3,5 (lO) -triene-17.beta.-ol methiodide in 120 ml of absolute pyridine 0.5 S lithium aluminum hydride are added After standing at room temperature for 20 minutes, water and a 5% aqueous sodium hydroxide solution are added to the mixture. The precipitated material is then filtered off. The piltrate is freed from pyridine in vacuo, and the residue is taken up in benzene and water. The benzene solution

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is separated off, dried over sodium sulfate and evaporated. The residue obtained is .das 3-methoxy-8a-ynethyl-17ot-propadienylöstra.-1,3,5 (10) -trien-17ß-ol.

Example 6: 3-MeUioxy-8a-methy 1 -1 7-3-propadienylostra -2,5 (10 ) -dien-17β-ol

a) 3-Methoxy-8a-methyl-17a-dirii «thylaminopropynyl esters £ .i" 2, 5

To a solution of 2 g of metallic lithium in J6 ml Ethylenediamine are 15 RiI 3-Dirnethylair.i nopropin dropwise added. This stretching thus obtained is dropwise a solution of 3.2 g of ^ -methoxy-Sa-ir.ethylöstra-2,5 (10) -dien-17-one Added to 20 ml of tetrahydrofuran. After standing at room temperature for 1 hours the mixture entered into ice water, this extracted with chloroform and the'Chloroformlösung evaporated. This gives the crude jJ-methoxy-Sa-methyl- ^ a-dimethylaminopropinylestra-2,5 (10) -dien-17ß-ol as a residue.

§! 5 (10) _z dien-17g-ol-metnjodid

The crude J5-methoxy-8a-methyl-17a-dimethylamino propynylestra-2,5 (10) -dien-17β-ol obtained in the process of section a) v-ird is dissolved in 40 ml of acetone and 6 ml of methyl iodide are added to the resulting solution. Neglecting hour Standing at 5 ° a precipitate forms, which is filtered off will. This precipitate consists of 3-methoxy-8a-methyl-17a-dimethylaminopropinylestra-2,5 (10) -diene-17ß ol methiodide.

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c) 3-17β-ol

To a solution of 4.2 g of 3-methoxy-8α-methyl-17oc-dimethylaminopropinylestra-2,5 (10) -dien-17β-ol "giethjodid 0.5 g of lithium aluminum hydride are added in 120 ml of absolute pyridine. After standing for 20 minutes at room temperature, water and a 5% aqueous sodium hydroxide solution are added to the mixture added and the precipitate formed abfil- *. trotted. The pyridine is removed from the filtrate in vacuo and the residue was taken up in benzene and water. The benzene solution is separated off, dried over sodium sulfate and evaporated. The residue remains here 3-methoxy-8a-methyl-17a-propadienylestra-2,5 (10) -diene-17βol return.

Example 7:; 5β-Methoxy-8a-methyl-17 <x -propadienylestra-4-en-17β-ol

Using the instructions in sections a), b) and c) of the Example 6 described method and replacement of the 3-methoxy-8amethylöstra-2,5 (10) -dien-17-one used as the starting compound in section a) through approx. equivalent proportions of 3ß-methoxy-8a-methylöstra-4-en-17-one arrives via the intermediate compounds j5ß-methoxy-8a-methyl-17adimethylaminopropinylestra-4-en-17ß-ol and its methiodide to form 5ß-methoxy-8a-methyl-17a-propadienylöstra - ^ - en-17ßol.

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Example 8: 1 · 53-ethyl-3-fflethoxy-8a-methyl-1 · 73-propa ■ -dienylgona-2,5 (10) -dien-17β-ol

Using the instructions in sections a), b) and c) of the Method described in Example 5, but with the replacement of the 5-methoxy-8a-methylestra-1,3 * 5 (10) -trien-17-one used as the starting compound in section a) through approx. equivalent proportions of rjß-ethyl-1-methoxy-8x-methylgona-2,5 (10) ~ dien-17-one obtained via the intermediate stages 15β-ethyl-5-methoxy-8a-methyl-17a-dimethylaminopropinylgona-2,5 (10) -dlen-17β-ol and its methiodide is 13ß-ethynyl-> methoxy-8a-methyl-17a-propadienylgona-2,5 (10) -dien-17β-ol.

Example ft: ^ -Methoxy-l ^ -methyl- ^ ct-propadienylostra ^, 5 (10) -dien-17ß-ol

a) 3-Methoxy ~ llg-methyl-17a-N, N-dimethylaminopropynylc) stra- ·

1.8 g are added in small portions to 120 ml of ethylenediamine metallic lithium was added with stirring at a temperature between 50 ° and 60 ° under nitrogen. After completion the addition, the blue solution obtained is heated to 75 ° to 85 ° for 1 1/2 hours, with a pale yellow Reaction mixture is obtained. This is cooled to 10 ° and 20 g of N, N-dimethylamino-2-propyne are added dropwise over the course of 5 minutes offset. Stirring is continued at room temperature for 1 hour and the mixture thereafter with a solution of 2.6 g of 5-methoxy-11ß-methylestra ~ 2.5 (10) -dien-17-one in 40 ml of tetrahydrofuran was added. To Further stirring at room temperature for 4 hours is done in ice water. cooled and 100 ml of a saturated

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ten sodium chloride solution added under nitrogen. Then 250 ml of diethyl ether are added. The two phases are separated and. the aqueous phase extracted ^ times with benzene. The combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After the solvent has been removed, the residue is recrystallized from diethyl ether. The jJ-Methoxy-11ß-Hiethyl-lTct-N, N-dlmethylaminoprc-pinylestra-2,5 (10) -diene-17ß-Ql melts between 170 ° and 175 °,

b) 3-methoxy-llß-πlethyl-175 ■ -M, K-diκIethylaπiinopropiπylöstra-

15 ml of methyl iodide are added to a solution of 2.5 g of 5-methoxy-11ß-methyl-17oc-N _J M-dimethylaminoproplnylestra-2,5 (10) -dien-17ß-ol in 60 ml of acetone. The solution is left to stand at 5 ° for 18 hours, a precipitate being formed. This precipitate is filtered off and recrystallized from acetone. The 5-methoxyllß-methyl-17a-N, N-dimethylaminopropinylestra-2,5 (10) -diene- W 17ß-ol-methiodide thus obtained melts between 255 ° and 260 ° (with decomposition).

1Ι & Ι2Ϊ

To a suspension of 3.1 g of 3-methoxy-llß-methyl-17a-N, N-dimethylaminopropinylestra-2,5 (10) -dien- ^ ß-ol-methiodide in 100 ml of anhydrous tetrahydrofuran, 5 ml of a 70% solution of sodium di (methoxy-

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ethoxy) aluminum hydride in benzene, with 10 ml of tetrahydrofuran was diluted. The reaction mixture is then left at the temperature of the room accept and stir for 2 hours. This gives a complete solution. The excess of the aluminum hydride is decomposed by adding water and the tetrahydrofuran is removed under reduced pressure. The aqueous residue is extracted with methylene chloride and the organic phase is dried over sodium sulfate. After removing the solvent, the residue is recrystallized from diethyl ether / hexane (Ii2). That 3-methoxy-11ß-methyl-17a-propadienylöstra-2,5 (10) -dien-17ß-ol thus obtained melts at 135 °.

Example 10: 3-Methoxy-13g-ethyl-11ß-methyl-17a-propa ~ dienylgona-2,5 (10) -dien-17β-ol

Using the procedure described in sections a) to c) of Example 9 and replacing 3-Methoxy-11ß-methylöstra-2,5 (10) -dien-17-one used as the starting compound in section a) by equivalent proportions of 3-methoxy-13ß-ethyl-11ß-methylgona-2.5 (10) -dien-17-one is obtained via the intermediate stages 3-methoxy-13ß-ethyl-11ß-methyl-17a-N, N-dimethylaminopropinylgona-2,5 (10) -dien-17ß-ol and 3-methoxy-13β-ethyl-11β-methyl-17a-N, N-dimethylaminopropinylgona-2,5 (10) -diene-17βol-methiodide 3-methoxy-13ß-ethyl-11ß-methyl-17a-propadienylgona-2,5 (10) -dien-17ß-ol.

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Example 11; jS-Aethylendioxy- ^ a-propadienylöstra ^, 9 (10), ll-trien-17β-ol

^a ) 3; Aethylendioxy-17a-N, N-dimethylaminopropinylöstra-5 (l0) _J 2i 191 ζ I ir

To 500 ml of ethylenediamine, which is at a temperature between 50 ° and 60 ° is stirred under nitrogen, 5.2 g metallic lithium added. After the addition is complete

w is heated, the resulting blue solution for 1 hour at 95 ° to obtain a pale yellow reaction mixture is obtained. This is cooled to 10 ° and 58 g of N, N-diiriethylamino-2-propyne are added dropwise over the course of 5 minutes. Stirring is continued at room temperature for one hour and the mixture is then treated with a solution of 11 g of ^ -Aethylenedioxyöstra-4,9 (10), 11-trien-17-one in 150 ml of tetrahydrofuran. The mixture is then stirred at room temperature for 24 hours. It is then cooled in an ice-water bath, the mixture with 1000 ml of a saturated aqueous sodium chloride solution

_{fc is} added and the organic phase is separated off. This is dried over sodium sulfate and then freed from the solvent. The residue is recrystallized from acetone / petroleum ether (1: 1), 3-ethylenedioxy-17a-N, Nd.mnethylaminopropinylöstra-4,9 (10), ll-trien-17β-ol being obtained.

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^6OO - ⁶ Wf9327

b) 3-ethylenedioxy-17α-N, N-dimethylaminopΓOpinylöstra-

To a solution of 2.6 g of 5-ethylenedioxy-17a-N, N-dimethylaminopropinylestra-4,9 (10), ll-trien-17β-ol 20 ml of methyl iodide are added in 70 ml of acetone. The solution will be during Maintained at 5 ° for 18 hours and then freed from the solvent. The residue is recrystallized from acetone, the 3-ethylenedioxy-17α-N, N-dimethylaminopropinylestra-4,9 (10), ll-trien-17β-ol-methiodide is obtained.

c) 3-; ethylenedioxy-17a-propadienylöstra-4,9 (10), ll-triene-170; oil

To a suspension of 5.2 g of 3-ethylenedioxy-17a-N, N-dimethylaminopropinylestra-4,9 (10), 11-trien-17β-ol-methiodide 16 ml of a 0.85 molar solution are added dropwise to 100 ml of anhydrous tetrahydrofuran while cooling with ice of lithium aluminum hydride in tetrahydrofuran added. The reaction mixture is left to stand at room temperature accept and then stir for 1 1/2 hours to obtain complete solution. After that, will added water with cooling, the excess of the hydride is decomposed. After further addition of water, a precipitate forms. This is filtered off and dissolved in methylene dichloride solved. This solution is dried over sodium sulfate and evaporated. This gives 3-ethylenedioxy-17a-propadienylöstra-4,9 (10), ll-trien-17ß-ol, which is characterized by its IR absorption spectrum.

10 9 8 4 5/1953

Example 12; 9a-Met hyl ° 17ffi ° pr * opadieny l83tra-2,5 (10) -die n-

^a ) Η? ΐΐ £.? ζ2ϊ! ϊ5ϊ5? ΐ5ϊϊ52δΓ2Ρΐ '£% 1- ° 92: Ε ^ί 2 ^ 3 "' 12I ^tra " ² »5 ( ¹⁰ -) ~ diene-3,17§-diol-3- methyl ether

To 150 ml of ethylenediamine, which is kept at a temperature between 50 ° and 60 ° with stirring in a nitrogen atmosphere, 2 ^ 2 g of metallic lithium are added in portions. After the addition is complete, the blue solution obtained is heated to 75-35 ° for 1 1/2 hours, a pale yellow reaction mixture being obtained. This is cooled to 10 ° and treated with 24 g of N, N-dimethylamino- 2-propyne was added over a period of 5 minutes. Thereafter stirred v / hile 1 hour at room temperature and the mixture was added a solution of 3 * 2 g of 3-methoxy-9a-methylöstra-2,5 (lO) -diene-17-one in ¹ IO ml tetrahydrofuran. The mixture is then stirred for 16 hours at room temperature. It is then cooled in an ice-water bath and 200 ml of a saturated aqueous sodium chloride solution are added under nitrogen. Then add 300 ml of benzene. The two phases are separated and the aqueous phase is ^{extracted 3 ma} -l ^with benzene. The organic phases are combined and washed with a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed, the 17a-N, N-dimethylaminopropinyl-9a-methylestra-2,5 (10) -diene-3,17β-diol-3-methyl ether being obtained as an oil. ■

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b) 17a-N, N-dimethylaminopropynyl-9 ^ -!]] eth ^ loestra-2 _i 5 (10) -diene-3,17ß-diol-3-methyl ether methiodide

To a solution of 3.8 g of 17a-N, N-dimethylaminopropinyl-9a-methylestra-2,5 (10) -diene-3,17ß-diol-3-methyl ether in 90 ml of acetone v / earth 50 ml of methyl iodide are added. the The solution is kept at 5 ° for 18 hours, a precipitate being formed. This is filtered off and recrystallized from methanol / acetone (1: 5). The α-NiN-dimethylaminopropinyl-α-methylestra-2,5 (10) -diene-3,17β-diol-5-methyl ether methyl iodide thus obtained melts at 240-243 ° (with decomposition).

c) 9a; methyl-17a-grogadienylöstra-2 _i 5j [102 _:: dien-3 ₁ 17g-

To a suspension of 3, Jg 17cc-N, N-dimethylaminopropinyl-9oc-methylöstra-2,5 (10) -diene-3,17β-diol-3-methyl ether methiodide in 100 ml of anhydrous tetrahydrofuran 10 ml of a 70 ^ oigen solution of Sodium di (methoxyethoxy) aluminum hydride in benzene, the is diluted with 25 ml of tetrahydrofuran, added. Thereafter, the reaction mixture is left to stand until it is the room temperature assumes and stirred for 2 hours. A complete solution is achieved here. The excess the aluminum hydride is decomposed by adding water and the tetrahydrofuran under reduced pressure distilled off. The aqueous residue is extracted with methylene chloride and the methylene chloride solution is dried over sodium sulfate. After removing the solution

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9a-methyl-17a-propadienylöstra-2,5 (10) -diene-5,17ß-diol-3-methyl ether is obtained by means of this as OeI.

Example 13:

Using the information in sections a), b) and c) of Example 4 and replacement of the method described there in section a) used as the starting compound 11ß-hydroxyestrone methyl ether through suitable starting compounds the following quaternary connections are obtained:

1) 17a-Dimethylaminopropinyl-6-methylenestra-4-en-3ßi17ßdiol-methiodide

2) 17α-Diethylaminopropynyl-7-ethylidene-13-ethylgona-4-ene-3,17β-diol Ethomethanesulphonate (using diethylaminomethanol instead of dimethylaminomethanol in the process of section b) and ethyl methanesulfonate instead of methyl iodide in the process of section c)).

3) 17α-Dimethylaminopropynyl-5- {10a, 9β) -androstene-3β, 17β-diol-methiodide.

4) 17a-ethylpropylaminopropinyl ~ j5-ethylenedioxyöstra-1 (10), 5-dien-17ß-ol-metho-p-toluenosulphonate (using ethylpropylaminomethanol instead of dimethylaminomethanol in the process of section b) and methyl ptoluene sulphonate instead of methyl iodide in the process of Section c)).

5) ^ α-Dimethylaminopropynyl-IIIa, 12a-methano-3-tetrahydropyranyloxyestra-1,3,5 (10) , 6,8- pentaen-17β-ol-methiodide

10964 B / 1953

- 45 - 600-62WB

6) ^ a-Dimethylaminopropinyl-jJ-ethylenedithio-la, 2α-methanoandrostan-17ß-ol-methiodide.

7) 17α-Dimethylaminopropynyl ~ 10β, 11β-methanoestra-5-ene 5β, 11α, 17β-triol-methiodide.

8) ^ a-Dimethylaminopropinyl-rj-äthyl-J-äthylendioxy- · 5β, 10β-methanogona-17β-ol -methiodide.

Stage d)

Using the method described in section e) of example 2 described method, but replacing the ^ -Cyclopentyloxy- ^ a-dimethylaminopropinylestra-5i5-dien-17ß-ol-methiodide used there through approx. equivalent proportions of those obtained above in steps a), b) and c) qua ternary connections one arrives at the following Compounds of formula I:

1) 6-methylene-17ot-propadienylöstra-4-en-i; 3β, 17β-diol.

2) 7-ethylidene-15-ethyl-17α-propadienylgona-4-en-3β, 17β-diol,

3) 17a-propadienyl-5 <10a, 9ß) -androsten- ^ ß, 17ß-diol (17apropadienyl-5-i'etroandrosten'-3ß, 17β-diol).

4) 5-ethylenedioxy-17a-propadienylöstra-l (10), 5-dien-17ß-ol.

5) Hoc, 12a-methano-17a-propadienyl-3-tetrahydropyranyloxyestra-1,35,5 (10), 6,8-pentaen-17β-ol.

6) 3-Ethylenedithio-la, 2a-methano-17a-propadienylandrostan-17ß-ol.

7) 10β, Hβ-Methano-17α-propadienylöstra-5-en-3β, Ha, 17βtriol.

8) 13-Ethyl-3-ethylenedioxy-17a-propadienyl-5ßilOß-methanogona-17ß-ol.

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Example l4 ; 6a, 7as-

dienylandrast-4-en-33,17ß-dio l A suspension of j5öö mg 6aj, 7a-Difluoromethano-7ß-

methiodide in 6 ml of tetrahydrofuran is added a mixture of 200 mg of sodium dihydroMs- (2-metho>: yätfeoxy) aluminate and 3 nil benzene at room temperature, then stirred for 24 hours and the mixture a solution of 300 mg of sodium sulfate in 5 ml added dropwise to a 2 M aqueous sodium hydroxide solution. Then it is filtered off and the FiIt rat diluted with 20 μl of ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. Then we obtain the 6a, 7a-DIfluaoFöinethano-7ßfluoro-17a-propadienylandrost-4-en-3.beta. »l? Ss-diol.

The oa ^ a-Difluorometfiano-Tß-fluoro-lTa-li-piperidinopropiriylandrost-4-en-3ß, l? Ss-diol-methiodide is obtained using the method described in sections a) to c) of Example 4.

109845/1953

Claims (6)

600-6248 / B claims: 1. / Process for the preparation of compounds of the formula I, CH = C = CH, wherein R, represents an alkyl group having 1-3 carbon atoms and the ring D is a 5- or 6-membered ring and ρ q is the remainder of steroids, with the restriction that this remainder does not have the formula XXI XXI in which Z comprises the rings A and B and the substituents attached to them and and by the following formulas Zl Z2 109845/1953 ₁₆ R, c I H Ζ6 ZlO ζ8 TO Ζ12 Ζ15 is reproduced, wherein R, for hydrogen, an alkyl group with 1-5 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, an alkanoyl group with 2-4 carbon atoms or a tetrahydropyranyl group, R, ^ for hydrogen, a 6a-methyl group or a 7a -Methyl- 109845/1953 - 49 - 600-62 & Wf 9327 group, R-jg for hydrogen or a methyl group, R ₁₇ . represents hydrogen, fluorine, chlorine or a methyl group and R ₁ Q represents an alkanoyl group having 2-4 carbon atoms or an alkyl group if the ring D and the substituents on it have the structure XXII "OH CH = C = CH- ^R l " —- Rill ^x * XXII in which R _{1 has the} above meaning and R _{11 represents} hydrogen, hydroxy or an alkanoyloxy group with 2 carbon atoms, characterized in that compounds of the formula II, where R, the ring D and ρ q have the above meaning and either R _p and R_, are identical or different and each represent an alkyl group having 1-5 carbon atoms or Rp and R, together with the nitrogen atom, are pyrrolidino, piperidino or Form Hcmopiperidinoring, Ri ₁ denotes an alkyl group with 1-5 carbon atoms and X * - 'for the anionic residue of a mineral acid, with the exception of the fluoride ion, the anionic residue of an alkylsulfonic acid or the residue of an aromatic sulfonic acid, with a hydride ion source consisting of compounds of formula X 109845/1953 Ie Υ® W ₁ - H-Tl ■ w where Y is an alkali metal or alkaline earth metal ion, for example a lithium, sodium, potassium. Calcification or magnesium ion, M aluminum, gallium or boron and W ,, W and W-. are the same or different and each 2 3 ■ or
hydrogen, an alkyl, alkoxy, / alkoxyalkoxy group, in which the alkyl or alkylene radicals each have up to 6 carbon atoms and compounds of the formula XI, W_ - M - H
5 wherein M has the above "meaning and W ₁ , and W ₁ - are the same or different and each represent hydrogen or an alkyl group having 1-6 carbon atoms, treated in an organic medium which is not detrimental to the reaction. 2. The method according to claim 1, characterized in that compounds of the formula Ie, CH = C = CH Ie wherein R-J stands for methyl, ethyl or n-propyl, produces, by using compounds of the formula He 109845/1953 ORIGINAL INSPECTED where R ', and 600-6248 / B Hey have the above meaning, goes out. 3. The method according to claim !, characterized in that compounds of the formula I ¹ , 1 OH c— CH = C = CH, in which Rl has the above meaning and the wavy line indicates that the hydroxyl group can be in position α or β, produced by one of compounds of the formula II ¹ , ΘΙ ² ₂ -n-; II ' where Rj, , R, R ₁ ^, the wavy line above has meaning, goes out. 109845/1953 600-62 '4 4. Process for the preparation of compounds of the formula XX ¹ , ..- »- CH = C = CH XX ¹ wherein R ^{1 has} the meaning given in claim 2, characterized in that the hydroxyl group of compounds of the formula Γ ¹ , wherein R-! has the above meaning and d. the wavy line that. has the meaning given in claim 5, oxidized zn a keto group. 109845/1953 600-62 > \ S / B 5. Compounds of the formula CII-C = CH, I ¹ wherein R, is methyl, ethyl or n-propyl, and the Wavy line indicates that the hydroxyl group can be in position α or 3. ' 6. Therapeutic composition characterized by the content of compounds of the formula I '. The patent attorney 109845/1953