DE2166715A1 - NEW 17 ALPHA-PROPADIENYL STEROIDS - Google Patents

Description

New ITfli-Propadienyl Steroids.

The invention relates to new ster end compounds, which in 17o6-position have a propadienyl radical. In the US PS 3,962,165 are already formulas of such 17 ^ -propadienyl-substituted Steroid compounds with a hydroxyl group or alkoxy or alkanoyl group shown in the 3-position, while in US Pat. No. 3,962,166 the corresponding 3 keto compounds of these 17 (* H? ropadienyl-substituted steroids as Process products of the manufacturing processes described there are given in terms of formulas. However, it has been shown that the Compounds cannot be produced by the processes disclosed in this patent specification, which is why these 17 # - propadienyl-substituted steroid compounds as new in the sense of the Patent Act must be viewed.

In the older, but not previously known, own patent application P 19 58 533.2 or the one that has been eliminated therefrom Patent applications are methods of making compounds of formula XX

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beoehriccen, where K is an alkyl ^ ruppo rp.it! -J K atoivien and R. j Waö ^ ersOüi f, a H ^ ur-oxyfv'apprj or a Ai.kö.noy: i.o ;; ye; ruppe with 2-4 carbon ciuoriiou boclirauoi ·, and x "^" y for dsn iioüt of a steroid of Koriiici XXl sicm

7X1

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- tr- 6oc-b2'i8 / B

wherein Z denotes the strings A and B and the substituents attached to them u: r.fasst and by the following formula image cr

ZlO

Z12

^R 1Y

ZlV

215

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is reproduced. In these formulas Z1-Z15, R-., For hydrogen, an alkyl group with 1-3 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, an alkanoyl group with 2- ^l \ carbon atoms or a tetrahydropyranyl group, R ₁ - for hydrogen, a βα -Fi et hy! Group or a 7 ^ -Methylgruppe, Rw- for hydrogen or a methyl group, R "for hydrogen, fluorine, chlorine or a methyl group and R ₁ Q for an alkanoyl group with 2-4 carbon atoms or an alkyl group.

P It has now been recognized that in this way also connections of formula I,

wherein R, has the above meaning, the ring D has a 5- or 6-membered ring and p "^" q represent the rest of steroids with the restriction that these cannot be residues of steroids defined by the group χ y, in the case of the ring D and the substituents on it have the structure XXII,

Oh

^ lA ^ " ^H 2 XXII

wherein R ₁ and R ₁ ,, have the above meaning, get by using compounds of the formula II,

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wherein R ₁ , the ring D- and p ^ ~ 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, one. Form pyrx'olidino, piperidino or homopiperidino ring, R _{1 is} an alkyl group with 1-3 carbon atoms and X ^ is the anionic radical of a mineral acid with the exception of the fluoride ion, the anionic radical of an alkylsulphonic acid or the anionic radical of an aromatic sulphonic acid, with a hydride ion source consisting of compounds of the formula X

Y® W, -M-H X

¹ I.

wherein 1® is an alkali metal or alkaline earth metal ion, for example a lithium, sodium, potassium, calcium or magnesium ion, M aluminum, gallium or boron and VL, V. ' and W ^ equal or are different and are each hydrogen, an alkyl, aiko: ·: '; / - / alkoxyalkoxy group, in which the alkyl or alkylene radicals each have up to 6 carbon atoms, mean and Compounds of formula XI,

VL-M-H "■ XI

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

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Preferred sources of hydride ions used are lithium aluminum hydride, Lithium borohydride, sodium dihydro-bis- (2-methoxyethoxy) -aluminate, lithium gallium hydride, magnesium aluminum hydride, Lithium diisobutylmethylaluminium hydride, lithium tri- methoxy aluminum hydride, diethyl aluminum hydride and diborane. '

The compounds of the formula II can contain an anionic radical X , for example a chloride, bromide, iodide, methanesulphonate or p-toluenesulphonate ion, preferably an iodide ion. R _1, R and R, are preferably in each case for a metal thylgruppe ψ. _ -.

Medium The (inert) organ used in this process! cal / (delete

solvent) 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 reaction is expediently carried out at temperatures between -4o ° and + 120 ° C., for example at the boiling point of a reaction mixture. It is advisable, however, to choose a f ... temperature between -10 ° and + 50 ° C. Although the reaction proceeds more rapidly at higher temperatures, it is advantageous to work at lower temperatures, since here-. with purer end products are obtained. It is also advantageous to carry out the reaction in an inert atmosphere, for example in a nitrogen atmosphere, and preferably to protect the reaction mixture from any moisture.

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

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When using the method according to the invention one arrives at to compounds of formula I with a high degree of purity and im essentially free of acetylene derivative contamination.

The quaternary ammonium compounds of the formula II used as starting compounds according to the invention are obtained by using compounds of the formula III

III

wherein R- ,, Rp, R ^ ,, P ~ "~ q and the ring D have the above meanings have, by reaction with compounds of the formula XII,

R ₂₊ -X XII

where Rj, and X have the above meanings, quaternized.

The quaternization of compounds of the formula III takes place conveniently in an inert organic solvent, for example acetone at temperatures between -20 ° and + 50 ° C, wherein neither the solvent used nor the reaction temperature are critical. Preferably used here as a connection of the formula XII methyl iodide is used.

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The compounds of the formula III can be obtained by

a) compounds of the formula IV,

OH

iv

where R- ,, φ- ^ and the ring D have the above meanings sit, with compounds of the formula XIII,

R ₀ -N-CH ₀ -OH XIII 2 1 2

wherein R ₀ and R-, have the above meaning or with a mixture consisting of formaldehyde and compounds of the formula XIV,

R ₀ - NH XIV

wherein R ₀ and R- have the above meaning, converts or

b) by adding compounds of the formula V

wherein R ₁ <p q ', and the ring D have the above meaning, with organo-metal compounds of the formula XV,

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PC = C-CH ₂ -NR ₂ XV

R,

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 is hydrolyzed.

The procedure described in section a) can be carried out under the for the implementation of a Mannich implementation of known conditions. Preferably the process is carried out in the presence of copper ions and small amounts of a weak acid, for example acetic acid. The copper ions is obtained by adding, for example, copper chloride. Suitable reaction temperatures are between 10 ° and 80 ° C, preferably between 40 ° and 70 ° C. The reaction is preferred carried out in an inert organic solvent, for example dioxane or tetrahydrofuran.

The procedure listed under b) is expediently under the conditions known for the reaction of acetylides with ketones. The reaction is preferably carried out in an anhydrous organic solvent at temperatures between - ^ 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 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 ethyl-1enediamine 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 an 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-dimethylamino-2-propynyl lithium is used as the starting compound, which is prepared in situ in ^ ethylenediamine, Ethylenediamine can also be used as a further solvent for the reaction.

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

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

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In the compounds of the formula I, the ring system can contain, for example, up to 5 double bonds. Based on the ring system with a cyclopentanophenanthrene or an equivalent structure, the double bonds are in certain combinations, for example in the positions 1,5,5 (10); 4; 5 (10); 3.5; or 4,9 (10) or k, 9 (10), 11 arranged. The carbon atoms in the ring system can be substituted or unsubstituted. For example, the ring system can contain the following substituents (where the position designation refers to a cyclopentanophenanthrene system):

a) up to 4 alkyl groups with 1-4 carbon atoms and cycloalkyl groups with 3-7 carbon nst of fa turnen, these groups are preferably arranged in the positions 1,6,7,8,9,10,11 and 12, with 2 Cycloalkyl groups are preferably not attached to the same or adjacent carbon atoms;

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, tetrahydro furan-2-yloxy groups, tetrahydropyran-2-yloxy groups, Acyloxy groups with 2-4 carbon atoms and trimethylsilyloxy groups. which are preferably in positions 3 and / or 11;

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ά) up to 2 keto, ethylenedioxy, ';

Ethylenedithio and oximino groups, which are preferably in positions 5 and / or 11 " can;

e) up to 2 halogen substituents, consisting of fluorine, chlorine and bromine, these substituents are preferably in the 6, 7 and 11 positions, if the carbon atoms are ethylenic or aromatic, unsubstituted or in the positions 8 and / or 9 are located, if 'fluorine is used as the halogen will;

f) up to 2 substituents, those located next to one another or connect next adjacent ring carbon atoms, for example Epoxy, methylene; Polymethylene with 2-4 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 1 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 converted into other compounds of the formula I and in compounds which have the Compounds of formula I are similar, for example converted into compounds of formula XX. These Conversion .can, for example, by acylation, tetrahydropyranyl ation, oxidation, for example quinone oxidation of the hydroxyl group present, hydrolysis of the ketals or enol ethers, dehydration of the quinones, reduction of the keto groups or etherification can be carried out. Such conversions are preferably carried out if certain substituents are undesirable in the reaction Way could be changed. For example, one in the compounds of the formula II can Keto group are at least partially converted into a hydroxyl group during the reduction of the compound. Accordingly, if compounds of the formula I to be prepared that contain a keto group, the formation of the keto group as the last stage, for example perform by oxidation of a hydroxyl group. The conversion of compounds of the formula I, with certain Subjecting groups to further reaction forms part of the present invention.

This leads to compounds of the formula .XX ^{1, for example}

OH

XX '

wherein R ^ is methyl, ethyl or n-propyl, by reduction of compounds of the formula II ',

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V-

600-62 4 H / Ii

R ₂ .

C = C-CH ₂ -NR ₅

II ¹

where Bf,

and X have the above meaning and the

f ,, Rp, R-,

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 3-hydroxy group of the compounds of the formula I ^{1 obtained}

OH

CH = C = CH

I ¹

HO

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

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

The oxidation of the ^ -hydroxy group of the compounds of formula I ^! to a keto group can conveniently be carried out using oxidizing agents, the usual-

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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-dichlorobenzoquinone and activated manganese dioxide. The oxidation is preferably at temperatures between 10 ° and 50 ° C, in particular between 20 ° and j50 ° C, in an inert organic Solvent, for example a cyclic ether such as ioxane or a tert. Alcohol, such as tert. Butanol, carried out.

The compounds of the formula XX ¹ thus obtained can be isolated and purified in a manner 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 ¹ are valuable intermediate compounds for the preparation of compounds of the formula XX '. The. However, compounds of the formula I ^{1 also} have extraordinarily favorable pharmacodynamic, but in particular progestational, properties.

The compounds of the formula I ¹ and the process for their preparation also form part of the present invention.

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The compounds of the formula XX ¹ have extremely favorable pharmacodynamic properties which, in accordance with the results of the known Clauberg test, manifest themselves in a progestational effect. The compounds of the formula XX ¹ can therefore be used in fertility control and to regulate menstruation and the menstrual cycle * -

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 'can be administered alone or together with suitable estrogenic agents. The estrogenic agents can use, for example, in a daily amount of 0.1 mg. The estrogenic ingredients can interact with the compounds of the formula XX 'mixed together or the estrogenic active ingredients can be used alone in the first part of the menstrual cycle and then along with compounds of Formula XX 'in the later days of the cycle.

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

A formulation suitable for oral administration is a tablet which can be prepared in a manner known per se Mixing the following ingredients results in:

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Component e

lYct-Propadienylb'stra- ^, 9-dIen-17β-ol-3-one

Tragacanth

Lactose

Cornstarch

Talk

Magnesium stearate

Weight

ο, 05 2 5 ο, 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

wherein R, has the above meaning, R is hydrogen
- ax

or methyl and R _ is a 3-7 cycloalkyl group preferably with 5-7 carbon atoms means

b). Compounds of the formula Ib,

CH-C = CH.

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where R, has the above meaning and R, is an alkyl group with "means 1-4 carbon atoms

c) compounds of the formula Ic,

.L-- CH = C = CH,

Ic

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

<k ^, R.a

or

(Ql)

(Q2)

(05)

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,

Γ OK

wherein R ^{f has the} above meaning;

Id

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e) compounds of the formula Ie,

- CK-C = CfI ,.

wherein -R ^{1 has the} above meaning,

f.) compounds of the formula Ig,

CH

wherein R- has the above meaning.

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

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

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wherein R ', R ₂ , R-., R ^ and X ^ ^{J are as defined} above, 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 an estrogenic effect. The compounds of the formulas Ia, Ib P and Ic can therefore be used for fear control purposes.

The amount of compounds of the formula Ia to be administered daily is between 0.1 and 10 mg, of compounds of the formula Ib between 0.02 and 10 mg and of compounds of the formula Ic between 0.01 and 10 mg. The compounds are preferably administered in equally divided doses twice a day or in sustained release form. However, the amount of the compounds to be administered daily is 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
lJL ...- CH = C = CH ,,

You

where R ^f , has the above meaning and the ring R in the structures

can occur, used v / ground. The connections of the Formula Ih can be obtained by adding compounds of the formula Id by the action of aqueous-acidic conditions subject to 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 water-miscible organic solvents such as a lower alcohol such as methanol. If to form the acidic conditions 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

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to

hydrolytic rearrangement expediently by action a strongly acidic medium, d. i. with a pH of less than 3 or otherwise one weaker acidic medium, d. i. with a pH of, for example, up to 4 "for a comparatively longer period of time for example more than J5 hours. If, however, connections of the formula Ih, in which the ring R has the structure (R2), the hydrolytic Rearrangement, preferably in a weaker acidic medium, during a comparatively shorter one "Period, for example less than 3 hours. A strongly acidic medium is obtained with the help of strong inorganic or organic acids, for example Sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or oxalic acid. A weakly acidic medium is obtained

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

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

ι ■ "" * i ° f

¹ I CH = C = CH ,.

Ii

wherein R ₁ ¹ has the above meaning, are used. However, the compounds of the formula Ie also have pharmacodynamic, in particular progestational, properties. The compounds of the formula Ii can be obtained by subjecting compounds of the formula Ie to a cleavage reaction by the action of an aqueous acid.

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The cleavage reaction can, for example, be mild or highly acidic conditions. For this purpose hydrochloric acid has proven to be the acid., Sulfuric acid, acetic acid and oxalic acid as well as aromatic and lower aliphatic acids Sulphonic acids, such as p-toluenesulphonic acids, have been found suitable. The reaction can, for example, at a pH of above 2, preferably between 3> and 5> using oxalic acid or · acetic acid, expediently for a period of less than 5 hours. As the reaction temperature it is expedient to choose a temperature between 0 °. and 100 ° C, preferably between 20 ° and 70 ° C. Besides the water required for the reaction, the reaction mixture can also contain an inert organic solvent, for example a lower alkanol such as methanol. If, however, the acid used under the reaction conditions is liquid, an excess of it can be used as a solvent.

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

in which R, has the above meaning, can be used. Too " Bonds of the formula Ik can be obtained by making compounds of the formula Ig by the action of aqueous acid subjected to a cleavage and rearrangement reaction.

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 hydrogen chloride acid. The exposure to the acid should be for a relatively short period of time, for example less than 3 hours. The reaction can also take place under weaker acidic conditions, for example

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at a pH above 2, for example between 3 and 5i can be performed. Here you leave organic Acids such as oxalic acid or acetic acid for a comparatively longer period of time, for example more than Act on compounds of the formula Ig for 3 hours. A temperature, for example, is used as the reaction temperature selected between 0 ° and 50 ° C. The reaction can be carried out using a mineral acid / one with water m ischable solvent, for example a lower alcohol such as methanol. If, however the acid is liquid under the reaction conditions, for example acetic acid, an excess of it can serve as a solvent. Additional solvents can be used however, can also be used.

The compounds of the formulas Ih, Ii and Ik have gomäss the results of the Clauberg test indicate a progestational effect. The compounds can therefore be used in fertility control and for regulating the menstrual cycle

The amount of compounds of the formula Ih to be administered daily should be between 0.01 and 30 mg, of compounds of the formula Ii between 0.1 and 30 mg and of compounds of the formula Ik between 0.05 and 50 mg. The compounds are preferably administered in equal doses twice a day or in sustained-release form. The compounds of the form In Ih, Ii and Ik can be used in the same form and in the same composition as the compounds of the formula XX ¹ . '

The invention is described in the following examples. In these examples, all temperatures are given in 0 ^° C .; A temperature between ± .0 ° and 30 ° is regarded as room temperature, unless otherwise stated.

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Example 1; 17ct-Propadienylöstra-4,9-dien-17β-ol-3-one

a) Mixture of ^ a-ethynylestra- ^, 9-diene ~ 3oc, 17ß and 33, 17β-diol

225 S 17cc-ethinylostra-4,9-dien-17β-ol-3-one are placed in a reaction vessel and added 4500 ml of dry methanol and the resulting mixture at room temperature with stirring in small portions for 3 hours βθ g sodium borohydride added. Stirring is continued for a further hour. Then 500 ml of the reaction mixture are grounded

W; ■

^w water was carefully added and the mixture was evaporated in vacuo at 40 ° to a volume of 2000 ml. The evaporation residue is added to a mixture consisting of 4000 ml of a saturated aqueous sodium chloride solution and 4000 ml of water. An OeI is deposited here. After repeated 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 17oc-ethynylestra-4,9-diene-3a, 17β-diol and 17oc-ethynylestra-4,9-diene-3β, 17β-diol.

b) ^ a-Dimetnylamiriopropiriylöstra ^, 9-dien-3oc, 17ß- and -30, 17ß _: diol

236 g of a mixture consisting of 17a-ethynylöstra-4,9-diene-3a, 17ß- and> 3ß, 17ß-diol, 2250 ml p-dioxane, 225 ml di- • ir.ethylaminomethanol, 3> 75 g copper chloride and 135 ml

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Glacial acetic acid are added to a vessel and the mixture stirred at 50 ° for 1 1/2 hours. Then 100 ml 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 of water entered. A solution of 165 g of water-free potassium carbonate in 1000 ml of water is added to the mixture thus obtained. It is then extracted repeatedly with methylene chloride. The methylene chloride extracts are combined, twice with a saturated one Washed aqueous sodium chloride solution, dried over anhydrous sodium sulfate and in vacuo to approx. 5000 ml evaporated. The evaporation residue is made with charcoal treated and filtered off. The filtrate is evaporated to a syrup. The remaining p-dioxane is in a high vacuum removed. What remains is an oil that is a mixture of lToc-Dimethylaminopropinylöstra- ^, 9-ciien-3a, 17ß- and -Jß, 17β-ώίο1 represents.

c) Methiodide of ^ / Oc-Dimethylarninopropiriylöstra-'l, 9-diene-

265 S of a mixture of 17a-dimethylaminopropinylöstra- ^, 9-dieri-j5a, -17ß- and -3ß, 17ß-diol and 2650 ml of acetone are in brought a vessel and the resulting mixture is added dropwise 265 ml of methyl iodide over half an hour with stirring 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. After that, the The crystals formed are filtered off, washed with ice-cold acetone and dried in vacuo to remove the acetone. This gives the methydide of 17a-dimethylaminopropiiiylö3tra-4,9-diene-j5a, 17ß- and -Jß, 17ß - diol.

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220 g of the methiodide salts obtained in section c) and 66OO ml of dry pyridine are placed in a vessel. The mixture obtained in this way is stirred and 49 g of lithium aluminum hydride are added in portions, with care is taken 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 $ 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 "Piltrat and the washing liquid are combined and evaporated in vacuo to a syrup. This is in 15ΟΟ ml

Toluene added. The toluene is distilled off in vacuo and the residue is taken up in methylene chloride. The methylene chloride solution is mixed with water and then with a saturated aqueous sodium chloride solution washed. The methylene chloride solution is then dried over anhydrous sodium sulfate and filtered off and evaporated to a syrup. The syrup comes in 2000 ml Acetone (after undissolved material was filtered off). The acetone is then removed in vacuo. Man receives as residue an oil, which is made from a mixture of 17oc-Propadienylöstra-4,9-dlen-3a, 17ß and 3ß, 17ß-diol.

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e) 17α-Propadienylöstra-4,9-dien-17β-ol-3-one

1380 S of a mixture consisting of 17α-propadienylestra-4,9-diene-3a, 17β-and-3β, 17β-diol (comply with section d)) and 1380 ml of p-dioxane are introduced into a vessel. A solution of 12.5 S 2,3-dicyano-5,6-dichlorobenzoquinone in 69Ο ml of p-dioxane is slowly added to the mixture, the temperature of the mixture being kept at about 30 °. Mixture is then stirred for 1 hour at room temperature and added to a solution of 103.5 S anhydrous potassium carbonate and 44 g Natriumdithionid in 1000 ml of water, the temperature is further kept at or below 3O ^0th The reaction mixture is then poured into 8000 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 evaporated in a high vacuum. The residue is taken up in diethyl ether and the ethereal solution is filtered through an aluminum oxide column. Here, after evaporation of the solvent, the 17cc-Propadienylöstra-4,9-dien-17β-ol-> one from the Snip, 111-113 °.

Example 2 : ^ -Cyclopentyloxy- ^ a-pr opa dienylostra- ^, 5-dien-17ß-ol

a) 3-Cycloperityloxy-17α-dimethylaminoprΰpinylöstra-3, 5-dien-17β-ol

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

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dropwise 5.3 g of dimethylaminopropine dissolved in 10 ml Tetrahydrofuran added. After the end of the Aethane development becomes a solution of 1.716 g of 3-cyclopentyloxyöstra-3,5-dien-17-one in 30 ml of tetrahydrofuran added dropwise, the temperature during the addition between 0 ° and 5 ° and after the addition is complete is held between 20 ° and 25 ° for a further 4 hours. Then 100 ml of a 2 M aqueous sodium, added hydroxide solution and the mixture in vacuo at a temperature not exceeding 30 °, to a volume

t lumen of 100 ml evaporated. The evaporated mixture P

is extracted 5nial with 25 ml of diethyl ether each time, with to facilitate separation from the salt-containing aqueous phase is centrifuged. The combined ethereal extracts are evaporated and the excess of Removed dimethylaminopropine. This gives the 3-cyclopentyloxy-17α-dimethylaminopropT.nyiöstra-3,5-aien-17β-ol.

b) 3-cyclopentyloxy-17oc-dyne; ethylaininopropinylestra-3 _i 5-dien-17β-ol-me.thjodid

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

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c) ^ -Cyclopentyloxy-iYoi-propaGienylösti'a- ^, 5-dien-17g-ol

To a suspension of 2.5 g of I-cyclopentyloxy- ^ cc-dime tnylaminopropinylestra- ^ i S-dien-lTß-ol-methyl iodide in 50 ml of tetrahydrofuran are added at -75 ° ^C. 9, ~ ml of a 0.525 molar lithium aluminum hydride solution in tetrahydrofuran added. After the addition is complete, the mixture is warmed to -10 ° and stirred at this temperature for about 90 minutes until a clear solution is formed. 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 evaporated in vacuo to a volume of 100 ml. This evaporation residue is extracted 5- »al with 20 ml of diethyl ether each time, and centrifugation is also carried out as described above. The combined ethereal solutions are dried over potassium carbonate and then evaporated. The residue obtained is 5-cyclupentyloxy-17cc-propadienylöstra-3,5-dien-17β-ol.

Z>

Using the instructions in sections a), b) and c) of the Example 2 described method, but under. Replacement of the 3-cyclopentyl used there as the starting compound oxyöstra-3,5-dien ~ 17-one by equivalent proportions of the in KoI. A of the compounds listed below in Table 1, the end connections obtained are those in KpI. B of Table 1 listed compounds:

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Zl

TABLE 1

A) Starting Connections B) Ending Connections

a) jJ-Cydopentyloxy-lj ^ -äthylgona- a)

3,5-dien-17-one, ethyl-lToc-propadienyl

gona-J, 5 "d-i en-17ß-ol

b) ^ -Cyclohexyloxy-l ^ -äthylgona- b) jS-Cyclohexyloxy-ljJ-J5,5-dien-17-one ethyl-17a-propadienyl

gona-3,5-dien-17β-ol

c) ^ -Cyclopentyloxy-o-methylöstra- c) ^ -Cyclopentyloxy-6-3,5-dien-17-one

Example 4: ^ -Merhoxy-JJg- propadionylöstra-1, J>, 5 (10) -tricn-llß, 17ß-diol

a) 3-methoxy-17a-ethinyluslra-1,3 _J 5 (10) -triene _:: llß _i 17ß-diol

To a mixture consisting of 10 g of lithium acetylia / ethylenediamine complex and 80 ml of dimethyl sulfoxide, a solution of 5 g of 11β-hydroxyestrone 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 the mixture poured into 1500 ml of egg swassez. The mixture is neutralized by adding 2N hydrochloric acid and the brown precipitate formed is filtered off. This is dried in vacuo at 60 ° and then in The acetone solution is decolorized by treatment with animal charcoal, then filtered off and hexane is added to the filtrate, whereby the J-methoxy-1Ta-ethynylestra-1 ^ .SClOj diol with a melting point of 178-179 ° is precipitated.

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b) ^ -Methoxv-lYa-M.N-dimethylaminopropinylöstra-l, J, 5 (10) -

To a solution of 3 g of 3-methoxy-17a-äthinylöstra-1,3,5 (10) -triene-llß, 1.7ß-diol in 25 ml of dioxane, which still contains 1.7 ml of glacial acetic acid, 3 nil Ν, Ν-Dlmethylaminomethanol and 100 mg Copper chloride added. The reaction mixture is stirred for 1 1/2 hours at a temperature between 60 ° and 70 ° held. Thereafter, the solvents are removed under reduced pressure and the residue between the same Volume fractions of diethyl ether and an aqueous sodium hydroxide solution, which contains enough sodium hydroxide to keep the solution alkaline. The aqueous phase is extracted twice with diethyl ether after separation and the combined diethyl ether phases washed with water and dried. The diethyl ether is then evaporated under vacuum, using the ^ -Methoxy- ^ a-NjN-dirnethylaminopropinylöGtra-i, 3,5 (10) -triene-11ß, 17ß-diol is obtained in the form of a raw foam.

c) N ^ NJj ^ Trim ^^^^^^^^ (10) -trlen-11ß, 17ß-diol)} propynyl jammonium iodide

To a solution of 3 g of crude 3-methoxy-17a-N, N-dimethylamine-propynylestra-1,3,5 (10) -triene-11ß, 17ß-diol (obtained according to the process of section b)) in 30 ml of acetone 20 ml of methyl iodide are added. 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, Μ-trimethyl-N-r3 ^l -il '- (3-methoxy-17a-estra-1,3,5 (10) -trienllß, 17ß-diol) j propynyl jammonium iodide melts at (under Decomposition) "

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d) 3-methoxy-17a-propadienylöstra-1,3,5 (10) -triene-llß,

- - —— - - - - - ——— - - - - - - - - - - - - - - - - .— - - - ..—— »-

To a suspension of 2.76 g of N _1, N, N-trimethyl-N- [3 ¹ ~ l ^{1 - (5-methoxy-17a-estra-l, 3 _J 5 (l0) -triene-LLSs _J 17ß- diol)} propynyljarnmonium iodide (prepared according to the method of section c)) in 20 ml of anhydrous tetrahydrofuran is added in λ portions while cooling with ice, a solution of 455 mg of lithium aluminum hydride in 40 ml of tetrahydrofuran. 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 2N 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. These are then evaporated to a volume of approx. 5-10 ml and diluted with 5 times their volume of diethyl ether. The 3-methoxy-17cc-propadienyl solution precipitates here, 3,5 (10) -triene-llß, 17ß -diol with a melting point of 155-156 °.

k Example 5 · 3 - ethoxy-8a-mGthyl-17g-propadienylöstra-1,3>

5 (10) -trien-173-bl

a) J-Methoxy-Sa-methyl- ^ a-dimetiiylamoriopropinylestra-1,3-5 (10) _z triene-17β _: ol

15 ml of 3-diroethylaminopropin are added dropwise to a solution of 2 g of metallic lithium in 36 ml of ethylenediamine. This 50 obtained reagent is added dropwise

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wise a solution of jS, 2 g of I-methoxy-Sa-methylontral, 3,5 (10) - trien-17-one in 20 ml of tetrahydrofuran was added. After about 5 hours of standing at room temperature, the mixture is poured into ice water, extracted with chloroform, the chloroform solution is evaporated and the 3-re thoxy-8cc-methy 1-17 «-dimethylaminopropinylestra-1,3.5 (10) is obtained -trien-17ß-ol.

b) ^ -Mcthoxy-8a-iTiethyl-17cc-dirriethy.la: ninopropinylöstra-

The rone j5-methoxy-8a-met) iyl-17oc-dimethylaminopropinylestra-1,5i 5 (10) -trien-17ß-ol obtained in the process of section a) is dissolved in 40 ml of acetone and β ml of methyl iodide is added to the solution. After standing at 5 ° for 18 hours, a precipitate separates out and is filtered off. This precipitate consists of ^ methoxy-8a-rnethyl-17CT-dimethylaminopropinylöstra-l ^ _J, 5 (l0) -trien-17-ol-rnetnjodid.

c) J> -Metho>: y-8cx-n! ethyl-17a-propadienylöstra-1,5i. trien-17ß-ol

To a solution of 4.2 g of 3-methoxy-8a-methyl-17a-dimethylaminopropinylestra-1,3,5 (10) -trien-17β-ol-methiodide 0.5 ß lithium aluminum hydride is added to 120 ml of absolute pyridine, After standing for 20 minutes at room temperature, the mixture Water and a 5% aqueous sodium hydroxide solution added. The precipitated material is then filtered off. The filtrate is freed from pyridine in vacuo, and the Rucksta.no absorbed in benzene and water. The benzene solution

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is separated off, dried over sodium sulfate and evaporated. The residue obtained is the ^ -Methoxy-Sa-methyl-17erpr opadienylös tra-1, ~ $, 5 (10) -triene-17ß -öl.

Example 6: 3-Kc thoxy-8a-methyl-17'cx-propadienylestra-2,5 ( 10 ) -dien-17β-ol

a) 3-Methoxy-8a-methyl-17oc-dimethyla! ninoprüpinylcJstra-2 _i 5 (102-d.ien-17β-ol

15 ml of I-dimethylaminopropyne are added dropwise to a solution of 2 g of metallic lithium in 1/6 "of P-ethylenediamine. A solution of 3.2 g of 3-methoxy-8a-methylestra-2,5 is added dropwise to the reagent thus obtained (10) ~ dien-17 ~ one in 20 ml of tetrahydrofuran is added. After standing for 1 hour at room temperature, the mixture is poured into ice water, this is extracted with chloroform and the chloroform solution is evaporated. Methyl-1Ya-dimethylaminopropinylestra-2,5 (10) -dien-17β-ol as residue.

_k b) ^ -Methoxy ^ a-methyl-lYa-dimethyla ^ inopropinylestra- ^ 2,5 (lO) -dien-17ß-ol-methyodide

The crude I> - methoxy-8a-riethyl-17a-dimethylaminopropinylestra-2,5 (10) -dien-17ß-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 thus obtained . After standing at 5 ° for 18 hours, a precipitate forms, which is filtered off. This precipitate consists of ji-hiethoxy- 8a-methyl-17a-dime thy larninopropinylestra-2,5 (10) -diene-17ßol-methiodide.

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c) 5-methoxy-8a-methyl-17oc-propadlenylö ^v s-tra ~ 2 _J 5 (10) -diene 17β ₌ ol

To a solution of 4.2 g of jJ-methoxy-Sa-methyl-1Tcx-dimethylaniinopr'opinylüi5tra-2,5 (10) -dien-17β-ol-oneethiodide 0.5 S lithium aluminum hydride is added to 120 ml of absolute pyridine. After standing for 20 minutes at room temperature, the Gemisca is mixed with water and a 5 A aqueous sodium hydroxide] solution was added and the precipitate formed was filtered off. The pyridine is removed from the filtrate in vacuo and the residue is taken up in benzene and water. The benzene solution is separated off, dried over sodium sulfate and evaporated. The residue remains here > -Methoxy-8a ~ methyl-17ci-propadiene; ylöstra-2, 5 (10) -dien-17β-ol return.

Example 7: ^ ß-Methoxy-3a-meth7 / l-17cc-propadlenylöstra- ⁱ ten-17ß-ol

Using the procedure described in sections a), b) and c) of Example 6 and replacing that described in section a) 3-Methoxy-8ccmetnylöstra-2, ^ (I0) -dien-17-one used as the starting compound through approx. equivalent proportions of> ß-methoxy-8a-methylöstra-4-en-17-one reaches via the intermediate compounds 3ß-methoxy-8a-methyl-17ocdimethylaminopropinylestra-4-en-17ß-ol and its methiodide to form ^ -Methoxy-Sa-methyl-D ^ a-prcpadienylostra - ^ - en-17ß ~ oil. ■

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Example 8; 13β- Ethyl-3-methoxy-8oc-methyl -] / ^ - propadienylgona-2, 3 (.1O) - dione-17β-ol

Using the method described in sections a), b) and c) of Example 5, but replacing the 3-methoxy-8a-methylöstra-1,3,5 (10) -trien- 17-on through approx. Equivalent proportions of lJß-ethyl- ^ - methoxy- · Sx-methylgona-2,5 (10) -dien-17-one are obtained via the intermediate stages 13ß-ethyl-5-methoxy-8a-methyl-17a-dime thylarninopropiny] gona-2,5 (10 ') - dlen-17ß-ol and its methiodide the l> b-Aetnyi-j5-methoxy-8a-methj ^r l-17a-propadienylßona-2, 5 (10) -dicn- 17ß ~ ol.

Example 9 : J'-M ethoxy-lljB-methyl-17o-propadienylc) stra-2, 5 ('10) -di cn -17fl-ol ·

a) 3-methoxy-11ß-rriothyl-17a-N, N-dirnethylaminopropiny] .östra-2j5 (10) -diene-ΐγρ-οΐ

1.8 g are added in small portions to 120 ml of aetriylenediamine metallic lithium with stirring at a temperature between .50 ° and 60 ° added under nitrogen. After the addition is complete, the blue solution obtained is during 1 1/2 Hours heated to 75 ° to 85 °, 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. The running is continued at room temperature for 1 hour and the mixture thereafter with a solution of 2.6 g of I-methoxy-11ß-metnylöstra-2,5 (10) -disn-17-one added in 40 ml of tetrahydrofuran. After further stirring at room temperature for 4 hours in?: iswasser. cooled and 100 ml of a saturated

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ten sodium chloride solution was added under nitrogen. Then 250 ml of diethyl ether are added. The two phases are separated and the aqueous phase is extracted once 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 thus obtained 3-methoxy-LLSs-methyl-17a-N, N-dimethylaminopropinylöstra-2,5 (lO) -diene-17.beta.-ol melts between I7O ⁰ and 175 °.

b) J-methoxy-llp-methyl-l ^ ß-NiN-dinietl'iylaniinopropinylestra-2,5 (: iO) -dien-17ß-ol-yne-iodide

To a solution of 2.5 g of 3-r'iethoxy-liß-methyl-17c (-N, N-dimethylaminoprop: inylestra-2,5 (10) -dien-17ß-ol in 60 ml of acetone, 15 ml of methyl iodide were added. The solution will be during Left to stand at 5 ° for 18 hours, a precipitate being formed. This precipitate is filtered off and recrystallized from acetone. The 3-methoxyl-β-riethyl-17a-N, N-dimethylaii) inopropinylestra-2 thus obtained, 5 (10) -diene-17ß-ol-methiodide melts between 255 ° and 260 ° (with decomposition) .

iSll} 2izii§ZSil} iliI ^stl ' ^a ~ ² ' 5 (l0) -dien-17ß-ol

To a suspension of 3.1 g of 5-methoxy-11ß-methyl-17ct-N, N-dirnethylaminopropinylestra-2,5 (10) -dien-17β-ol-methiodide in 100 ml of anhydrous tetrahydrofuran, 5 '' of a 70% solution of sodium dl (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. A complete solution is obtained here. 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 / Ilexane (1: 2). That 3-methoxy-11β-methyl-17β-ol in this way obtained melts at Ij55 °.

Example 10: ^ - He tJioxy-l? Ss-äthy 1-1 Iß-methyl-17a-pro pa dicn yl gona-2,5 (10) -dicn-17ß-ol

Using the method described in sections a) to c) of Example 9 and replacing the J-methoxy-11ß-methylestra-2,5 (10) -dien-17-one used as the starting compound in section a) by equivalent proportions 5-Methoxy-13ß-ethyl-11ß-methylgona-2,5 (10) -dien-17-one is obtained via the intermediate stages J> - Methoxy-13ß-ethyl-11ß-methyl-17a-N, N-dimethylaminopropinylgona- 2,5 (lO) -dien-17ß-ol and 3-methoxy-l ^ ß-ethyl-llßmethyl-17a-N, N-diniethylaminopropinylgona-2,5 (10) diene-17ßol-methjodid the J-methoxy- lJß-ethyl-11ß-methyl- ^ oc-propadienylgona-2,5 (10) -dien-17ß-ol.

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Example 11: ^ -Aethylendioxy-lYa-propadlenylöstra- ^ l, 9 (l0), ll-trien-riss-ol

^d ioxy-17a-N, N ~ dlmethylaminopropinylöstra-5 (10)

5> 2 g of metallic lithium are added to 500 ml of ethylenediamine, which is stirred at a temperature between 50 ° and 60 ° under nitrogen. After the addition is complete, the blue solution obtained is heated to 95 ° for 1 hour, a pale yellow reaction mixture being obtained. This is cooled to -10 ° and 5'8 SN, N-dimethylamino-2-propyne are added dropwise over the course of 5 minutes. Stirring is continued at room temperature for one hour and a solution of 11 g of 3-ethylenedioxyöstra-4,9 (10), ll-trien-17-one in 150 ml of tetrahydrofuran is then added to the mixture. The mixture is then stirred at room temperature for "2.4 hours". It is then cooled in an ice-water bath, 1000 ml of a saturated aqueous sodium chloride solution is added to the mixture 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, N-dimethylaniinopropinylostra-4,9 (10), ll-trien-17β-ol being obtained.

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b) I-ethylenedioxy-1Ya-N.M-dirnethylarninopropinylestra-4,9 (10), 11triene -]. 7ß-ol-methiodide

To a solution of 2.6 g of 3-ethylenedioxy-17a ~ N, N-dirnethylaminopropinylestra-'t, 9 (10), II-trien ~ 17β-ol in 70 ml of acetone is added to 20 ml of methyl iodide. The solution will be during Held at 5 ° for 18 hours and then freed from the solvent. The residue is recrystallized from acetone, where the 3-ethylenedioxy-17a-N, N-diniethylaminopropinylöstra-4,9 (10), ll-triene-17ß-ol-Fnethjodid is obtained.

c) 3-ethylenedioxy-17α-propadienylöstra- · ^ι ^ ■, 9 (10), ll-trien-173-ol

To a suspension of 5.2 g; 5-ethylenedioxy-17a.-N, N-dimethylaminopropinylöstra-4,9 (10), ll-trien-17ß-ol-methiodide in 100 ml of anhydrous tetrahydrofuran are under Ice cooling 16 ml of a 0.85 molar solution dropwise of lithium aluminum hydride in tetrahydrofuran added. The reaction mixture is allowed to reach room temperature by standing and then stirred for 1 1/2 hours, a complete solution is obtained. Then water is added with cooling, with the excess of the hydride is decomposed. After further addition of water, a precipitate forms. This is filtered off and dissolved in ethylene dichloride solved. This solution is dried over sodium sulfate and evaporated. This gives the ^ -Aethylenedioxy-17a-propadienylöstra-4,9 (10), ll-trien-17ß-ol, which is characterized by its IR absorption spectrum.

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Example 12: 9a-methyl-17a-propadjenylöstra-2,5 (10) -dle n- 3,17ß-diol -> - niothy lather

a) lYa-N, N-dimethy.latninopropynyl-9 ^ - ^iriG> thylüstra ~ 2, 5 (10) -dicn-3i17ß-diol-1-methyl ether

2.2 g of metallic lithium are added in portions to 150 ml of ethylenediamine, which is kept at a temperature between 50 ° and 60 ° with stirring in a nitrogen atmosphere. After the addition is complete, the blue solution obtained is heated to 75 ° -85 ° for 11/2 hours, a pale yellow reaction mixture being obtained. This is cooled to lo ° and mixed with 24 g of N, N-dimethylamino-2-propyne over a period of 5 minutes. Thereafter, the mixture is stirred at room temperature for 1 hour and a solution of), 2 g ~ j> - \ Aethoy, y- 90> -methylöstra-2, 5 (10) -dien ~ 17 ~ one in 40 ml of tetrahydrofuran is added. The mixture is then stirred for 16 hours at room temperature. Anüchllesserid is cooled in an ice-water bath and 200 ml of a saturated aqueous sodium chloride solution is added under nitrogen. Then add JOO ml of benzene. The two phases are separated and the aqueous phase extracted ^ times 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-dimethylaminopropynyl-9a-niethylöstra-2,5 (10) -diene-3,17ß-diol-3-methyl 1-ether being obtained as an oil.

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b) 17 "-N, N-dimethylaminopropynyl-9a-methyl-oestra-2 _i 5 (10) 2 diene-3, 17β-diol-3-roethyl ether-nictniodide

30 ml of methyl iodide are added to a solution of), 8 g of 17a-N / N-dimethylaminopropinyl-9a-niethylöstra-2,5 (10) -diene-3,17ß-diol-3-methyl ether in 90 ml of acetone. The solution is kept at 5 ° for 18 hours, a precipitate being formed. This is filtered off and recrystallized from methanol / aceton (1: 5). The 17a-N, N-dimethylaminopropiny] - 9 ^ - ^f i ^ie thylöstra-2,5 (10) -diene-3,17ß-diol-3-methyl ether methiodide melts at 2 ^ 0-2 ^ 3 ° (with decomposition).

c) 9a2 _i _3; _{; L} diol-3-methyl ether

To a suspension of 1>, 3 g 17a-NiH dimethylaminopropinyl-9a-methylöstra-2,5 (10) -diene-3i17ß-diol-3-mcthyläther-methiodide in 100 ml of anhydrous tetrahydrofuran under ice-cooling 10 ml of a 70 $ A solution of sodium di (methoxyethoxy) aluminum hydride in benzene, which is diluted with 25 ΠΊ-1 tetrahydrofuran, is added. Then the reaction mixture is left to stand until it reaches room temperature and stirred for 2 hours. A complete solution is achieved here. The excess of the aluminum hydride is decomposed by adding water and the tetrahydrofuran is distilled off under reduced pressure. 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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by means of the ^ -Methyl-lTcc-propadienylöstra-2, i5 (10) -diene-3,17ß-diol-> methyl ether as OeI.

Example 33: Levels a), b) and c)

Using the method described in sections a), b) and c) of example h and replacing the 11β-hydroxyestrone methyl ether used as starting compound in section a) with suitable starting compounds, the following quaternary compounds are obtained:

1) ITa-Dimethylaminopropinyl-o-ynethylonostra - ^ - en-Jß, 17ßdiol-methiodide

'2) 17a-Dräthylaminopropinyl-7-äthyliden-13-äthylgona- ^J l · - en ~ 3, 173-diol Aethomethansuiphonat (using dietnylaminomethanol instead of dimethylaminomethanol in the process of section b) and ethyl methanesulfonate instead of methyl iodide in the process of section c))

3) 17 "a-Dimethylaminopropinyl-5- _(lOa: 9SS) -androsten-3.beta., 17ßdiol-inethjodid.

4) 17uc-ethylpropylaminopropinyl-3-ethylenedioxyöstra-1 (10) 5-diene-17ß-ol-metho-p-toluenosulphonate (using of ethylpropyiaminomethanol instead of dimethylaminomethanol in the process of section b) and methyl ptoluene sulphonate instead of methyl iodide in the process of section c)).

5) i7α-Dimethylaminopropinyl-llα, j ^ a-methano-j-tetrahydropyranyloxyöstra-1,5i 5 (10), 6,8- • pentaen-17β-ol methiodide

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6) 17a-dimethylaminopropinyl-3-ethy] endithio-la, 2 amethanoandrostane-17ß-ol-methiodide.

7) 17α-Dimethylaminopropinyl-10β, 11β-niethanoösura "5-en

8) 17cc-dimethylaminopropinyl-13-ethyi-3-aet / 'iylenedioxy-5β, 10β-ir.ethanogona-17β-ol -rnettiodide.

Stage d)

Using the method described in section c) of Example 2, but replacing that there used 3-cyelopentyloxy-17α-dimethylaminopropinylestra-3,5-diene-17β "ol methiodide through, approx. equivalent proportions of. obtained above in steps a), b) and c) quaternary connections one arrives at the following Compounds of formula I:

1) 6-Methyleri-17a-propadienylüc.tra - ^ - en-l> ß _J , 17ß-diol.

2) 7-ethylidene-13-ethyl-17cc-propadienylgona- ' ^l ' t-en-3ß, 17ß-dio3

3) 17α-propndienyl-5 <10a, 93) -androsteri-5ji, 17β-ciiol '(17apropadienyl-5-retroandrosten-3βi17β-diol).

¹ O 3-ethyleridioxy-17a-propadionylestra-1 (10) _i 5-diene »17β-ol. _

5) lla, 12a-kethano-17a-propadioriyl -;) ~ tetrahydropyranyloxyöotra-i, 5,5 (10), 6 _> 8-pentaen-17β-ol.

6) 5-Ethylenedithio-loc, 2a-methano-17 ^ - propadienylandrostan-17ß-ol.

7) 10 [beta], 11 [beta] -methano-17a-propadiGrlylüStra-5-en-3 [beta], lla, 17 [beta] triol.

8) 13-Ethyl-3-ethylenedioxy-17a-propadienyi-5ß _i 10ß-rnethanogona-17ß-ol.

BATH ORIGINAL

509817/1099

600-62

Bey play] h; 6tt , 7 "-D'inAUjrQni et.h? I no-7f3-fluoro ~ 17a-propa dicnyla ndror.t- ^j ! -En-3ß, ΐγβ-d io 1

A suspension of;> 00 mg 6a, 7a-Difluoromethano-7ßfluoro-1 7a-N - piperidinopropinylandrost- ' ^! 'r-en-3β, 17β-diolmothiodide in 6 ml of tetrahydrofuran is added to a mixture of 200 mg of sodium dihydrobis (2-methoxyethoxy) aluminate and 3 ml of benzene at room temperature. Thereafter hours during 2h 'and the stirred mixture, a solution of 300 mg of sodium sulfate in 5 ml of a 2 N aqueous sodium hydroxide solution was added dropwise. It is then filtered off and dac. .Filtrate diluted with 20 ml of ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. Then the 6a, 7a-difluoromethano-7pi'luoro-17a-propadienylandrost-H-en-3ß, 17ß-diol is obtained.

The 6a-7a _J Difluoromethano-7.beta.-fluoro-17a-N-pJ peridinopropinylandrost-4-en-3.beta., 17-diol-.methjodid obtained using the methods described in Example 4 in sections a) to c).

ORiG / js | _AL

509817/1099

Claims (1)

Patent claims: 1. "ITOi-propadienyl steroids of the general formula I _c - CH = C - CH wherein R, represents an alkyl group having 1- ^ carbon atoms and the ring D is a 5- or G-membered ring and ρ q represents the remainder of steroids, with the restriction that this remainder does not have the formula XXI XXI where Z is the rings A and B and those attached to them Substituents includes and and by the following formulas Zl Z2 BATH 509817/1099 • ο zV 600- 62 ^ 8 / b / in z6 H I Il ZlO "28 Target ZX2 Z15 is reproduced, wherein R ₁ for hydrogen, an alkyl group with 1-5 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, an alkanoyl group with 2-Λ carbon atoms or a tetrahydropyranyl group, R, r for hydrogen, a 6a-Methy! group or a 7ct methyl 509817/1099 BATH ORIGINAL $ 0 6θθ-62 ^ 8 / Β / ΐτΐ group, R-, r for hydrogen or a methyl group, R for hydrogen, fluorine, chlorine or a methyl group and R, η for an alkanoyl group with 2-4 carbon atoms or an alkyl group, if the ring D and the substituents on it have the structure XXII OH XXII have, wherein R, has the above meaning and R ₁ ^ is hydrogen, hydroxy o "which is an alkanoyloxy group with 2.-Λ carbon atoms. 2i compounds of the formula Ie, OH η! Io where R] is methyl, ethyl or n-propya 3. Compounds of the formula I ¹ , OH
1 ι -.- CK-C = CH, I ^{1 ßAD} OR / Q _{/ NAL} 509817/1099 - "9ΤΓ- 600-6248 / 3 / HI wherein R ₁ 'has the above meaning and the wavy line indicates that the hydroxyl group can be in position α or β. 4. Medicinal products containing compounds of the formula I. 3700 / ST / SE BAD ORIGtNAL 509817/1099