DE2124951A1 - New steroid compounds and methods of making them - Google Patents

Description

Sandoz AG.
Basel

Patent attorneys "

Dr. W. Schalk, DipWng. P. Throws'

DipUng. G. Donnenberg

Df. V. SeVMiseMiGwarak

Dr. P. V / einheU, Dr. D. Gudel FrankfurtlM., Gr. Etchenfusimer sir.

Gases 600-6414

New -ae and procedures for their

Manufacturing

The present invention relates to compounds of the formula I,

CH.

wherein R, for methyl, ethyl or n ~ propyl and

represents hydrogen, methyl, an acetoacetyl group or an alkanoyl group with 2-4 carbon atoms and processes for the preparation of compounds of the formula I.

According to the invention you can either

b) obtain compounds of the formula I by adding compounds of the formula II,

CH

R, L ". CK = C = CIL.

wherein R-. and R _{2 have the} above meaning and Z for the

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Rings A and B and their substituents and through the structures

Z2

or

wherein R., door is an alkyl group having 1-4 carbon atoms and either both R ^ are each an alkyl group with 1-4 carbon atoms or both R ^ together with the oxygen atoms form an ethylenedioxy or n-propylenedioxy group, is reproduced, subjected to a cleavage and rearrangement reaction by the action of an aqueous acidic medium or

b) obtain compounds of the formula I by adding compounds of the formula III,

III

wherein R, and Rp have the above meaning, rearranged or

c) to compounds of the formula Ib,

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for an al-

kanoyl group with 2-k carbon atoms can be achieved by adding compounds of the formula Ic,

EAR,

CH.

wherein R, has the above meaning · and

wherein R has the above meaning, acylated or

d) to compounds of the formula Id,

CH

0 0 II H 0-C-CH ₂ -C-CH ^

1.L- CHx = C-CH ₂

Id

in which R, has the above meaning, can be obtained by acetoacetylating compounds of the formula Ic.

According to the method described in section a), a strongly acidic medium with a pH of 3 or below, for example between 1 and 2, is allowed to act on compounds of the formula II for a relatively short time, for example less than hours. For the production of the strongly acidic

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The medium used is, for example, oxalic acid, p-toluenesulphonic acid or a mineral acid such as hydrochloric acid. However, the process can also be carried out in one be carried out in a weakly acidic medium, for example at a pH value above 3 *, preferably between 3 and ρ »but here the exposure time can be longer, be for example more than 3 hours. Organic ones are used to produce the weaker acidic medium Acids such as oxalic acid or acetic acid. The reatetion can take place at temperatures between 0 ° and 100 ° C, preferably between 15 ° and 50 ° C, in an inert water-miscible solvent, preferably a lower alcohol such as methanol. If the water-soluble organic acid is liquid under the reaction conditions 1st, an excess of these can form the reaction medium. However, additional solvents can also be used. The presence of water is essential.

The rearrangement of compounds of the formula III described in section b) can be carried out either under basic or under acidic conditions. Here ·

can both in the presence of water and under anhydrous Conditions to be worked.

The rearrangement under basic conditions is expedient carried out in an inert organic solvent, for example dioxane, methanol or ethanol. As the reaction temperature is a temperature between 20 ° and 120 ° C, conveniently between 20 ° and 30 ° C or the boiling point of the reaction mixture, chosen and the reaction

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carried out between 1/4 hour and 6 hours. Aqueous basic conditions are obtained when using for example aqueous sodium or potassium hydroxide solutions, preferably in a concentration of 0.01N up to 2 N. If non-aqueous basic conditions are used, these are expediently obtained by using of alkali metal (hiederklkoxden, for example Sodium methoxide.

The rearrangement under acidic conditions can take place under the conditions specified for the process in section a). In the method of section b), however, in contrast to the method of section a), the presence of Water not essential, so that in the process of section b) the presence of water-miscible solvents not necessary if the procedure is carried out in the absence of water.

The method described in section c) can be used in a for the acylation of tert. Hydroxyl groups carried out in the usual way are used, for example, as acylating agents Acyl halides or anhydrides. In this process, however, strongly acidic conditions should be avoided. To prepare compounds of the formula Ib which have an acetyloxy group in position 17 [3], the acylating agent used is preferably acetic anhydride, which contains calcium hydride in dissolved form. For the production of connections of the Formula Ib is more suitable for the procedure in section c)

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than the procedures of sections a) and b).

The method described in section d) can, for example be carried out in such a way that compounds of the formula Ic are reacted with diketene. The implementation is expedient in an inert organic solvent such as benzene, toluene or mixtures of these solvents and in the presence of small proportions of organic tert. Amines such as pyridine. This implementation is expedient carried out at relatively low temperatures, for example between -5 ° and + 35 ° C. For the production of compounds of the formula Id, the method of section d) is more suitable than the method of sections a) and b).

The compounds of formula I thus obtained can be isolated in a known fell · W _e ise and cleaned.

Compounds of the formula II which have a methoxy group in the 17 [beta] position contain, can be obtained by corresponding compounds of the formula II which are in position 17ß a Contain hydroxyl group, for example with 1 to 1.2 equivalents of a strong base such as lithium amide, sodium amide or potassium amide in liquid ammonia or methyllithium in diet nylon treated at temperatures between -80 ° and + 30 ° C and the compounds of the formula II obtained in this way, which have an anionic structure in the 17 [beta] position, with 1-50 Reacts equivalents of methyl iodide.

Compounds of the formula II .. which have an acetoacetyloxy group in position 17 [beta] contained can be obtained by

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Compounds of the formula II which have a hydroxyl group in the 17 [beta] position contain, acetoacetylated. The acetoacetylation of compounds of the formula II which have a hydroxyl group in the 17 [beta] position may contain, for example, among those in the procedure des Abechni% te-s d) specified conditions.

Compounds of the formula II which have an alkanoyloxy group in the 17 [beta] position may be obtained by making compounds of the. Formula 11, which is a hydroxyl group in pitch 170 contain, acylated * The acylation of compounds that Formula II, which contain a hydroxyl group in position 17ß, can, for example, under the procedures in paragraph c) conditions described.

Compounds of the formula II which have a hydroxyl group in the 17 [beta] position can be prepared by adding compounds of the formula IV,

■ η 9 ^H 'Φ ⁵

• 1 A- CsC-CH ₀ -NR,

2 ι 6

R ₇

IV

wherein R, and Z have the above meaning and either R ₁ - and R _{0 are} identical or different and each stand for an alkyl group with 1-5 carbon atoms or R, - and R ^ together with the nitrogen atom a pyrrolidino, piperidino or Form homopiperidino group, R _{7 means} an alkyl group with 1-5 carbon atoms and 5 (P for the anionic

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2124957

The radical of a mineral acid with the exception of the fluoride ion or the anionic radical of an alkylsulfonic acid or the anionic Radical of an aromatic sulfonic acid, in an organic medium which is not disadvantageous for the reaction with the aid of a hydride ion source, ordered from compounds of the formula XX,

^ Pw ₁ - lP- H XX

where M is aluminum. Gallium or boron, Y stands for an alkali metal or an alkaline earth metal ion, for example lithium, sodium, potassium, calcium or magnesium ion and W ₁ , W 2 and W are identical or different and are hydrogen, an alkyl, alkoxy or Alkoxyalkoxy groups in which the alkyl and alkylene radicals each have up to 6 carbon atoms and compounds of the formula XXI,

Vi,

\ W -MH

where M has the above condition and Wj, and W, - equal or are different and each represents hydrogen or an alkyl group with 1-6 carbon atoms are reduced.

Preferably used hydride ion sources are lithium aluminum hydride. Lithium borohydride, lithium gallium hydride, magnesium aluminum hydride, Lithium dilsobutylmethyl aluminum hydride, lithium trimethoxy aluminum hydride, Diethylaluminum hydride, diborane and sodium di (methox.yäthoxy) aluminum hydride, where expediently the last-mentioned sodium di (methoxyethoxyV aluminum hydride is preferably used.

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In the compounds of the formula IV, DC "can, for example, be a chloride, bromide, iodide, methanesulfonate or p-toluenesulfonate ion, however, it is preferably an iodide ion. Rj-, Rg and R "are preferably each methyl.

The organic medium used in the above process, which is not detrimental to the reaction, is expedient aprotic. It can be made from a cyclic or straight-chain ether such as diethyl ether or tetrahydrofuran or dioxane and aromatic solvents such as benzene, toluene or pyridine or mixtures of these solvents, but preferably consist of benzene, tetrahydrofuran or mixtures of benzene and tetrahydrofuran. The reaction is preferably carried out at temperatures between -40 ° and + 80 ° C, for example between -10 ° and + 50 ° C carried out. Preferably, any moisture is excluded in the reaction.

The compounds of the formula III used as starting compounds in the process of section b) form exactly the same as the process for their preparation forms part of the present invention.

Compounds of the formula III can be obtained by adding a weaker acidic aqueous solution to compounds of the formula II Let the medium act.

The action of a weaker acidic aqueous medium on compounds of the formula II takes place among those in the process of section a) specified conditions.

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In this case, however, the action is preferably carried out for less than 3 hours. The compounds of formula III are isolable intermediate compounds of the process of section a), if this process is less acidic Conditions is carried out.

The starting compounds used in the preparation of compounds of the formula II which contain a hydroxyl group in the 17 [beta] position Compounds of the formula IV used are obtained by quaternizing compounds of the Formula V,

OH «ς

wherein

₁ -,

and Z have the above meaning, with help

of compounds of the formula XXII,

R _? -X XXII

where Ry and X have the above meaning.

The quaternization of compounds of the formula V with the aid of compounds of the formula XXII is expediently carried out in an inert organic solvent, especially in acetone at temperatures between -20 ° and + 30 ° C, especially

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however between -5 ° and + 10 ° C, although the temperature is not critical.

Those used as starting compounds in the above process Compounds of the formula V can be obtained by adding compounds of the formula VI,

VI

wherein R and Z have the above meaning with organometallic compounds of the formula XXIII.

- CH ₂ - N XXIII

what-in R. and R _{n have the} above meaning and P for a

D ° g

active metal or the halide of an active metal " for example lithium, sodium, potassium, aluminum, zinc, magnesium oromide or magnesium iodide is in one

organic medium and hydrolyzed the reaction product.

The preferred compound of the formula XXIII is N, N-D3-methylamino-2-propynyl lithium used, which is conveniently in situ, for example by dissolving metallic Lithium in Aethylendiatnin and addition of Ν, Ν-Dimethyl-

1 098i; 0/1816

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amino-2-propyne to the solution is obtained.

The inert organic used in the reaction of compounds of the formula VI with the compounds of the formula XXIII The medium is expediently anhydrous and becomes preferably selected according to the organometallic compound used. For example, if P for magnesium bromide Magnesium iodide or lithium, the medjum is preferably a cyclic or straight-chain ' Ether, for example diethyl ether or tetrahydrofuran, and, if P stands for sodium, liquid ammonia / diethyl ether as the medium, Ethylenediamine / tetrahydrofuran, dioxane, Pyridine or dioxane / pyridine is used. If as a compound of the formula XXIII N, N-dimethylamino-2-propynyl lithium is used, which is prepared in situ in ethylenediamine, the ethylenediamine can be used as an additional in the reaction Solvents can be used. The temperature to be maintained in this reaction is not critical, however, it is advantageous to work between -30 ° and + 50 ° C, in particular between -20 ° and + 30 ° C. The following hydrolysis can be carried out in a known manner, for example with With the help of water or a highly concentrated salt solution, for example a saturated aqueous ammonium or Sodium chloride solution or an aqueous solution of a base.

The compounds of the formulas XX, XXI, XXII and XXIII are 2 ^ known.

The compounds of the formula VI can be obtained by adding compounds of the formula VII,

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CH

VII

wherein R ^ and Z have the above meaning, oxidized.

The oxidation of compounds of the formula VII takes place in the for the oxidation of sec. Hydroxyl groups to keto groups usual way. For example, the oxidation process known as Oppenauer oxidation can be used for this purpose, that with the aid of a metallic alkoxide and a ketone, for example aluminum isopropoxide and 2-butanone he follows. A suitable reaction temperature is between 60 ° and 130 ° C. The oxidation is conveniently carried out in a solvent such as benzene or toluene.

The compounds of the formula VII, wherein Z has the structure Z, can be obtained by adding the aromatic Ring of compounds of formula VIII,

OH

CH.

VIIT

lh in which R ₁ and R- have the above meaning, reduced.

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The reduction of compounds of the formula VIII is expediently carried out using the so-called Birch reduction process, with the help of a light metal, for example sodium, potassium or lithium in liquid Ammonia and in the presence of a proton donor, for example a lower alcohol such as tert. Butanol or ethanol. In this reduction process, the ammonia conveniently forms the reaction medium and the temperature and pressure should be adjusted in this way. ensures that the ammonia remains in a liquid state. The reaction is preferably carried out at temperature between -70 ° and + 30 °, but preferably at the boiling point of ammonia. Appropriately done the reaction at atmospheric pressure in an inert organisehen Solvent, for example an ether such as tetrahydrofuran.

However, compounds of the formula VII in which Z has the structure Zl can also be obtained by using compounds of formula IX,

IX

wherein R, and R, have the same meaning as above, a Birch reduction process subject.

The reduction of compounds of the formula IX can be carried out in the done the same way as this for the reduction of

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Compounds of formula VIII is indicated.

The Z structures of the compound used according to the invention

*)
fertilize represent protected forms of rings A and B, which have an unsaturated structure and an oxo group in position 3. The production of such Z structures is described in the literature, for example compounds which have the structures Z2 and ZJ can be produced in a known manner from compounds which have a structure Z1. Accordingly, compounds of the formula VII in which Z has the structure Z2 or Z3 can be obtained in a manner known per se from compounds of the formula VII in which Z has the structure Zl.

In the structures of Zl, Z2 Iind Z5 are R, and R ^ preferably unbranched alkyl groups, but in particular door Metnyl. Of the structures Z, the structure Zl is preferred.

Compounds of the formula VIII can be obtained by placing the carbonyl group in position 17 of the compounds of Formula IX reduced.

The reduction of the carbonyl group in position 17 of the compounds of the formula IX can umhydride with the help of a light metal hydride, for example sodium borohydride or Li thiumaluniini using ethanol or a mixture of ethanol and methylene chloride as solvent, if sodium boron

?. ^c y hydride and using tetrahydrofuran as solvent, if lithium aluminum hydride are used as reducing agent.

. _ΜΆ 1Q98ÖU / 1815 bases stable

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Compounds of the form] IX can be obtained by those in position 17 of the compounds of the formula X,

CH

where R, and FU have the above meaning Ketal bond splits.

10

The cleavage of the ketal bond can take place in the manner customary for such reactions. For example compounds of the formula X can be exposed to the conditions described in the method of section a) strongly acidic conditions are preferred.

The compounds of formula X can be obtained by d.ic carbonyl function in position 11 of the compounds of Formula XI,

XI

where R, and R ^ have the above meaning, reduced,

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The reduction of the carbonyl group in position 11 of compounds of the formula XI can be carried out in a manner known per se, for example with the help of the Wolff-Kishner reduction method. Here are compounds of the formula XI by treatment with hydrazine or a mixture of hydrazine dihydrochloride and ilydrazine hydrate in one with Water-miscible solvent which has a boiling point of at least 210 °, for example di- or triethylene glycol at temperatures of about 130 ° in their hydrazone convicted. The hydrazone is then, for example, by heating the mixture to boiling, in the presence an alkali metal hydroxide, for example potassium or sodium hydroxide with separation of water to form compounds of Formula X decomposes.

Compounds of the formula XI can be obtained by adding compounds of the formula XII,

XII

wherein R, and R, have the above meaning with compounds of the formula XV,

- Q.

XV

where '4 is an acid residue of a mineral acid, but not Jedocu stands for a fluoride or for the acid residue of an organic sulfo acid, in the presence of a strong base.

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2124351

As compounds of the formula XV, for example Methylehlori, d, methyl iodide, methyl bromide, matnylarylsulfonate, e.g. methyl p-toluene sulfonate and methyl alkyl sulfonate, for example methyl methanesulfonate use.

The in the implementation of compounds of the formula XII with compounds of the formula XV present can under the formula XVI,

M-A XVI

wprin M for an alkali metal e.g. sodium or potassium and A for hydrogen, an alkoxy group with 1-6 carbon atoms or a --NHp or -CHp-SOp-C H -, - group stand, be summarized ..

The reaction of compounds of the formula XII with compounds of the formula XV can conveniently In a inert gas atmosphere, for example in a nitrogen atmosphere carried out at temperatures between -10 ° and + 60 ° will. Preferably, however, the reaction is carried out so that the initial phases of the reaction in one Carries out ice-cooled medium and then the temperature rise to room temperature, for example leaves. The reaction is expediently carried out in an inert organic solvent, for example tert. Butanol or dimethyl sulfoxide carried out. If, however, the

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bonds of the formula XV under the reaction conditions are liquid, an excess of these compounds, for example a 10 to 200-fold excess Form reaction medium. The preferred compound of Formula XV is methyl iodide and the preferred compound dor formula>! V1 potassium tert. -butoxide.

The compounds of the formulas XV and XVI are known.

"Compounds of the formula XII can be obtained by one dio 11-hydroxy group of the compounds of the formula XlII,

Γ1Λ "

XIII

wherein R. and R, have the above meaning, to a keto group oxidized.

üie oxidation of the 11-hydroxy group of the compounds of the formula XLII takes place in a for the oxidation of selc. Alkyl hydroxy groups to carbonyl groups known manner. Appropriately

15) one uses the von Pfitzner and Moffatt in J. Am. Chem.

Soc üY, 566I and 567Ο (196'3) described method. To carry them out, use is made of dimethyl sulfoxide, dicyclonexylcarbodiimide and, as the proton source, an anhydrous prior.p-ioric acid or dichloroacetic acid. The reaction is purposeful

.? 0 annoyingly in an inert organic solvent, for example an aromatic hydrocarbon such as benzene,

The reaction temperature chosen is more normal 109850/1815

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wise a temperature between 15 ° and 35 ° C, preferably between 20 ° and J0 ° C. The oxidation of the 11-hydroxy group of compounds of the formula XIII can, however, also using a Jones reagent (J. Cnem. Sog. 1946 , 39, and Reagents for Organic Synthesis, Fieser and Fieser, p. 142).

Compounds of the formula XIII can be obtained by
one the phenolisehe hydroxyl group of compounds of the
Formula XIV

HO

XIV

wherein R _{1 has the} above meaning, etherified.

The etherification of the phenolic hydroxyl group of compounds of the formula XIV can be carried out in a manner known for the etherification of phenolic hydroxyl groups. Alkylating agents can be, for example, alkyl iodide use and, if R- is methyl, used one expediently methyl iodide.

The dilution of the phenolic hydroxyl group of the compounds of the formula XIV is expediently carried out under basic Conditions, for example in the presence of anhydrous potassium carbonate. Appropriately, one uses at this reaction an inert organic solvent, for example a lower alcohol such as methanol. The Rea-

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tion temperature can be between 60 ° and 100 ° C, but it is advantageous to carry out the reaction at the boiling point of the reaction mixture. If as a solvent Alcohol is used, the alkyl groups should expediently of alcohol and alkylating agent match.

The compounds of the formula XIV are known.

The compounds of the formula I obtained according to the invention have extremely favorable pharmacodynamic properties, which is particularly in a progestational Effect, as can be seen from the results of the well-known Clauberg test, express. The compounds of the formula 1 can therefore be used in the fearability control will.

The amount of compounds of the Formula I should be between 0.01 and approx. 50 mg. These doses can be given in one dose or in divided doses of 0.005 up to 25 mg twice a day or in prolonged-release form. However, the amount of substance administered depends on body weight independent.

The compounds of the formula III are valuable intermediate compounds for the preparation of compounds of the formula I. However, the compounds of the formula III are also favorable pnarmakodynamisohe properties and here in particular a progestational effect. The one to be administered daily The amount of compounds of the formula III corresponds to that to be administered Amount of compounds of the formula I.

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For the above use, the compounds of the formulas I and III can be used together with pharmaceutically acceptable carriers and other customary additives. Administration can either take place orally in the form of tablets, capsules, elixirs, suspensions or solutions or parenterally in the form of injection solutions, suspensions or emulsions.

A characteristic composition suitable for oral administration in a capsule can consist of the following components:

Ingredients Se wlcnt (mg)

17β-Hydroxy-9a-methyl-17apropadienylestra-4-en-3-one 0.5

inert solid diluent medium (starch, lactose,

Kaolin) 249.5

If in the compounds of the formula IR _{3 stands} for an alkanoyl radical, this preferably means an unbranched alkanoyl radical.

In the examples below, all temperatures are given in degrees Celsius. The room temperature means a temperature of 25 ° C.

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Example 1: 9a-methyl-17 "-propadienylestra-4-en-173-ol-3-one

a) 7-Ethylenedioxy-11ß-hydroxy-3-methoxyestra "-l _i 3» 5 (10) -triene A mixture of 15 g of 17-ethylenedioxyestra-1,3 »5 (10) -triene-3, llß-diol and 30 g of anhydrous potassium carbonate in 75 ml of methanol and 60 ml of methyl iodide are heated to boiling for 3 hours with stirring. The mixture is then cooled and diluted by adding 200 ml of water. The methanol and methyl iodide are distilled off under reduced pressure and the aqueous residue Extracted twice with methylene chloride. The combined organic extracts are washed with a saturated aqueous sodium chloride solution and dried iX'oc.v sodium sulfate. After removal of the solvent, a residue is obtained which, after recrystallization from diethyl ether, 17-ethylenedioxy-11β-hydroxy-3- metnoyy-

Lb öfitr-a-.l,?, 5Ü0) -trien from m.p. 1? 5-1? 6 ° erptibt.

b) 17-Aetri £ 1 endioxy- im

To a curled solution of 5 »13 S 17-ethylenedioxy-11-hydroxy-3-mettiOxyöstra-1,3» 5 (10) -triene in 25 ml of dimethyl sulfoxide and 25 ml of benzene, 3 ml of pyridine and 9.3 g of N.N-dicyclohexylcar'Öödiimid are added. This mixture will cooled and treated with 1.5 ml of dichloroacetic acid. Thereafter is stirred at room temperature for 1 1/2 hours and then added by adding 50 ml of diethyl ether diluted the mixture. A solution of 4 g of oxalic acid in 10 ml

2 ^:; Methanol is added dropwise. This gives a suspension which is stirred for 40 minutes at room temperature and then filtered off. The FH Council will

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evaporated to dryness and partitioned between methylene chloride and a 10 '^ strength aqueous sodium bicarbonate solution. The organic phase is separated off, washed with water and dried over sodium sulfate. The solvent is then evaporated in vacuo. The residue is placed on a silica gel column and treated with chloroform, the different. which percentage contains methanol, eluted. The fractions eluted with chloroform containing 5 % methanol are pooled and evaporated to dryness. This gives a residue which is recrystallized from hexane / diethyl ether (1: 1). The 17-ethylenedioxy-j5-methoxyestra-1,5,5 (10) -trien-II-one thus obtained melts at 122-123 ° C.

c) 17-ethylenedioxy-32 ^met i} ° ^x y ~ 92 "" ^m ® ^tn y ^lo ' ^stra ~ - ^l -i5> 5 ( ¹ Q) ^- ^ iSi-I 11-one

To a stirred solution, cooled with ice, of 10.5 g of 17-ethylenedioxy-3-methoxyestra-1,3,5 (10) -trien-II-one in 300 ml of methyl iodide are in a nitrogen atmosphere for 10 minutes 120 ml of a 1.1 molar solution of potassium tert-butoxide in t-butyl alcohol were added. Then leave the temperature rise to room temperature and stir the mixture for a further 18 hours. Then one carries in 500 ml of water and extracted twice with methylene chloride. The united organic Extracts are washed with water and dried over sodium sulfate. Obtained after removal of the solvent an oil which is recrystallized from diethyl ether. This gives 17 ~ ethylenedioxy-3-methoxy-9a-methylestral, 3 * 5 (10) -trien-II-one from m.p. 142-145 °.

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d) 17-ethylenedioxy-3-methoxy-9oc-methylöstra-1,5,5 (10) -triene

A mixture of 53 ^ g 17 ~ ethylenedioxy-3-methoxy ~ 9a-methylöstra-1,3,5 (10) -trien ~ ll-one, 1 g hydrazinedine hydrochloride and. 5 g of hydrazine hydrate in 35 S triethylene glycol is heated to a temperature of 130 ° and held at this temperature for 2 1/2 hours. 1.8 g of spherical potassium hydroxide are then added and the temperature is increased to 210 °. This temperature is maintained for 2 1/2 hours, a mixture of hydrazine and water being slowly distilled off. The reaction mixture is then cooled and diluted with water. A precipitate forms which is filtered off. The filter residue is dissolved in methylene chloride and the solution is dried over sodium sulfate. After removal of the solvent a residue remains, which is recrystallized from hexane / diethyl ether. Here you get the lT
1, J, 5 (10) -triene of m.p.

e) 9i-Methylestrone thy lather

1 ml of 2N hydrochloric acid is added to a warm solution of 220 mg of IT-ethylenedioxy-3-methoxy-9a-methylöstra-1,3,5 (10) -triene in 5 ml of methanol and the mixture is heated to boiling for 5 minutes . Crystals form on cooling and are filtered off. The crystals are washed with small portions of diethyl ether. The 9a-methylestrone methyl ether obtained in this way melts at 190-192 ⁰ .

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A solution of 6 g of 9a-methylestrone methyl ether in 90 ml Tetrahydrofuran and 90 ml of 1-butanol is boiling to 200 ml Ammonia added. Then 2.8 g of metallic lithium are added to the mixture in small portions for 10 minutes added, and the resulting blue solution heated to boiling for 6 hours with stirring. Then you let the ammonia evaporate for about 1 hour and add 30 ml of methanol and also 300 ml of a saturated one aqueous sodium chloride solution and 200 ml of benzene to the remaining mixture. The phases formed are separated and the organic phase is washed with a saturated aqueous sodium chloride solution. After drying over anhydrous Sodium sulfate, the solvent is evaporated. The residue is recrystallized from methanol. The received 3 - Methoxy-9a-methylestra-2,5 (10) -dien-17-ol melts between 116 ° and 120 °.

e)> ~ ^{! vl} etnoxy-9ot-methylestra-2,5 (10) -dien-17-one

A mixture of 5 g of 3-metnoxy-9a-methylöstra-2,5 (10) -dienl? -Ol, 4.5g aluminum isopropoxide, 45 ml benzene and 45 ml 2-butanone is heated to the boil under arenas for 22 hours, using a water separator. Thereafter is cooled and mixed with 100 ml of a 2N aqueous sodium hydroxide solution and then with 50 ml of benzene. The organic layer is separated, washed with water and a saturated sodium chloride solution, and dried over anhydrous Dried sodium sulfate. After removing the solution

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by means of a residue obtained from diethyl ether / Hexane (1: 1) is recrystallized. The 3-mer, hoxy-9a-methylöstra-2,5 (10) -dien-17-one obtained melts between 155 ° and 158 °.

η) i-MGthoxy-9a-methyl-17; iN, N-ditne thylaminopropinylestra- ² > 5 (i2)

2.2 g of metallic lithium are introduced in portions into 150 ml of ethylenediamine with stirring and in a nitrogen atmosphere at a temperature between 50 and 60 °. After the addition is complete, the blue solution obtained is heated to 75-35 ° for 1 1/2 hours. A pale yellow reaction mixture is obtained here. This is cooled to 10 ° and 24 g of Ν, Ν-diraethylamino-2-propyne are added over the course of 5 minutes. The mixture is then stirred for a further hour and then a solution of 3.2 g of 3-methoxy-9oc-methylestra-2,5 (10) -dien-17-one in 40 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 16 hours. It is then cooled in an ice / water mixture and 200 ml of a saturated aqueous sodium chloride solution and then 300 ml of benzene are added in a nitrogen atmosphere. The phases formed are separated, and the aqueous phase extracted 3 ^m al NIIT benzene. The organic phases are combined and washed with a saturated aqueous sodium chloride solution. It is then dried over anhydrous sodium sulfate and the solvent is evaporated. This gives 3-methoxy-9ameth7AL-17a-N, N-dimethylaminopropinylestra-2,5 {10) -diene-17ßol as an oil.

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5-methoxy ~ 9a-methyl-17a-N, N-cHmethylaminopropinylestra-

To a solution of 3.8 g of 3-methoxy-9a-methyl-17a-N, N-dimethylaminopropinylestra-2, -5 (10) -dien-178-ol 30 ml Methy.1 iodide are added in 90 ml of acetone. The received 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 J-methoxy-ga-methyl- ^ a- ^ N-dimethylaminopro-1.0 thus obtained pinylestra-2,5 (10) -dien-17ß-ol-methiodide melts at 240-243 ° (with decomposition).

j) 3-Met (ioxy-9a-methyl-17 «-propad.ienylöstra-2 _>

To a suspension of 3 * 3 g of 3-methoxy-9a-methyl-17a-N, N> »- III methylaminopropinylestra-2,5 (10) -dien-17β-ol-methiodide 10 ml of a 70% solution of sodium di (methoxyethoxy) aluminum hydride are added to 100 ml of anhydrous tetrahydrofuran while cooling with ice in benzene mixed with 25 ml of tetrahydrofuran diluted was added. The reaction mixture leaves then assume room temperature and stir for hours, with complete solution occurring. By adding The excess of the hydride is decomposed by water and the tetrahydrofuran is removed under reduced pressure. The aqueous residue is extracted with methylene chloride and the methylene chloride solution over anhydrous sodium sulfate dried. After the solvent has been removed, the 3-methoxy-9ot-methyl-173c-propadienylöstra-2,5 is fed (I0) -dione-17ß-ol as OeT, which is sufficiently pure for the subsequent implementation.

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k) 9a-methyl-17a-propadienylestra-4-en-17β-ol-3-one

To a solution of 600 mg of I-methoxy ^ oc-methyl- ^ oc-propadjenylöstra ~ 2,5 (10) -dien-17ß-ol 5 drops of concentrated hydrochloric acid are added in 10 ml of methanol and the mixture was allowed to stand for 1 1/2 hours at room temperature. Then with a mixture of Ice and water diluted and a saturated aqueous sodium bicarbonate solution added slowly until the mixture no longer shows an acidic reaction. Then with diethyl ether extracted and the ethereal solution dried over anhydrous sodium sulfate. After removal of the solvent a residue is obtained which is recrystallized from diethyl ether. The 9 <x -methyl-17 "-propadienylöstra-4-en-17β-ol-> one obtained in this way melts at 218-220 °.

Example 2: 17ß-acetoxy-9ot-methyl-17oc-propadienylöstra-

4-en-j5-on

A mixture of 0.05 S calcium hydride and 5 ml acetic anhydride is heated to the boil for one hour. Then 0.5 g of 17a-propadienylöstra-9a-methyl- ^J 4-one-17β-ol-3-one are added and the mixture is heated to the boil for a further J hours. It is then cooled and the mixture poured onto ice. After extracting with methylene chloride, the methylene chloride solution is washed with a saturated aqueous sodium bicarbonate and then with water. It is then dried over anhydrous sodium sulfate and the solvent is evaporated off in vacuo. This leads to 17ß-acetoxy-9a-methyl-17ct-propadienylöstra-4-en-; 5-one

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Example 3t ^ ß-Acetoacetoxy-ga-fflethyl- ^ ct-propadienylöstra-4-en-3-one

To a solution of 1 g of 9α-methyl-17α-propadienylöstra-4-en-17β-ol-3-one in a mixture of 18.5 ml of benzene, 9.25 ml of toluene and 0.23 ml of pyridine, 1.8 nil are added dropwise at 0 ° Diketene dissolved in 9 ml of benzene was added. The mixture is kept at 25 ° for 3 hours. By washing the mixture with an ice-cold 0.1 N aqueous sodium hydroxide solution and water. Dry the mixture over anhydrous Sodium sulfate and evaporation to dryness gives the ^ ß-acetoacetoxy ^ a-methyl- ^ a-propadienylöstra - ^ - en ^ - on.

Example 4: 17β-Methoxy-9a-methyl-17a-propadienylestra-4- e n-3-one

a) 3,17β-Dimethoxy-9a-methyl-17a-prbpadienylöstra-2 ₁ 5 (10) -diene

To a solution of lithium amide in liquid ammonia (made from 73.5 mg of lithium and 25 ml of ammonia) is added a solution of 3.3 g of ga-methyl ^ -methoxy- ^ a-propadienylöstra-2,5 (10) -dien-17ß-ol in 50 ml of diethyl ether. Thereafter, for 2 hours at the boiling point of the ammonia held and added 2.5 g of methyl iodide. After removal of the ammonia is added 50 ml of water and the ethereal phase is separated off. This is evaporated, the residue being the 3,173-dimethoxy-9a-methyl-17a-propadienylestra-2,5 (10) -diene is obtained.

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b) 17β-Methoxy-9a-methyl-17a-propadienylöstra-4-en-3-one

Using the method described in section k) of Example 1, but replacing that there used 9 # -methyl-17α-propadienylestra-2,5 (10) -diene-3,17β-diol-3-methyl ether by equivalent proportions of 3,17ß-dimethoxy-9a-methyl-17ot-propadienylöstra-2,5 (10) -diene 17ß-methoxy-9cx-methyl-17oc-propadienylöstra-4-en-3-one is obtained.

Example 5: 9a-methyl-17oc-propadienylestra-4-en-17β-ol-3-one

a) 9a-methyl-17a-propadienylöstra-5 (10) -en-17ß-ol-3-one

A solution of 12 g of 3-methoxy-9a-methyl-17a-propadienyl-Ö3tra-2,5 (10) -dien-17ß-ol in 80 ml of glacial acetic acid and 20 ml of water is stirred at room temperature for 2 hours. The mixture is then poured onto ice and neutralized with an IN aqueous sodium hydroxide solution. the precipitated crude title compound "is treated with methylene chloride extracted several times. The combined methylene chloride extracts are washed with water over sodium sulfate dried and then evaporated in vacuo. The raw title compound obtained is made from dieth: / ether / dioxane (1: 1) recrystallized. The 9a-methyl-17ce-propadienylöc.tra-5 (-10) -en-17β-ol-3-one obtained in this way melts at 129-131 °.

b) 9oc-Methyl-17a-propadienylöstra-4-en-17ß-ol-3-one

Using that described in section k) of Example 1 Process, but with replacement of the 3-methoxy-9a-methyl-17oc-propadienylöstra-2,5 (10) -dien-17'3-ol used there through approx. equivalent proportions of 9ac-methyl-

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17a-propadlenylöstra-5 (10) -en-17ß-ol-5-one is obtained to 9a-methyl-17a-propadienylöstra-4-en-17ß-ol-3-one from m.p. 218-220 °.

Example 6: 9q-Methyl-17g-propadienylöstra-4-en-17β-ol · 3-one

To a solution of 1 g of 9 <x -methyl-17a-propadienylöstra-5 (10) -en-17ß-ol-3-one 100 mg of sodium methoxide are added in 10 ml of methanol and the resulting mixture is added Stirred at room temperature for one hour. Then 20 ml of water are carefully added and the resulting Crude product * that precipitates is filtered off. After recrystallization from diethyl ether, 9α-methyl-17-xpropadienylöstra-4-en-17β-ol-3-one is obtained from m.p. 218-230 °.

Example 7:

Using the in sections a) to k) of the

Process described in Example "1, but if W of the 17-ethylenedioxyestra-1,3,5 (10) -triene-3, 11ß-diol used there in section a) as the starting compound is replaced by equivalent proportions of

a) 13-ethyl-17-ethylenedioxygona-1, 3.5 (10) -triene ->. llßdiol or

b) 17-ethylenedioxy-13-n-propylgona-1,3 * 5 (10) -triene- ! 5.113-diol is obtained

a) 13-Ethyl-9oi-methyl-17a-propadienylgona-4-en-17ß-Ql-3-en " or

n) 9ix-methyl-13-n-propyl-17oc-propadienylgona-4-en-17β-ol ^{> on} 109850/1815

Claims (1)

600-6414 Claims Process for the preparation of compounds of the formula ÜL-CH-OOL wherein R, for methyl, ethyl or n-propyl and R ₂ for hydrogen, methyl, an acetoacetyl group or an alkanoyl group with 2-4 carbon atoms, characterized in that either a) reaches compounds of the formula I by adding compounds of the formula II, OR ₂ CH c-CH = C II where R, and R _? Have the above meaning and Z stands for the rings A and B and their substituents, and by the structures Zl Z2 or 109850/1815 .600-6414 where R, stands for an alkyl group with 1-4 carbon atoms and either both R ₁ ^ each denote an alkyl group with 1-4 carbon atoms or both R ₂ , together with the oxygen atoms, form an ethylenedioxy or an n- propylene dioxy group, is shown , subjected to a cleavage and storage reaction by the action of an aqueous acidic medium. . · b) zti compounds of the formula I arrive by adding compounds of the formula III, CH IH have the above meaning, besieged where R .. and
or c) to compounds of the formula Ib CH. R ° V
¹ J ^ -CH = C-CH ,, Ib in which R, has the above meaning and Rp "stands for oine alkanoyl group with 2-4 carbon atoms , by using compounds of the formula Ic, 109850/1815 600-6414 CH. wherein R, has the above meaning, acylated or c) to compounds of the formula Id, 0 0 Il M O-C-CH ₂ -C-CH ^ CH Id in which R, has the above meaning, can be obtained by acetoacetylating compounds of the formula Ic. 2. "Ancestors for the preparation of compounds of the formula III, CH = C = CH, III 109850/1815 600-6414 2 7 24951 wherein R, for methyl-ethyl or n-propyl and Rp for hydrogen, Methyl, an acetoacetyl group or an alkanoyl group with 2-4 carbon atoms, characterized in that that one on compounds of the formula II, OR,
R-. L / λ. CH = C = CH, CH II wherein R ₁ and R have the above meaning and Z stands for the rings A and D and their substituents and by the structures CH., R ₄ O Zl or wherein R, represents an alkyl group with 1-Ή carbon atoms and either both R ^ are each an alkyl group with 1-4 Mean carbon atoms or both Rj. Together with the An ethylenedioxy or an n-propylenedioxy group form, is reproduced, allows a weaker acidic aqueous medium to act. 1 0 9 8 ¹ U) I 1 8 1 b 600-6414 Compounds of formula I, OR, l C? - CH = C = CH where R- stands for methyl, methyl or n-propyl and R _{2 stands} for hydrogen, methyl, an acetoacetyl group or an alkanoyl group with 2-4 carbon atoms. 4. Compounds of the formula III, OR, CH = C = CH, III wherein R, is methyl ,. Ethyl or n-propyl and R_ for Are hydrogen, methyl, an acetoacetyl group or an alkanoyl group with 2-4 carbon atoms. 5. Therapeutic composition characterized 'by the Content of compounds of the formula I. 6. Therapeutic composition characterized by the content of compounds of the formula III. 37OO / ST / SE S, The patent attorney » 109850/1815