DE2119328A1 - New steroid compounds and methods of making them - Google Patents

Description

Sandoz AG.
Basel

Pdentanwalt

Dr. W. Schalk, DipUng. P. Wirth

Dip! .-! R: g. G. Demenberg

Dr. V. Schd-acl-Kowarzik

Dr. P. Weinhold, Dr. D. Gudel

Frankfurt / M., Gr. Eschenheimer Sh *.

Case 6OO-6365

You rai

New-e- ^ R and procedures for their Manufacturing

The present invention relates to compounds of the formula I, - OH

CH = C = CH ₂

where R is methyl, ethyl or n-propyl, and processes for their production.

According to the invention, compounds of the formula I can be obtained by either

a) compounds of the formula II,

CH = C = CH.

II

wherein R has the above meaning with compounds of the formula X,

Py

109846/1829

- 2 - 600-6365

^z i

z ₂ z ₅

wherein Z, Ζ _χ , Z ₂ and Z, are identical or different and each represent chlorine, bromine or cyano, treated in an inert organic solvent or

b) compounds of the formula III

OH

.CH = C = CH ₂

III

wherein R has the above meaning and K is a ketal group means that the ketal group is split off under aqueous acidic conditions.

The process specified under a) is preferably carried out in an inert gas atmosphere, for example a nitrogen atmosphere, preferably with the exclusion of water and using, for example, cyclic ethers such as dioxane or tetrahydrofuran, as inert organic solvents. In this process, the temperature should be between 15 ° and 60 ° C, preferably between 20 ° and 35 ° C. The preferred compound of the formula X is that
2,3-dichloro-5,6-dicyano-1,4-benzoquinone is used.

10984 6/1829

- 3 - '600-6365

The elimination of the ketal group indicated under b), the is in position 3, can be carried out under weak or strongly aqueous-acidic conditions. The acidic conditions are with the help of water-soluble inorganic or organic acids, for example Hydrochloric acid, sulfuric acid,

Acetic acid and oxalic acid and with the aid of aromatic and lower aliphatic sulfonic acids such as p-toluenesulfonic acid. The cleavage can, for example, at pH values above 2, preferably between 3 and 5 by treatment with oxalic acid or acetic acid, conveniently for less than 3 hours, preferably at temperatures between 0 ° and 100 ° C, in particular between 20 ° and 70 ° C, and carried out in the presence of an inert organic solvent, for example a lower alcohol such as methanol. However, if the acid used is liquid under the reaction conditions, an excess of it can be used as a solvent.

The ketai group of the compounds of the formula III can, for example, by the formula XVI

XVI

R ₅ O

are expressed in which either R ^ and Rj. are the same or different and each denotes an alkyl group with 1-4 carbon atoms or Rj, and R ₁ - together with the oxygen atoms an ethylenedioxy or an n-Pro-

10984 6/1829

- 4 - 600-6 ^ 65

form pylenedioxy group. Palls here R ₂ and R 1 - stand for an alkyl group with 1-4 carbon atoms, these preferably each mean a methyl group. K preferably represents an ethylenedioxy group.

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

The starting compounds used in process a) Compounds of the formula II can be obtained by adding compounds of the formula IV,

OH

IV

wherein R and K have the above meaning, subjecting the ketal group to cleavage under weakly acidic conditions.

The cleavage of the ketal group in position 3 of the compounds of the formula IV can be carried out under known conditions which the double bond in position 5 (10) cannot change. For example, it is advantageous for the cleavage to take place at pH values above 2, preferably between 3 and 5 »during a comparatively short period of time, for example less than 3 hours. The weak acidic conditions can be obtained by using suitable acids such as acetic acid and oxalic acid. However, it is also possible, the splitting off of the protective group in position

109846/1829

- 5 - 600-6365

to carry out the compounds of formula IV under the conditions given in process b).

The compounds of the formulas III and IV can be used under the formula y,

- CH = C = CH ₂

where R has the above meaning and A is the radicals

or

b)

stands, in which K has the above meaning, are summarized.

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

VI

wherein A and R have the above meaning and either R ₁ and Rp are identical or different and each represent an alkyl group with 1-3 carbon atoms or R, and Rp together with the nitrogen atom form a pyrrolidino, piperidino or homopiperidino group, R-. represents an alkyl group with 1-3 carbon atoms and XX represents the anionic radical of a mineral acid with the exception of the fluoride ion or the

109846/1829

- 6 - 600-6365

ahionischen radical of an alkyl sulfonic acid or an aromatic sulfonic acid is in an organic medium which is suitable for carrying out the reaction, a hydride ion source treated, the onnectivity from \ ^r of formula XI,

Y ³ IL -MH XI

¹ I.

where M is aluminum, gallium or boron, Y ^ a. Alkali or alkaline earth metal ions, for example a lithium, sodium, potassium, calcium or magnesium ion and W 1, Wp and W are identical or different and are hydrogen or an alkyl, alkoxy, alkoxyalkoxy group, wherein the individual alkyl or «alkylene groups

each have Ms of 6 carbon atoms, mean, and Compounds of Formula XII

W _c -MH XII

wherein M has the above meaning and W ₂ , and Wp- are identical or different and each represent hydrogen or an alkyl group having 1-6 carbon atoms.

Preferred used hydride ion sources are lithium aluminum hydride, Lithium borohydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium gallium hydride, magnesium aluminum hydride, Lithium diisobutylmethyl aluminum hydride, lithium trimethoxy aluminum hydride, Diethylaluminum hydride, diborane and sodium dimethoxyethoxyaluminium hydride, v; o of preferably Lithium aluminum hydride is used.

109846/1829

- 7 - 600-6365

In the compounds of the formula VI, X ^ can for example stand for a chloride, bromide, iodide, methanesulfonate or p-toluenesulfonate ion, of which the iodide ion is preferred. R ,, Rp and R., preferably represent a methyl group. The organic medium used in the reaction to prepare compounds of the formula V is preferably aprotic. The medium can, for example, form cyclic and straight-chain ethers such as diethyl ether, tetrahydrofuran or dioxane and aromatic solvents such as benzene, toluene or pyridine. However, pyridine or tetrahydrofuran or mixtures thereof are preferably used. The reaction temperature is preferably between -40 ° and + 80 ° C., in particular between -10 ° and + ¹ K) ⁰ C. During the reaction, it is advantageous to exclude any moisture.

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

VII

wherein A, R, R, and Rp have the same meaning as above, by reaction with compounds of the formula XIII,

R ₃ -X XIII

wherein R, and X have the above meaning, quaternized.

1098A6 / 1C29

2113328

The reaction of compounds of the formula VII with the compounds of the formula XIII is expedient in an inert organic solvent, preferably acetone, at temperatures between -20 ° and + 30 ° C, preferably carried out between -5 ° and + 10 ° C, although the reaction temperature is not critical.

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

r> 0

VIII

wherein A and R have the above meaning, with an organometallic Compound of Formula XIV

XIV

wherein R, and Rp have the above meaning and P for the Residue of an active metal or an active metal halide, for example lithium, sodium, potassium, aluminum, Zinc, magnesium bromide or magnesium iodide, reacted in an inert organic solvent and hydrolyzed the reaction product.

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

10 9 8 4 6/1 829

- 9 - 600-6365

The solvent used in the reaction of compounds of the formula VIII with compounds of the formula XIV depends on the organometallic compound used selected. For example, if P for magnesium bromide Magnesium iodide or lithium, the solvents used are preferably cyclic or straight-chain ethers, for example diethyl ether or tetrahydrofuran is used and, if P is sodium, the solvent exists preferably from a mixture of liquid ammonia / diethyl ether, a mixture of ethylenediamine / tetrahydrofuran, Dioxane, pyridine or a mixture of dioxane / pyridine. When using N, N-dimethylamino-2-propyllithium, which is produced in situ in ethylenediamine, can Ethylenediamine can be used as an additional solvent. The reaction temperature, which is not critical, should preferably between -30 ° and + 50 ° C, in particular between -20 ° and + 30 ° C. The subsequent hydrolysis that is carried out in a manner known per se, can with the help of water or a highly concentrated aqueous salt solution for example a saturated aqueous sodium chloride solution.

The compounds of the formula VII can, however, also be obtained by adding compounds of the formula IX,

IX

1 0 9 8 Λ 6/1 829

- ίο - 600-6565

2,9328

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

XV

wherein R ₁ and R _{2 have the} above meaning, is reacted.

The reaction of compounds of the formula IX with compounds of the formula XV is carried out under the usual conditions of a Mannich reaction. The reaction is preferably carried out in the presence of copper ions, which are obtained, for example, by adding copper chloride, and small proportions of a weak acid, for example acetic acid. The Uaisetzungs temperature should in this case between 10 ° and 80 ° C _s and preferably between 50 ° and 70 ° C, amount "as reaction medium is preferably chosen an inert organic solvent such as a cyclic ether such as tetrahydrofuran or dioxane.

The compounds of the formula IX used as starting compounds can be based on compounds of the formula VIII known manner, for example by reaction with an organometallic compound containing an ethynyl group getting produced.

The compounds of the formulas VIII, IX, X, XI, XII, XIII, XIV and XV also used as starting compounds are known.

109846/1829

The compounds of the formula I obtained according to the invention possess extraordinarily favorable pharrcaliodynp.rr.iccliG Kir ^ r.- · Shafts and grains can therefore be used as remedies. In particular, these compounds have, as can be seen from the results of the known Clauberc test can, a progestational effect, the connections cer Formula I can therefore be used to control fertility to regulate menstruation and the menstrual cycle ν ei-ve η dot become.

The amount of compounds of the formula I to be administered daily should be between 0.1 and I > Q mg, which are preferably administered in smaller doses between 0.05 and 15 mg twice daily or in sustained-release form. These doses are independent of body weight.

For medical use, the compounds of Formula I alone or together with a suitable estrogen active compound, the latter being administered, for example, in an amount of 0.1 mg. The most effective estrogen Compound can either together with compounds of formula I or initially "alone in the first part of the menstrual cycle and together with compounds of formula I in the given later days of the cycle.

For their medicinal use, the compounds of the formula I can be pharmaceutically acceptable together with Carriers and other common additives mixed and either orally in the form of tablets, capsules, elixirs, suspensions or solutions or parenterally in the form of Ir..je; t ~ tion solutions, suspensions or emulsions are administered.

109846/1829
BATH ORIGINAL

- 12 - 600-6365

The compounds of formula I can accordingly in the above forms of administration for regulating the menstrual cycle used in mammals.

Preferred forms of administration for oral use are hard-filled capsules and tablets, respectively Contain 0.05 to 30 mg of the active ingredient.

A capsule that is manufactured in a manner known per se may contain, for example:

Components Weight parts

Compound of the formula I, for example 17β-hydroxy-17α-propadienylöstra-4,9 (10), II-trien-3-one 1

Inert solid diluent

(Starch, lactose or kaolin) 349

The invention is described in the following examples, in which the temperature is given in degrees Celsius and the room temperature is 25 ° C.

1 09846/1 82.9

- 13 - 6OO-6365

Example 1; 17β-Hydroxy ~ 17α-propadienylestra-4,9 (10), 11-trien-3-one

To a mixture consisting of 10.8 g of a Lithiumacetylidäthylendiarain complex in 60 ml of dimethyl sulfoxide is a solution of under a nitrogen atmosphere at room temperature 9.2 g> Aethylendioxyöstra-5 (10), 9 (II) -dien-17-one in 80 ml Dimethyl sulfoxide added. The reaction mixture is during Stirred for 4 1/2 hours and then poured into ice water. This creates a precipitate which is filtered off. Of the The filter residue is dissolved in methylene chloride, the methylene chloride solution is dried over sodium sulfate and finally the solvent evaporates. The residue is recrystallized from diethyl ether, the 3 ~ ethylenedioxy-17ocäthinylöstra-5 (10), 9 (II) -dien-17β-ol of m.p. 153-154 °.

b) 3-Ethylenedioxy-17a-N _i N-dimethylaminopropinylestra-5 £ 10} _i

To a solution of 2.5 g of 3-ethylenedioxy-17α-äthinylöstra-5 (10), 9 (II) -dien-17β-ol 2.5 ml of N, N-dimethylaminomethanol, 80 mg of copper chloride and 1.4 ml are added to 25 ml of dioxane Add glacial acetic acid. The reaction mixture is stirred and then for 2 1/2 hours at a temperature between 60 ° and Left at 70 °. It is then cooled and diluted with ice water containing sodium bicarbonate, whereby the amount of sodium bicarbonate is calculated in such a way that the solution remains alkaline. The organic compounds are with Extracted methylene chloride and the methylene chloride extract

109846/1829

- 14 - 600-6565

dried over sodium sulfate. Thereafter, the methylene chloride is evaporated and the residue crystallized from acetone / petroleum ether (Sdpkt 6O-9O ^0th) (1: 1) to give the> ethylenedioxy-17a-N, N-dimethylaminopropinylöstra-5 (10), 9 (11) - dien-17β-ol of m.p. 16I-163 ^{0 is} obtained.

b ¹ ) jJ-Aethylendioxy- ^ a- NjN-dimethylaminopropinylestra-

To 500 ml of ethylenediamine, which is kept under stirring and in a nitrogen atmosphere at a temperature between 50 ° and 60 °, 5 * 2 g of metallic lithium are added in portions. After the addition is complete, the blue solution obtained is heated to 95 ° for one hour, a pale yellow reaction mixture being obtained. This is cooled to 10 ° and 58 g of N, N-dimethylamino-2-propyne are added dropwise over the course of 5 minutes. Thereafter, stirring is continued for one hour at room temperature, and a solution of 11 g of 3-ethylenedioxyöstra-5 (10), 9 (II) -dien-17-one in 150 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 24 hours. After cooling (in an ice / water mixture) 1000 ml of a saturated aqueous sodium chloride solution are added and the organic phase formed 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), the 3-ethylenedioxy- 17a-N, N-dimethylaminopropinylestra-5 ( 10 ), 9 ( 11 ) -dien-17β-ol having a melting point of 16I- I65 receives ^0.

109846/1829

- 15 - 600-6565

c) 2i ^Aetil 5rlendioxy-lTa-N, N-dimethylaminopropinylestra-

To a solution of 2.6 g of 5-ethylenedioxy-17oc-N, N ~ dimethylaminopropinylestra-5 (10), 9 (II) -dlen-17β-ol 20 ml of methyl iodide are added in 70 ml of acetone. The solution will be during Maintained at 5 ° for 18 hours and then evaporated the solvent. After recrystallization of the residue from acetone one obtains the 5 ~ ethylenedioxy-17ot-N, N-dimethylaminopropinylestra-5 (10), 9 (II) -dien-17β-ol- · meth from M.p. 229-250 °.

d) 3-Aethylenediox ^ -17a-propadienylöstra-5 (10), 9 (11) -dien-17ß-ol

To a suspension of 3.2 g of I-ethylenedioxy-rfa-N ^ N-dimethylaminopropinylestra-5 (10), 9 (H) -dien-17ß-ol-methiodide 16 ml of a 0.85 molar solution are added dropwise to 100 ml of anhydrous tetrahydrofuran while cooling with ice of lithium aluminum hydride in tetrahydrofuran was added. The reaction mixture is then left at room temperature accept and stir it for 1 1/2 hours, during which complete dissolution occurs. Then, with cooling Water added in order to decompose the excess of the hydride and with further addition of water it forms Precipitation. This is filtered off and dissolved in methylene chloride. The organic solution is over sodium sulfate dried and evaporated, whereby the 3-Ae, thylendioxy-17a-propadienylöstra-5 (10), 9 (11) -dien-17ß-ol receives.

109846/1829

- 16 - 600-6365

2,719328

A solution of 500 mg of ^ -Aethylenedioxy-lTa-propadienylöstra-5 (10), 9 (11) -dien-17ß-ol in 10 ml of glacial acetic acid and 2 ml of water is stirred at room temperature for 2 hours. Thereafter the solution is poured into an ice-water mixture and the precipitate formed is filtered off. The filter residue is dissolved in diethyl ether and the solution is dried over sodium sulfate. After removing the sodium sulfate the solvent is removed by filtration. The residue is treated with hexane, an amorphous Solid forms. This is characterized by an IR absorption spectrum. where curves are obtained which are those for ketones in a ring with 6 carbon atoms, where their double bond is not conjugated to other double bonds are typical.

To a solution of 800 mg of 17ß-hydroxy-17a-propadienylöstra- 5 (10), 9 (II) -dien-3-one in 20 ml of dioxane, in a nitrogen atmosphere is stirred at room temperature, 800 mg of 2,5-dichloro-5,6-dicyano-1,4-benzoquinone are added. It arises a reddish solution in which a precipitate forms rapidly. After stirring for 2 hours, the mixture is filtered off and the The filtrate is diluted with 200 ml of water. This is then extracted with diethyl ether. The organic solution is eiper aqueous sodium dithionide solution and an aqueous potassium carbonate solution and finally washed with water. It is then dried over sodium sulfate and the diethyl ether is evaporated. This gives the 17ß "Hydroxy-17a-propadienylösträ" i-

-οη as an amorphous solid that with the help

109846/1 8 29

- 17 - 6OO-6365

an infrared, ultraviolet and NMR spectrum characterized where a ketone group is found at position 3 which is conjugated to other double bonds.

example 2: ITß-Hydroxy-lTa-propadienylb'stra- ^, 9 (10) .. ll-trlen-3-on

a) 3 Ȁethylenedioxy-17a-N, N-dimethylaminopropinylestra-4,9

^^ T ^^ K fllff ^^ 9 ^ P * ^^ r tP ^^ · * ^ * W ^ ■ ^ ' ^^ 9 ^ Q ^ Φψ Kr ■■ · ■ · ■ ^^ T ^^ ί ^ * ^ ^^ Τ ^^! ■ · f ^ V ^^ t 9 ^ ^ rW ^ MB ^^ · ^^^ "ff ^ P ^ C ^ ^ * ^^ W ^ K * Λ ^ ^ V ^^ β ^ ^ ^ W ^^? ^ H ^ β * β ^^ ^^ P Ρ'ί '^^' ^ W eW ·· ι ^ β ^^

Using the method described in Example Ib '), but replacing 3-Aethylendloxyösträ-5 (10), 9 (II) -dien-17-one by approx. equivalent proportions of 3 "- ethylenedioxyöstra-4,9 (10) _i ll-trien-17-one leads to 3-ethylenedioxy-17oc-N, N-dimethylaminopropiny Löstra-4,9 (10),

Using the procedure described in Example 1 q) ^ but with replacement of 3-Aethylendiojf.y-17a-N, N-diine · ' thylaminopropinyl 8stra-5 (10), 9 (11) "dien" 17 "" oil by approx. Equivalent of parts of 3 "-Atthylenedioxy" 17 "'- N, N'" diinethylaroi " nopropinylö§tra «4,9 (10), ll-triene» 17ß-ol leads to 3-ethylt ndio ^ r-l7a-N, N-difflethylaminopropinylöstra ^, 9 (10), 11

0) S ^ Aefchylenedioxy-lXcx

Unfetr Verwtndung dt «in Btiipiel I ü) btsehriebenen i Gideon with replacement of

109846/1829

- 18 - 600-6365

by approximately equivalent proportions of 3-ethylenedioxy ~ 17 <x-N, N-dimethylaminopropinylestra-4,9 (10), II-trien-17β-ol methiodide leads to 3-ethylenedioxy-17α-propadienylöstra-4,9 (10), II-trien-17β-ol.

Using the method described in Example 1 e), but replacing jS-Aethylendicxy-Uoc-prc padienylöstra ~ 5 (10), 9 (ll) -dien-17β-ol by approx. equivalents Shares of ^ -Aethylendioxy- ^ a-propadienylöstra 4,9 (10), ll-trien-17ß-ol leads to 17ß-hydroxy-17apropadienylöstra-4,9 (10), ll-trien - ^ - on.

Example 5; 15-ethyl-17ß-hydroxy'-17g ~ propadienylgona-

Using the in example la), b) and c) to f) described process, but with replacement of the 3-Aethylenedioxyb'stra-5 (! 0) r9 (II) -dien ~ 17 ~ one used as starting compound in section a) through approx. equivalent proportions of 1> ethyl> äthylendioxygona-5 (10), 9 (ll) -dlen ~! 7 »on one arrives at 15-ethyl-17β-hydroxy-17a-pxO-padienylgona - ^, 9 (10), ll-triene »5-one where the intermediate compounds 13-ethyl-5-ethylenedioxy-Ί7α-N, N-diroethylaminopropinylgona «5 (10), 9 (II) -dlen-17β-ol its methiodide, the 5 "ethyl-idioxy'-15-ethyl-'17a-propadienylgona" -5 (10), 9 (H) elien "317" ol and 15-ethyl * 17ß-hydroxy-17a-propadienylgona- § (10), 9 (l!) "Serve".> "© n are formed.

108848/1829

- 19 - 600-6365

2119 - 28

Example 4; 13-n-PiOpyl-17β-hydroxy-17 "-propadlenylgona-M, 9 (10), ll-trien-3-one

Using the in example la), b) and c) to f) described process, but with replacement of the 3-Aethylendioxyöstra-5 (10), 9 (II) -dien-17 ~ one used as starting compound in section a) through approx. equivalent proportions of 13-n-propyl-3-ethylenedioxygona-5 (10), 9 (II) -dien-17-one lead to 13-n-propyl-17β-hydroxy-17ct-propadienylgona-4,9 (10 ), ll-trien-3-one, with 13-n-propyl-13-ethylendloxy-17oc-N, N-dimethylaminopropinylgona-5 (10), 9 (11) -dien-17β-ol as intermediate compounds and its methiodide 3-ethylenedioxy-13-n-propyl-17ct-plΌpadienylgona-5 (10), 9 (II) -dien-17β-ol and 13-n-propyl-17β-hydroxy-17oc-propadienylgona-5 (10), 9 (H) -dien-3-one formed will.

109846/1829

Claims (2)

6OO- 6365 Claims '1. J Process for the preparation of compounds of the formula I, CH = C = CH, wherein R is methyl., ethyl or n-propyl, thereby marked that one either a) compounds of the formula II, CH = C = CH, II wherein R has the above meaning with compounds of the formula X Z. wherein Z, Z ,, Zp and Z, are the same or different and each mean chlorine, bromine or cyano, treated in an inert organic solvent or 1098A6 / 1829 6OO- 6365 2 11 9 * 128 b) compounds of the formula III, CH-C = CH, III wherein R has the above meaning and K is a ketal group means subjecting the ketal group to cleavage under aqueous acidic conditions. 109846/1829 2. Compounds of the formula I, - CH = C-CH _n Wherein R stands for methyl, ethyl or n-propyl. 3 · Therapeutic composition characterized by the content of compounds of formula I. The patent attorney! 109846/1829 BATH ORIGINAL