DE1958533A1 - Substituted steroids and methods of making them - Google Patents

Description

** # «· *. 19585 Π "

Dr wSchalk, DipWng.P.Wirth Sandoz AG. 'DipUng.G-Dannenberg

Basel ^% S £% A Case oOQ-6248

Substituted steroids and processes for their manufacture

The invention relates to compounds of the formula Ih, in which R ₁ denotes alkyl having 1-3 carbon atoms, R _? represents hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R ^ represents hydrogen, hydroxy or / lkanoyloxy with 2-4 carbon atoms and Z represents the rings A and B as well as substituents on them and is represented by the formulas Zl to Z9, in which R _{1 is} hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, R ^ - is hydrogen, 6a-methyl or 7a-methyl, R is hydrogen or methyl and Rn is hydrogen, fluorine, chlorine or methyl, with the proviso that - if the rings A and B are represented by the formula Zl, where Rg is hydrogen. and R ₀ and R_, which can be the same or different, are hydrogen or alkanoyl with 2-4 carbon atoms - R ^ then represents hydrogen.

The invention also relates, as a specific group, to

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within the compounds of the formula Ih, the compounds of the formula Ih *, in which R, is alkyl with 1-3 carbon atoms, R is hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R. is hydrogen, hydroxy, or? -lkanoyloxy with 2-4 carbon atoms and Z denotes the rings A and B as well as substituents located on them and through the formulas Zl to Z9 is shown * in which R ₅ - solid substance, alkyl with 1-3 carbon atoms, cycloalkyl ajit 5-7 carbon atoms or / Ikanoyl with 2-4 carbon atoms means »R, - for hydrogen _s 6a-l3eti ^ -1 or 7 <^ - is methyl, R_ is hydrogen or methyl and Rg is hydrogen, fluorine, chlorine or methyl * with the Massgaoe ^ that - ^ i

1) if the hinges A and B are reflected in the foreel images Z ^, Z6, Wi or ZS, where stands for hydrogen, R_Mesers «3, fr or llkaiM ^ l with 2- & Kcä.lenst <rffeisten te - l3utet;

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f I ^ö 5 85 33

2) if the rings A and B are represented by the formula Zl, where IL- and R ^ stand for hydrogen -, R _? then represents methyl,

3) if the rings A and B are represented by the formula Zl are shown, where R ^. stands for hydrogen, R and Rc »which are the same or different can mean hydrogen or alkanoyl with 2-4 carbon atoms -, R ^, then stands for hydrogen,

Finally, as a special group within the compounds of the formula Ih, the invention relates to the compounds of the formula Is in which R ₁ denotes alkyl with 1-3 carbon atoms, R ₂ denotes hydrogen or alkanoyl with 2-4 carbon atoms and Zs denotes the A rings and B and substituents thereon is and

1) is represented by the formula Z6s,

2) is represented by the formula Z4s, where

represents hydrogen or methyl,

3) is shown by the formula Z7s, where R ^f for hydrogen or alkanoyl with 2-4

PS

Carbon atoms,

4) is represented by the formula Z8s, or

ORIGINAL INSPECTED 009824 / 20U

5) is represented by the formula Zl's, where FL is hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms.

Certain ring structures A and B of compounds of the formulas Ih 'and Is, which are represented by the formulas Z and Zs, can be attacked by the reaction conditions under which either the starting materials used in the last stage are prepared or in the last stage himself works. It is therefore a preferred feature of the invention to protect those Z or Zs structures, which could be attacked by the above-mentioned reaction conditions, by customary protective groups which are stable under the respective reaction conditions. Correspondingly protected groups can easily be converted into the desired Z or Zs structures in a known manner. In the described in the following reactions, the Z and Z-structures can be möglieh present in unprotected or protected preferably Forra j unless otherwise stated usher in cases where ^ appropriately protected Porten.

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The inventive method for the preparation of compounds of the formula Ih 'is characterized in that one

a) for the preparation of compounds of the formula Ip, wherein R,, Rl, Z and the other measures of the Definition according to formula Ih 'and Rp represents hydrogen or methyl, compounds of the formula V in which R, R, R ^ ,, Z and the other provisions correspond to the definition according to formula Ip, R 'and R-JA * which can be the same or different, stand for alkyl with 1-3 carbon atoms or together form a pyrrolidino or piperidino ring with the nitrogen atom, R. for alkyl with 1-3 Carbon atoms and Y is a nucleofugic leaving group with a complex metal hydride Reacts in an inert solvent, or

b) for the preparation of compounds of the formula Ir, in which R ,, Z and the other provisions correspond to the definition according to formula Ih ', and the condition also applies that R, - does not represent hydrogen, R' and Β.ί the same Have the same meaning as R and Rk, but with at least one of the substituents in the positions J, 16a and 17ß, ie the substituents

" ⁰ ^, Rj. And -OR ', stands for / * lkanoyloxy with 2-4 carbon atoms, compounds of the formula Ig, in which R ₁ , Z and the other provisions according to the definition

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^ 958533

Formula Ih 'and R''and R ^ ^{1 have} the same meaning as R _? and R ^ ,, but at least one of the substituents in position 3, 16a and 17β is hydroxy, acylated with an acylating agent having 2-4 carbon atoms, or

c) for the preparation of compounds of the formula Iq, in which R ,, R ^, Z and the further provisions of the definition according to formula Ih 'correspond to compounds of the formula In, in which R, R ^ ,, Z and the further provisions correspond to the definition according to formula Ih ', reacts with a methylating agent,

and protected Z-structures into unprotected Z-structures transferred *

The invention further oetrifft process for the preparation of compounds of formula Is, characterized in that

as) for the preparation of compounds of the formula Ips * in which R, Zs and the other provisions correspond to the definition according to the formula Is. Compounds of the formula Vs, in which Η,. » In addition, the other criteria correspond to the definition according to the formula Is ^ Rl and H ^ 1 * which may be identical or different, stand for alkyl with 1-J carbon atoms or together with the nitrogen atom form a pyrrolidino or piperidino ring, R, _Q

INSPECTED

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Denotes alkyl with 1-3 carbon atoms and Y means a nucleofugic leaving group with a complex metal hydride in an inert one Reacts solvent, or

bs) for the preparation of compounds of the formula Isr, in which R and Zs correspond to the definition according to formula Is, and the condition also applies that R does not represent hydrogen, R 'has the same meaning as R_, but with at least one of the substituents R _c and R 'denote alkanoyl with 2-4 carbon atoms, compounds of the formula Isg, in which R and Zs correspond to the definition according to formula Is, and R' ^{1 has} the same meaning

cS

has like R, but at least one of the substituents R ″ and R stands for hydrogen,

eiS z>

acylated with an acylating agent with 2-4 carbon atoms,

and protected Zs structures in unprotected Zs structures convicted.

In process a) the complex metal hydride can be, for example, lithium aluminum hydride. The implementation can be carried out at temperatures between about -80 ° and + 80 ° C., an example of an inert solvent being Use diethyl ether or tetrahydrofuran

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can. Neither temperature nor solvent are critical. The nucleofuge group Y ~ can, for example, be a chlorine, bromine, iodine, methanesulphonate or p-toluenesulphonate ion. In process a) the substituents RI ₀ * R 'and R''are preferably each the same and preferably each represent methyl,

The acylation process b) can be used in the acylation be carried out by steroid alcohols in a known manner. A method is preferred in which only the OH group in position 17 is acylated.

In the compounds of the formula Ih ¹ or Is, which have a large number of OH groups, one OH group in position 3 is secondary or phenolic, one OH group in position 16a is secondary and one OH group in position 170 is tertiary. When / eylierung known lent react W initially ^ phenolic secondary "and sehliessllch the tertiary hydroxy groups, while a saponification first to the phenolic, then can the secondary and schliesslicii occurs at the tertiary hydroxy groups. Accordingly, depending on the to be acylated hydroxy groups strength and degree For the acylation in the J and / or ΐόα position, acids, acid halides or acid anhydrides of the formulas i-COOH, ACO-Hal and (ACO) O, in which A is alkyl

INSPECTED

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with 1-3 carbon atoms and Hal stands for bromine or chlorine, and use mixtures thereof. If a cetyl group is desired, acylation is preferably carried out with acetic anhydride. The acylation can be carried out in the presence of an inert solvent or in an excess of acylating agent. Preferably, it is carried out in the presence of an acid-binding agent, for example pyridine, operating at temperatures between -10 ° and 50 ⁰ C. For / cylation of all three positions one can work under more severe conditions, ie in the presence of a strongly acidic catalyst such as p-toluenesulfonic acid or perchloric acid. When using such catalysts, enol acylates, preferably esters of “isopropenyl alcohol”, ie isopropenyl acetate, can be used in addition to the abovementioned acylating agents; the person skilled in the art is familiar with other illegal measures. How the desired combination of free OH groups and acylated positions can be achieved therefore does not need to be discussed in more detail.

The methylating agent used for process c) for example a methyl halide, preferably methyl iodide. This is preferably in an excess, for example between about 1 and 50 ^ equivalent halide per / equivalent of the Union of the formula In, are used. The compound which contains the anion of the formula In can be obtained by using compounds of the formula Ih,

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where R _{p is} hydrogen, treated with a strong base, for example sodium or potassium amide, in liquid ammonia or with methyl lithium in diethyl ether. The reaction with a strong base may be at temperatures between about -j50 ° and +30 ⁰ C, using from 1 to 1.2 equivalent of strong base per equivalent of compounds of formula Ih are performed.

Processes as) and bs) can be carried out under the conditions described for processes a) and b).

The compounds of the formulas Ih and Is can be isolated in a known manner.

Compounds of the formula V can be prepared by reacting compounds of the formula III, in which R., R_, Rh » ^ lO ^iR io ' ^{Z and} ^ ^ie other provisions correspond to the definition according to formula V, with compounds of the formula VI, in which R, - Has the above meaning and Y 'has the meaning of Y, in an inert solvent, for example acetone, at temperatures between -20 ° and +30 ⁰ C.' Neither temperature nor solvent are critical. Compounds of the formula IHa, special form of compounds of the formula III, in which R ^, R ^, R ^ _Q , -R ^ ₀ * Z "and the other provisions correspond to the definition according to formula III, can be obtained by adding compounds of the formula II, where R, R ^, Z and the other provisions correspond to the definition according to formula III,

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with compounds of the formula IV in which X is lithium, sodium, potassium, -MgBr, -MgJ, - or ψ- and R 'as well as R ¹ * have the above meaning, reacts and hydrolyzes the reaction product.

The reaction can in an inert solvent, at temperatures between -30 ° and + 100 ⁰ C, preferably -20 ° C and +50 ^0, are performed. The hydrolysis can be carried out in a known manner in a neutral or basic aqueous medium, for example water or a saturated ammonium chloride solution. The solvent used for the reaction depends on the respective metal content of the compounds of the formula IV. * If X is -MgBr, -MgJ or lithium, diethyl ether or tetrahydrofuran can be used. If X is sodium, the solvent used can be liquid / ammonia diethyl ether, liquid ammonia tetrahydrofuran, dioxane, pyridine or dioxane-pyridine. Neither temperature nor solvent are critical.

The compounds of the formula IHa can also be obtained by adding compounds of the formula VIII in which R, R ^ ,, Z and the other cash additions correspond to the definition according to formula Ih ', with compounds of formula IX, in which R 'and R' 'have the above meaning under Mannich reaction conditions implements.

The reaction is preferably carried out in the presence of Cu ⁺ ions

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and small amounts of a weak acid, for example acetic acid, at temperatures between 10 ° and 80 ° C, preferably 50 ° and 70 ⁰ C, in an inert solvent, for example dioxane or tetrahydrofuran, performed.

* Compounds of the formula Vs can be prepared analogously, like the compounds of the formula V *

Compounds of the formula Vs are obtained by reacting compounds of the formula IIIs, in which R, R'_, R **, Zs and the other provisions correspond to the definition according to formula Vs, with compounds of the formula VI, in which R ₁ and Y ¹ Have the above meaning in an inert solvent, e.g. acetone, at temperatures between -20 ° and + 3O ⁰ C. neither temperature nor solvent are critical,

. For compounds of the formula III one can use analogous Way get how to compounds of formula TIIa.

Certain compounds of the formulas II (including the compounds analogous to those compounds of the formula II which are used for the preparation of compounds of the Formula Ills can be used), III, IHa, VIII and IX are known and can be prepared by processes described in the literature. Those connections of the formula II (including the compounds analogous to those compounds of the formula II which are used to produce

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ORIGINAL INSPECTED

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position of compounds of the formula Ills used are), III, IHa, VIII and IX, which are not specifically described in the literature, can be followed produce analogous processes. Some of those used for making compounds of formulas Ih and Is The starting materials are other compounds of the formulas Ih and Is.

The compounds of the formulas IV and VI are known and can be prepared by processes described in the literature will.

Method for protecting such Z and Zs structures that must be protected, i.e. those structures that contain carbonyl and hydroxyl groups are in the, Known literature. See, for example, "The Protection of Carbonyl and Hydroxyl Groups" by John F.W. Keana in "Steroid Reactions, An Outline for Organic Chemists", Carl Djerassi, Holden-Day Inc., San Francisco (1963), Chapter 1.

The compounds of the formula Ih are valuable pharmaceuticals. They are particularly suitable as fertility inhibitors. The compounds of the formula Ih 'and Is, in which Z stands for the structures Zl to Zj5 and Zs stands for Zl's, have an estrogenic effect. The compounds of the formula Ih ¹ and Is, in which Z represents the structures Z4 to Z9,

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or Zs stands for the structures Z4s to Z8s progestatlonal.

The dose to be administered daily is between about 0.01 and 10 mg. Suitable doses for internal administration are between about 0.005 and Io mg, mixed with a solid or liquid carrier or diluent,

A preferred compound is 17α-propadienylöstra-4-en-3β, 17β-diol.

A pharmaceutical preparation - e.g. * a capsule with the compounds according to the invention as active ingredient can be formulated as follows: 2.5 parts by weight lTa-Propadienylöstra- ^ - en- ^ lTß-diol, 2 parts by weight Tragacanth, 8? Parts by weight lactose, 5 parts by weight corn starch, 3 parts by weight talc, 0.5 parts by weight magnesium stearate "

The NMR spectra given in the following examples were measured at 60 megahertz in CDCl -, - solution, using tetramethylsilane as the standard.

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CH = C = CH You

Zl

R ₁ -O

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7 ι Η

Z6

Z7

Z8

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600-6248

- - -CH = C = CH ,. I --- R.,

Ih ¹

OR

2s

--CH = C = CH,

Zs

Is

Z6s

Z4s

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R ' _a 0 H

Z7s

Z8s

Zl's

OR

2p -CH = C = CH ₂ IP

OO 9 824/2 OU

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CH = C = CH,

Ir

CH = C = CH,

'-Nile

^R 4 Ig

CH = C = CH, Iq

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R Γ ¹ X

J ^ -CH-C-CH ₂

OH

CH = C = CH,

B H

Zs

In

Ips

<CH = C = CH,

Isr

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CH = C = CH,

AWAY

Zs

Isg

II

III

ORiGiNAL INSPECTED

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R '
¹⁰

R ¹ '

¹⁰

IHa

y ^{R [o}

^R io Ills

R ^1
10

¹ · 10 IV

^K 10 ^rt 10

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-ν / ^1ο

ρ 'ρ' ι

^R 10 ^R 10

Vs

VI

VIII

HO-CH ₂ -I

^R io

Ίο

IX

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Example 1 ; 17a-propadienyl-3-methoxyöstra- 1,3, 5 (10) -trien-17-ol

trien-17ß ₌ ol_

A mixture of 15.8 g of rTa-ethynyl-jJ-methoxyestral, 3.5 (10) -trien-17β-ol, 15.0 ml of dimethylaminomethanol, 500 mg of copper (I) chloride, 8.5 ml of glacial acetic acid and 125 ml Dioxane is ^{kept at 70 °} C. for 5 hours. Ice water is then added, the pH is adjusted to 10 and the title compound is extracted with ether. A foam remains with [α] - "8.84 (c = 1, CHCl,).

(3- ■ -1- "

b)

trien-17P-ol-methiodide

A mixture of 10.0 g of the above process product, 290 ml of acetone and 87 ml of methyl iodide is kept ^{at 0 ° C. for 24 hours.} The desired product precipitates in crystalline form and is isolated by filtration, mp: 237-239 ° C.

°) 17a- ropadienyl-3; methoxyestra-1,3,5j [102-trien-17β-ol

A suspension of j5, OO6 g of the compound obtained above) driving product in 65 ml of anhydrous tetrahydrofuran is at -75 ° G with 11.25 ml of a 0.525 molar lithium

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aluminum hydride tetrahydrofuran solution added. After stirring for 2 hours at -10 ⁰ C a clear solution which is kept overnight at room temperature is obtained. It is cooled to 0 ^° C., saturated aqueous ammonium chloride solution is added and the title compound is extracted with ether. This gives a quantitative yield, calculated over all of the above process steps, of crystalline material with a melting point of 129.5-130.5 ° C .; [aJ _D = + 7.18 ° (c = 1, CHCl3).

Example 2 : Among those described in Example 1

Conditions and use of the following ■ raw materials :

a) 17a- ^ ethynyl-5-methoxyestra-1,315 (10), 7-tetraen-17β-ol

b) 17a-ethynyl-3-methoxyestra-l, ^, 5 (10), 6,8-pentaen-17β-ol

c) 17α-ethynylestra-4-en-17β-ol

d) 3-Cyclopentyloxy-17a-äthinylöstra-1,3,5 (10) -trien-17ß-ol

e) 3-ethoxy-17a-äthinyl-13-äthylgona-1,3,5 (10) -trien-17ß-ol

f) 17a-ethynyl-3-methoxy-7a-methylestra-1,3,5 (10) -trien-17β-ol

g) 17a-ethynyl-16a-hydroxy-3-methoxyestra-1,3,5 (10) -trien-17β-ol

h) 17α-ethynylestra-4-en-3317β-diol

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one arrives at :

a) 17α-Propadienyl-3-methoxyestra-1,3,5 (10), 7-tetraen-17β-ol

b) 17a-Propadienyl-j5-methoxyestra-1,3,5 (10), 6,8-pentaen-17β-ol

c) 17α-Propadienylöstra-4-en-17β-ol

d) 3-Cyclopentyloxy-17 <x ~ propadienylestra-1,3j5 (10) -trlen-17β-ol

e) 3-ethoxy-17a-propadieny1-13-äthylgona-1,3 * 5 (10) trien-17ß-ol

f) 17a-Propadienyl-3-methoxy-7a-methylestra-1,3,5 (10) -trien-17β-ol

g) 17a-Propadienyl-16a-hydroxy-3-methoxyöstra-1,3> 5 (10) trien-17ß-ol

h) 17a-Propadienylöstra-4-en- ^ 17ß-dioJ, m.p. 72-79 ° C.

Example 3 : 17a-Propadienyl-3-methoxyestra-2,5 (10) - - dien-17β-ol

a) 17a ^ Dimethylaminqpropiny]) - 3-methoxyestra-2 _i 5 _i (102-dien-17ß-ol

One made from 1.50 g of magnesium, 4.68 g of ethyl bromide and 70 ml Tetrahydrofuran prepared Grignard mixture is added dropwise with 5 * 3 g of dimethylaminopropin, dissolved in

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10 ml of tetrahydrofuran are added. After cessation of yethan development is added a solution of 1.716 g j5-Methoxyöstra-2,5 (10) -diene-17-one in 30 ml tetrahydrofuran was added dropwise, the temperature being maintained during the addition to 0-5 ⁰ C to react, and you then 4 hours at 20-25 ⁰ C. After adding 100 ml of 2N sodium hydroxide solution, the mixture ^{is concentrated in vacuo at temperatures not exceeding 30 °} C. to a total volume of 100 ml. The concentrate is extracted with ether (5 x 25 ml), centrifuging to facilitate phase separation. The title compound is obtained by evaporating the dried ether solutions and suctioning off an excess of dimethylaminopropine that is present.

(? - -1-b) 17a ^ imethylaninapropinyl) -3-methoxyöstra-2,5 (10) -

2.0 g of the process product obtained above are dissolved in 30 ml of acetone. After adding 3.5 g of methyl iodide, the mixture is kept at 8 ° C. for 18 hours. The title compound crystallizes out and is filtered off and washed with anhydrous ether.

To a suspension of 2.5 g of the compound obtained above

0 0 9 8 2 kl 2 0 U RAn

BATH

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Fahrensproduktes in 50 ml of tetrahydrofuran are added at -75 ° C 9.3 ml of a 0.525 molar lithium aluminum hydride-tetrahydrofuran solution. The mixture is brought to -10 ⁰ C and up to obtain a clear solution (about 90 min.) Was stirred, and then kept for 12 hours at room temperature. There are 100 ml aqueous 2N sodium hydroxide Ψ solution containing 50 ml of di-tert-butyl cresol contains added, whereupon the mixture is concentrated in vacuo to a total volume of 100 ml. After extraction with 5 × 20 ml of ether, phase separation using a centrifuge, drying of the ethereal solutions over potassium carbonate and evaporation, 17α-propadienyl-3-methoxyestra-2,5 (10) -dien-17β-ol is obtained.

Example 4; 1 7a-Propadienylöstra-5 (10) -en-17β-ol-3-one

2.0 g of 17a-propadlenyl-3-methoxyestra-2,5 (10) -dien-17ß-ol, obtained wet Example 3, are dissolved in a mixture of 20 ml of glacial acetic acid and .2 ml of water. After 2 hours adds 200 ml of water are added and the product is extracted with ethyl acetate (5 × 10 ml). After evaporation of the ethyl acetate extracts one arrives at 17a- ropadienylostra-5 (10) -en-17β-ol-3-one as a crystalline pesticide with a melting point of 116-122 ° C.

Example 5 : 17α-Propadienylüstra-4-en-17β-ol-3-one

5.5 g of 17a-propadienyl-3-methoxyestra-2,5 (10) -dien-17ß-ol,

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obtained according to Example 3 * In a mixture of \ 50 ml of methanol and 1.5 ml of HN aqueous hydrochloric acid dissolved and held for 30 minutes at 3O ⁰ C. After dilution with 100 ml of water, the product is extracted with methylene chloride (5 × 15 ml.). After evaporation of the dried methylene chloride solution and subsequent recrystallisation of the residue from cyclohexane gives pure 17a-Propadienylöstra-4-en-17.beta.-ol-3-one, mp. 130-133 ⁰ C.

Example 6 : Following the procedure of Example 3

and 5 are obtained using the following / starting products:

a) Oestrone-3-tetrahydropyranyl ether

b) 3-methoxy-7a-methylöstra-2 _J 5 (10) -dien-17-one

c) 3-ethylenedioxy-6a-methylandrosta-5-en-17-one

d) 3-Aethylenedioxyöstra-5 (10), 9 (II) -dien-17-one

e) 3-ethylenedioxy-6-fluorandrosta-4,6-dien-17-one

f) 3-ethylenedioxy-6-chlorandrosta-4,6-dien-17-one

g) 3-Ethylenedioxy-6-methylandrosta-4,6-dien-17-one h) 3-methoxy-13-ethylgona-2i 5 ( ¹ O) -Cli ^e n-17-one

i) 13-n-Propyl-3-tetrahydropyranyloxygona-2 _i 5 (10) -dien-17-one

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* the following connections;

a) 17α-Propadienylöstra-1,3,5 (10) -triene-3 »17β-diol

_b ) 17α-Propadienylöstra-4-en-17β-ol-3-one

c) 6a-methyl-17a-propadienylandrost0 - ^ - en-17ß-ol-3-one

d) 17a-Propadienylöstra-4,9 (10) -dien-17ß-ol-3-one,

as a non-crystalline product with an U.V. spectrum in ethanol of / \ = 302.5 m / uJ £ = 14.100J one NMR spectrum with singlets at 5.7 ppm and -1.8 ppm and an IR spectrum of 3590 cm "and 1950 cm

e) 6-fluoro-17α-propadienylandrosta-4,6-dien-17β-ol-3-one

f) 6-chloro-17a-propadienylandrosta-4,6-dien-17ß-ol-3-one

g) 6-methyl-17α-propadienylandrosta-4,6-dien-17β-ol-3-one h) 13-Ethyl-17a-propadienylgona-4-en-17ß-ol-3-one '

i) 17ot-Propadienyl-13-n-propylgona-4-en-17β-ol-3-one

Example 7 : The procedure of example or example 4 is obtained using the following starting materials;

a) 3-Methoxy-7a-methylestra-2,5 (10) -dien-17-one

b) 3-methoxy-13-ethylgona-2,5 (10) -dien-17-one

following connections;

a) 7a-methyl-17a-propadienylöstra-5 (10) -en-17ß-ol-3-one

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b) l ^ -Aethyl- ^ a-propadienylgona -5 (10) -en-17ß-ol-3-one

Example 8 ; 17β-fleet oxy-jS-methoxy-17α-propadieny sol tral, 3,5 (10) -triene

A solution of 297 mg 8 ^ a-propadienyl - ^ - methoxyöstra-l, 3,5 (10) -trien-17-ol (Example Ic) and 12 mg of p-toluenesulfonic acid in 6 ml of isopropenyl acetate is held l8 hours at room temperature . Aether is added, the solution is evaporated to dryness after washing with ice-cold sodium bicarbonate solution and drying over magnesium sulfate and, after recrystallization from methanol, 17β-acatoxy-3-methoxy-17a-propadienylöstra-l, j3> 5 (10) -triene from M.p. 89-90 ⁰ C Ca] = + 9.27 ° (c = Γ, CHCl),

Example 9 s According to the procedure given in Example 8, using the following starting products:

a) 17a-propadienylöstra-1,3,5 (10) -triene-; j, 17ß-diol 17o * -propadi pnyl - /

b) / 13-n-propylgona-4-en-3β, 17β-diol

following connections:

a) 3,17β-Diacetoxy-17a-propadienylöstra-1,515 (10) -triene

b) ^ ßi ^ ß-Diacetoxy- ^ a-propadienyl-lJ-n-propylgona-4-en

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Example 10 : 3,17ß-Dimethoxy-17a-propadienylbstral, 3,5 (10) -triene

Procedure A

a) 3> 17ß-Dimethoxy-17a-dimethylaminopropinylestraiz2i5 (Lö) _I triene _: methiodide

( _? - -1-A mixture of 37 ^, 4 mg 17 ^ / dimethylamine </ propynyl) -5-methoxycstra-1,315 (10) -trien-17ß-ol and 10 ml dry ether is at 10 ⁰ C with 0.89 ml of a 1.2 molar ethereal ethereal lithium solution was added. The batch is kept at room temperature for 10 minutes and then 5.2 ml of methyl iodide are added, whereupon a crystalline precipitate is formed. The title compound with a melting point of 180-183 ° C. is obtained by filtration.

b) 3,17β-Dimethoxy-17a-'propadienylöstra-1,3,5 ^ 102-triene

The process product obtained above is according to the example Ic reduced. After purifying the mixture obtained over Silica gel (elution with trichlorocarbon-benzene 1: 1) gives the>, 17ß-dimethoxy-17a-propadienylestr-1,315- (10) -triene.

Procedure B

To a solution of lithium amide in liquid ammonia,

G0982 W2G1 4

- 33 - 600-6248

made from 73.5 mg lithium and 26 ml NH ,, becomes a Solution of 3.24 g of 17a-propadienyl-3-methoxyestra-1,3,5 (10) -trien-17β-ol (Example 1) added in 50 ml of diethyl ether. The mixture is kept at reflux temperature for two hours and is added then 2.5 g .Methyl iodide, whereupon the ammonia is allowed to evaporate. After adding 50 ml of water and separating off the ether phase and washing with ether, subsequent evaporation of the dried ether solutions the 3,17ß-dimethoxy-17a-propadienylöstra-1,315- (10) -triene is obtained.

Example 11 ; According to the procedure of Examples ^ a, IQa, b (method / Q or 5 is obtained using the following starting materials;

a) 3-Methoxyestra-2,5 (10) -dien ^ l7-one

b) 3-methoxy-13-ethylgona-2,5 (10) -dien-17-one

c) 3-methoxy-7a-methylestra-2,5 (10) -dien-17-one

following connections ;

a) 17ß-Methoxy-17a-propadienylöstra-4-en-3-one

b) 13- / ¹ ethyl-17β-methoxy-17a-propadienyl gona -4-en-3-one

c) 17β-Methoxy-7a-methyl-17a-propadienylöstra-4-en-3-one

00982A / 20U

600-6248

Example 12 ; 3fl.178-dlacetoxy-17a-propadienylöstra-4-en

According to Example 8, the compound mentioned in the title is obtained using 17a- propadienylöstra-4-en- 3§17ß-diol . NMR spectrum:

13-CH- = S 0.94 ppm

rrß-OCOCH, = (J * 1.97 ppm

3-OCOCH ₃ = 6 2.04 ppm

Example 13 ; 3ß-rAcetoxy-17a-propadienylestra-4-en-17ß-ol

0.8 g of 17a-Propadienylöstra-4-en-3? 17ß-diol (Example 2h,) are added to a solution of 4.4 ml of acetic anhydride in 13.0 ml of pyridine, the resulting mixture is 17 hours at room temperature (20 ⁰ C), then poured into 100 ml of water and extracted 5 times with 10 ml of methylene chloride each time. The combined methylene chloride extracts are dried over anhydrous sodium sulfate, the solvent is evaporated in vacuo, and after recrystallization of the residue from 95 # igem. Ethanol obtained the title compound with a melting point of 107-1O8.5 ° C

009824 / 20U

Claims (1)

- 35 - 600-6248 Claims; Process for the preparation of compounds of the formula Ih ', in which R ₁ denotes alkyl with 1-3 carbon atoms, R ₃ denotes hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R ^, hydrogen, hydroxy or alkanoyloxy with 2-4 Represents carbon atoms and Z denotes the rings A and B as well as substituents located thereon and is represented by the formulas Zl to Z9, in which R _n . Is hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, R ^ is hydrogen, * 6a-methyl or 7 <* - methyl, R_ is hydrogen or methyl and Rg is hydrogen, Is fluorine, chlorine or methyl, with the proviso that - 1) if the rings A and B are represented by the formulas Z4, Z6, Z7 or Z8, where Rg stands for hydrogen, R ₁ . Is hydrogen or alkanoyl with 2-4 carbon atoms and R ^. Represents hydrogen -, R ₀ then represents methyl, 009824/201 A - 36- 600-6248 2) if the rings A and B are represented by the formula Zl, where R ^ and R ^ for hydrogen stand -, R then represents methyl, 3) if the rings A and B are represented by the formula Zl, where R ^ - for hydrogen fc, Rp and Rj-, which are the same or different can be hydrogen or alkanoyl with 2-4 Carbon atoms mean -, Rj. Then for hydrogen stands, characterized in that one a) for the preparation of compounds of the formula Ip in which R ₁ , R ^, Z and the other provisions correspond to the definition according to formula Ih 'and R_ is hydrogen or methyl, compounds of the formula V in which R, R, R ^, Z and the other provisions correspond to the definition according to formula Ip, R ¹ and R ″, which can be the same or different, stand for alkyl with 1-3 carbon atoms or together form a pyrrolidino or piperidino ring with the nitrogen atom, R for Alkyl with 1-3 carbon atoms and Y * "denotes a nucleofugal leaving group, reacts with a complex metal hydride in an inert solvent, or 009824/20 1 A -37- 600-6248 b) for the preparation of compounds of the formula Ir, in which R, Z and the other provisions correspond to the definition according to formula Ih ', and the condition also applies that R does not stand for hydrogen, R' and R ₂ ! have the same meaning as R and R ^, but at least one of the substituents in the positions J5, 16a and 17ß * ie the substituents -OR, -, R ₂ ! and -OR ', for alkanoyloxy with 2-4 carbon atoms, compounds of the formula Ig, in which R, Z and the other provisions correspond to the definition according to formula Ih' and R ' ¹ and R ₂ !' have the same meaning as R _p and R ₂ ,, but at least one of the substituents in position 3, 16a and 17ß is hydroxy, acylated with an acylating agent having 2-4 carbon atoms, or c) for the preparation of compounds of the formula Iq, in which R, R ₂ , Z and the further provisions of the definition according to the formula. Ih 'correspond to compounds of the formula In, in which R ,, R ₂ ,, Z and the other provisions ^{correspond to the definition according to formula Ih 1,} are reacted with a methylating agent, and protected Z-structures converted into unprotected Z-structures. 009824 / 20U - 38 - 600-6248 2. Process for the preparation of compounds of the formula Is, in which R is alkyl having 1-3 carbon atoms, R for hydrogen or alkanoyl with 2-4 carbon Atomen stands and Zs stands for the rings A and B as well as substituents on them and 1) is represented by the formula Z6s, 2) is represented by the formula Z4s, where R, ^ stands for hydrogen or methyl, 3) is represented by the formula Z7s, where R 'for hydrogen or alkanoyl with 2-4 carbon 5s Material atoms, 4) is represented by the formula Z8s, or 5) is represented by the formula Zl ¹ S, where Rj. Denotes hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, characterized in that one as) for the preparation of compounds of the formula Ips, where R, Zs and the other provisions correspond to the definition according to formula Is, compounds of the formula Vs, in which R, Zs and the other provisions correspond to the definition according to formula Is, R'_ and R '', which are the same or different Q09824 / 20U - 39 - 600-6248 can be, stand for / alkyl with 1-5 carbon atoms or form a pyrrolidino or piperidino ring together with the nitrogen atom, R ₁₀ denotes alkyl with 1-3 carbon atoms and Y denotes a nucleofuge leaving group, with a complex metal hydride in an inert solvent implements, or bs) for the preparation of compounds of the formula Isr, where R. and Zs correspond to the definition according to formula Is, and the condition also applies that R_ does not stand for hydrogen, R 'the same 5 dS Has the same meaning as Rp, but at least one of the .substituents R and R 'denotes alkanoyl with 2-4 carbon atoms, compounds of the formula Isg, in which R and Zs correspond to the definition according to formula Is, R ″ has the same meaning as R, but where at least one of the substituents Ri ¹ and R _{K is} hydrogen, acylated with an acylating agent having 2-4 carbon atoms, and protected Zs structures converted into unprotected Zs structures. 009824 / 2QU - 40 - 600-6248 3 · Process for the preparation of compounds of the formula V, in which R ₁ , R ₂ , R ₁ ^, Z, RJ _Q , R | _Q , R ₁₀ and Y ~ have the meaning given in claim 1, characterized in that compounds of the formula III in which R., R-, Rj., R ₁₀ , Z and the other provisions of claim 1 with respect to formula V definition given correspond, with compounds of formula VI wherein R .. has the above meaning and Y ¹ * is as defined in claim 1 for Y, are reacted in an inert solvent medium. k, a process for the preparation of compounds of the _# formula Vs, according to the definition of claim 2, characterized in that compounds of the formula IIIs, wherein R ₁ , R | _Q , Rj ', Zs and the other provisions correspond to the definition given in claim 1 with regard to formula Vs, with compounds of the formula VI in which R. _Q and Y * correspond to the definition according to claim 3, are converted into an inert solvent. 009824 / 20U - 41 - 600 - 6248 % 5. Compounds of the formula Ih in which R. is alkyl with 1-3 carbon atoms, R "is hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R _{2 is} hydrogen, hydroxy or alkanoyloxy with 2-4 carbon atoms and Z is the Rings A and B as well as substituents located thereon and is represented by the formulas Zl to Z9, in which R ₁ . Denotes hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, Rg is hydrogen, 6a-methyl or 7a-methyl, R _{7 is} hydrogen or methyl and Rg is hydrogen, fluorine, chlorine or methyl, with the proviso that - if the rings A and B are represented by the formula Zl, where R ^ stands for hydrogen, as well as R ₀ and R-, which can be the same or different, hydrogen or alkanoyl with 2- 4 carbon atoms mean -, Rj. Then represents hydrogen. 6 «compounds of the formula IhS as defined in i according to claim 1. 7 · Compounds of the formula Is, see definition according to claim 2. 1 H; 8. Medicinal product containing a compound according to claim 5 to 7. ' The patent attorney 009824/2014