DE1966922A1 - NEW SUBSTITUTED STEROIDS - Google Patents

Description

concerning
-Le steroids

The invention relates to new steroid compounds which have a propadienyl radical in a 17% position. US Pat. No. 3,962,165 already shows formulas of such 17-f-propadienylüubstituierten steroid compounds with a hydroxyl group or alkoxy or alkanoyl group in the 3-position, while US Pat. No. 3,962,166 shows the corresponding 3 keto compounds of these 17 ^ -propadienyl-substituted steroids are given in terms of formulas as process products of the manufacturing processes described there. It has been shown, however, that the compounds cannot be prepared by the processes disclosed in this patent specification, which is why these X- propadienyl-substituted steroid compounds must be viewed as new within the meaning of the Patent Act.

The invention now relates to such 17 ^ £ -propadienyl-substituted steroid compounds as shown in the attached formulas in formula Ih and in which R ^ denotes alkyl with 1-3 carbon atoms, R ₂ denotes hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R, hydrogen, ilydrux / or alkanoyloxy with 2-4 carbon atoms and '.'- the rings A and B as well as flubstituenten thereon

b υ U ti W /! O 9 7

ORIGINAL

denotes and is represented by the formulas Zi-Z8, and in which R, denotes hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, Rg denotes hydrogen, 6co-methyl = or 7 <* - is methyl, R _{7 is} hydrogen or methyl and R _{Q is} hydrogen, fluorine, chlorine or methyl, with the proviso that, if the rings A and B are represented by the formula Z1, where Rg stands for hydrogen, as well as Rp and Rj-, which can be the same or different, denote hydrogen or alkanoyl with 2-4 carbon atoms, R then represents hydrogen. -. ■■■ -. "

The invention also relates to, as a special group within the compounds of the formula Ih / the compounds of the formula Ih ', in which R ^ is alkyl with 1-3 carbon atoms, R _{2 is} hydrogen, methyl or alkanoyl with 2-4 carbon atoms, R ^ Represents hydrogen, hydroxy or alkanoyloxy with 2-4 carbon atoms and Z denotes the rings A and B as well as substituents located thereon and is represented by the formulas Z1 to Z9, in which R ₁ - hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms, Rg is hydrogen, 6oc- methyl or T ^ t-methyl, R _{7 is} hydrogen or methyl and Rg is hydrogen, 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 are shown, where Rg stands for _{hydrogen = = substance, R 1} - is hydrogen or alkanoyl with 2-4 carbon atoms and Ri is hydrogen -, Rp then stands for methyl,. - -

-3 -

B 0 9 84 7/1097 bad original

196692t

2) if the. Rings A and B through the formula Zl are shown, where Rg 'and. R ^ for. hydrogen stand-, R then methyl: represents, Γ .V ".

3) if the rings A and B are represented by the ^ formula picture. Zl. are shown, where R .. stands for hydrogen * Rp and R ₁ -, which can be identical or different, 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 ₀ denotes hydrogen or alkanoyl with 2-4 carbon atoms and Zs denotes the A rings and B and substituents thereon and C

1) is represented by the formula Z6s,.;

2) is represented by the formula Z4swege "ben, where

stands for hydrogen or methyl, -: \

3) is represented by the formula Zfs, where R ^{1 is} hydrogen or alkanoyl with 2-4; -; Carbon atoms,;. ._ ■ _-_-- ^: y - _: ~:

4) is represented by the form image Z8s ,, or

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5) is represented by the Pormelbild Zl's, where R ₁ - is hydrogen, alkyl with 1-5 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 represented by the reaction conditions. Conditions are attacked under which either the " starting products used in the last stage are prepared, or the last stage itself works. It is therefore a preferred feature of the invention, those Z or Zs structures, which by the above-mentioned reaction conditions could be attacked by customary protective groups which are stable under the respective reaction conditions. Correspondingly protected groups can easily be converted in a known manner into the desired Z or Zs structures - And Zs structures are therefore in the cases in which appropriately protected forms are possible, in unprotected or preferably protected form, unless otherwise stated.

' BATH

509817/1097

mm *

The inventive method for the preparation of compounds of the formula Ih ¹ is characterized in that one

a). for the preparation of compounds of the formula Ip,

in which R, Rk, Z and the other stipulations correspond to the definition according to formula Ih 'and Rp stands for hydrogen or methyl, compounds of the formula V in which R ₁ , - "R"', "- Rn / Z and the others Requirements correspond to the definition according to formula Ip, R ₁ 'and RjJL / which can be the same or different, stand for alkyl with 1-3 carbon atoms or together with the nitrogen atom form a pyrrolidino or piperidino ring, R for alkyl with! > Carbon atoms and -Y denotes a nucleofugic leaving group, reacts with a complex metal hydride in an inert solvent, or

b) for the preparation of compounds of the formula Ir,

"where R,, Z and the other provisions ^{correspond to the definition | according to formula Ih 1} , and the condition that R ₁ - is not hydrogen,""Rp and Rl have the same meaning as R and -'Ru, however, at least one of the .Substltuenten in the positions 3, ΐβα and l? ß, ie the substituents

" ⁰ R ^, R ^ and -QR ', stands for / \ lkanoyloxy .- with 2-4 carbon atoms, compounds of the formula Ig, in which R, Z and the other provisions of the definition

: BAD ORIGINAL

5098 17/10 # 7.

Formula Ih ^{correspond to 1} 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 17ß is hydroxy, acylated with an acylating agent with 2-4 carbon atoms, or

c) for the preparation of compounds of the formula Iq, in which R ¹ _{, R 2} , Z and the further provisions correspond to the definition according to formula Ih 1 ', compounds of the formula In in which R, R ₂ , Z and the further provisions Correspond to the definition according to formula Ih ', reacts with a methylating agent,

and protected Z-structures converted into unprotected Z-structures. ·.

The invention also relates to a process for the preparation: of compounds of the formula Is ⁵ , 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 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 can be the same or different, stand for alkyl with iJ carbon atoms or together with the nitrogen atom form a pyrrolidino or plperidino ring, Rt ₀ '

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-T-

Alkyl with 1-3 carbon atoms means / and Ύ "\ * a nucleofugic leaving group; means · 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 stand for hydrogen, Ro has the same meaning as R _p ;> however, at least one of the substituents Rj- and R ^ are alkanoyl with 2-4 carbon atoms, compounds of the formula Isg, in which R and Zs correspond to the definition according to the formula Is ^ Rp ^{1 has} the same meaning as R ₀ , but at least one of the substituents R ₀ 'and R _c stands for hydrogen, acylated with an acylating agent with 2-4 carbon atoms.

and protected Zs structures into unprotected Zs structures convicted. ^ - -

In process a) the complex metal hydride can be, for example, lithium aluminum hydride. The reaction can be carried out at temperatures between about -8o ° and + 8O ⁰ C, and to use as an inert solvent, for example diethyl ether or tetrahydrofuran

ORIGINAL

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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 R _1n * R 'and R ¹ ' are preferably each the same and preferably each represent methyl.

The acylation process b). Can be used in the acylation of steroid alcohols are known to be carried out. A method is preferred in which only the OH group in position 17 is acylated.

In the case of the compounds of the formula Ih 'or Is, which have a Having a large number of OH groups is one OH group in position 3 secondary or phenolic, an OH group secondary in position 16a and an OH group in position 17ß tertiary. It is known that they react during acylation first the secondary "Ξ * phenolic" and finally ■ * the tertiary hydroxyl groups during a saponification first on the phenolic, then on the secondary and finally takes place on the tertiary hydroxyl groups. Accordingly, depending on the to be acylated Hydroxy group strength and degree of acylation selected will. For the acylation in position 3 and / or 16a can be acids, acid halides or acid anhydrides of the formulas ACOOH, ACO-Hal and (ACO) 0, in which A is alkyl

BATH ORIGINAL

509817/1097

with .1- ^ carbon atoms and Hal stands for bromine or chlorine, as well as use their mixtures. If. If a / cetyl group is desired, acylation is preferably carried out with acetic anhydride. The acylation can be carried out in. · 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 a Säureblndemitteis, for example pyridine to give 50 operates ^and-0 C at temperatures between -10 °. Acylation of all three positions can be carried out under harsher 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 agylating agents. All other measures are familiar to a person skilled in the art. How the desired combination of free OH groups and acylated positions can be achieved therefore does not need to be discussed in more detail.

■ ■ '.-. : ■ - .. '■■ / ■■. ■ ■ ■■', ;; V; ■■ For process c) - the methylating agent used is, for example, a methyl halide, preferably methyl iodide. This is preferably used in an excess, for example between about 1 and 50 equivalents of halide per equivalent of the union of the formula In. The compound which contains the anion of the formula In can be obtained by adding compounds of the formula Ih,

509817/1097; , bad original

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where fU is hydrogen, treated with a strong base, for example sodium or potassium amide, in liquid ammonia or with methyllithium in diethyl ether. The reaction with a strong base may be at temperatures between about -30 ⁰ and +30 ⁰ C, using 1 to 1,2 · Aequrvalent of strong base per equivalent of compounds of formula Ih are performed. ; -

The methods as) and bs) can be found under the for Carry out procedure a) or b) described conditions. ;

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

Compounds of the formula V can be prepared by reacting compounds of the formula III, in which R, R_, Rl, R ^ qjH ^ q, Z and the other provisions correspond to the definition according to formula V, with compounds of the formula VI, in which R, above 'e has the meaning and Y' the meaning of; Y has, in an inert solvent, for example acetone, at temperatures between -20 ° and + 3O ⁰ CV Neither temperature nor solvent are critical. ■ "--.- Compounds of the formula IHa, special form of compounds of the formula III, in which L '; R ₂₁ , R', .RJ- ', Z'- and the other provisions correspond to the definition according to formula III, can be obtained By connecting _: -. ■ compounds of the formula II, in which R, R ^, Z and the other provisions correspond to ^{the definition according to formula III 1,}

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BATH ORIGINAL

with compounds of the formula TV, in which X is lithium, sodium, potassium, -MgBr, -MgJ, - or ^ - and R ¹ and RjI have the above meaning, and the reaction product is hydrolyzed.

The reaction can in an inert solvent., .-, at temperatures between -30 ° and + 100 ⁰ C, preferably

-20 ° and +50 ⁰ C. The hydrolysis can be M

in a known way In a neutral or basic aqueous medium, for example water or a ge ' saturated ammonium chloride solution. That Solvent used for the reaction rautet according to the respective Mefcall share of the compounds of Formula IV. If X is -MgBr, -MgJ or lithium, dietary ethers or tetrahydrofuran can be used. If X means sodium, liquid ammonia diethyl ether can be used as a solvent: liquid ammonia tetrahydrofuran, Use dioxane, pyridine or dioxane-byyridine .: Neither Temperature and solvents are critical.

The compounds of the formula III can also be obtained by combining compounds of the formula VIII, in which R ₁ , R ^, Z and the other provisions ^{correspond to the definition according to formula Ih 1} ', with compounds of the formula IX, in which R' and Rl 'above Importance. Have, implemented under Mannich reaction conditions. .

'' ■■ "+ 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 Lösüngs- "medium, for example dioxane or tetrahydrofuran, transit / out."

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

Compounds of the formula Vs are obtained by reaction; of compounds of the formula IIIs, in which R, R ', R-JA * Zs and the further provisions correspond to the definition according to formula Vs, with compounds of the formula VI in which R and Y 'have the above meaning in an inert Solvent, e.g. acetone, at temperatures between -20 ° and + j50 ° C. Neither temperature nor solvent are critical,

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

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 Ilis can be used), m, IHa, VIII and IX are known and can be described in the literature Process are produced. Those compounds of the formula II (including those related to those compounds compounds analogous to formula II, which are used to produce

509817/1097

Preparation of compounds of the formula IIIs), III, lilac, VIII and IX, which are not specifically described in the literature, can be prepared by "analogous processes. Some of those used for the preparation of compounds of the" formulas Ih and Ts 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. , -

Method for protecting such Z and Zs structures that are protected; must be, ie structures containing carbonyl and hydroxyl groups, are known in the literature. See, for example, "The Protection of Carbonyl and Hydroxyl Groups" by John FW, Keana in "Steroid Reactions," An Outline for Organic Chemists ", Carl" Djerassi, Holden-Day Inc., San Francisco (1963), Chapter 1. _:

Die'Verbindungen of the formula Ih are valuable pharmaceuticals. They are particularly suitable as fertility inhibitors. The compounds of the formula Ih 'and Is ,. at which Z for the structures Zl to Z3 or /. Zs for. Zl ¹ S is estrogenic. The compounds of the formula Ih ¹ and Is, in which Z represents the structures Zk to 29,

509817/1097 badoriqinau

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or Zs stands for the structures Z4s to Z8s, have a progestatlonal effect.

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

A preferred compound is 17cx-Propadienylöstra ~ 4-en-

A pharmaceutical preparation - for example a capsule, with the compounds according to the invention as active ingredient can be formulated as follows: 2.5 parts by weight of 17α-propadienylöstra-4-en-3β _i 17β-diol, 2 parts by weight of tragacanth, 87 parts by weight. -Parts of lactose, 5 parts by weight of corn starch, 3 parts by weight of talc, 0.5 parts by weight of magnesium stearate.

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

BATH ORIGINAL

509817/1097

βθΟ-6248 / ΐ:

OR,

- _fc - * CS = C = CH

You

Zl

RoO

Z2

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600-6248

Ζ5

R ₁ -OH

Ζ7

H, H

Ζ8

5098 17/1097

OR,

.., -, CH = C = CH, --- Ri,

rf

Z -

OR

2s ^v _:

..__ CH = C = CH,

H.

Zs

600-6248 / ^.

IhV

Z6s

R,

7 ι Η

509817/1097

H I 'J-

ZJs

Zl's

Hi H

Z8s

2p

CH-C-CH ₂

■ R,

Ip

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6οο-β248 / ϋ £

Ir

C - CH = C = CH ,.

t ι

---- CH = C = CH, IS Iq

509817/1097

CH = C = CH,

A- B H

In

OH

¹ L CH = C = CH,

Ips

Zs

^0R 2s
^ CH = C = CH,

ft.

Isr

Zs

5 0 9 817/1097

-ZL 6θΟ-6248; / ΐί-

Zs

1866922

^0R 2s

- - GH = C = CH,

B J H

Isg

Λ I B

II

OR

2p ■

_r - ~ -C H = G-

t t

10 III

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600-6248 /.^

Zs

10

■ OR

2p

-C = C-CH ₂ -N

io Ac-

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HIa

C D

AWAY

■ ^R io

Ills

IV

C. R. OH Y
■ "■" - +
>) /> ν ^{/ R} 10 \
D. ^R 1O ^R 10 ί

Zs

Vs

^R io ^Y ' VI

VIII

HO-

10 IX

50981771097

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Example 1 : 17a-Propadienyl-j-muthoxyostra-1,2, trien-17β-ol

A mixture of 15 * 8 g ^ a-ethynyl-J-methöxyöstra-1,3 * 5 (10th) -trien-17ß- "ol, 15 * 0 ml dimethylaminomethanol, 500 mg copper-I-chloride, 8.5 ml glacial acetic acid and 125 ml of dioxane is kept for 5 hours at 70 ⁰ C Ansehliessend ice water is added, the pH adjusted to 10 and the title compound with / ether extracted, there remains a foam back with OJ_ ... -.. "8.84 (s = .1 / CHCl).

trien-17ß-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) ^ a-Propadienyl-J-methoxyestra-1,3r5ClO) -trien-17β-ol

A suspension of 3.006 g of the mixture obtained above Fahrensproduktes in 65 ml of anhydrous tetrahydrofuran is at -75 ° C with 11.25 ml of a 0.525 molar lithium ".

5 0 9 817/1097 ^BAD -

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 ⁰ C, sets saturated aqueous ammonium chloride solution and extracted ID to the title compound with ether. In this case, one obtains a quantitative'Ausbeute, calculated over all the above process steps, the crystalline material of mp 129,5-1-3Q, 5 ⁰ C. j |

[aI ₀ = + γ, ι8 ^ο (c = 1, CHCl). -

Example 2 : Under the conditions described in example 1 and using the following / ■ output st of fe : .. ■ - "■. ■" .-. :

a) 17a-ethynyl-3-methoxyöstra-J., 3,5 (10), 7-tetraen-17β-ol :

b) lYa-ethynyl - ^ - methoxyÖstra-1,>, 5 (10), 6/8: -pentaen-17ß-ol . :

c) 17α-ethynylestra-4-en-17β-ol

d) 3-Cyclopentyloxy-17cx-äthinylöstra-l, 3, 5 ⁽¹ - Q) * "" _trien-17-ol:

e) ^ -Aethoxy- ^ a-äthinyl-lJ-äthylgona-l, ^, 5 (10) - trien-17ß-ol

f) 17a-ethynyl-3-methoxy-7a-methylÖstra-1,3 / 5 (10,) -trien-17ß-ol _:.

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

h) E.

BATH ORIGINAL

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one arrives at ;

a) 17a-Propadienyl-3-methoxyestra-1,3,5 (10), 7-tetra "en 17β-ol

b) 17ct-Propadienyl-j5-meth.oxyüstra-1, jJ _J 5 (10) _i 6 _J 8-pentaen-17β-ol

c) 17cx-Propadienylöstra-4-en-17β-ol

trien-17ß-ol ·· "*" ".

e) 3-ethoxy-17cx-propadIenyl-13-ethylgona-1 _> ^, 5Cl6) -trien-17ß-ol

f) 17cc-Propadienyl - ^ - methoxy-7a-methylös tra-1, ~} _t 5 (10) trien-17ß-ol

g) 17a-propadienyl-16a-hydroxy-3-methoxyöstra-1,3 * trien-17ß-ol

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

Example 3 : 1 7a-Propadienyl-3-rnethQx, yöstra-2, 5 (10) - . dien-17ß-ol

α) 17a- ^ imethylarninQ ^ ropiny]} - 3-methoxyüstra-2 _i , 5_ (l02-dien-17ß-ol

One from 1.50 g magnesium, 4.68 g ^ ethyl bromide and 70 ml Tetrahydrofuran produced Grignard mixture is added dropwise with 5.3 g of dimethylaminopropine, dissolved in

_{17 /} -j 097 GAD ORIGINAL

1966322

10 ml of tetrahydrofuran are added. After the. Ethane Development added a solution of 1.716 g of 3-Methoxyöstra-2,5 (10) -diene-17-one in JO ml of tetrahydrofuran was added dropwise to, the temperature / is maintained during the addition to 0-5 ⁰ C, and one then M- hour at 20-25 ⁰ C allowed to react. After adding 100 ml of 2N sodium hydroxide solution, the mixture is concentrated in vacuo to a total volume of 100 ml at temperatures not exceeding 150 ° C. The concentrate becomes ™

extracted with ether (5 x 25 ml), for relief centrifuged the phase separation. By evaporation of the dried ethereal solutions and suction an existing excess of dimethylaminopropine one obtains the title compound. '

b) 17a2Öimethylamino ^ ropinyl) -j5-methoxyöstra-2 _i 5 (

c) IZtti ^ oEsdienyl- ^ - methox ^ östra-g ^^^ lOl- ^

To a suspension of 2.5 g of the compound obtained above

dien-17ß-ol-methiodide _:

2.0 g of the process product obtained above

dissolved in j5'Q ^m l of acetone. After adding .3 * 5 S Metnyl- Ä

iodide, the mixture is kept at 8 ° C for 18 hours. the The title compound crystallizes out and is filtered off and glazed with anhydrous ether.

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product in 50 ml of tetrahydrofuran are added at -75 ⁰ C 9 * 3 ml of a 0.525 molar lithium aluminum hydride tetrahydrofuran solution. The mixture is brought to -1O ⁰ C and up to obtain a clear solution (about 90 min.) Was stirred, and then kept for 12 hours at room temperature. 100 ml.aqueous 2N sodium hydroxide solution, which contains 50 ml of di-tert.-butylcresol, are 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 by means of a centrifuge, drying of the ethereal solutions over potassium carbonate and evaporation, the 1Ta-propadienyl-1S-methoxyestra-2,5 (10) -dien-17β-ol is obtained.

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

2.0 g of 17α-propadienyl-j5-methoxyestra-2,5 (10) -dien-17β-ol, obtained according to Example J5, are in a mixture of 20 ml glacial acetic acid and 2 ml v / ater dissolved. After 2 hours, 200 ml of water are added and the product is extracted with it Ethyl acetate (5 x 10 ml). After evaporation of the ethyl acetate extracts 17ct-Propadienylöstra-5 (10) -en-17ß-ol-3-one is obtained as a crystalline solid with a melting point of 116-122 ° C.

Example 5 : 17α-Propadlenyl • oestra-4-en-17β-ol-3-one

5.5 g of 17α-propadienyl-5-methoxyestra-2,5 (10) -dien-17β-ol,

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obtained according to example j5> are in a mixture of 50 ml of methanol and 1.5 ml of UN aqueous hydrochloric acid dissolved and held at 50 ° C for 30 minutes. After dilution with 100 ml of water, the product is treated with methylene chloride extracted (5 χ 15 ml). After evaporation of the dried Methylene chloride solutions and subsequent recrystallization of the residue from cyclohexane is obtained in pure form 17α-Propadienylöstra-4-en "-17β-ol-j5-one of m.p.

Example 6 : Following the procedure of Example 3

as well as 5 are obtained using the following ' / starting products:

a) Oestron-jJ-tetrahydropyranyl ether -

b) _{3-MethQxy-7a-methylöstra-2,} 5 (lQ) -diene-17-one

c) "3-Aethylendioxy-6a-methylandrosta-5-en-17-o ⁿ '

d) 3-ethylenedioxy-6-fluΌrandrΌΞta-4-, 6-dlen-17-one.

e) ^ -Aethylendioxy-o-chlorandrosta - ^^ o-dien-l ^ -one

f) 3-Ethylenedioxy-6-ethylandrQsta-4 _> 6-dien-17-one

g) jJ-Methoxy-1 ^ -äthylgQna-a, 5 (10) -dien-17-one-

h) 13 ~ n-Propyl-3-tetrahydropyranyloxygona-2,5 (10) - ■ dien-17-on

09817/1097

following connections:

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

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

c) 6a-methyl-17a-propadienylandrosta-4-en-17ß-ol-3-one

d) 6-fluoro-17a-propadienylandrosta-4,6-dien-17ß-.ol-j5-one

e) 6-chloro-17a-propadifinylandrosta-4 _i 6-dien-17ß-ol-5-one

f) 6-methyl-17α-propadienylandrosta-4,6-dien-17β-ol-3-one

g) 13-Ethylene-17α-propadienylgona-4-en-17β-ol-3-one

h) 17α-Propadienyl-13-n-propylgona-4-en-17β-ol-3-one

Example 7 : Following the procedure of Example 3 -----

. Example 4 is obtained under Ver

Use of the following, starting product:

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

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

following connections:

a) 7a-Methyl-17a-propadienylöstra-5 (lQ) -en-17ß-Ol-3-one

50981 7 / 1Q97

BATH ORIGINAL

o? 8 / lL

b.) 1> - Ae thy 1- 17α- pr opadieny Igona - 5 (10) - en-17 β-ol-J- on

Example 8 ; ^ fi-ethoxy - ^ - methQxy-rfa-propadienylostral> 3x5 (10) -triene ■ - ";..;

A solution of 297 > 3 mg of ^ a-propadienyl - ^ - methoxyöstra-l, jj, 5 (10) -trien-17ß-ol. (Example lc) and 12 mg of p-toluenesulfonic acid in 6 ml of isopropenyl acetate is heated to room temperature for 18 hours held. Aether is added, the solution is evaporated after washing with ice-cold sodium carbonate solution. and drying over magnesium sulphate to dryness and after recrystallization from methanol the ^ ß-acetoxy - ^ - methoxy- ^ a-propadienylöstra-ljJiSClO) -triene of m.p. 89-90 ⁰ C, t] _D = + 9.27 * (c = 1 / CHCl ₃ ).

Example _9 · According to the comparison "specified in Example 8 - drive as one obtains using the following starting materials:

a) 17a-propadlenylöstra-1,3,5 (10) -triene-3 _i 17β-diol

b) / ^r l> n ^ propy-lgona-4-en'-3ß, 17ß ~ diol

the following connections:

a) 3,17β-Diacetoxy-17a-propadienylestra-l _i 3> 5 (10) ~ triene

b) ^ ßi ^ ß
4-en

09817/1097

'- 32 - βθΟ-6248 / ii

Example 10 ; j? * 17 ß-Dimethoxy-17α-pr opart lenylö stra h l, 3,5 (IQ) -triene

Procedure A

(? 1

A mixture of 374.4 mg Lya ybimethylamino / propynyl} ^ - methoxyOStra-1,3,5 (lO) -triene-17.beta.-ol and 10 ml of dry ether is 1O ml at ⁰ C with 0.89 a 1.2 molar essential ketnyllithium solution added. The batch is kept at room temperature for 10 minutes and then 3. »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-Dlmethoxy-17a-propadienylösti'a-1,3i

The process product obtained above is according to the example ic reduced. After purification of the mixture obtained on silica gel (elution with trichlorocarbon-benzene 1: 1) the 3,17ß-dimethoxy-17a-propadienylöstra-1,3,5- (10) -triene is obtained.

Procedure B

To a solution of lithium amide in liquid ammonia,

5 098 17/1 0 9 7: _ _: bad original

οΌ0-ο248 /

made from 73. »5 mg lithium and 20 ml NfL, becomes a Solution of 5.24 g

trien-17β-ol (Example 1) in 50 ml of diethyl ether added. The mixture is kept at the reflux temperature for two hours and then 2.5 g of ethyl iodide are added, whereupon the ammonia is allowed to evaporate. After adding 50 ml of water and separating off the ether phase and washing with ether, followed by evaporation of the dried ether solutions, the 3,17β-dimethoxy-17ci-propadienylestra-1,3 _J 5-H (10) -triene is obtained. . · '

Example 11 : According to the procedure of Examples 3a, IQa, b (process ") and 5, using the following starting products:

a) 3-methoxyestra-2,5 (10) -dien-17-one

b) 3-methoxy-13-ethylgOna-2,5 (10) -dien-17-one e) 3-methoxy-7a-methylöstra-2,5 (10) -diene-17'-Qn

following connections :

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

b) 13-ethyl-17β-methoxy-l · 7α-propadienylgorιa: 4-en-3 ^- one ■; ;

c) 17β-Methoxy-7a-methyl-i7Gt-propadienylöstra- ⁱ l-en-3-one ■ ', - "-'

BATH ORIGINAL

- 34 - 600-6248

Example 12 : j ^ L ^ ß-Diacetoxy- ^ a-propadlenylöstra ^ -en

According to Example 8, using'17α-propadienylöstra-4-en-j $ 17β-diol the compound named in the title. NMR spectrum: ".- '" ■ -

= 6 ο, 94 ppm 17β-0C0CH = (Γ ι, 97 ppm 3-OCOCH = S 2, 04 ppm

Example 13 : 5ft "acetoxy-17a-propadienylestra-'4-en-17β-ol

0.8 g of 17a-propadienylöstra-4-en-3 /} l7ß-diol (Example 2h) become a solution of 4.4 ml of acetic anhydride in 13.0 ml of pyridine are added, the resulting mixture is Stirred for 17 hours at room temperature (20 ° C), then in Pour 100 ml of water and add 5 times 10 ml of methylene ^ chloride extracted. The combined methylene chloride extracts are dried over anhydrous sodium sulfate, the solvent is evaporated in vacuo, and after Recrystallize the residue from 95%. "'. Aethano-1 the title connection from the Snip. Obtained IO7-IO8.5 ° C.

Siteiϊ / ίiff

BAD ORiGiNAL

Claims (2)

DI ?. T? C ^ τ ·. -SS -fr2 48/11 New claims 1.j New steroids of formula I, OR Rl 2 1 L-- CH = G = OH, where R ₁ denotes alkyl with 1-3 carbon atoms, R "denotes hydrogen , methyl or alkanoyl with 2-4 carbon atoms, R denotes hydrogen, hydroxy or alkanoyloxy with 2-4 carbon atoms. and. Z denotes the rings A and B as well as substituents located thereon and is represented by the shape of the image Zl-ZS. 5 0981771097 BATH ORIGINAL 600-C248 / ITJ Z5 Z6 Z7 Z 8 where R- hydrogen, alkyl with 1-3 carbon atoms / Cycloalkyl with 5-7 carbon atoms or alkanoyl with 2-4 carbon atoms means, R, for hydrogen, 6cx-methyl or 7cc ~ methyl, R_ is hydrogen or methyl and R _{0 is} hydrogen, fluorine, chlorine or methyl is, with the proviso that, if the rings A and B are represented by the formula Zl, v / above R stands for hydrogen, as well as R_ and R _f, which can be the same or different. Mean hydrogen or alkanoyl with 2-4 carbon atoms, R. then represents hydrogen. 2. Medicines, characterized by the content of Compounds of formula I. 509817/1097 BATH ORIGINAL