DE2426778A1 - 1.3-OXYGENATED 8ALPHA-OESTRATRIENE - Google Patents

Description

SCHERiNGAG

Patent department

Berlin, den ^L: "'^

1.3-oxygenated 'Sa-estatrienes

Addition to patent application P 23 36 434.3 - '■

In the main patent (patent application P 23 36 43-4.3)

1.3-oxygenated 8a-estatrienes of the general formula I are described '■.

(I), wherein

one of the groupings

> 3

-B? or

R ¹ ,

in which the -0-R groups can be α- or ß-, ⁵ a hydrogen atom, an acyl, alkyl, cycloalkyl

or oxygenated saturated heterocyclic

Rest,

an IT-lower alkyl group,

509851/1047

Board of Directors: Hans-Jurgen Hamann · Karl Otto Mittclstenscheid

Dr. Gerhard _β.ΐ5ρύ Dr. Hor & t V / itzel

Deputy: Dr. Christian Bruhn ■ Dr. Heinz Hanns © Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppon Company headquarters: Berlin and Di> rqkam ·· r ·.

Tsles :! 81 77? A schb d · Telegrams: Scheringchemie Berlin PootBcheck account: BerlinWest 11 75

SCHERING AG

Patent department

ß a hydrogen atom or a substituted or unsubstituted one mean saturated or unsaturated hydrocarbon radical.

These compounds exhibit a favorable dissociated pharmacological Effectiveness on. Because of their strong vaginotropic and weak uterotropic effects, they are preferred for treatment suitable for women in the postmenopause.

In further development of the main patent.

(Patent application P 23 36 434.3) has now been found that compounds the general iOrmel I, in which R and / or R ^ represent a sulfonic acid residue, one at least equal have favorable dissociated pharmacological efficacy.

The present invention accordingly relates to 1,3-oxygenated 8a-estatrienes of the general formula I a

(la), in which

5098S1 / 104 7

Board of Directors: Hans <Jürgen Hamann Karl Otto Mittelstenscheid Postal address: SCHERING AG D-1 Berlin 65 - P.O. Box 6S 0311

? ^d f ° ΑÄ

g Otto Mttelstenscheid Postal address: SCHERING AG D1 Berlin 65 P.O. Box 6S 0311

Ste.?v ^e : D ^a r ^rd Ch?, ^ Fan ° ΑÄu Hannse Postscheck account: Berlin-West 11 75-101. Bank.eit number 10010010

Chairman of the Supervisory Board: D, Eduard v. Schwartzkoppen

and AG Kamen HRBCSI

one of the groupings

SCHERING AG

Patent department

0-R '

-K-

or

O-R-

in which the -0-R groups can be ^{oc- or ß-, R 1} , R ⁵ a hydrogen atom, an acyl, alkyl, cycloalkyl or sauer.stoffhaltigen saturated heterocyclic radical or a sulfonic acid radical, where at least one of Residues R ¹ or B? represents the sulfonic acid ^{residue, R 2 is} a lower alkyl group,

R is a hydrogen atom or a substituted or unsubstituted one mean saturated or unsaturated hydrocarbon radical.

The acyl radicals are those from physiologically acceptable acids in embossing. Preferred acids are organic carboxylic acids with 1 - 15 carbon atoms, those of the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic Belong to series. These acids can also be saturated and / or polybasic and / or substituted in the usual way. As examples alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms may be mentioned for the substituents.

509851/1047

Board of Directors: Hans-Jürgen Hamann ■ Karl Otto Mittelstenscheid

Dr. Gerhard Raspe ■ Dr. Horst Witzel

Deputy: Dr. Christian Bruhn Dr. Heinz Hannse Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters: Berlin and Bergkamtn

Commercial register. AG Charlottenburg S3 HRB 283 and AG Kamen HRB 0051

Postal address: SCHERING AG D-1 Berlin 65 PO Box 65 0311 Postal check account: Berlin-West 11 75-101. Bank code 10010010 Berlin Commerzbank AG. Berlin. Account no. 108 7005 00. Bank code 100 400 Berliner Discnnio-Bank AG, Berlin. Account no. 241 / 5Oeo. Bank code 100 70C GO Berliner Hanclcls-Gosellschaft - Frankfurter Bank -. Berlin, Account no. 14-21.2. Bank code 100 202UO

SCHERING AG

- M- - "Patent Department

The following acids may be mentioned as examples: formic acid, acetic acid, Propionic acid, butyric acid, isobutyric acid, valeric acid, Isovaleric acid, caproic acid, enanthic acid, caprylic acid, Pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, Myristic acid, pentadecylic acid, trimethyl acetic acid, Diethyl acetic acid, tert-butylacetic acid, cyclopentylacetic acid, Cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, Phenoxyacetic acid, mono-, di- and trichloroacetic acid, amino-

1 r

acetic acid, diethylarainoacetic acid, piperidinoacetic acid, korpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, isonicotinic acid ₉ furan-2-carboxylic acid.

Preferred alkyl radicals S or R are lower alkyl radicals with 1-5 carbon atoms which can be substituted or branched in the usual way. As examples of the Substituents may be mentioned as halogen atoms or i-lower alkoxy groups. The methyl or ethyl group are particularly preferred.

Examples of cycloalkyl groups are those with 3-8 Carbon atoms into consideration, of which the cyclopentyl group is preferred.

Suitable saturated oxygen-containing heterocyclic radicals are those which differ from Heterocyclen'mit at least one Derive oxygen atom in the ring and those in the oxygen atom-containing Ring are perhydrated. The tetrahydrofuryl- and the Tetrahydropyranyl ^ st, of which the Tetrahydropyranylrest preferred is ^ .g 9 8 5 1/10 4?

Board of Directors: Hans-Jürgen Hamann · Karl OHo Mitlelstenscheid Postal address: SCHERING AG ■ D-1 Berlin 65 ■ Postfach 65 03 11

i? ^r \ 9 ^your i? ^rd , -S ^aSi ? ⁶ "1 ^r · Horst Witzel Postscheck-Account: Berlin-West 11 75-101, bank code 100 100 10

Ste »v .: Dr.Chnstian Bruhn -Dr. He. «Hannse _Ber , _{rner Commpr2h} , _{nk AG Bf> r | in Kon; o} . _{No w5700} , cc B ^ Me ^ .M 100400

Chairman of the Supervisory Board: Dr. tduard v. Schwartzkoppen Berlin Disccüito-c.im .. AG. Ε5ί Π.η. Account Ni. 241 üu; j L, »kv.MI! 0J Λ0 OJ

Registered office of the company: Berlin and business name _R „,, _n . _rw .._ .. _r .-, .. ",," ,. i ,,,. r. , _n "i, ..., _r ρ ,,, ι _(i ,,.""

Commercial register; AG CharloUenburg h HRB 283 and AG Kamen HHB 0051 - κΓηί2-ΐ! Ϊ́Γ A ^ nMAl ΓθϋÜ00 ""'

Sponsorship training

1 «5

As SuIfonsäurereste R or R are those of aliphatic, cycloaliphatic and aromatic sulfonic acids having 1-15 carbon atoms, and amino sulfonic acids in. Question, <ü ^e can contain additional substituents. Aliphatic sulfonic acids should preferably contain 1-6 carbon atoms and can be substituted, for example, by halogen such as, for example, chlorine. The following aliphatic sulfonic acids may be mentioned as examples: methanesulfonic acid, ithanesulfonic acid, β-chloroethanesulfonic acid, butanesulfonic acid. Cyclopentane and cyclohexane sulfonic acids are preferably suitable as cycloaliphatic sulfonic acids. Aromatic sulfonic acids are preferably benzenesulfonic acid, p-rr-toluenesulfonic acid and p-chlorobenzene sulfonic acid. Examples of aminosulfonic acids are ΙΤ, Ν-disubstituted aminosulfonic acids, the two substituents being alkyl radicals with 1-6 carbon atoms or an alkylene group with 4-6 members, optionally interrupted by a heteroatom such as nitrogen, oxygen or sulfur. Examples include: N, N-dimethylaminosulphonic acid, IT, N-diethylamino sulphonic acid, N, IT-bis (ß-chloroethyl) aminosulphonic acid, N, N-diisobutylaminosulphonic acid, N, E "-dibutylaminosulphonic acid, pyrrolidino, piperidino , Piperazino, N-methylpiperazino, and morpholino sulfonic acids.

509851/1047

Board of Directors: Hans-Jürgen Hamann · Karl Otto Mittelstenscheid

Dr. GerfinrcJ n -:. P '. · Cr Horst WmzoI

Deputy: Dr Christian Brunn · Or. Heinz Hannso Chairman of the Supervisory Board: Dr Eduard von Scnwartzkoppen Seat of Gesullv.hilt P.irlm and Pr-r-jiramr-n

Postal address: SCHERING AG · DI Berlin 65 ■ Pcs! «Ach 65 03 Vi Postscheui-Ki.-.io. Berlin-Wo ". 11 75-101. Bii» '-!'! / ;. ·: '.00 ICO 10 Berliner Co'n ^ erzS ^ nk AG Po'! In. Account-t »r 1 ^ 8 / v. ', - ¹ ; ..0. b Berliner D: ic: r: j-Eiii <AC. L ·: · ί.- · ». KsT.o-Nr.24vi .-. i L.-. im'li-Berliner H.; tJ- 3-G -.- '. t.-3i-, i't - Fr-.i. ^ rser Bank - öifiin.

! Vi: i.jij

Patent department

"O

Lower alkyl groups are possible as substituents R, of which, for example, the methyl, ethyl, propyl and Butyl group may be mentioned. Preferred radicals are the methyl or ethyl group.

As hydrocarbon radicals R are alkyl, alkenyl or alkynyl groups with up to 6 carbon atoms, examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, ethynyl, propenyl, Butadienyl, butadiinyl radical. The radical can also be substituted in the customary manner, with “halogen atoms, among others, being possible as substituents. Preferred hydrocarbon radicals R are the ethynyl or chloroethinyl radical.

The invention also relates to medicaments which contain 8a-estratrienes of the general formula Ia as an active ingredient.

The pharmaceutical specialties are produced in the usual way by combining the active ingredients with the

509851/1047

KrUvATD Ho ™ W ₁ Ue? ^{r! Ott} ° ^{Mitto! Stens} * eid Postal address: SCHERING AG - DI Berün E5 - Posifa * 65 03

Steilv .: Dr. Christian Bruhn ■ Dr.Hemz Hsnnse postal check account; Berlin-Wes! 11 75-101. 03r.k: e: Uahi 100 100

VcrsiWender des Aufsich! Sra! S: Dr. Eduard v. Schv / artzkopoen Berliner Coirrr-erzbank AG Berlin. Kar.:or-.r. 1387CCi 00.Ba- * ΐΐ'ιζΜ ICO V

SüzoerGesellscfiafi: 8erhn and EerqKamen ■ Berliner Discc .-. 'O-bank AG. bc-riin. Ko-: o · .-. 2ii54 / ^ Bän, .. i-Uuh! 1CC iui -j

Trade register; AG Charlottenburgs3HRB233 u.AG Kamen HRB0051 Beriiner Hanui>: s-Gc-seliscfta «- fr.irS ^ -. Er Bank -.ΒβΠ.π.

Konlo no. 14 - ^: 2. Barikieitz number 100 2 ^ 2> 3

SCHERINGAG

Patent department

2A26778

see carrier substances commonly used in pharmacy, diluents, Geschinackskorrigentien etc. in the desired form of application, such as tablets, coated tablets, capsules, solutions, etc., transferred. The active ingredient concentration in the formulated Medicines depends on the form of application. Thus, a tablet preferably contains 0.01 to 10 mg; Solutions for parenteral administration contain 0.1 to 20 mg / ml solution.

The dosage of the medicament according to the invention can vary with the form of administration and the particular compound selected. In addition, it can vary according to the respective Treated change. In general, the inventive Compounds administered at a concentration that is effective -Can produce results without causing any adverse or harmful side effects; so they will for example, administered at a dose level generally ranging from about 0.02 mg to about 20 mg, although under certain circumstances Modifications can be made so that a dose level greater than 20 mg, for example up to 50 mg, is used will. However, a dose height in the range of approx.

V *

509851/1047

Chairman: Hans-Jürgen Hamann · Karl Otto Mittelstenscheid Telex: 181777a »chb ύ ■ Telegrams: Scheringehemio Berlin

Dr. Gerhard Raspe - Dr. Horst Witzel

Deputy: Dr. Chris.tiün Brunn ■ Dr. Heirr Hannse '■ Postal check account: Berlin-West 1175

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen
Company headquarters: Berlin and Derqkamon
Commercial register: AG Charlotlenburg 9.3 HRB 283 and AG Kamen 5 HRB 71

_ Patent Department

- O ~ "

SCHERiNGAG

it department

Preferably 0.05 mg to about 5 mg is used

The compounds of general formula Ia can be prepared thereby be that according to the main patent (patent application

P 23 36 4-34-.3) an enol acylate in a manner known per se of the general formula II

0-R ⁵

12 ζ

wherein R and R have the meaning given above and R ^ a Represents acyl group, oxidized and optionally then, depending on the desired meaning of A-B, isomerized and / or reduced and / or split off ether or ester groups and / or esterified and / or etherified free hydroxyl groups.

The oxidation of the compounds of general formula II in which R ^ is one of the commonly used for protecting hydroxyl groups acyl groups used, preferably an acyl group in the last

509851/1047

Board of Directors: Hans-Jürgen Hamann - Kar! OUo Mittelstenscheid TeIn: 1 81 777 »schb d - Telegrams: Scheringchemie Berlin

Dr. Gerhard Raspe Dr. Horst Witzel _. . , "",.,.,. ,, "-

Deputy: Dr. Chr.st. to Bruhn ■ Dr Heinz Hannse - Postscheck Konlo: Borl.n-West 1175-

SCHERiNGAG

~ 9 ~ PalentartftöiltftcP Π Π Ο

borrowed the desired meaning, such as an acetyl, Butyryl, heptanoyl group means, can be carried out with peracids. Examples of peracids include ": Perbenzoic acid, peracetic acid, m-chloroperbenzoic acid, monoperphthalic acid etc. The oxidation can also be carried out with lead tetraacylates, such as, for example, complex tetraacetate will.

Purely the implementation of the measures, if necessary, to which the

- r Γ

Product of the oxidation can then be subjected to various methods are known to those skilled in the art, which are described below.

If the product of the oxidation is a 17ß-acyloxy-16a.l7a-epoxy compound, the subsequent isomerization can be carried out both by reaction with acids, such as sulfuric acid, Perchloric acid etc., as well as by treatment with isomerization catalysts, such as silica gel, aluminum silicates, etc.j or by heating above the melting point. If the product of the oxidation is a 17-keto-16ß-acylate, so can isomerization by strong bases, one of which.Alkali ■ are preferred, for example with potassium hydroxide solution, soda solution, sodium hydroxide solution.

.1 ' Pi-.

5 0 9 8 5 1/10 4 7

Board of Directors: Hans-Jürgen Hamann · Karl Otto Mittellenscheid - Teles: 181 777a schb d · Telegrams: Scheringchemie Berlin ^

. iÄÄft; Κ " ¹ Αζ Hann _{= 0} " Posischeck account: BerLn-Wao, Il 75

Chairman of the / wjfsiclilsrats: Dr. Eduard v. Schwarzenkoppen Headquarters of the Go.ifMfschail: Rertm and Berqkamon Handolsregistc-r: AG Chartottenburg U3 ΗΓ'Β 203 and AG Kamon 5 HRB 71

SCHERiNGAG

- 3.0 - Patent Department

A 17-keto group contained in the oxidation product can then be reduced by methods known per se. For example, the reduction can be carried out by reaction with hydrogen in the presence of a customary catalyst, such as, for example, Raney-nickel, platinum. In addition, the hydrogen can be transferred from metal hydrides to the 17-keto group. Particularly complex hydrides, such as, for example, sodium hydride borate, lithium hydride aluminate, sodium hydride trimethoxy borate, lithium hydride tri-tert.-butoxoaluminate, etc., have proven particularly useful as hydrogen donors. '"'

The reduction can also be carried out by known methods with an organometallic compound in which the organic radical R denotes and which is an alkylmagnesium halide, such as, for example, methylmagnesium bromide or iodide, an alkenylmagnesium and / or alkenylzinc halide, such as for example vinyl magnesium bromide or allyl magnesium bromide, an alkynyl magnesium halide, such as ethynylmagnesium bromide, propynyl magnesium bromide or propynyl zinc bromide, or an alkali metal acetylide, such as potassium acetylide, can also act in situ with the compound used to react with the organometallic reducing agent -Keton gebraclj | 5. So one leaves

- 11 -

■ '. ■

509851/1047

Board of Directors: Hans-JOrgen Hamann - Karl OHo MittetslenscheW Telex: 1 81 777a schb d ■ Telegrams: Scheringehemio Berlin

Or. Gerhard Raspe · Dr. Horst Witzel. Postal check account: Berlin-West Ii 75

Deputy: Dr. Christian Bruhn Dr. Heini Hannso
Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppan
'' Seat of the company: Berlin and Bernkamon
Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen 5 HRB 71

SCHERiNGAG

_ 11 _ < "Patent Department

ntabteilunq

for example for reaction with organometallic alkynyl compounds an alkyne on the ketone in a suitable solvent, ■ .Chloralkyne or alkadiyne and an alkali metal, preferably in the presence of a tert. Alcohol or ammonia if necessary act under increased pressure. . -

A 16-keto group can then also according to "known" Procedures are reduced. For example, be the reduction with metal hydrides or from sodium and alcohols nascent hydrogen mentioned.

An epoxy group contained in the oxidation product can be reduced will. The reduction can be catalytic, for example , with hydrogen in the presence of metal catalysts, such as Platinum or palladium, or with reducing agents, "for example Hydrido compounds, such as LiÄIHn, ITaBEL, etc. take place.

Free hydroxyl groups can then be esterified or etherified will. Esterified or etherified hydroxyl groups can be converted into hydroxyl groups. Also these procedural measures

Λ ^v <·

take place according to methods known per se.

-12 -

509851/1047

Board of Directors: Hans-Jurgcn Hamann · Karl Otto Mittelstenscheid Tolcx: 1 81 777a schb d - Totegrams: Scheringchemie Berlin

Dr. Gerhard Rasp * - Dr. Horst Wilzol

Deputy: Dr. Christian-Bruhn - Dr. Heinz-Hannse '■ Postal check account: Berlin-West 1175

, Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen
Seat of the company: Berlin and B ^ rqkarnen
Commercial register: Au Charlouenburg 03 HRB 283 and AG Kamen 5 HRB 71

SCHERiNGAG

~ "12 ~ Patent Department

The esterification in the ¹¹¹¹ Cl 3 position is preferably not carried out

/respectively. Pyridine / acid chloride ..

Pyridine / acidic acid hydrideN at room temperature. For veratherung m 1- and p-positions serve alkylating compounds, such as preferably Diazomethane, bialkyl sulfate, other etherification reagents are for example cycloalkyl halides and dihydropyran.

For esterification of the β-hydroxyl group in 1,3 (16) -di (tri) esters and or the 16- and / or 17-hydroxy group in 1,3-dieters for example, acid anhydrides are left on the steroid in the presence of strong acids such as p-toluenesulfonic acid, HClO ^, or pyridine / acid anhydride, if appropriate, act in the heat. The latter methods can also be used to free hydroxy compounds directly into the tri- or tetraacylate to convict.

1,316 triesters and 1,3 dieters can use dihydropyran in the presence a strong acid such as p-toluenesulfonic acid into the corresponding 16- and / or 17-tetrahydropyranyl ether transferred will. The etherification of the 16- and / or 17-OH group in the Invention according to en 1,3-diethern with an alkyl radical is preferred carried out with alkyl halides in liquid ammonia.

-13 -

509851/1047

Board of Directors: Hans-Jörgen Hamann · Karl Otto Miltcistcnscheid Tetei: 1 81777a cchb d · Telegrams: Schoringchemio Berlin

Dr. Gerhard Raspe - Dr. Horst Witjel. «!. ■■," ..., "=

Stell ».; Dr. Christen Bruhn Dr. Honz Hannse "Poslechcck-Konlo: Bertm-Wast It 75

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen

Seat of the company: Berlin and Derckar: ii? N

Commercial register: AG Charloltenburg 93 HHB 203 and AG Kamen 5 HRB 71

SCHERiNGAG

- Patent Department

The OH groups can be released from 1,3-diacyl or msulfonyl-17-tetrahydropyranyl derivatives or 1,3 _f "16-triaeyl or trisulfonyl-17-tetrahydropyranyl derivatives by alkaline saponification.

The ether cleavage is carried out according to methods known per se. Examples include the cleavage with pyridine hydrochloride or pyridine / concentrated hydrochloric acid in the case of increased Temperature (180 - 220 ° C) or with hydrohalic acids in Presence of lower carboxylic acids at temperatures below 150 ° C, the cleavage of tetrahydropyranyl ethers takes place under mild conditions by adding acid.

In general, one will start from enol acylates in which R is already present in the ultimately desired meaning. To increase the yield, however, it may be useful to use such To start with compounds in which the hydroxyl groups in the 1- and 3-positions are esterified or etherified.

The 8a-oestratrienes of the general formula Ia, which are in 16a and 17a-position have a hydroxyl group, can also be thereby obtained that a tetraene of the general formula III

- 14 -

509851/1047

Board of Directors: Hans-Jürgen Hamann · Karl Otto Miltelstensch.id Telex: 181777 »schb d ■ Telegrams: Scheringchemi. Berl.n

Dr. Gorhard Raspi Dr. Horst Wilzol Postscheck account: Berlin-West 11 75

Deputy: Dr. Chnolian Druhn Dr. Heinz Hann 30. '

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen

Seat of the company: Berlin and Berqkamnn .., "-.

Commercial reoistor: AG Cha + Iottenburg 93 HRB 283 and AG Kamen 5 HRB 71

"X 4 · '- PatentgijiijinMjsj-, π r-τ ^

"j I I Q

(in),

wherein R and E have the meanings given above, with osnium tetroxide treated and reductively cleaves the osmiate obtained.

The δα-estatriene of the general forael Ia, which is described in 16a- and 17ß- or 16ß- and 17a-position have a hydroxyl group, can also be obtained by the fact that nan a tetraene of the general Formula III converted into the corresponding 16,17-epoxide and then opens the oxirane ring of the epoxide obtained.

The implementation of the tetraene of the formula III with osmium tetroxide and the reductive cleavage of the osmiate, for example with an aqueous solution of mannitol, ITatriuinhydrogensulfit or with Lithium hydridoaluminate takes place in a manner known per se.

- 15 -

■ 1 ·

Pz-. ■ f

509851/1047

Board of Directors: Hans-Jörgan Hamann · Karl Otto Mlttelstenscheid. Teten: 181 777a schb d · Telegrams: Schoringchomie Borlin Dr. Gerhard Raspe - D '. Horst Wilzel ■ _D. . .. "..", "_ · _ Deputy: Dr. Chnst. To B _ru ! M - Dr. Heinz Hannse Postecheck account: Berlin-West II 75

'' Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen

Sitl tier society: Berlin and Bcrqfcnmen

■ j c. _ 'Palcntaiiieilun

SCHERING AG

itaiiieilunq

The reaction of the etraene of the formula III is epoxide and the subsequent opening of the gxirane ring is also grounded _; . carried out according to processes known per se. The epoxide can be produced, for example, by reacting the tetraene of the formula III with peracids, peracids such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, etc. being possible; it can also be carried out by converting the tetraene of the formula III to the halohydrin, for example by reaction with hypobromous acid to give the bromohydrin, and subsequent ring closure with alkalis, for example potassium hydroxide solution. The oxirane ring can be opened by acid hydrolysis, for example in the presence of sulfuric acid, perchloric acid, or by reaction with metal hydrides, such as, for example, lithium hydridoaluminate, sodium hydridoborate, etc.

The 16, 17-dihydroxy compounds can optionally through subsequent esterification or etherification in the ultimately desired end products of the formula lauber.

The starting compounds can, as in the example of rac-1.3.17-triacetoxy-8a-estra-1.3. "5 (10) .16-tetraene (A), of

-16 -

509851/1047

Board of Directors: Hans-Jörgen Hamann-Karl Otto Mitlelstenscheid Tel: 1 81? 77a schb d · Telegram: Scheringcfcemie Berlin Dr. Gernard Raspe - Dr. Horst Witzel Deputy: Dr. Christian Brunn ■ Or. Heinz Hannse '· Postal check account: Berlin-West 1175-

Chairman of the Supervisory Board: Dr. ELdoard v. Schwarfzkoppen Company headquarters: Berlin and Borqkamon Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen S HRB 71

SCHERING AG

- 16 - Patent Department

optically active! .J -. ^ - Triacetoxy-Sa-ostra-l. 3 ^ 5 (10). 16-tetraene (B) and vcP. 1.5-Diaeetoxy-8o: -östra-1.3 «5 (10) .16-tetraene (C) described.

As -rac »-1.5.17-1? Ria.cetox7 ^ -3a-östra-1.5.5 (10)» IS-tetraene To a suspension of 17 g of Mg turnings in 15 ml of abs. A trace of iodine and 2 ml of ethyl bromide are added to THF and, after heating to 50 ° C., vinyl chloride is slowly introduced until the temperature drops to room temperature. 250 ml of abs are added dropwise during the introduction. THF too. In this Vinylgrignardlösung added dropwise ml abs at 20 ⁰ C the solution of 52.4 g of 6.8-dimethoxy-tetralone in 84th THF and 82 ml abs. Slowly pour in benzene and let it stand under Έ ~ in the refrigerator with a laugh. After warming to room temperature, the ash is added to the mixture of 84 ml of glacial acetic acid and 350 ml of ice water, the mixture is stirred for 30 minutes, the aqueous phase is separated off and extracted with benzene. The combined organic extracts are washed neutral with UaHCO ^ solution and water and dried. In this solution of the. 38 g of 2-methyl-cyclopentanedione are added to vinol compound. (1.3) and 160 mg of potassium hydroxide (powder), concentrated to half, carefully added dropwise 170 ml of methanol and heated to boiling for 3 hours under Ng. It is left to room temperature

-17- -

509851/1047

D ° Gertrd "Ä? Ä, S" lÄ ° "° ^{Miltelstensche} '·' ^1. T..e, M 8t 777a« chb d - Tetegran, ™: Sch.ri.gch.mi. ßer.in

Deputy: Dr. Christian Brunn Dr. Heinz Hanns »Postecheck account: Berlin-West 11 75

Chairman of the Supervisory Board: Dr. Eduard v. Schwartjkoppcn

Company headquarters: Berlin and Berqkampn Commercial register: AG Charlollenburg 93 HRB 283 and AG Karren 5 HRB 71

- 17 - Patents ^ i ^ η η

cool ₂ dilute with ether and remove the excess 2-methylcyclopentanedione ~ (1,> 3) by extraction with 10% sodium hydroxide solution "after neutral washing with water", drying and evaporation is recrystallized from ethanol ".66 gl ₀ 3 is obtained -Dimethoxy-8 _e 14 - seco-lo3 ° 5 (10) o9 (H) -östratetraen 14 ₀ 17-dione $ Melting point 87 / 88-89 ° C _e

A solution of 69 g of lo5-dimethoxy-8 ₀ 14 ~ seco-1. 3 »5 (10) ^ oestratetraen-14 _e 17-dionine 9 ^ -0 ml the benzene is mixed with 3 S p-toluenesulfonic acid and heated to the boil for 20 minutes. Uach itfird cooling with cold TTaHOO ^ solution ₉ extracts washed neutral with water and dried "Each recrystallization from acetone / hexane gives over charcoal 60 g of rac-1,3-dimethoxy-1 '3' 5 (10) 8 _{0 O} 14 ~ oestrapentaen ~ 17-one; Melting point 120-121 ⁰ C.

0.120 mg of rac.-lo3-dimethoxy-l _e 3 _s 5 (10) .8.14-oestrapentaen-17-one in 40 ml of THF in the presence of 60 mg of palladium / CaCO-, (5%) at room temperature below 50 atü EU printing within. Hydrogenated for 17 hours. "Then the catalyst is filtered off, the filtrate is evaporated and the residue is converted from methanol.

j. "

crystallized "This gives 20 mg rac ₀ -1.3 ~ dimethoxy - 8a-östra- · 1.3.5 (lO) -trien-17-one; Melting point 158 / 59-16O ° C.

-18 -

- * t ■

509851/1047

Board of Directors: Hans-Jürgen Hamann · Karl Otto Mittetstenscheid. Telex: 181 777a ochb d Telegrams: Schoringchemie * Berlin

Dr. Gerhard Raspo Dr. Horst Witzel '-. . . , ^,. _r,, . ... ,. - _c

Deputy: Dr. Chnst. To Bruhn Dr. Heinz Hannse Poslscheck-Konio: Borl.n-Wost 11 75

'' Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen

Registered Office: Berlin and Bcrqkair.on

Commercial register: AG Charlultcnburg 93 HRB 283 and AG Kamen 5 HRB 71

JabiejluBg "™"

£, k Lu I I o

tqii 25 S-pyridine hydrochloride and 2.5 g of r £ c _o r-3ct! -estr = -l "5o5ClO) ~ trien" is on 17-under ITp IMD Rülirsn heated for 3 hours at 200 ⁰ C! laughing cooling ₉ Zugabs iron 123 ml of pyridine and 12 ml of acetic anhydride and stirring for 1 hour at room temperature, the solution in ice water / Eiaöl is added, stirred for 1/2 hour _s filtered off and reclaimed the crude product (2.5 g) by gradient © hroaatogr-apiiie ( 60 g SiOp 1 methylene chloride / 10 % acetone) purified. After Ilmloristallisierung from methanol 710 mg i? Ac.-l - ^ - Eis-cetosy-Sa-östra-l.3.5 (lO) -trien-17-on5 Schnelz-

point 179 Ms 180.5 ° C.

A mixture of 5 g

ΊΠ1-

trien-17-one, 100 ml of isopropenyl acetate and 14.4 g of p-toluenesulfonic acid 21 hours with gentle I ^ stream to 105 ° G heated "Mach heating to 125 ⁰ C are" slow 50 ml of isopropenyl acetate is distilled off. iTach cooling are eye is 10 ml of pyridine, there v;.. ird diluted with methylene chloride saturated with _s Ifatriunhydrogencarbonatlösung and water and dried over sodium sulfate The solvent is evaporated under Yalaium iTach chromatography on 260 g SXO2 gives 3 S oily rac-1.3-17- Triacetoxy-8a-östra-1.3 «5 (10) .16-tetraene, which is processed further as a crude product.

-19 -

J!

Pz-,

5,9851 / 1047

Board of Directors: Hans-Iargsn Hamann · Karl Otto MittelienscheisJ Telex: f BI 777a schb d · Telegrams: Soharingchemie Berlin Dr. Gerhard RaspS ■ Dr. Karst Wiizel Ste.V: Dr. Chrisäian B.'uhn Dr. Heinz Hanns »· Postacheck-Kpnto: Berlin-West 11 75

• Board of Directors of the Supervisory Board: Or. Eduard v. Schwartzkoppen

Company headquarters: Berten and Bergkamen

SCHERINGAG

'. _ 19 _. . "" W 778

When using vön. ^ - Ethyl-cyclopentan-dione-Cl. ^) "Or 2 ~ Propylcyclopentan-dione - (lo3) "U ^ d. Further processing- · according to A v / erden:

-rac o -1 » 3- ^ -Triacetoxy-IS-methyl-Sct-östra-1. 3- 5 (10) 16-tetraene

rac-1.J »ly-triacetoxy-IS-ethyl-Sa-estra-1.3.5 (10) .16-" tetraene.

When using isopropenyl butyrate instead of isopropenyl acetate in the last stage is obtained:

rac. -1.3-! Priaceto: jqy-17-butyryloxy-8a-oestra-l. 3 ", 5 (10). 16-tetraene.

B: opt.-akt.-1.3.lV-Triacetoxy-Sa-oestra-1.3 »5 (10) .16-tetraene To a suspension of 42 g of 3-hydroxy-8a-oestra-1.3.5 (10) -trien-17-one in 600 ml of glacial acetic acid vrerden 120 g of lead tetraacetate, then stirred for 3 minutes at room temperature under Peuch- __ tiglreitsabschluss and then poured the batch into 600 ml of ice water. The precipitate is filtered off with suction, washed with water and the fi lt is rescued and dissolved in diethylene chloride.

• "'-20 -

509851/1047

Board of Directors: Hans-Jürgen Hamann · Karl Otto Mittelstenscheid. Telex: 18t 777a schb d - Telegrams: Scheringchemie Berlin

Steik ° - ^ r ^rd cirrs ^P tfanBr'uhn ^r - ^S Dr'HcfnzHannse Poslacheck account: Berlin-West 11 75

■ 'Chairman of the Supervisory Board: Dr. Eduard v. Schwarzenkoppen

Seat of the company: Berlin and Qcr <ikamcn,

Commercial register: AG Ci.arlottenburg 93 HRB 283 and AG Kamen 5 HRB 7t

SCHERiNGAG

_ 20 - Patent qfatoiliwsH η η ο

took. The Subst; The solution is washed neutral with sodium hydrogen carbonate solution and water, dried and concentrated. The concentrate is nit methylene chloride over 400 g of silica gel (• "r 10% water) filtered The substance-containing fractions are combined and the solvent removed. This gives 7 g of Sa-estra-1,4-dien-10ss-acetoxy-3cl7-dione _t the as Raw product processed

A solution of IJ ₅ O g of Sa-estra-l ^ -diene-Loss-acetoxy-3 · 17-dione in 235 s * l acetic anhydride is added dropwise 0.7 e of concentrated sulfuric acid and stirred for 3 hours at room temperature ,, wherein slowly gpht the substance in solution. The batch is then poured into 10 times the amount of ice water, to which 7 S sodium carbonate is added, it is stirred for 1 hour and then filtered off. The washed and dried residue is recrystallized from mineral oil / methylene chloride. 7 S 1,3-Maeetoxy-8a-östra-l _e 3 «5 (10) -trien-17-one with a melting point of 208-211 ° 0 | [-α] ²⁰ = - ^ 89 ° (CHCl ,, c - 0.5).

A mixture of 5 g of 1.3-Diaceto ^ -8a-ostra-1.3.5 (10) -trien-17-one, 100 ml of isopropenyl acetate and 14.4 g of p-toluenesulfonic acid is heated to 105 ° C. for 21 hours under a gentle stream of ITg.

- 21 -

509851/1047

Board of Directors: Hans-JOrgen Hamann · Karl Oüo Miilalstenscheid Te! E «: 1 81 777a schb d - Telegrams: Soheringchomio Berlin

Dr. Gerhard Raspe Dr. Horst jokes! . ^ _. ,, ,, ".- ..,. .. ^ c

Deputy: Dr. Chr.st. to Bruhn ■ Dr. Ho.nz Hannso Posischeck account: Borlm-West II 75

.'Chairman of the Supervisory Board: Dr. ESdjard v. Schv / artzkoppsn
Seat of the Geseilschifr Berlin and Berqkamon
Handelartgistur: AG Cfuiriottcntjutj 93 HRB 2S3 and AG Kamen 5 HRB 71

SCHERING AG

-21 - ■ "" "'?' Ϊ"? 6 7 7 8

After heating to 125 ° C, slowly ground 50 ml of isopropenyl acetate distilled off. After cooling, 10 ml of pyridine are added, it is diluted with methylene chloride, with saturated Washed sodium hydrogen carbonate solution and water and dried over sodium sulfate. The solvent is used evaporated under vacuum. After chromatography on 260 SiC ^ 3 g of 1,3-17-triacetoxy-8a-oestra-1.3-5 (10) .16-tetraene are obtained as oil that is further processed as a raw product.

The following is obtained analogously:

opt.-act.-1.3.ly-Triacetoxy-ie-methyl-Sa-östra-le 3.5 (10) .16-tetraene.

C: opt.-akt.-1.3-diaceto xy-8a-oestra- l. 3 ° 5 (10) .16-tetraene 2 g 1.3-dimethoxy-8a-oestra-1.3-5 (10) -triene-17- on v / erden added to a solution of 3 ^ g of tosylhydrazine in 80 ml of methanol and heated to boiling for 4 hours. After cooling and crystallization of the substance of the precipitate of 1.3 Dimethozy-17 tosylhydrazono-8a-estra-1,3,5 (10) -triene _Λ is sucked off. ", Which was suspended in 40 ml abs. Ether v / ill. The suspension is An ethereal solution of methyllithium is added dropwise while stirring, and after 2 hours it is

- 22-

5,9851 / 1047

Board of Directors: Hans-Jürgen Hamann ■ Karl Otto Milletslenschoid Tolex: I 81 777a schb d · Telegrams: Schoringchemie Berlin

Dr. Gerhard Raspii ■ Dr. Horst Witzol

Stell ».: Dr. Christian Bruhn Dr. Heinz Hannse 'Postscheck-Kopto: Gerlin-WuBl 1175. . "

-'For & itzencier of the supervisory board: Dr. Eduard v. Schwartzkoppen
Seat of the Ge'.cilochäli: Bcrl.n and EJrt.'nkamün
Handclsrcg'ätar: AG Ct.ailoltenburfl S / 3 Hf- (B 283 and AG Kamen 5 HRB 71

SCHERiNGAG

carefully decomposed with water, extracted with ether, washed neutral with water, dried "and evaporated.

The residue of 1.3-dimethoxy-8a-oestra-1.3.5 (10) .16-tetraene is treated with 20 g of pyridine hydrochloride under E _P and

egg.

Stirring heated to 200 ^° C. for 3 hours. After cooling, 80 ml of pyridine and 8 ml of acetic anhydride are added. The mixture is stirred for 1 hour at room temperature below melting point, then precipitated in ice water and filtered off. The substance is taken up in methylene chloride, the solution is washed neutral with water, dried and evaporated. 1 _a J-diacetoxy-Sa-oestra-1 is obtained. 3 «5 (10) .16-tetraene.

The following examples serve to illustrate the invention. The compounds of the invention are obtained both as racemates and as enantiomers. It is obvious to the person skilled in the art that the racemates can be separated into the enantiomers by separation methods such as are generally known for the separation of optical antipodes. The invention thus includes racemates and enantiomers.

09851/1047

SCHERING AG

Patent department

example 1

Me solution of 400 mg 1.3.16a-trihydroxy-8a-estra-1,3,5 (10) -trien-17-one in 5 ml of pyridine is added at O ⁰ C and 1.5 ml of methanesulfonyl chloride and 3 days at 0-1O ⁰ C stirred. It is then poured into ice water (acidified with HCl), filtered off and the residue is dissolved in methylene chloride. After chromatography on, 250 mg of le3 »16a-Tris-mesylo3cy-8a-östra-1.3» 5 (10) -trien-17-one «are obtained,
The following is obtained analogously:

1.3.16ß-Tris-mesylo2cy- = 8a-oestra-l ₀ 3 _a 5 (10) -trien-17-one from 1.3 «16ß-0} rihydroxy-8a-oestra-1.3.5 (10) -triene-17 -on.

Example 2

_ffl l «3« 16 «.17ß-Tetrakis-mesylo3cy-8a-östra-1.3.5 (10) -trien

Mg to a solution of 400 Sa-estra-1.3.5 (10) -triene-1.3.16a.17ßtetrol in 5 ml of pyridine are added at 0 ⁰ C 2 ml of methanesulfonic acid chloride and stirred for 3 days at 0-10 ° C. It is then poured into ice water (acidified with HCl), filtered off and the residue is dissolved in methylene chloride. After purification by chromatography on SiO ₂ , 220 mg of rac are obtained. l _a 3 _e 16a.l7ß-Tetrakis-mesyloxy-8a-oestr-1.3.5 (10) -triene.
The following are obtained analogously:

1.3.16ß.17ß-Tetrakis-mesyloxy-8a-oestr-1.3.5 (10) -triene from 8a-östra-1.3.5 (10) -trien-1.3.16ß.l7ß-tetrol.

5 09851/1047

- 24 -

Board of Directors: Hans-Jürgen Hamann Karl Otto Mittelstenscheid Postal address: SCHERING AG D-1 Berlin 65 Postfach 65 0311

Stell ": D? Ä ^ Hannse Postscheck-Account: Berlin-West 1175-101. Bankle.tzah! 10010010

Chairman of the Supervisory Board · Dr EHinrrt'v qrhwartrknnnpr, Berliner Commerzbank AG. Berlin. Account number 1OB 700,600 bank code 10040000

Chairman oes Auis._htsrats. Ur. Eduard v. Scnwartzkoppen Berliner D.sconto-Bank AG. Berlin. Account no. 241 / S008 BankleiWaOi 100 700

S and AG Kamen H _R B00 ₅ 1

SCHERING AG

Patent department

1.3-16ß, l? A-TetrakiS "mesyloxy-8a-oestr-1.3.5 (10) -triene from 8a-östra-1.3.5 (10) -trien-1.3.16ß.l7a-tetrol.

Example 3

1.3-16a-Tris- (diethylamino-sulfonyloxy) -17a-ethinyl-8a-oestra-1.3.5 (10) -trien-17β-ol

A Grignard solution is prepared from 5> 6 g kg of shavings and 15? 7 saline ethyl bromide in 8 ml of absolute tetrahydrofuran (THF), which is added dropwise to 94 ml of a saturated solution of acetylene in absolute THF while cooling with ice. Acetylene is then passed in for 1 hour at room temperature and then a solution of 1.3 g of 1.3-16a-triacetoxy-8a-b "stra-1.3.5 (10) -trien-17-one in 60 ml of absolute THF is added dropwise at room temperature stirred for a further 20 hours under Up at 70 ⁰ G. Then, the residue (is decomposed with saturated ammonium chloride solution and extracted with Ither. The ethereal solution- is washed until neutral successively with ammonium chloride solution and water, dried and evaporated. 17a-lthinyl-8a-estra -l.3.5 (10) -triene-1.3.16a.17ß-tetrol) is dissolved in 10 ml of dimethyl sulfoxide (DMSO), the solution is mixed with 1 g of FaH stirred nitrogen. is then added the solution of 4 g of diethylamine © sulfonyl chloride in 8 ml DMSO, leaving 25 hours at room temperature to stir. the mixture is then placed in acetic ice water (NaCl) and extracted with ether, "the Xtherphase is neutral with water washed,

509851/1047 -25-

Board of Directors: Hans-Jürgan Hamann · Karl Otto Mitielstenscrieid Postal address: SCHERING AG ■ D-1 Berlin 65 · Postfach 65 03

ΑΑΪΓΑ Hanns »Poetscheck account. Berlin-West 11 75-101. Bankle.tzahl, 00 10010

Bli ε ^ £ B. KMN "<» ^ '

Chairman of the Board of Directors: Dr. Ed ^ rC ν ScnwartzKoppen Berliner ε ₌ ^ £ Be, .m. KoMo no. "<» ^ '

^^ I ^^^ . AG Kamen HRB0051

Patent department

- 25 -

dried and evaporated. After chromatographic purification 500 mg of 1.3.16a-tris (diethylamino-sulfonyloxy) -17a-ethinyl-8a-oestra-1.3.5 (10) -trien-17β-ol are obtained on SiOo.

Example 4

1.3 «16a-Tris- (piperidino-sulfonyloxy) -17a-ethinyl-8a ~ oestra-1.3« 5 (10) · trien-17ß-ol

According to the process described above, 1.3 · 16α-triacetoxy-8a-oestra-1.3-5 (10) -trien-17-one is obtained by reaction with piperidino-sulfonyl chloride 1.3 «16a-tris (piperidino-sulfonyloxy) -17a-ethinyl-8a-oestra-1.3.5 (10) -trien-17ß-ol.

- 26 -

509851/1047

Chairman: Hans-Jürgen Hamann · Karl OHo Mittelstenscheid

Dr. Gerhard RaspS Dr. Horst Witzel Deputy: Dr. Christian Bruhn Dr. Heinz Hannse Chairman of the Supervisory Board: Dr. Eduard v. Schwartzköppen Seat of the company Eirlin and BerqKamen

Commercial register. AG Charlottenburg 93 HRB 283 and AG Kamen HRB 00S1

Postal address: SCHERING AG ■ D-1 Berlin 65 · PostfacH 55 0311 Postal check account: Berlin-West 11 75-101, bank code 10010010 Berlin Commerzbank AG. Berlin. Account no. 108 7006 00. Bank code 100 400 Berliner Disconto-BankAG. Berlin. Account no. 2Ί1 / 5003, bank code 100 700 Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, account no. 14-362, bank code 100 202 00

Claims (1)

Claims
1.j 1.3-oxygenated SCHERING AG Patent department c-Oestratrienes of the general formula I a. (Ia) according to the main patent ............. in which one of the groupings (Patent application P 23 36 434.3), E ² O-R- -R- ... Jt O-R- or in which the -O-R groups can be α or ß, τ: ^ a hydrogen atom, an acyl, alkyl, cycloalkyl or oxygen-containing saturated heterocyclic radical or a sulfonic acid radical, where at least one of the radicals R ¹ or R * represents the sulfonic acid radical, a lower alkyl group, a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon radical
"mean. 509851/1 (K7 " Board of Directors: Hans-Jürgen Hamann · Karl Otto Millelstenecheid Or. Gerhard Raspä - Or. Horst Witzul ^ tellv .: Dr. Christian Bruhn Dr. Heinz Hannse Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters: Berlin and Biirrjkamen Commercial register: AG Charlottenburg S3 HRB 283 and AG Kamen 5 HRB Telex: 181777a schb d - Telegrams: Scheringchemie'Berlin Postal check account: Berlin-West 11 75 ' SCHERING AG Patent department 2.) 1.3.16a-Tris-mesyloxy-8-oestra-1.3.5 (10) -trien-17-one. 3.) 1.3.16β-Tris-mesyloxy-8-oestra-1.3.5 (10) -trien-17-one. 4.) l _e 3.16a.l7ß-Tetrakis-mesyloxy-8-oestr-1.3.5 (10) -triene. 5.) 1.3.16ß.17ß-Tetrakis-mesyloxy-8-oestr-1.3.5 (10) -triene. 6.) 1.3.16ß.17a-tetrakis-mesyloxy-8-oestr-1.3.5 (10) -triene. . 7o) 1.3 «16a-Tris ~ (diethylamino-sulfonyloxy) -17a-ethinyl-8a oestra-1.3.5 (10) -trien-17ß-ol _e 8.) 1.3.16a-Tris- (piperidino-sulfonyioxy) -17a-ethinyl-8aestra-1.3 _e 5 (10) -trien-17β-ol. e) Medicaments based on a compound according to claim 1-8. ,) Yerfahren for the production of 8a-estatrienes of the general Pormel Ia (Ia), where R, R and A \ ^ have the meaning given above, characterized in that according to the main patent 509851/1047 Board of Directors: Hans-Jürgen Hamann · Karl Otto Mittelstenscheid Dr. Gerhard Raspe ■ Dr. Horst Witzel Deputy: Dr. Christian Brunn Dr. Heinz Hannse Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters - Berlin and Bergkamen " Commercial register: AG Charlottenburg93 HRB283 and AG Kamen HRB0051 - 28 - Postal address: SCHERING AG D-1 Berlin 65 PO Box 65 0311 Postal check account: Berlin-West 11 75-101, bank code 10010010 Berliner Commerzbank AG. Berlin. Account no. 108 7006 00. Bank code 100 400 Berliner Dlsconto-Bank AG. Berlin account no. 241/5003. Bank code 100 700 CD Berliner Handels-Gesellschaft - Frankfurter Bank -. Berlin, account no. 14-362. Bank code 100 20200 ν. . - SCHERiNGAG - pa - patent department (Patent application P 23 36 434.3) in per se "known way an enol acylate of the general formula II 0-R- (II), 1 ? 5 wherein E and R have the meaning given above and R ^ represents an ester group, oxidized and optionally then, depending on the desired meaning of R and A> ^ - n isomerized and / or reduced and / or ether - or Splitting off ester groups and / or esterifying and / or etherifying free hydroxyl groups. ) Process for the preparation of 8a-estatrienes of the general formula Ia ¹ - 29 - 509851/1047 Board of Directors: Hans-JOrgen Hamann ■ Karl Otto Mittelstenscheid Dr. Gerhard Rasp * Dr. Horst Witzel Slelly .: Dr. Christian Bruhn - Or. Heinz Hannse Chairman of the do3 Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters: Berlin and Berqkamen Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen 5 HRB 71 Telex: 1BI 777a schb d - Telegrams: Scheringchemie Berlin Postscheck-Account: Berlin-West H 7.5. SCHERiNGAG - 29 - Patent Department wherein R, R und.R ^ have the meaning given above and the. -0-R groups can be in the oc or ß position, characterized in that that in a known manner, a tetraene of the general formula III (in), TP
where R and R have the meaning given above, a). treated with osmium tetroxide and then the ne Osmat reductively splits or
b) epoxidized and then opens the oxirane ring and, if appropriate, then, depending on the desired meaning of R ¹ and R *, splitting off ether or ester groups and / or esterifying and / or etherifying free hydroxyl groups. 00851/1047 Board of Directors: Hans-Jürgen Hamann · Kart Otto Mittelstenachaid Telex: ΐ St 777a schb d ■ Telegrams: Scheringchemie Berlin Dr. Gerhard Raspo Dr. Horst WiUoI. "... '" .., - Deputy: Dr. Christian Bruhn ■ Dr. Heinz Hannse Postscheck account: Berlin-West 11 75