DE2336434A1 - 1,3-disubstd. 8 alpha oestratrienes - oestrogens with minimal uterotropic activity - Google Patents

Abstract

Cpds. of formula (I) are new: alkylenedioxy 16alpha, 17alpha or 16Beta, 17Beta; R1 and R3 = H3, acyl, alkyl, cycloalkyl, or satd. O-contg. heterocyclyl; R2 = lower alkyl; R4 = H or opt. unsatd. or substd. hydrocarbyl; R5 and R6 = H, lower alkyl, aralkyl or opt. substd. phenyl). Prepn. is basically by oxidising corresp. (17-acyloxy)-DELTA16- cpds. opt. followed by convention acylations etc. (I) have strong vaginotropic but weak uterotropic activity useful for treating oestrogen insufficiency e.g. menopausal disorders. Pref. dose is 0.03-5 mg/day.

Description

SCHERiNGAG

Patent department

Berlin, July 11, 1975

1.3-oxysenated 8a-üstratriene

The present invention "relates to I-oxygenated 8a-estratrienes of the general formula I.

(I), v / orin

Av τ, one of the groupings

0-R-

-R-

I X) -

0-R-

or

in which the -O-R - ^ - groups can be α- or ß-,

1 ⁵ p

R, R- ^ a hydrogen atom, an acyl, alkyl, cycloalkyl or oxygenated saturated heterocyclic

Rest,

R is a lower alkyl group,

5 09816/0936

SCHERING AG

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 question. 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.

The following acids may be mentioned as examples: formic acid, acetic acid, Propionic acid, butyric acid, isobutyric acid, yaleric 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, Methyl acetic acid, tert-butylacetic acid, cyclopentylacetic acid, Cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, Diethylaminoacetic acid, piperidinoacetic acid, morpho-

509816/0936

SCHERINGAG

Patent department

¹ I-JULI i97j

linoacetic acid, hilclic acid, succinic acid, adipic acid, Benzoic acid, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid.

1 3
Preferred alkyl radicals R or R "^ are IT-lower alkyl radicals with 1-5 carbon atoms, which can be substituted or branched in the usual way. Examples of the substituents are halogen atoms or 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.

Come as saturated oxygen-containing heterocyclic radicals those in question which are derived from heterocycles with at least one oxygen atom in the ring and those in the oxygen atom-containing Ring are perhydrated. The tetrahydrofuryl- and the tetrahydropyranyl radical, of which the tetrahydropyranyl radical is preferred.

Lower alkyl groups are suitable as substituents R,

5098 16/0936

SCHERINGAG

Patent department

1 JULY 1, 1973

of which "for example the methyl, ethyl, propyl and Butyl group may be mentioned. Preferred radicals are the methyl or ethyl group.

The hydrocarbon radicals R are alkyl, alkenyl or Alkynyl groups with "up to 6 carbon atoms are considered," for example the methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, ethynyl, propenyl, butadienyl and butadiynyl radicals may be mentioned. The remainder can also be substituted in the usual way, with halogen atoms, inter alia, being possible as substituents can. Preferred hydrocarbon radicals R are the ethynyl or ChloräthinyIrest.

The compounds according to the invention have a favorable dissociation Pharinacological effectiveness on · They are preferred because of the strong vaginotropic and weak uterotropic effects suitable for the treatment of postmenopausal women. They are also pharmacological as intermediates for manufacture valuable steroids.

The invention accordingly also relates to medicaments, the 8a-oestrienes of the general formula I contain as active ingredient.

509816/0936

SCHERINGAG

Patent department

¹ 1st mi ί373

The production of the drug specialties takes place in the usual way Way, by combining the active ingredients with the carrier substances, diluents, Flavor corrections etc. in the desired application form, such as tablets, dragees, capsules, solutions etc., convicted. The active ingredient concentration in the soibrmulierte Medicines depends on the form of application. 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 medicaments according to the invention can change with the form of administration and the particular compound selected. In addition, it can change depending on the person being treated. In general, the compounds of the invention are administered at a concentration which can produce effective results without causing any adverse or harmful side effects; so they are administered, for example, at a dose level which ύοχι in the range of about 0.02 mg to about 20 mg is _S although under certain circumstances, modifications can be made, so that a dose of more than 20 mg, used mg for example, up to 50 will. However, a dose level in the range of approx.

509816/0936

,,, -, "SCHERiNGAG

L OOD H OH Patent Department

1 1st Ji'LI 1973

from about 0.05 mg to about 5 mg is preferably used.

The compounds of general formula I can be prepared in this way be that in a known V / eise an enol acylate of the general formula II

0-R ⁵

(II),

12 5

wherein R and R have the meanings given above and Ir has one 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 acyl groups and / or free hydroxyl groups esterified and / or etherified.

The oxidation of the compounds of general formula II, in where R ^ one of the commonly used to protect hydroxy groups acyl groups used, preferably an acyl group in the last

5 09816/0936

~ 7 ~ Patent Department

1 JULY 1, 1373

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

For the implementation of any measures to which the oxidation product is then subjected various methods are known to those skilled in the art, which are described below.

If the product of the oxidation is a 17ß-acyloxy ~ 16ct.l7cc-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, aluminosilicates etc. or by heating above the melting point. If the product of the oxidation is a 17-keto-IGß-acylate, so the isomerization can be carried out with strong bases, of which alkalis are preferred, for example with potassium hydroxide solution, soda solution,

Caustic soda.

5 09816/0936

SCHERiNGAG

1 IMi,: r .;

'· ■ J να ;>:;

A 17-eeto group contained in the oxidation product can then can be reduced by per se "known processes. For example, the reduction can be carried out by reaction with hydrogen in the presence of a common catalyst, such as Raney nickel, platinum, take place. In addition, the hydrogen can be transferred from metal hydrides to the 17 ~ keto group. As hydrogen donors have particularly complex hydrides, such as sodium hydridoborate, Lithium hydridoaluminate, sodium hydride trimethoxoborate, Lithium liydridotri-tert-butoxoaluminate etc. proven .

The reduction can also be carried out by known methods using an organometallic Compound to be carried out in the organic

Zj.

Radical R and which is an alkyl magnesium halide, such as methyl magnesium bromide or iodide, an alkenyl magnesium and / or alkenyl zinc halide, such as vinyl magnesium bromide or allyl magnesium bromide, an alkynyl magnesium halide, such as ithynyl magnesium bromide, propynyl magnesium bromide or propynyl zinc bromide, or an alkali metal acetylide, like potassium acetylide, can act. The one used as a reducing agent organometallic compounds can also be formed in situ and made to react with the 17-ketone. So you let

5 09816/0936

_ Q _ Patent Department

ϊ. JOIi U3

for example for reaction with organometallic alkynyl compounds on the ketone in a suitable solvent alone, 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 likewise according to known methods Procedures are reduced. For example, be the reduction with ketal hydrides or from sodium and alcohols nascent hydrogen mentioned.

An epoxy group contained in the oxidation product can be reduced. The reduction can be carried out catalytically, 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 LiAlH ,, ₂ ITaBIL _45, etc.

Free hydroxyl groups can then be esterified or etherified. Esterified or etherified hydroxyl groups can be incorporated into the Hydroxy groups are transferred. These process measures too are carried out according to methods known per se »

509816/0936

? ^ RASA SCHERINGAG

_ ₁₀ - ZJJb434 _{patent department}

ι July 1st nn

The acylation in the 1- and 3-positions is preferably carried out with Pyridine / acid anhydride "at room temperature. For etherification in the 1- and 3-positions, alkylating compounds are used, as is preferred Diazomethane, dialkyl sulfate, other etherification reagents are for example cycloalkyl halides and dihydropyran.

For esterification of the 173-hydroxy group in 1,3 (l6) -di (tri) esters and "or the 16- and / or 17-hydroxy group in 1,3-dieters lets nan on the steroid for example acid anhydrides in the presence of strong acids, such as p-toluenesulfonic acid, HClO ^, or pyridine / acid anhydride, if necessary act in the heat. The latter methods can also be used to free hydroxy compounds directly into the tri- or tetraacylate to convict.

1,3,16-iriesters and 1,3-dieters can with 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 1,3-dieters according to the invention having an alkyl radical is preferred carried out with alkyl halides in liquid ammonia.

509816/0936

- JLJL - Patent Department

11 JUU 1973

From 1, J-diacyl-IV-tetrahydropyranyl derivatives respectively 1,5,16 -Triacyl-iy-tetrahydropyranyl derivatives can by alkaline saponification the OH-G groups are released.

The ether cleavage is carried out according to methods known per se. Examples include the cleavage with pyridine hydrochloride or pyridine / concentrated hydrochloric acid at elevated temperature were (180-220 ⁰ C) or with Halogenv / on Hydrogen acids in the presence of lower carboxylic acids at temperatures below 150 C, the cleavage of Tetrahydropyranyläthern is carried out under mild conditions by the addition of 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 can 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 I, which are in 16a and 17oc position have a hydroxyl group, can also be thereby obtained that a tetraene of the general formula III

5 09816/0936

SCHERING AG

Patent department

11.Jülil3? 3

(IH),

-ι ρ

wherein R and R have the meaning given above, treated with osmium tetroxide and reductively cleaves the osmiate obtained.

The Sa ~ oestrienes of the general formula I, which are in 16a and 17ß- or 16ß- and 17oc-positions have a hydroxyl group, can also be obtained by using a tetraene of the general Formula III converted into the corresponding 16,17-Spoxid 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, ITodium hydrogen sulfite or with Lithium hydridoaluminate takes place in a manner known per se.

509816/0936

- 13 - Patent Department

11 '. JUL! 1373

The conversion of the tetraene of the formula III to the epoxide and the subsequent opening of the oxirane ring are also carried out according to processes known per se. The epoxide can be prepared, for example, by reacting the tetraene of the formula III with peracids, perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, etc. being suitable as peracids; 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 lithium hydridoaluminate, I sodium hydridoborate, etc.

The 16, 17-dihydroxy compounds can optionally converted into the ultimately desired end products of the formula I by subsequent esterification or etherification.

The starting compounds can, as in the example of rac-1.3.17-triacetoxy-8a-oestra-1.3.5 (10) .16-tetraene (A), of

509816/0936

Patent department

1 July 1st, 1373

optical, active 1.3.17-Triacetox7-8a-östra-1.3.5 (10) .16-tetraene (B) and vco-1,3-diacetoxy ~ 8a-estra-1.3.5 (10) .16-tetraene (C) "described, produced v / ground.

A: rac.-1.3. ^ - Triacetoxy-ere-östra-l.3 »5 (10) .16-tetraene To a suspension of 17 g of Mg turnings in 15 ml of abs. THF is given a trace of iodine and 2 ml of ethyl bromide and then redirects. Warm up slowly to 50 ° C until the temperature drops to room temperature vinyl chloride. 250 ml of abs are added dropwise during the introduction. THF too. The solution of 52.4 g of 6,8-dimethoxy-tetralcm in 84 ml of abs. THI ¹ and 82 ml abs. Benzene slowly and let stand overnight in the refrigerator under Np. After warming to room temperature, the batch is added to the mixture of 84 ml of glacial acetic acid and 350 ml of ice water, stirred for 30 minutes, the aqueous phase is separated off and extracted with benzene. The combined organic extracts are washed neutral with NaHC (X solution and water and dried. 38 g of 2-methylcyclopentanedione (1.3) and 160 mg of potassium hydroxide (powder) are added to this solution of the vinol compound, concentrated to half, 170 ml of methanol are carefully added dropwise and the mixture is heated to boiling for 3 hours under Ng

5098 16/0936

I5 - Patent Department

1 1st JOLi 1973

cool, dilute with ether and remove the excess 2-methylcyclopentanedione- (1.3) by extraction with 10% strength Caustic soda. After washing neutral with water, drying and evaporation, it is recrystallized from ethanol. You get 66 g of 1,3-di-ethoxy-8.14-seco-1.3.5 (10) .9 (II) -ostratetraen-14.17-dione; Melting point 87 / 83-89 ° C.

A solution of 69 g of 1,3-dimethoxy-S.14 - seco-l. 3.5 (10) .9 (H) -östratetraen-14.17-dione in 940 ml dist. Benzene is mixed with 3 S p-toluenesulfonic acid and heated to the boil for 20 minutes. After cooling, it is extracted with cold NaHCO ^ solution, washed neutral with water and dried. After recrystallization from acetone / hexane over charcoal, 60 g of rac.-1,3-dimethoxy-1.3 · 5 (10) .8.14-oestrapentaen-17 ~ one are obtained; Melting point 120-121 ⁰ C.

0.120 mg rac.-1.3-dimethoxy-1.3-5 (10) .8.14-oestrapentaen-17-one in 40 ml TSF v / earth in the presence of 60 mg palladium / CaCO ₇ (5%) at room temperature below 50 atm Hp pressure hydrogenated within 17 hours. The catalyst is then filtered off, the filtrate is evaporated and the residue is recrystallized from methanol. 20 mg of rac.-1,3-dimethoxy-8a-oestra-1.3.5 (10) -trien-17-one are obtained; Melting point 158 / 59-160 ° C.

5 09816/0936

»Atentabteilung

1 I JULY 19/3

- 16 - Patent Department

A mixture of 25 g of pyridine hydrochloride and 2.5 g of rac-1,3-Dinethoxy-8a-estra-1,3,5 (10) -trien-17-one is heated for 3 hours at 200 ⁰ C under ITp and stirring. After cooling, adding 120 ml of pyridine and 12 ml of acetic anhydride and stirring at room temperature for 1 hour, the solution is poured into ice water / TaCl, stirred for 1/2 hour, filtered off and worked up. The crude product (2.5 g) is purified by gradient chromatography (60 g SiOo; methylene chloride / 10 % acetone). After recrystallization from methanol, 710 mg of rac.-l.3-Macetoxy ~ 8a-oestra-1.3 «5 (10) -trien-17-one; Melting point 179 to 180.5 ⁰ C.

A mixture of 5 S rac. ~ 1.3-diacetoxy-8ct-oestra-1.3.5 (10) -trien-17-one, 100 ml of isopropenyl acetate and 14.4 g of p-toluenesulfonic acid is on for 21 hours under a gentle stream of Np Heated to 105 ° C. After heating to 125 ^° C., 50 ml of isopropenyl acetate are slowly distilled off. After cooling, 10 ml of pyridine are added, it is diluted with methylene chloride, washed with saturated IT atx ^ iunhydrogencarbonat solution and water and dried over sodium sulfate. The solvent is evaporated in vacuo. Chromatography on 260 g of SiOp gives 3 S oily rac.-1.3.17-triacetoxy-8a-estra-1.3.5 (10) .16-tetraene, which is further processed as a crude product.

5098 16/0936

"~ 17 ~ Patent Department

11 JULY73

When using 2-ethyl-cyclopentanedione- (l »3) or 2-Propylcyclopentan-dione- (1.3) and further work-up according to A are obtained:

rac.-1.3.17-Triacetoxy ~ lß ~ methyl ~ 8a ~ oestr-1.3.5 (10) .16-tetraene

rac. -1.3. ^ -Triaceto ^ -lS-ethyl-Sct-östra-l. 3.5 (10). 16-tetraene.

If isopropenyl butyrate is used instead of isopropenyl acetate in the last stage vjlrd:

rac-1,3-triacetoxy-17-butyryloxy-8a-estra-1.3.5 (10) .16-tetraene.

B: opt.-akb.-1.3 » 17-J riacetox y -8a-östra-1.3.5 . (1. 0) . 16-tetraene 120 g of lead tetraacetate are added to a suspension of 42 g of 3-hydro: xy-8a-oestra-1.3.5 (10) -trien-17-one in 600 nil glacial acetic acid, then stirred for 3 minutes at room temperature with the exclusion of moisture and then poured the batch into 600 ml of ice water. The precipitate is filtered off with suction, washed with water and the filter residue is dissolved in ethylene chloride.

509816/0936

SCHERiNGAG

_{sponsor lab} 1 JUL 1! 1973

took. The substance solution is washed neutral with sodium hydrogen carbonate solution and water, dried and concentrated. The concentrate is filtered through 400 g of silica gel (+ 10 % water) with ethylene chloride. The substance-containing fractions are combined and freed from the solvent. This gives 7 g 8a _{dione-estra-1,4-dien-10ss-acetoxy-17.3-t} which is further processed as a crude product.

A solution of 13> 0 g of Sa-Östra-l. ^ - diene-lOß-acetoxy-3 · 17-dione in 235 ml of acetic anhydride is treated dropwise with 0.7 ral concentrated sulfuric acid and stirred for 3 hours at room temperature, the substance slowly in solution. The batch is then poured into 10 times the amount of ice water to which 7 S sodium carbonate is added, the mixture is stirred for 1 hour and then filtered off. The washed and dried residue is recrystallized from methanol / methylene chloride. 7 g of 1,3-diacetoxy-8a-oestra-1.3.5 (10) -trien-17-one with a melting point of 208-211 ° C. are obtained. «[" Α] ²⁰ = + 89 ° (CiICl ₅ ,, c = 0 , 5).

D ^

A mixture of 5 g of 1,3-diacetoxy-8a-oestra-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 upstream.

509816/0936

- I9 -. Patent department

11. J ¹ J-! 1973

After heating to 125 ° C., 50 ml of isopropenyl acetate are slowly added '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 will evaporated under vacuum. After, chromatography on 260 SiOo 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.-1.3.17-Triacetoxy-18-methyl-8a-estra-1.3 · 5 (10) .16-tetraene.

C: opt.-akt.-1,3-piacetoxy-8q-5stra-1.3.5 (10) «ie-tetraene 2 g of 1,3-dimethoxy-8a-estra-1.3.5 (10) -trien-17-one become added to a solution of 3 »4 g of tosyhydrazine in 80 ml of methanol and heated to boiling for 4 hours. After the substance has cooled and crystallized out, the precipitate of 1,3-dimethoxy-17-tosylhydrazono-8a-estra-1.3.5 (10) -triene is filtered off with suction, which is dissolved in 40 ml of abs. Ether is suspended. An ethereal methyllithium solution is added dropwise to the suspension while stirring. After 2 hours it will

509816/0936

- 20 - Patent Department

1 1st Jr-I -m

carefully decomposed with water, etherified with water washed neutral, dried and evaporated.

The residue of l ^ -Dimethoxy-Soc-östra-l. 3 · 5 (1Ο) .16-tetraene is treated with 20 g of pyridine hydrochloride and Np under stirring for 3 hours at 200 ⁰ C heated. After cooling, 80 ml of pyridine and 8 ml of acetic anhydride are added. It is stirred for 1 hour at room temperature under Np, then precipitated in ice water and filtered off. The substance is taken up in methylene chloride, the solution washed neutral with water, dried and evaporated. 1,3-Diacetoxy-8a-oestra-1.3 · 5 (10) .16-tetraene is obtained.

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

example 1

g rac.-1.3-17-triacetoxy-8a-oestra-1.3.5 (10) .16-tetraene

509816/0936

atentabcilung

1 1 JUL * '-73

• ^ Patent Department

in 70 ml methyl enchl or id with the addition of 3 g sodium sulfate sicc, 0.36 g of sodium acetate and 2.2 ml of stabilized peracetic acid in Epoxidized for 2 hours at room temperature. The reaction mixture is at ice temperature with water, sodium carbonate solution and Ash neutralized water and dried over sodium sulfate. To Filtration, the solvent is evaporated. The remaining residue of 1.5 g of rac.-1.3.17ß-Ti "iacetoxy-16a.l7a-epoxy-8aöstra-1.3" 5 (10) -triene is reacted according to Example 2 without further purification.

Inalog are received:

rac.-1.3 · 17β-triacetoxy-16a · 17a-epoxy-18-methyl-8a-estra-1.3.5 (10) -triene

rac.-1.3.17-Triacetoxy-16a.17a-epoxy-18-ethyl-8a-oestra-1.3.5 (10) -triene.

Example 2

500 mg of rac.-1.3.17-a? Riacetoxy-16a.l7a-epoxy-8a-oestra-1.3.5 (10) -triene are suspended in 50 ml of methanol and 10 ml of 5N sulfuric acid mixed. After stirring for 15 hours, the substance went into solution. The solution is used on a rotary evaporator concentrated, the concentrate in ice-cold saturated sodium chloride

509816/09 3 6

- Ί * - ~~ Patent department

11_ July is73

given solution, filtered off the precipitate, taken up in ethyl acetate and washed neutral with sodium chloride solution. To Recrystallization from acetone / hexane gives 175 ^ g of rac.-1.3 · 16a-trihydroxy-8a-estra-1.3 «5 (10) - fcrien - 17 - one.

The following are obtained analogously:

rac.-1.3 «16a -'-Drihydroxy-18-methyl-8a-estra-1.3.5 (10) -trien-17-one rac. -1.3.16a-G? Rihydroxy-18-ethyl-8a-oestra-l. 3.5 (10) -triene-17 ~ one.

Example 3

150 mg rac. ~ 1.3 »16a-trihydroxy-8a-estra-1.3.5 (10) -trien-17-one are taken up in 20 ml of pyridine and with 10 ml of acetic anhydride offset. After stirring for 5 hours at room temperature is poured into ice water, the precipitate is filtered off and taken up in ether. The essential solution is saturated with Washed sodium chloride solution until neutral, dried and evaporated. Recrystallization from methanol gives 100 mg of rac.-1.3.16a-Q? Riacetoxy-8a-oestra-1.3.5 (10) -trien-17-one.

The following are obtained analogously:

rac.-1.3.16a-Triacetoxy-18-methyl-8a-oestra-1.3.5 (10) -triene-

509816/0936

Patent department

11. JOLi 1373

rac.-1.3.16a-Triacetoxy-IS-ether-yl-8a-oestra-1.3.5 (10) -trien-17-one.

By using caproic anhydride or enanthic anhydride instead of acetic anhydride v / earth: rac.-1.3 · 16a-Tris-hexanoylo2qy-8a-estra-1.3 · 5 (10) -trien-17-one

Example 4

500 mg rac.-1.3.17ß-Triacetoxy-16a.l7cc-epoxy-8a-östra-1.3.5 (10) trien are added with 16 g of silica gel in 25 ml of methylene chloride Isomerized at room temperature in 25 hours. 400 mg are obtained rac.-1.3 «16a-Triacetoxy-8a-oestra-1.3.5 (10) -trien-17-one.

Example 5

To a mixture of 3 g of rac.-1.3 «16a-trihydroxy-8a-estra-1.3.5 (10) -trien-17-one 0.15 ml of perchloric acid (70%) are added to 300 ml of ethyl acetate and 25 ml of acetic anhydride, after stirring for 5 minutes at room temperature, 25 ml of pyridine added. It is concentrated on a rotary evaporator, the residue in ice water / HaCl, precipitated, stirred for 30 minutes to obtain the To decompose excess acetic anhydride, and filtered off. The precipitate is taken up in ether, the solution with saturated Washed brine, dried and evaporated.

509816/0936

- 2A- - Patent Department

11.MM973

Kan receives 1.5 g of rac.-1.3. Löcc-Triacetoxy-Sa-östra-l. 3.5 (10) -triene-17-one.

The following are obtained analogously:

rac.-l.3 16a-Triaceto: xy-18-iaethyl-8a - östra-l.3 5 (10) -triene-

rac.-1.3 «16a-Tris-heptanoyloxy-8a-estra-1.3-5 (10) -trien-17-one.

Example 6

500 mg of rac.-1.3.17ß-Ti ^> iacetoxy-16a.l7a-epoxy-8a-oestra-1.3.5 ('l0) -triene are added in 10 ml of THF to a suspension of 500 mg of lithium tetrahydridoaluminate in 15 ml of abs. THF is added dropwise while cooling with ice. After stirring at room temperature for 1 hour, 10 ml of glacial acetic acid are carefully added. The solution is diluted with ether and washed neutral in succession at ice temperature with dilute hydrochloric acid, dilute sodium hydrogen carbonate solution and saturated sodium chloride solution and worked up. A mixture of 240 mg of rac.-1.3.16a.l7ß-tetr8hydroxy-8a-oestra-1.3.5 (10) -triene and 60 mg of rac.-1.3-16a.l7a-tetrahydroxy-Sa-oestra-1.3 is obtained. 5 (10) - 'brien.

Example 7

500 mg rac.-l.3.16a-triacetoxy-8a-oestra-1.3.5 (10) -trien-17-one v / ground in 10 ml THF to form a suspension of 500 mg lithium tetra-

509816/0936

- 25 - Patent Department

Π. JULY 19/3

hydridoaluminate in 15 ml of abs. TEF was added dropwise with ice cooling. After stirring for 1 hour at room temperature, 10 ml of glacial acetic acid were carefully added. The solution is diluted with ether and washed successively with dilute hydrochloric acid, dilute sodium hydrogen carbonate solution and saturated sodium chloride solution and worked up at ice temperature. 300 mg of rac.-1.3 · 16a.17ß-tetrahydroxy-8a-estra-1.3 · 5 (10) ~ triene are obtained.

Analog are obtained;

rac. -1.3 16a. 17β-Tetrahydroxy-18-methyl-8α-estra-1 «> 3 «5 (10) -triene rac.-1.3» 16a.17ß-tetrahydroxy-18-ethyl-8a-estra-1.3e5 (10) -triene.

Example 8

2 g of rac.-1.3 «17-Ti'ia-cetoxy-8a-estra-l« 3 »5 (10)» 16-tetraene are dissolved in 40 ml of glacial acetic acid and 2 ml of acetic anhydride with 5-5 g of lead tetraacetate for 15 hours at room temperature touched. The mixture is evaporated on a rotary evaporator _β The residue is taken up in Essigester and washed with saturated Uatriumchloridlösung neutral. Small amounts of starting substance are separated off by preparative thin-layer chromatography. After elution with acetone it is re-acetylated with acetic anhydride and pyridine. After working up and recrystallization from methylene chloride /

5 09816/093 6

- 26 - Patent Department

1 JULY 1, 1973

Isopropyl ether gives 700 ing rac.-l. 3 «16 [beta] -triacetoxy-8ocöstra-1.3.5 (10) -trien-17-one.

The following is obtained analogously:

rac.-l.3.leß-trihydroxy-lS-methyl-Sa-östra-l.3.5 (10) -triene-

Example 9

500 mg of rac.-1.3.16ß-triacetoxy-8a-oestra-1.3.5 (10) -trien-17-one in 10 ml of THF are added dropwise to a suspension of 500 mg of lithium aluminum hydride in 15 ml of THF while cooling with ice. To
1 hour of stirring at room temperature v / earth 10 ml of glacial acetic acid carefully added. The solution is diluted with ether and washed neutral in succession at ice temperature with dilute hydrochloric acid, dilute sodium hydrogen carbonate solution and saturated sodium chloride solution. After working up, 250 mg of rac.-1.3.16ß.17ß-tetrahydroxy-8a-estra-1.3.5 (10) -triene are obtained.

Analogously to v / ird we get:
rac.-1.3.16ß.17ß-Tetrahydroxy-18-methyl-8a-estra-1.3.5 (10) -triene.

5 09816/0936

- 27 - Patent Department

1 1st JUU 1073

Example 10

To a mixture of 2 g of rac.-1.3.16a.l7ß-tetrahyaroxy ~ 8aestra-1.3.5 (10) -triene in 200 ml of ethyl acetate and 15 ml of acetic acid anhydride 0.1 ml of 70% perchloric acid are added, after stirring for 5 minutes, 20 ml of pyridine are added. It is worked up according to Example 5, yield 700 mg of rac.-1.3.16a.17ß-tetraacetoxy-8a-oestra-1.3.5 (10) -triene.

Example 11

100 mg of rac-1.3.16ß.l7ß-Tetrahyuroxy-8a-estra-1.3.5 (lO) -triene be taken up in 15 ml of pyridine and -versetzt with 7 ₅ 5 ml of acetic anhydride. After stirring for 5 hours at room temperature, work-up is carried out as in Example 3. Yield 65 mg of rac-1.3.16ß.17ß-tetraacetoxy-8a-estra-1.3.5 (10) -triene.

Example 12

1 g of 1.3.17-T3? Iacetoxy-8a-oestra-1.3.5 (10) .16-tetraene are in

35 ml of methylene chloride with the addition of 1.5 g of sodium sulfate sicc., 0.2 g sodium acetate and 1.1 ml stabilized peracetic acid in

Epoxidized for 2 hours at room temperature. The reaction mixture is at ice temperature with water, sodium carbonate solution and Washed neutral with water and dried over sodium sulfate.

5 09816/0936

28 - Patent Department

ULi 1573

After filtration, the solvent is evaporated. The remaining one Residue [0.5 g opt.-akt.-1.3.17ß-triacetoxy-16a.l7aepoxy-8oc-oestra-1.3 «5 (10) -triene] is reacted according to Example 13 without further purification.

Example 13

500 mg of 1.3.17ß-triacetoxy-16a.l7a-epoxy-8a-oestra-1.3.5 (10) -triene are isomerized with 15 g of silica gel in 25 ml of methylene chloride at room temperature in 3 hours. 350 mg is obtained OPTION akb. 1.3 »16a-triacetoxy-8a-estra-1.3.5 (lO) -triene-17-one of melting point 230-237 ⁰ C (methanol / acetone).

Example 14-

Ig opt.-akt.-1.3.17-triacetoxy-8a-estra-1.3.5 (10) .16-tetraene are stirred in 20 ml of glacial acetic acid and 1 ml of acetic anhydride with 2.7 g of lead tetraacetate for 15 hours at room temperature. the Mixture is evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and washed with saturated sodium chloride solution washed neutral. Small amounts of starting substance are separated off by preparative thin-layer chromatography. After elution with acetone, acetylation is carried out with acetic anhydride and pyridine. After work-up and recrystallization from methyl

509816/0936

"~ <-9 ~" Patent Department

11.JÜU1973

lenchlorid / isopropyl ether are obtained 700 mg OPTION ~ akt.l.3.16ß triacetoxy-8a-estra-1.3.5 (lO) -triene-17-one of melting point 220-224 ⁰ C (methanol / acetone).

Example 13

From 5.6 g of Mg turnings and 15.7 ml of ethyl bromide in 78 ml of abs. THF a Grignard solution is prepared, which in 94 ml of a saturated Solution of acetylene in abs. THP "is added dropwise with ice-cooling. Acetylene is then added for 1 hour at room temperature initiated and then a solution of 1.4 g of 1.3 · 16α-triacetoxy-8a-oestra-1.3.5 (10) -trien-17-one in 60 ml abs. THF was added dropwise at room temperature and for a further 20 hours under ^ at 70 ° C stirred. Then it is decomposed with saturated ammonium chloride solution and extracted with ether. The essential solution is successively washed neutral with ammonium chloride solution and water, dried and evaporated. The residue becomes Hachacetylation dissolved in 20 ml of pyridine, with 10 ml of acetic anhydride added and left to stand for 5 hours at room temperature. Revenge pouring into ice water and processing will be Purified crude product by chromatography on silica gel. 5OO mg of 1.3.16a-triacetoxy-17a-äthinyl-8a-oestra-1.3.5 (lo) -

trien-17β-ol as an amorphous powder; [α] ²⁰ = + 23-6 ° (CHClO.

D ^y

5 09816/0936

- 30 - Patent Department

11 JUU 1973

Example 16

To a boiling suspension of 1.4 g of IL-jCO ^ in 5 ml of acetone a solution of 475 mg Östra-1.3.5 (10) -triene-1.3.16a.l7ß ~ tetrol and 0.6 ml of dimethyl sulfate in 2.5 ml of acetone were slowly added. After refluxing for 4 hours, add sis water given, stirred for 1 hour, filtered and worked up. After chromatographic purification on silica gel, 1,3-dimethoxy-8a-oestra-1.3 · 5 (10) -triene-16a is obtained.

Example 17

To a solution of 900 mg of 1,3-dimethoxy-8a-oestra-1.3.5 (10) -triene-16a.l7ß-diol in 45 ml abs. Benzene v / earth 1.35 ml dist. Dihydropyran and 10 mg of p-toluenesulfonic acid are set. The solution is stirred for 1.5 hours at room temperature, then washed neutral with a sodium hydrogen carbonate solution and V / ater, dried and evaporated. 800 mg of 1,3-dimethoxy-16a.17ß-bis (tetrahydropyranyloxy) -8a-estra-1.3.5 (10) -triene are obtained.

Example 18

A solution of 500 mg of 1.3.16a-triacetoxy-8a-oestra-1.3.5 (10) -trien-17-one in 20 ml of methanol is mixed with 10 ml of 0.1 η sodium hydroxide solution and treated for 4 hours at room temperature below Ή2

5098 16/093 6

"" pi ~ 'patent department

11. JOLi 1973

stirs. It is then diluted with ethyl acetate, washed neutral with water, dried and evaporated. 1.3 «17ß-trihydroxy-8a-estra-1.3.5 (10) -trien-16-one is obtained.

Example 19

A solution of 1.38 g of 1,3-diacetoxy-8a-estra-1.3.5 (10) .16-tetraene and 1.0 g of osmium tetroxide in 15 ml of pyridine is stirred for 2 hours at room temperature. Then, while stirring, a Solution of 1.8 g of sodium hydrogen sulfite in 30 ml of water and 20 ml Pyridine was added, the mixture was stirred for 10 minutes and extracted with methylene chloride. The methylene chloride solution is dried and evaporated. The residue is dissolved in 5 ml of pyridine and heated with 3 ml of acetic anhydride on the steam bath for 30 minutes. To Pouring into ice water, working up, drying and evaporation gives 1.3.16a.l7oc-tetraacetoxy-8a-oestra-1.3.5 (10) -triene.

Example 20

A solution of 350 mg of 1,3-J-diacetoxy-8a-oestra-1.3.5 (10) .16-tetraene in 15 ml of ether is mixed with 7 ml of a 12% ethereal monoperphthalic acid solution. After 7 _S stand for 5 hours at room temperature, is worked up. 1.3-Diacetoxy-16a.l7a-epoxy-8a-oestra-1.3.5 (10) -triene is obtained, which is used as

509816/0936

Patent department

1 January 1, 1973

~ ^ ' Patent department

Raw product heated to boiling with 30 ml of glacial acetic acid for 2-3 hours will. After concentration in vacuo, the residue is esterified with 2 ml of pyridine and 2 ml of acetic anhydride for 1.5 hours heated on the steam bath under Np. After giving into ice water it will taken up in methylene chloride and worked up. After chromatographic purification on SiOo 1.3 »16.

Example 2 1

A suspension of 330 mg of 1,3-diacetoxy-8a-estra-1.3 »5 (10) .16-tetraene, 10 ml of abs. Dimethyl sulfoxide and 0.6 ml of V / ater \> / ird at about 12 ⁰ C in portions with 280 mg of N-bromosuccinimide. After 30 minutes, it is worked up and the residue is heated on the steam bath for one hour with 10 ml of 3% strength methanolic potassium hydroxide solution. It is then neutralized with glacial acetic acid, evaporated and worked up. This gives 1,3-diacetoxy-16ß.17ß-epoxy-8oc-oestra-1.3.5 (10) -triene, which is heated to boiling with 5 ml of glacial acetic acid for 3 hours. It is then concentrated in vacuo, the residue is _{heated under N 2} in 3 ml of pyridine with 3 ml of acetic anhydride on the steam bath for 1.5 hours, poured into ice water and worked up.

509816/0936

SCHERINGAG

33- - ~ wT _V T Patent Department

I I. J'Jd 13/0

After chromatographic separation, 1.3 · 16α.17Β-tetracetoxy-8a-oestra-1.3.5 (10) -triene is obtained and 1.3.16ß.17a-tetraacetoxy-8a-estra-1.3.5 (10) -triene.

Example 22

1.25 g of YLJSO-z and 1.4 ml of cyclopentyl bromide are added to a solution of 0.95 g of 8a-Östra-1.3-5 (10) -triene-1.3.16oc.l7ß-tetrol in 30 ml of ethanol. The suspension is heated to boiling for 5 hours with stirring and Np, after cooling it is poured into ice water and filtered. The residue is taken up in ether, the organic phase washed neutral, dried and evaporated. After purification by chromatography, 0.35 g of 1,3-bis-eyclopentyloxy-8a-oestra-1.3.5 (10) -triene-16a.17ß-diol is obtained.

5 09816/0936

Claims (1)

~ 34 - Patent Department 11 JUU 1973 Claims ί. 1.3-oxygenated 8a-oestratrienes of the general formula I. (I), wherein one of the groupings O-R- -R- or in which the ~ 0-R groups can be α or ß, 3
R, .R- ^ a hydrogen atom, an acyl, alkyl, cycloalkyl or oxygen-containing saturated heterocyclic radical, a lower alkyl group, a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon residue
■ mean. 5098 1 6/0936 Patent department ΐ 1st JOiI 1973 2.1.3.16a-a? Rihydroxy-8a-oestra-1.3.5 (10) -trien-17-one. 3. 1.3.16a-Triacetoxy-8a-estra-1.3.5 (10) -tr ± en-17-one. 4 ·. 8a-östra-1.3-5 (10) -trien-1.3.16α.17ß-tetrol. 5. 8a-Östra-1.3.5 (10) -trien-1.3.16a.l7a-tetrol. 6. 1.3.less-triacetoxy-Sa-oestra-1.3.5 (10) -trien-17-one. 7. 8a-Östra-1.3.5 (10) -trien-1.3.16ß.l7ß-tetrol. 8 1.3.16a. 17ß - ^? Etraacetoxy-8a-östra-l. 3.5 (10) -trien. 9. 1.3.16ß.17ß-tetraacetoxy-8a-estra-1.3.5 (10) -triene. 10.1.3.16a-Triacetoxy-17a-ethinyl-8a-oestra-1.3.5 (10) -trien-17ß-ol. 11. 1.3-Dimethoxy-8a-oestra-1.3.5 (10) -triene-16a.17ß-diol. 12. 1,3-dimethoxy-16a. 17β- "bis- (tetrahyropyranyloxy) -8aestra-1.3.5 (10) -triene. 5 09816/0936 Patent department JULY 11, 1973 13.3.17ß-Trih7tLroxy-8a-östra-l. 3.5 (10) -trien-16-one. 14.3.16a.l7a-tetraacetoxy-8a ~ oestra-1.3.5 (10) -triene. 15. -1.3-Diacetoxy ~ 16ß.17ß-epoxy-8a-estra-1.3 * 5 (10) ~ triene. 16. 1.3-Bis-cyclopentyloxy-8a-oestra-1.3 · 5 (10) -triene-16a.17ßdiol. 17. Medicaments based on a compound according to claim 1 - 18. Process for the preparation of 8a-estatrienes of general Formula I. 1 2
where R, R and A ^ _{B have} the meaning given above, characterized in that in a known manner 509816/0936 Patent department 1 I.Jüt! 1973 an enol acylate of the general formula II O-R- (II), 12 5 in which E and R have the meaning given above and Έ / represents an acyl group, oxidized and optionally then, depending on the meaning of R and A ^ -n isomerized and / or reduced and / or split off ether or acyl groups and / or free hydroxyl groups are esterified and / or etherified. 19. Process for the preparation of 8a-estatrienes of the general Formula Ia R ¹ -0 (Ia), 5 09816/0936 Patent department 1 JULY 1 1S73 wherein R, R and R ^ have the meaning given above and the -0-R groups can be in the α or ß position, characterized in that that in a known manner, a tetraene of the general formula III (HD, 1 2
where R and R have the meaning given above, a) treated with osmium tetroxide and then reductively cleaves the osmate obtained or b) epoxidized and then opens the oxirane ring and optionally then, depending on the desired meaning of R and Ή / ether or acyl groups, and / or free hydroxyl groups esterified and / or etherified. 509816/0936