AU625450B2 - 11beta-phenyl-4,9,15-estratrienes, their manufacture, and pharmaceutical preparations containing them - Google Patents

Description

PcrWETOG INTERNATIONALE ANMELDL INTERNATIONALE ZUSAM MJ~ (51) Internationale Patentklassifikation 4 C07J 1/00, A61K 31/565 C07J 41/00 AU-AI -20762/88 NISATION FOJR GEISTIGES E1GENTUM A nat 4.tes Blro H C ETAGOE I D 4 GLB ETL PATENTWESENS (PCT) (11) Internationale Verdffentlichungsnummer: WO 89/ 00578 Al (43) Internationales Veroffentlichungsdatum: 26. Januar 1989 (26.01.89) (21) Internationales Aktenzeichen: (22) Internationales Anmeldedatum: (31) Prioritiitsaktenzeichen: (32) Prioritatsdatum: (33) Prioritiitsland: PCT/DE88/00447 15. Juli 1988 (15.07.88) P 37 23 788.8 16. Juli 1987 (16.07.87) (71) Anmielder (fafr alle Bestimmungsstaaten ausser- US): SCHERING AKTIENGESELLSCHAFT BERLIN UND BERGKAMEN [DE/DE]; Mflerstrall 170/178, D-1000 Berlin 65 (DE).

(72) Erfinder;und Erfinder/Anmelder (nur fulr US) OTTOW, Eckhard Sonnenallee 124, D-1000 Berlin 44 (DE).

HOFwitEISTER, Helmut [DE/DE]; Weislingenstrage 4, D-1000 Berlin 28 SCHOLZ, Stefan [DE/DE]; Lfitzenstra~e 9, D-1000 Berlin 31 NEEF, Giinter [DE/DE]; Darmstddter Strage 9, D-1000 Berlin 15 ELGER, Walter [DE/DE]; Schorlemer Allee 12 B, D-1000 Berlin 33 BEIER, Sybille [DE/DE]; Uhlandstrage 121, D-1000 Berlin 31 CHWA- LISZ, Krzysztof [PL/DE]; Luzerner Strage Id, D- 1000 Berlin 45 (DE).

(81) Bestimmungsstaaten: AU, DK, Fl, HU, JP, US.

Verdffentlicht A'fit internationalem Recherchenberich t.

AUSTRALIAN

1 3FEB 1989 PATENT OFF~ICE (54) Title: 11 o-PHENYL-4,9, 15-ESTRATRIENES, THEIR RATIONS CONTAINING THEM MANUFACTURE, AND PHARMACEUTICAL PREPA- (54) Bezeichnung: 1 11-PHENYL-4,9,15-ESTRATRIENE, DEREN HERSTELLUNG UND DIESE ENTHALTENDE PHARMAZEUTISCHE PRXPARATE (57) Abstract New I11-phenyl-4,9,15-estratrienes have general formula (I) where X is an oxygen atom or an N-OH hydroxyimino grouping, RI is a hydrogen atom or a methyl group, R 2 is a hydrogen atom, or an alkyl(I or acyl residue with I to 10 carbon atoms, R 3 is a hydrogen atom, a cy anomethyl group, -((ffvCH),CH 2 Z, where n 1, 2, 3, 4 or 5, Z -H or -OR 5 where R 5 is a hydrogen atom or an alkyl or acyl group with I to 10 C atoms, or -(CH 2 )mnC=C-Y, where mn 0-2 and Y is a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, X alkoxyalkyl or acyloxyalkyl group with I to 10 C atoms, R 4 is a x/Y -cstraight-chain or branched-chain, saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms, containing the grouping represented by formula where X is as defined above. The compounds possess antigestagen and antiglucocorticoid properties.

(57) Zusammenfassung Es werden neue I I -Phenyl-4,9,15-estratriene der allgemeinen Formel beschrieben, wormn X ftir emn Sauerstoffatom oder eine Hydroxyiminogruppierung N -OH, R 1 f~r emn Wasserstoffatom oder eine Methylgruppe, R 2 f~lr emn Wasserstoffatom, einen Alkylrest oder einen Acylrest mit jeweils I bis 10 Kohl enstoffato men, R 3 fir emn Wasserstoffatom, eine Cyanmethylgruppe, -(CH 2 )nCH 2 Z, wobei n die Ziffern 0, 1, 2, 3, 4 oder 5, Z -H oder -OR 5 mit R 5 in der Bedeutung eines Wasserstoffatoms oder einer Alkyl- oder Acyigruppe mit jeweils I bis 10 Kohlenstoffatomen, oder ftir -(CH2))mC -C- Y, wobei mn 0-2 und Y emn Wasserstoff-, Chior-, Fluor-, Jod- oder Bromatom, eine Alkyl-, Hydroxyalkyl-, Alkoxyalkyloder Acyloxyalkylgruppe mit jeweils I bis 10 Kohlenstoffatomen bedeuten, R 4 fMr einen geradkettigen oder verzweigten, gesiittigten oder ungesiittigten Koh lenwasserstoffrest mit bis zu 8 Kohlenstoffatomen, der die Gruppierung mit X in der oben genannten Bedeutung enthitlt; stehen. Die Verbindungen besitzen antigestagene und antiglucocorticoide Wirksamkeit.

71 r f -1- 118-PHENYL-4,9,15-ESTRATRIENES, THEIR MANUFACTURE AND PHARMACEUTICAL PREPARATIONS CONTAINING SAME The invention relates to the subject matter characterized in the Patent Claims, i.e. new 11-phenyl-4,9,15-estratrienes, methods for their production and pharmaceutical preparations containing these compounds.

The compounds in accordance with the invention are characterized by the general formula I

R

1 3 1(I) where X implies an oxygen atom or a hydroxyimino grouping N-OH, R stands for a hydrogen atom or a methyl group, 2 R implies a hydrogen atom, an alkyl radical or an acyl radical with in each case 1 to 10 carbon atoms, 3 R stands for a hydrogen atom, a cyanomethyl group,

-(CH

2 )nCH 2 Z where n implies the numbers 0, 1, 2, 3, 4 or 5 5 Z -H or -OR with R having the significance of a hydrogen atom or an alkyl or acyl group with in each case 1 to 10 carbon atoms, or for -(CH -CaC-Y where 2 m m 0 2 and Y implies a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group with in each case 1 to carbon atoms, 4 R stands for a straight-chain, saturated aliphatic

(C

1

-C

4 )-acyl residue.

-2- KThe alkyl and acyl groups contained in R2or the alkyl, 5 acyl or alkoxy groups contained in R and Y should in each case have 1 to 10 carbon atoms, preference being given to the methyl, ethyl, propyl, formyl, acetyl, propionyl, butyryl, benzoyl, methoxy and ethoxy groups.

The acyl radical R 4can contain up to 4 carbon atoms.

Acyl radicals wherein the 0 -C-group is directly linked to the phenyl ring are preferred, i.e. the formyl, acetyl, propionyl and butyryl groups.

R 4is preferably in the 3- or 4-position of the phenyl ring.

Preferred compounds of the general formula I are: 17-ethinyl-17B-hydroxy-lla--(4-acetylphenyl)-4,9,15-estra- K trien-3-one K 17-(prop-l-inyl)-17B-hydroxy-1i3-(4--acetylphenyl)-4,9,15estratrien-3-one 17-(prop-2-inyl)-17B-hydroxy-llB-(4-acetylphenyl)-4,9,15- 17 -ethi nyl -1 7B -hydroxy-lI 4-ace ty lphenyl) -18-methyl- 4,9, l5-estratrien-3--one 17-(prop-l-inyl)-17i3-hydroxy-ll3-(4-acetylphenyl)-18-methyl- 4 15-estratrien-3-one 17-(prop-2-inyl)-173-hydroxy-11L3-(4-acetylphenyl)-18methyl-4 15-estratrien-3-one -3- 17-methyl-173-hydroxy-113-( 4-acetyiphenyl F. trien-3-one 4 17-butyl-170--hydroxy-llO-(4-acetylphenyl)-4,9,15-estratrien-3 -one 17-(3-hydroxypropyl)-178-hydroxy-Ill-(4-acetylphenyl)- 4,9,15-estratrien-3-one l7-(prop-l-inyl)-173-hydroxy-11L3-(4-propionylphenyl)-4,9,lSestratrien-3-one 17-(prop-2-inyl)-17B-hydroxy-llL3-(4-propionylphenyl)-4,9,l5estratrien-3 -one 17-cyanomethyl-1713-hydroxy-llB-(4-acetylphenyl)-4,9,l5estratrien-3-one F The new 111-phenyl-4,9,l5-estratrienes of general formula I 4 are produced in accordance with the invention by the method decribed in Claim 3.

Prdutono the educts of general formula IIstarts from 17-keto steroids of general formula III :R R (European Patent Application 86101548.5, Publication-No.

190759) where K implies an acidic hydrolysable keto protection group and R 48has the same significance as R 4but con- K 1 tains a grouping instead Of where K stands for K or for a hydrogen atom and a protected hydroxyl group jointly.

In particular K represents a keto group blocked in the form of the ketal, thioketal, oxime or methyl oxime.

i- I [l

I

ii f 1 o; .i i l: 'i

II

i *I i -4- By e.g. modified Saegusa oxidation [Tetrahedron 42 (1986) 2971] of the corresponding enol compounds of the 17-ketone, the C-15 double bond is introduced into the D-ring. The trimethylsilyl enol ether required for example can be produced by converting the 17-ketone with lithium diisopropylamide in tetrahydrofurane into the corresponding enolate and blocking by trimethylchlorosilane. (Synthesis 1983, 1).

Compounds of general formula II,obtained after conversion of the C-17 keto group into the C-17 substitution pattern, in the significance of R 2 and R 3 ultimately desired in the final product of general formula I 1 4' 2 where R R and K have the above-described meaning, R 2 3' 2 3 and R have the same meaning as R and R and any existing hydroxyl and/or acyl and/or alkyne groups being if necessary protected, are subsequently treated with acid or an acidic ion exchanger to selectively split off water with subsequent production of the 4(5) double bond and at the same time to remove any existing protective groups. This acidic treatment takes place in a manner which is in fact conventional by dissolving the compound of formula II in a solvent miscible with water such as aqueous methanol, ethanol or acetone and allowing catalytic quantities of mineral or sulphonic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, perchloric acid or p-toluene sulphonic acid or an organic acid such as acetic acid to act on the e a s so f

A--

1B -4a- 111 solution long enough for the water to be split off and the protective groups to be removed. The reaction which takes place at temperatures of 0 to 100 OC can also be performed with an acidic ion exchanger. The course of the reaction can be followed by analytical methods, for example by thinlayer chromatography of specimens taken.

If in addition, protective groups which can only be split off in basic surroundings are present, a basic agent is allowed to react before or after acidic treatment.

The protective groups covered in the general formulae II and III by K, R' and R3' are groups which can be easily and III by K, R and R are groups which can be easily *i *aaa i1 ;i protective groups to be removed. The reaction which es place at temperatures of 0 to 100 OC can also b erformed with an acidic ion exchanger. The course of e reaction can be followed by analytical methods, or example by thinlayer chromatography of specimens aken.

If in addition, protecti groups which can only be split off in basic surrou ings are present, a basic agent is allowed to rea before or after acidic treatment.

The tective groups covered in the general formulae II 2' 3' split off in acidic surroundings, e.g. the ethylene dioxyketal, ethylene dithio-ketal, 2,2-dimethyltrimethylenedioxy-ketal, hydroxy-imino, methoxy-imino, tetrahydropyranyl, methoxy-methyl or methoxy-ethyl groups. To protect terminal acetylene groups, the trimethylsilyl or tert.butyldimethylsilyl groups are, for instance, used which can be split off in basic surroundings. If a compound of general formula II is used, in which K contains a protected hydroxyl group, this is subsequently converted to the oxofunctional group with an oxidizing agent normal for oxidation of allylic hydroxyl groups such as chromic acid, pyridine, pyridinium dichromate, pyridinium chlorochromate, manganese dioxide, silver carbonate on Celite. The preferred method involves reaction with manganese dioxide at temperatures between -20 OC and +40 OC.

The compounds thus obtained of general formula I with X having the significance of an oxygen atom can if required be converted into the oximes (formula I with X having the significance of hydroxy-imino grouping N OH where the hydroxyl group can be in the syn or anti position) by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 OC and +40 oC.

r Suitable tertiary bases are for example trimethylamine, triethylamine, pyridine, N,N-dimethylamino-pyridine, diaza-bicyclo[4.3.0]nonene-5 (DBN) and [5.4.0]undecene-5 (DBU) in which connection pyridine is preferred.

2 3 Introduction of the substituents R and R is carried out by the normal methods of C-17 side-chain build-up by nucleophilic addition to the 17-ketone and follow-up reactions ("Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol. 1-12).

The nucleophilic addition of HCECU in which U means a protective group, e.g. trimethylsilyl or tert.-butyldimethylsilyl or Y takes place with the aid of a compound of general formula MCaCU in which U has the above-mentioned significance and M represents an alkali metal.

The metal-organic compound can also be formed in situ and made to react with the 17-ketone. Thus for example acetylene and an alkali metal, in particular potassium, sodium or lithium in the presence of an alcohol or in the presence of ammonia can be allowed to react on the 17- ketone in a suitable solvent. The alkali metal may also be made to react in the form of for example methyl or butyl lithium.

Particularly suitable solvents are dialkyl ether, tetrahydrofurane, dioxane, benzene and toluene.

For the production of the 17-chloroethinyl compound, the metal-organic chloroethinyl compound is derived in situ from 1,2-dichloroethylene and an ethereal alkali-metal solution such as e.g. a methyl or butyl lithium solution and allowed to react with the 17-ketone in solvents such as tetrahydrofurane or diethylether.

t~nnf 17-Halogen ethinyl compounds can also be produced by halogenation of the corresponding ethinyl educt (Angew. Chem. 96, 720 (1984)).

Introduction of 3-hydroxypropine in the 17-position takes place by reaction of the 17-ketone with the dianion of the propargyl alcohol (3-hydroxypropine), for example the dipotassium salt of propargyl alcohol generated in situ, to the 17c(-(3-hydroxy-prop-l-inyl)-17f-hydroxy derivative or I with metallated derivatives of the 3-hydroxy-propine, for K example with l-lithium-3-(tetrahydro- pyran -2'-yloxy)prop-l-in-l-ide to the 17-[3-(tetrahydropyran -2'-yloxy)i prop-l-inyl]-173-hydroxy derivative.

Introduction of the homologous hydroxyalkyne groups takes place in a corresponding manner with homologues of propargyl alcohol.

Introduction of 3-hydroxypropane in the 17-position takes I place by reaction of the 17-ketone with metallated derivai tives of 3-halogen propanols, where the hydroxyl group in I the metallation step is present as an alcoholate (Tetrahedron Letters 1978, 3013) or as a protected functional i group to the 17 -(3-hydroxypropyl)-173-hydroxy compound or I to the compound protected at the terminal hydroxyl group.

The same protective groups are suitable as are mentioned I above.

i v Introduction of the homologous hydroxyalkane groups takes ae place in a corresponding manner with homologues of the 3-halogen propanols.

Build-up of the 17-cyanomethyl side-chain takes place/ in a manner which in fact is already familiar from the 17ketone, for instance by addition of MCH 2 CN with M implying an alkali metal, preferably lithium.

7 A Free hydroxyl groups in the 17-position and in the radicals 3' represented by R can be esterified or etherified in a manner already known as such.

Apart from this, reference is here made to EP-A 0 190'759 in which numerous compounds are described with the substii tuents for which claims are made here, with the difference j that the compounds described there do not possess a i -double bond.

The new compounds of general formula I are valuable pharmaceutical drujs. They have a strong affinity for the gestagen receptor without themselves possessing gestagenic activity. They are competitive antagonists of progesterone (antigestagens) since they displace the progesterone necessary to maintain pregnancy from the receptor. They are suitable for postcoital fertility control and for inducing abortions.

They can also be employed to counteract hormone-dependent ji disorders, to provoque menstruation and to induce labour.

i In addition, they can be used for treating hormone-dependent carcinomas.

Compounds of general formula I in accordance with the invention also exhibit antiglucocorticoid activity and can thus also be used as drugs in the treatment of corticoid-induced disorders (glaucoma) as well.as for combating side effects which may appear in the event of long-term treatment with glucocorticoids (Cushing syndrome). They thus also permit to combat disorders attributable to supersecretion of glucocorticoids, above all obesity, arteriosclerosis, hypertension, osteoporosis and diabetes as well as insomnia.

It has also been found that new compounds of general formula I not only exhibit very good antigestagenic and antiglucocorticoid effects but also that a separation of Ss the two effects can be observed.

The abortifacient activity was determined to define the antigestagenic effect.

The tests were carried out on female rats with a weight of approx. 200 g. After copulation, commencement of pregnancy was ascertained by demonstrating the presence of sperm in vaginal smears. The date on which sperm are detected was considered the 1st day of pregnancy dl The animals were treated with the substance to be tested or the solvent after nidation of the blastocysts from d5 p.c.

to d7 p.c. The animals were killed on d9 p.c. and the uteri were checked for implants and points of resorption.

Photos were made of all uteri. Lack of implants was considered as abortions.

The test substances were dissolved in a mixture of benzylbenzoate and castor oil (ratio of The vehicle volume per individual dose amounted to 0.2 ml. Treatment was subcutaneous The superiority of the compounds in accordance with the invention is to be shown by comparison of the biological properties of the compounds in accordance with the invention 11Q-(4-acetylphenyl)-178-hydroxy-17(-(prop-l-inyl)-4,9,15estratrien-3-one 113-(4-acetylphenyl)-17-hydroxy-17Cd-(prop-2-inyl)-4,9,15estratrien-3-one (B) with 11-(4-dimethylaminophenyl)-173-hydroxy-17(-(prop-lg, inyl)-4,9,(10)-estradien-3-one, RU 486 as described in EP-A 0 057 115 and with ll-(4-acetylphenyl)-170-hydroxy- 17c-(prop-l-inyl)-4,9-estradien-3-one as can be found in EP-A 0 190 759:

I

i I 10 TABLE 1 ABORTIVE TEST WITH PREGNANT RATS Substance Dose Abortion Rate mg/animal/day n aborting/n treated rats s.c.

4/4 A 1.0 4/4 0.3 4/4 4/4 B 1.0 4/4 0.3 4/4 3.0 4/4 C 1.0 2/4 0.3 0/4 4/4 D 1.0 4/4 0.3 4/4 i: ii .:i i r: ii i i i ~818 From Table 1 it can be seen that the compounds and (B) in accordance with the invention are fully abortive at a dose of 0.3 mg, i.e. they are more effective by a factor of than the already known compound RU 486 a substance which is to be considered as a standard (7th Int. Congress of Endocrinology July 1-7, 1984, Quebec City, Canada; Excerpta Medica, Amsterdam-Oxford-Princeton).

The abortive effect of the substances in accordance with the invention and was also determined using guinea pigs as test animals.

In this connection it was found that and surprisingly possess a strikingly higher abortifacient effect than the structurally related compound The test results gained from guinea pigs permit more reliable predictions to be made on the.abortive activity of the tested compound(s) to be expected in the case of humans than is permitted by the data gained with rats.

To identify the antiglucocorticoid activity, the effect of the substances in accordance with the invention on the tyrosine amino-transferase was determined. The test system is based on measurement of the activity of the liver enzyme tyrosine amino-transferase (TAT) in cultures of RHC (Rat Hepatoma Cells). The enzyme catalyzes the first step in the metabolism of tyrosine and can be induced by glucocorticoids both in the liver and in hepatoma cells. The activity is easy to measure in raw extracts (Granner and Tomkins, (1970) Meth. Enzymol. 15, 633). The enzyme converts the amino group of tyrosine to. 2-oxoglutaric acid. Glutaminic acid and p-hydroxy-phenylpyruvate are formed. The more stable p-hydroxy-benzaldehyde is formed from p-hydroxyphenylpyruvate in an alkaline solution. Its measured absorption lies at 331 nm. The TAT activity in RHC displays a dosage-dependent induction with cortisol (max. activity at M) or dexamethasone (max. activity at 10 The activity can be stimulated by a factor of 4 to 6 above the basal value. Simultaneous treatment with corticoid and antiglucocorticoid leads to a decrease in the TAT activity.

The compound in accordance with the invention exhibits in this test 20-50% and the compound in accordance with the invention shows less than 1% of the activity of the standard compound RU 486 The affinity of the compounds in accordance with the invention to the gestagen receptor is examined with the gestagen receptor binding test. In this test the displacement of the agonist by the antagonist is measured.

I-

<I

12 Cytosol from rabbit uterus homogenate which contains the receptor molecule a protein- is used in the test. This binds progesterone with high affinity and low capacity.

When these receptors are charged with 3H-progesterone in the presence of the unlabeled substance to be tested, the extent to which the 3H-progesterone is displaced from the receptor depends on the concentration ani binding affinity of the compound to be tested. After separation of the receptor-bound progesterone from the non-bound progesterone, the bi-nding can be determined as a percentage and this value plotted against the log of the molar concentration of the test substance. Characteristic dosage-dependent displacement curves are obtained and the concentration of the test substance can be determined which is required to oust the reference substance completely from the receptor.

The competition factor K as a measure of the binding strength is defined as the ratio of the concentration of the test substance to the concentration of the reference substance (progesterone) in which the two compounds exhibit equal displacement of H-progesterone from the progesterone receptor complex so that a low K-value indicates high binding strength (high affinity).

j 1 I i 13 TABLE 2 GESTAGEN RECEPTOR BINDING TEST Compound Rabbit uterus K (gestagen) A 1.9 B 2.9 C 2.9 D The table shows that of the test compounds in accordance with the invention quoted representatively, and compound is much stronger in its effect in the gestagen receptor binding test and compound is about the same strength as the standard compound To sum up it can thus be stated that the compounds in accordance with the invention display a clear dissociation of their antiglucocorticoid and antigestagenic properties both compared with each other and towards the standard compound RU 486, and the structurally similar compound A further striking property of the compounds in accordance with the invention is their high metabolic stability in comparison with the state-of-the-art compounds.

The invention thus also relates to drugs on the basis of the pharmaceutically tolerated compounds of general formula I, i.e.

compounds non-toxic in the doses used and, as the case may be, the normal adjuvants and vehicles.

The compounds in accordance with the invention can be processed in accordance with what are in fact familiar methods of'galenic medicine to produce pharmaceutical preparations

-J.

for enteral, percutaneous, parenteral or local application.

They can be administered in the form of tablets, coated tablets, gelatine capsules, granulates, suppositories, implants, injectable, sterile, aqueous or oily solutions, i suspensions or emulsions, ointments, creams and gels.

The active agent or agents can in this connection be mixed i with the adjuvants as are normally encountered in galenic pharmacy, e.g. arabic gum, talcum, starch, mannitol,

(R)

methylcellulose, lactose, tensides such as Tweens or

(R)

Myrj magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives and aromatic substances to improve the flavour essential oils).

The invention thus also involves pharmaceutical compositions which contain at least one compound in accordance with the invention as an active ingredient.

A unit dose contains approx. 1 to 100 mg of the active ingredient(s). The dosage of the compounds in accordance with the invention amounts to approx. 1 to 1000 mg per day in the case of humans.

~I~

I

EXAMPLE 1 17-(Prop-l-inyl)-178estratrien-3-one 6.1 g of 17-(prop-l-i methylenedioxy)-ethyl enedioxy)-9,15-estrad 100 ml of 70% aqueous hours at 50 OC in an cooled, the mixture i by addition of aqueou methylene chloride. T over sodium sulphate is chromatographed wi over silica gel. 3.5 white foam.

Crystallisation from the title compound.

Melting point: 162-16 The initial material a) In an inert atmosp dissolved in 290 ml o mixed with 50 ml of a ane). It is then agit 0 °C then cooled agai Ask-,i As hydroxy-ll-(4-acetylphenyl)-4,9,15nyl)-118-[4-[l,l- (2,2-dimethyltri- ]-phenyl}-3,3-(2,2-dimethyltrimethyliene-5c,178-diol is dissolved in acetic acid and is agitated for inert atmosphere. After having been s poured into iced water, neutralized s ammonia solution and extracted with he combined organic phases are dried and concentrated in vacuo. The residue th a mixture of hexane/acetic ester g of the title compound is isolated as acetic ester/acetone yields 3.25 g of 4 OC 420 14.80 (CHCl 3 c=0.505).

is prepared by the following method: here, 10 ml of diisopropylamine is f absolute tetrahydofurane at -10 oC, S1.6 m n-butyllithium solution (hexated for a further half an hour at n to -10 oC, whereafter 13.6 g of thyltrimethylenedioxy)-ethyl]- 3-(2,2-dimethyltrimethylenedioxy)-9ation as per European Patent Applicaication No. 190759, Example 6) disbsolute tetrahydrofurane is added etion of addition, the mixture is *s and then 17.2 ml of trimethylchlorowise. The reaction mixture is then 118- 4-[11,1-(2,2-dime phenyl -50-hydroxy-3, estren-17-one (prepar tion 86101548.5, Publ solved in 150 ml of a dropwise. After compl stirred for 15 minute silane is added dropm poured over ice-cold saturated sodium bicarbonate solution and the aqueous phase is extracted with acetic ester. The combined organic phases are washed several times with saturated ammonium chloride solution and concentrated in vacuo.

The residue is crystallized from 50 ml of acetonitrile.

13.2 g of 17-trimethylsilyloxy-113- 4-[LI,l-(2,2-dimethyltrimethylenedioxy)- ethylll-phenyl'-3,3-(2,2-dimethyltrimethylenedioxy)-9,16-estradien-5cL-ol is obtained.

1H-NMR (CD 2 C1 2 S 4.47 ppmi (lHi,m,H-16); 4.27 (lH,d Hz, H-11); 1.48 ppm (3H,s, H-CR 3 );1.21 H-CHI 3 1.01 ppm (3H, s, II-C11 3 83 (3FI, s, I-CH 3 )~0.54 ppm (3H,s, H-CIT 0.5 (3H,sJI-18); 0.15 ppm (911,s,3 x H-CR 3 Si).

b) 4.27 g of palladium(II) acetate is dissolved in 150 ml of absolute acetonitrile and mixed with 12.12 g of the compound prepared under The reaction mixture is stirred for 16 hours at room temperature, then filtered over silica gel and the filter residue washed well with methylene chloride. The organic phase is concentrated in vacuo and the 4 residue is chromatographed over silica gel. 10 g of llO3-{4-Clil-(2,2-dimethyltrimethylenedioxy)-ethyl--phenyl3 50c(-hydroxy-3, 3- 2-dimethyltrimethylenedioxy) dien-17-one is isolated as white foam.

HNR(CDCl 3 7.57 ppm (lE[,d J=5.5 Hiz, 7.18-7.37 ppm (4H,m,H-aromatic); 6.03 ppm (lH,m,H-16); 4.38 ppm (lH,d J=7.5 Hz, H-11); 1.52 ppm (311,sICH 3; 1.25 ppm (3H,s, H-CR 3 1.04 ppm (3H,s,H-CH 3 0.86 ppm (3FH,sjH-CH 3 0.75 ppm (3H,s,H-CH 3 0.55 ,ppm (3H,s,H-18).

c) 500 ml of absolute tetrahydofurane is saturated by passing methyl acetylene through it at 0 oC for 30 minutes.

iThereafter 42.2 ml of a 1.6 m solution of n-butyllithium in r| hexane is added dropwise at 0 to 5 After addition the i mixture is stirred for 15 minutes. A solution of 9.5 g of the compound prepared under b) in 50 ml of absolute tetrahydrofurane is then added drop for drop. After addition the reaction mixture is stirred for another 60 minutes, poured over iced water and the aqueous phase extracted with acetic 1 ester. The combined organic phases are concentrated in vacuo after they have been dried over sodium sulphate. The residue is chromatographed on aluminium oxide (neutral, stage III) with a mixture of acetic ester/hexane. 9.6 g of 17- (prop-l-inyl) -11 (2,2-dimethyltrimethylene- Sdioxy)-ethyl]-phenyl}-3,3-(2,2-dimethyimethyl enedioxy)- 9,15-estradiene-5(,173-diol is obtained as white foam.

SH-NMR (CDC1 3 7.2-7.4 ppm (4H,m,H-aromatic); 5.95 ppm |i (1H,d J=6 Hz, H-15); 5.7 ppm (lH dd J=6 and J=2 Hz, H-16); 4.4 ppm (IH.d broad J=8 Hz, 1.92 ppm (3H,s,

H-CH

3 1.52 ppm (3H,s,H-CH 3 1.25 ppm (3H,s,

H-CH

3 1.03 ppm (3H,s,H-CH 3 0.88 ppm (3H,s,H-CH 3 0.56 ppm (3H,s,H-CH 3 0.52 ppm (3H,s,H-18).

Ai K- nf EXAMPLE 2 17-(Prop-2-inyl)-173-hydroxy-11-(4-acetylphenyl)-4,9,15estratrien-3-one 350 mg of 17-(3-trimethylsilyl-prop-2-inyl)-173-hydroxy-ll3- (4-acetylphenyl)-4,9,15-estratrien-3-one is dissolved in methanol and stirred at 23 OC for 1.5 hours after addition of 387 mg of potassium carbonate. This is poured into water and extracted with acetic ester. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed with a mixture of hexane/acetic ester over silica gel. 205 mg of the title compound is isolated as white foam. Crystallisation from ether yields 176 mg of the title compound.

Melting point: 152-154 0 C; ]20 156.80 (CHC13; c=0.500) iD 3 I The initial material is prepared in the following way: a) In an inert atmosphere 1.17 g of l-(trimethylsilyl)-l- 'i propine is dissolved in 500 ml of absolute tetrahydrofurane at -5 oC and mixed with 6.8 ml of a 1.6 m solution (hexane) of n-butyllithium. The mixture is then stirred for one hour at this temperature and then cooled to -78 OC, and 1.5 g of the compound prepared in accordance i with Example Ib) dissolved in 200 ml of tetrahydrofurane i is added drop by drop. After completion of the addition, the mixture is stirred for 15 hours at 23 Therafter the mixture is poured over cold saturated ammonium chloride solution and the aqueous phase is extracted with acetic ester. The combined organic phases are first washed with saturated sodium bicarbonate solution then with saturated common salt solution and concentrated in vacuo. The residue is chromatographed with a mixture of hexane/acetic ester over neutral aluminium oxide (activity 1.22 g of 17-(-trimethylsilyl-prop-2-inyl)-11f- {4-[1,1--(2,2-dimethyltrimethylenedioxy)-ethyl]--phienyl4- 3,3-(2,2-dimethyltrimethylenedioxy).-9,15-estradiene- 5c{,173-diol is obtained.

1 H-NMR (CD 2 C1 2 7.23 ppm, 7.29 ppm (411, AA BB system, J=9 Hz, H-aromatic); 5.93 ppm (lH,d J=6 Hz, H-16); 5.69 ppm (IH,dd J=~6 and 4 Hz, 4.38 ppm (1l1, d broad J=z8 Hz, H-11); 4.27 ppm (lH,s,OH); 2.45 ppm (2H,s,CH 2 1.49 ppm. (3H~s,H-CH93; 1.22 ppm (311,s,H-CH 3 1.04 ppm (3H,s,H-CH 3 0.86 ppm, (3H~sH-CH9; 0.58 ppm. (6H,s,H-18 and H-CH 3 0.18 ppm (9H,s,3x[H-CH 3 Si).

b) 1.2 g of the compound prepared under a) is dissolved in ml of 70% aqueous acetic acid and stirred at 50 0

C

for 15 minutes in an inert atmosphere. After the mixture has cooled it is poured into saturated sodium bicarbonate solution and extracted with acetic ester. The combined organic phases are iried over sodium sulphate and concentrated in vacuo. The residue is chromatographed with a mixture of hexane/acetic ester over silica gel.

After crystallisation from ether, 582 mg of 17-(3-trimethylsilyl-prop-2-inyl )-17f3-hydroxy-1113-(4-acetylphenyl)-4,9,15-estratrien-3-one is obtained as white crystals.

Melting point: 196-189 OC; [.oX 236 3 c 0.500)

Claims (7)

1. ll8-Phenyl-4,9,15-estratrienes of general formula I R 2 i R 0o R i where SX implies an oxygen atom or a hydroxyimino grouping N _OH, 1 i R stands for a hydrogen atom or a methyl group, R implies a hydrogen atom, an alkyl radical or an acyl i radical with in each case 1 to 10 carbon atoms, i 3 SR stands for a hydrogen atom, a cyanomethyl group, (CH 2 )nCH 2 Z where n implies the numbers 0, 1, 2, 3, 4 or S.2 n 2 5 5 i 5, Z -H or -OR with R having the significance of a I hydrogen atom or an alkyl or acyl group with in each case 1 to 10 carbon atoms, or for -(CH2) -C=C-Y where m 0 2 and Y implies a hydrogen, chlorine, fluorine, S iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxy- S. alkyl or acyloxyalkyl group with in each case 1 to carbon atoms, S R stands for a straight-chain, saturated aliphatic j (C 1 -C 4 )-acyl residue. S 4

2. 17-ethinyl-17O-hydroxy-11B-(4-acetylphenyl)-4,9,15-estra- trien-3-one

17-(prop-l-inyl)-173--hydroxy-113-(4-acetylphenyl)-4,9,15- estratrien-J -one 17- (prop-2-inyl) -173-hydroxy-113- (4 -acetyiphenyl) estratrien-3-one 17-ethinyl-1713-hydroxy-I1B-( 4-acetylphenyl )-18-methyl- 4,9,15-estratrien-3-one 17-(prop-l-inyl)-1713-hydroxy-113-(4-acetylphenyl)-18-methyl- 4,9, 15-estratrien-3 -one 17-(prop-2-inyl)-17L3-hydroxy-11f3-(4-acetylphenyl)-18- methyl-4, 9, 15-estratrien-3-one 17-methyl-173-hydroxy-1A3-( 4-acetyiphenyl) trien-3-one ]7-butyl-173-hydroxy-113- (4-acetyiphenyl) trien-3-one 17-(3-hydroxypropyl)-173-hydroxy-11t3-(4-acetylphenyl)- 4,9,15-estratrien-3-one 17-(prop-l-inyl)-17L3-hydroxy-1B-(4-propionylphenyl)-4,9,15- estratrien-3-one 17-(prop-2-inyi)-173-hydroxy-11i3-(4-propionylphenyl)-4, 9, estratilien-3-one 17-cyanomethyl-17f3-hydroxy-11f3-(4-acetylphenyl)-4,9, estratrien-3-one. -22- 3. Method for the preparation of compounds of general formula I where S J S. I X implies an oxygen atom or a hydroxyimino grouping N-OH, R stands for a hydrogen atom or a methyl group, R 2 implies a hydrogen atom, an alkyl radical or an acyl radical with in each case 1 to 10 carbon atoms, R 3 stands for a hydrogen atom, a cyanomethyl group, -(CH 2 CH 2 Z where n implies the numbers 0, 1, 2, 3, 4 or 5 5 5, Z -H or -OR with R having the significance of a hydrogen atom or an alkyl or acyl group with in each case I to 10 carbon atoms, or for -(CH 2 )m-CsC-Y where m 0 2 and Y implies a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxy- alkyl or acyloxyalkyl group with in each case 1 to carbon atoms, R stands for a straight-chain, saturated aliphatic (C 1 -C 4 )-acyl residue, characterized in that, in what is in fact a conventional man- ner, a compound of general formula II ck~: Ci -23- R2 R 3 (II), where R 1 has the above-explained significance, K implies an 2' 3' acidic hydrolysable keto protective group, R and R have the same significance as R and R any existing hydroxyl and/or acyl and/or terminal alkyne groups being if necessa- ry protected, R 4 has the same significance as R 4 but con- tains the grouping K 1 0 U I 1 instead of where K stands for K or for a hydrogen atom anda protected hydroxyl group jointly, is exposed to the action of an acidic agent which is capable of releasing a protected function (or functions) and of selective split- off of the 5c-hydroxyl group with simultaneous formation of the 4(5)-double bond and is subjected in the presence of protective groups only separable in basic surroundings to the action of a basic agent prior to or after the action of Sthe acidic agent, while a hydroxyl group possibly contained in K is oxidized and any existing free hydroxyl groups in 3' the 17-position and/or in R are if desired esterified or etherified, the product of general formula I with X having the significance of an oxygen atom being, if desired, then al- lowed to react with hydroxylamine hydrochloride in the presence of tertiary amines. 4. Pharmaceutical preparations characterized in that they contain compounds in accordance with Claims 1 or 2. Use of compounds in accordance with Claims 1 or 2 for the preparation of drugs. Aj A~- ,I ;:i k i:I FI I r i-i i -24- ABSTRACT New 11 phenyl-4,9,15-estratrienes of formula I *q t I 4 f are described, where f I i f X implies an oxygen atom or a hydroxyimino grouping N-OH, R stands for a hydrogen atom or a methyl group, R implies a hydrogen atom, an alkyl radical or an acyl radical with in each case 1 to 10 carbon atoms, R 3 stands for a hydrogen atom, a cyanomethyl group, -(CH 2 )nCH 2 Z where n implies the numbers 0, 1, 2, 3, 4 or 5 5 5, Z -H or -OR with R having the significance of a hydrogen atom or an alkyl or acyl group with in each case 1 to 10 carbon atoms, or for -(CH2) -C.C-Y where m 0 2 and.Y implies a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxy- alkyl or acyloxyalkyl group with in each case 1 to carbon atoms, R 4 stands for a straight-chain, saturated aliphatic (C 1 -C 4 )-acyl residue. The compounds have antigestagenic and antiglucocorticoid activity. -t V r iU! i s INTERNATIONAL SEARCH REPORT International Application No pCT l Ra/Ln AA.. I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols aoolv. Indicate all) According to International Patent Classification (IPC) or to both National Classification and IPC Int.C1. C 07 J 1/00; A 61 K 31/565; C 07 J 41/00 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols 4 Int.Cl. C 07 J 1/00; C 07 J 41/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched III. DOCUMENTS CONSIDERED TO BE RFLEVANT 9 Category Citation of Document, I' with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 3 A EP, A, 0190759 (SCHERING AG) 1,4,5 13 August 1986 see claims 1,4,5 A EP, A, 0051762 (SCHERING AG) 1,4,5 19 May 1982 see claims 1,10 A WO, A, 83/03099 (ROUSSEL-UCLAF) 1,4,5 September 1983 see claims 1,11,13 SSpecial categories of cited documents: 10 later document published after the International filing date document defining the general state of the art which is not or priority date and not in conflict with the application but considered to be of particular relevance cited to understand the principle or theory underlying the invention earlier document but published on or after the International document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other mean's ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the international Search Date of Mailing of this International Search Report September 1988 (30.09.1988) 24 Octobre 1988 (24.10.1988) International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE Form PCT/ISA/210 (second sheet) (January 1985) 2 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. DE 8800447 SA 23338 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The nmemhers are as contained in the European Patent Office EDI' ile on 17/10/88 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date EP-A- 0190759 13-08-86 DE-A- 3504421 07-08-86 AU-A- 5291386 14-08-86 JP-A- 61183296 15-08-86 DE-A- 3527517 29-01-87 EP-A- 0051762 19-05-82 WO-A- 8303099 15-09-83 OE-A- JP-A- US-A- AT-B- SE-A- FR-A, B DE-A- N L-A- LU-A- AU-A- GB-A, B JP-A- US-A- US-A- CA-A- CH-B- OA-A- CA-C- AU-B- 3042529 57108100 437 1529 E108 4-7 8300308 2522328 3307143 8300738 84667 1191383 2118186 58201800 4477445 4540686 1206471 657368 7567 1215353 562739

24-06-82 05-07-82 01-02-83 15-01-85 02--08-83 02-09-83 08-09-83 03-10-83 08-09-83 08--09-83

26- 10-83 24-11-83 16-10-84 10-09-85 24-06-86

29-08-86

31-03-85 16-12-86 18=06-87 C For more details about this annex -see Official Journal of the European Patent Office, No. 12/a2 7- INTERNATIONALER RECHERCHENBERIGHT Internationales Aktenzeichen PCT/ DE 88 /00447 1. KLASSIFIKATION DES ANMVELDUNGSGEGENSTANDS (bel mehrerer, Klasuitlkationssymbolon sind alle anzugeoefll Nach der Internationalen Patentkiassifikatiofl (PC) oder nach der nationalen Kiassifikation und der IPC Int Cl C 07 J 1/00; A 61 K 31/565; C 07 J 41/00 Hi. RECHERCHIERTE SACHGEBIETE Recherchierter Mindestpr~fstoff 7 Klassitikationssystemn K lassifi kationssymboe Int. C) A~ C 07 J 1/00; C 07 J 41/00 Recherchierte nicht zumn Mindestpriilstoff gehdrende Verdffentlichungen, soweit dite A EP, A, 0190759 (SCHERING AG) 1,4,5 13. August 1986 siehe Patentansprtiche 1,4,5 A EP, A, 0051762 (SCHERING AG) 1,4,5 19. Mai 1982 siehe Patentanspr~iche 1,10 A WO, A, 83/03099 (ROIJSSEL-IJCLAF) 1,4,5 September 1983 siehe Patentanspriiche 1,11,13 o esondere Kategarien von angegebenen Veroffentlichung, die den aligemeinen Stand der Technik Sp~tere Verbffentlichung, die nach dem internationalen An- definiert, aber nicht als besonders bedleutsam anzusehen ist meldedlatumn oder demn Priorit~tsdatum veriffentlicht worden alteres Dokument. dlas jedloch erst am oder nach dem interna- i und mit der Anmeldung nicht kollidiert, tandern nur zum tionalen Anmeldedatum veroffentlicht warden is Verstandnis des der Erfindlung zugrundeliegenden Prinzips oder der ihr zugrundeliegenden Theorie angegeben it Veroffentlichung, die geeignet ist, amnen Priorit~tsanspruch "X Veroffantlichung van besonderer Bedeutung; die baanspruch- zweifelhaft erscheinen zu lassen, odar durch die das Verof- te Erfindung kann nicht alt neu oder auf erfinderitcher Tdtig- fentlichungsdaturn amner anderan im Recherchenbericht ge. etbrhn-ercttwre naruien \Ierdffentlichung beiegt warden soll oder die aus ainern anderen besonderen Grund angegeben ist We ausgefiihrt) Verdffentlichung von besonderer Bedleutung; die beanspruch- er~fenlichngdiesic aufein m~dlihe Ofenbarng, ta Erfindung kann nicht als auf erfinderitcher Tbtigkeit be- e Vedentiung, ine Asich au ein mindce ffenbarun ruhand betrachtet waerden, wenn die Verdffentlichung mit aabenuznielaAstelnedehnee anht einer oder mehreren anderen Verdifantlichungen dieser Kate- bezahtgorne in Verbindlung gebracht wird und diese Verbindlung fUr Varoffentlichung, die var dam intarnationalen Anmeldedla- amnen Fachmann naheliegand ist turn, abar nach dam baanspruchtan Prioitatsdatum veroffant- vrdfniugie itiddrebnPanfaiiit licht warden istVVrfetihndeMtle esle aetaii s IV. BESCHEINIGUNG Datum des Abschlussas der internationalen Recherche Abtendedlatumn des internationalen Recherchenberichtt September 19882,40CT18 Internationale Recherchanbehdrde Unter as bev dfichtigtan Badianstaten Europajaches Patentamnt N A DER PUTTfEN Formblatt PCT/ISA/210 (Blatt 2) (januar 1985) ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT OBER DIE INTERNATIONALE PATENTANMELDUNG NR. DE 8800447 SA 23338 fn diesem Anhang sind die Nlitglieder der Patcntfamilien der im obengcnannten internationalen Recherchenbericht angeffihrten P'atentdokumente angegebeta. Die Angaben fiber die Familienmitglieder entspreehen dem Stand der Datei des Europiiischen Patentamnts am 17/10/88 Diese Angaben dienen nur zur Unterrichtung und crfolgen ohne Gewahr. Im Rcchcrchenbericht Datum der Mitglied(er) drDatum der angefiihrtes Patcntdokument Verdifentlichung Patentfamili Veroffentlichung EP-A- 0190759 13-08-86 OE-A- 3504421 07-08-86 AU-A- 5291386 14-08-86 JP-A- 61183296 15-08-86 OE-A- 3527517 29-01-87 EP-A- 0051762 19-05-82 OE-A- 3042529 24-06-82 JP-A- 57108100 05-07-82 US-A- 4371529 01-02-83 AT-B- E10847 15-01-85 WO-A- 8303099 15-09-83 SE-A, 8300308 02-08-83 FR-AB 2522328 02-09-83 OE-A- 3307143 08-09--83 NL-A- 8300738 03-10-83 LU-A- 84667 08-09-83 AU-A- 1191383 08-09-83 GB-A,B 2118186 26-10-83 JP-A- 58201800 24-11-83 US-A- 4477445 16-10-84 US-A- 4540686 10-09-85 CA-A- 1206471 24-06-86 CH-B 657368 29-08-86 OA-A- 7567 31-03-85 CA-C 1215353 16-12-86 AU-B- 562739 18-06-87 P FUr niihere Ejnzelhejcen zu diesem Anhang :siehe Amtsblatt des Europaischen Patentamnts, Nr.12/82