AU682373B2

AU682373B2 - 11-benzaldoxime-17beta-methoxy-17alpha- methoxymethylestradiene-derivatives, methods for their production and pharmaceuticals containing these substances

Info

Publication number: AU682373B2
Application number: AU70351/94A
Authority: AU
Inventors: Walter Dr. Elger; Gunther Dr. Kaufmann; Anatoli Dr. Kurischko; Michael Prof. Dr. Oettel; Gerd Dr. Schubert; Lothar Dr. Sobeck
Original assignee: Jenapharm GmbH and Co KG
Current assignee: Bayer Pharma AG
Priority date: 1993-09-20
Filing date: 1994-08-18
Publication date: 1997-10-02
Anticipated expiration: 2014-08-18
Also published as: HUT68315A; NO304988B1; HU9402695D0; CZ289801B6; NZ264228A; UA39101C2; CA2130515C; FI943688A; FI943688A0; CZ196994A3; JP2696672B2; CA2130515A1; ES2102144T3; EP0648779B1; DE4332284A1; EP0648779A3; ATE149513T1; PL179460B1; RU94029667A; SK95894A3

Abstract

11-Benzaldoxime-oestradiene derivatives of the general formula I <IMAGE> and their pharmaceutically acceptable salts, a process for their preparation and pharmaceutical compositions containing them are described. The described compounds display potent antigestagenic effects with lower glucocorticoid activity.

Description

Our Ref: 521396 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT .r Applicant(s): Address for Service: Jenapharm GmbH Otto-Schott-Str. D-07745 JENA

GERMANY

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 New 11 -benzaldoxime- 17beta-methoxy- 17alpha-methoxymethylestra diene-derivatives, methods for their production and pharmaceuticals containing these substances Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 L I~P -A IP Description This invention relates to new 11-benzaldoxime-estradiene derivatives, methods for their production, and pharmaceuticals containing these compounds.

li-substituted phenyl estratrienes are known. Patent specification EP 057 115 describes the production of llparyl-17a-propinyl estra-4,9-dienes, and patent specification DE 3 504 421 describes the reaction of 11p-(4formylphenyl) estra-4,9-diene-3-ons with hydroxylamines.

Both the llP-formyl phenylene residue and the 3-keto group are oximated. In addition, syn and anti isomers are formed at C-3. Nothing is known as yet about the effects of the described compounds.

Progesterone is secreted during menstruation, and in large amounts by the ovary and the placenta during pregnancy. Its regulatory significance has perhaps not Sbeen clarified in every respect.

What is safely known is that progesterone, together with 20 oestrogenes, produces the cyclic changes in the uterine mucosa during the menstrual cycle and pregnancy. After ovulation, an increased level of progesterone causes the uterine mucosa to adopt a condition that permits the embedding of an embryo (blastocyst). Conservation of the 25 tissues in which the embryo grows is also dependent on progesterone.

dramatic change in the muscular function of the uterus takes place during pregnancy. Response of the gravid uterine muscle to hormonal and mechanical stimuli thot induce labour in the non-gravid state is strongly reduced or non-existent. There can be no doubt that progesterone has a key function here, despite the fact that at certain stages of pregnancy, e.g. shortly before giving birth,

I

there is a high reactivity even at high bloodprogesterone concentrations.

Very high progesterone levels are also reflected by other typical processes during pregnancy. The composition of the mammary glands and the obstruction of the cervix until shortly before the date of birth-giving may serve as examples of this.

Progesterone contributes subtly to controlling ovulation processes. It is known that high doses of progesterone have anti-ovulatory qualities. They result from an inhibition of the hypophyseal gonadotropin secretion which is a prerequisite for the maturation of the follicle and for its ovulation. But on the other hand, it can be seen that the comparatively small quantity of progesterone secreted by the maturing follicle plays an active part in preparing and triggering ovulation.

Hypophyseal mechanisms (temporary, so-called positive feedback of progesterone to gonadotropin secretion) appear to have a great significance in this respect (Loutradie, Human Reproduction. 1991, 1238-1240).

The doubtlessly existing functions of progesterone in the maturing follicle and luteal corpus themselves have been less well analyzed. It can be assumed, eventually, that there are both stimulating and inhibiting effects on S 25 endocrinic functions of the follicle and the luteal corpus.

S. It may also be assumed that progesterone and prcgesterone receptors are of great importance for pathophysiological processes. Progesterone receptors have been found in endometriotic focuses, but also in tumours of the uterus, the mamma, and the CNS (meningiomas). The role of these receptors in conjunction with the growth behaviour of these pathologically relevant tissues is not necessarily dependent on progesterone levels in the blood. It has been proved that substances characterized as progesterone antagonists such as RU 486 Mifepristone (EP-0 057 115) and ZK 98299 Onapristone (DE-OS-35 04 421) tend to trigger far-reaching functional changes even at negligible levels of progesterone in the blood. It appears to be possible that modifications of the transcriptional effects of the progesterone receptor that is not filled with progesterone are decisive in this respect (Chwalisz, K. et al., Endocrinology, 12., 317-322, 1991).

The effects of progesterone in tissues of the genitals and in other tissue are brought about by interaction with the progesterone receptor. In a cell, progesterone bonds to its receptor with high affinity. This causes changes in the receptor protein: conformational changes, dimerization of 2 receptor units to form one complex, baring of the receptor's DNA bonding place by dissociating a protein (HSP 90), bonding to hormon-responsive

DNA

elements. Eventually, the transcription of certain genes is regulated. (Gronemeyer, H. et al., J. Steroid Biochem.

Molec. Biol. 1A, 3-8, 1992).

The effect of progesterone or progesterone antagonists does not only depend on their concentration in the blood.

The concentration of receptors in a cell is strongly regulated as well. Oestrogens stimulate the synthesis of progesterone receptors in most tissues. Progesterone inhibits the synthesis of oestrogen receptors and that of its own receptor. It is assumed that this interaction of oestrogens and gestagens goes to explain why gestagens and antigestagens can influence oestrogen-dependent processes without being bonded by the oestrogen receptor.

These relations are naturally of great importance for the therapeutical application of antigestagens. These substances appear to be appropriate for directly influencing female reproductive processes, e.g. for preventing nidation after ovulation, or for increasing uterine reactivity to prostaglandins and oxytocin in a later pregnancy, or for achieving metreurysis and cervix softening ("maturing").

Antigestagens inhibit ovulation in various species of subhuman primates. The mechanism of this effect has not yet been elucidated. Among the hypotheses discussed are an inhibition of gonadotropin secretion, and ovarian mechanisms based on disturbing para- and autocrinic functions of progesterone in the ovary.

Antigestagens are capable of modulating or weakening the effects of oestrogens although the majority of them does not have any oestrogen receptor affinity at the cytoplasmic level, and although they can cause an increase of the oestrogen receptor concentration. Similar effects in endometriotic focuses or tumorous tissue equipped with oestrogen and progesterone receptors justify the expectation of a favourable influence on pathologic conditions. Particular advantages with regard to exerting a favourable influence on pathologic conditions such as endometriosis might be achieved if an inhibited ovulation supplem:nted the inhibiting effects of an antigestagen acting in che tissue. Ovarian hormonal products and their stimulating effect on the pathologically altered tissue would also be reduced by inhibiting ovulation. It would be desirable to inhibit ovulation in severe cases of endometriosis to bring the tissue in the genital tract Swhich would normally be in constant reconstruction, into a reversible state of rest.

A method ±s being discussed with regard to contraception according to which an antigestagen treatment suppresses ovulation, and secretory transformation of the endometrium is induced by subsequent gestagen treatment. The days of treatment with antigestagens and gestagens and the treatment-free days result in a 28-day cycle with a regular withdrawal bleeding (Baulieu, Advances in Contraception 2, 345-51, 1991).

Antigestagens can have different hormonal and antihormonal properties. Anti-glucocorticoid properties are of particular therapeutical relevance. These are unfavourable for therapeutical applications mainly aimed at inhibiting progesterone receptors as they have undesired side effects when applied at the dosage required for such therapy which may prevent the application of a therapeutically sensible dose, or require that treatment be discontinued. Partial or complete reduction of glucocorticoid properties is an important prerequisite for a therapy using antigestagens, especially with indications that require therapy over several weeks or months.

04t** It is the purpose of this invention to provide new 11benzaldoxime-estra-4,9-diene derivatives of the general formula I

NOZ

OCH3

CH

2 0 CH3

(I)

and their pharmaceutically acceptable salts as well as a method for producing them. It is another purpose of this invention to provide pharmaceuticals containing a compound of' the general formula I or its pharmaceutically acceptable salt.

In general formula I,

NOZ

OCH

3

-CH

2

-CH

3

I)

C

Z is -CO-CH 3

-CO-OC

2 H-I, -CO-NH-phenyl, -CO-NH-C 2 HS1,

-CO-C

2 -Is, -CH 3 or CO-phenyl.

Preferred compounds according to this-invention are: ll3- (acetoximinomethyl)phenyl] -17j-methoxy-17amethoxymethyl-estra-4, 9-diene-3 -on, 1)3- [(ethoxycarbonyl) oximinomethyllphenyl} -17f3methoxy-17a-methoxymethyl-estra-4, 9-diene-3-on, l11f{4- [(ethylaminocarbonyl) oximinomethyl] phenyll -1713 -methoxy-17a-methoxymethyl-estra-4, 9-diene-3-on, 17f-methoxy-17a-methoxymethyl-1j3- 4- [(phenylaminocarbonyl) oximinomethyliphenyl) -estra-4, 9-diene-3-on, 143- (propionyloximinomethyl) phenyl] -17f3-methoxy-17 a-methoxymethyl-estra-4, 9-diene-3-on, 1113-[4- (methyloximinomethyl)phenyl3 -17f3-hydroxy-17cLmethoxymethyl-estra-4, 9-diene-3-on, and [4-(benzoyloximinomethyl)phenyll -17-hydroxy-17amethoxymethyl-estra-4,9-diene-3-on.

This invention furthermore relates to a method for producing compounds of the general formula I and their pharmaceutically acceptable salts, characterized in that a compound of the general formula II

NOH

HN OCH3 -'CH2-0-CH3 0 is esterified or etherified, and, if required, the resulting compound is salified.

Manufacturing of the compounds of the general formula I by esterification, etherification, or urethane formation may be carried out in a generally known way using acylating agents such as acid anhydrides or acid chlorides in the presence of bases, preferably pyridine, etherification using methyl iodide in the presence of bases, preferably potassium tert. butanolate, or using diazomethane in methanol; urethane formation by reacting with 20 alkyl or aryl isocyanates in inert solvents, preferably toluene, or by reacting carbamoylchlorides in the presence of bases, preferably triethylamine.

i The parent compound of the general formula II is manufactured from Sc,l0a-epoxide III (I I I)

H

3

CQ

H

3

CO

for example, N6d~lec Bull. Soc. chim. France (1970) 2548].

Introduction of the phenyl residue to the 1lip position while forming a A9(lO),ScL hydroxy structure IV is achieved by a Cu(I) salt catalyzed Grignard reaction (Tetrahedron Letters 1979, 2051) with a p-bromobenzaldehyde ketal, preferably p-bromobenzaldehyde dimethyl ketal at temperatures between 0 0 C and 3C 0

C.

*04*

OCH

3

H

3

CO

H

C 4

C.

Vkq*C 4e 4 4 4***44 I v)

H

3

CO

H

3

CO

The -CH 2

-O-CH

3 group is introduced to the 17 position in a generally known way via the spiroepoxide V by reacting with trimethyl sulfoniun iodide and potassium tert.

butanolate in dimethyl suif oxide [(abner et al.; J.

prakt. Chem. 314, 667 (1972); Arzneim. Forsch. 30, 401 (1973)] and PCH3

H

3

CO

H

V)

H

3

CQ.

H

3 C0' a 4 a 4..

4 @0 O4Ot a.

a. 0 a.

a subsequent ring opening using alcoholates [Ponsold et al. Z. Chemn. 11, 106 (1971)] The resulting 17ax-CH 2

-O-

CH

3 compounds VI 0 CH 3

H

3

CO

H OH

-CH

2

-O-CH

3

VI)

H

3 CO

H

3

CO'

may either be decomposed into their respective aldehydes by acid hydrolysis, preferably using toluene-p-sulfonic acid in acetone (Teutsch et al. DE 2801416), or be converted, following etherification of the free hydroxyl groups with alkyl halogenides in the presence of potassium tert. butanolate, first into 5a,17p diethers (Kasch et al. DD 290 893) which are then transformed into their respective aldehydes by acid hydrolysis, preferably using toluene-p-sulfonic acid in acetone; the aldehydes thus obtained are converted into compounds of the general formula II by reacting them with hydroxylamine.

The resulting compound of the general formula I according to the invention is converted, if required, into an acid addition salt, preferably a salt of a physiologically compatible acid. Common physiologically compatible anorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic 20 acid, adipic acid, and benzoic acid. Other acids that can be used are described, for example, in Fortschritte der Arzneimittelforschung, vol. 10, pp. 224-225, Birkhduser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977).

Acid addition salts are normally obtained in a generally *tooknown way by mixing the free base or its solutions with 0 the respective acid or its solutions in an organic solvent, for example, a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone such as acetone, methylethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofurane or dioxane. Compositions of the abovementioned solvents may be used for improved crystallizing. In addition, physiologically compatible hydrous solutions of acid addition salts of the compound according to formula I may be produced in a hydrous acidic solution.

The acid addition salts of compounds of the general formula I can be converted into a free base in a generally known way, e.g. using alkalies or ion exchangers. Other salts can be obtained by reacting this free base with anorganic or organic acids, especially acid3 suited for forming pharmaceutically acceptable salts. These and other salts of the new compound, such as its picrate, may be used to purify the free base: the free base is converted into a salt, the salt is separated, and the base released from the salt again.

Another object of this invention are pharmaceuticals designed for oral, rectal, subcutaneous, intravenous or intramuscular applications that contain as an active ingredient, apart from the usual substrates and diluents, "a compound according to the general formula I or its acid addition salt.

The pharmaceuticals of the invention are produced in a 20 known way using the usual solid or liquid substrates or diluents and the common adjuvants used in pharmaceutical engineering and with an appropriate dosage depending on the intended mode of application. Preferred formulations are those forms suitable for oral administration, for 25 example, tablets, film tablets, drag6es, capsules, pills, powder, solutions, suspensions, or depot forms.

6 Consideration may be given also to parenteral formulations such as injection solutions. Suppositories represent another form of application.

Tablets may be obtained, for example, by intermixing the active substance with known adjuvants, for example, inert diluents such as dextrose, sugar, sorbitol, mannite, polyvinylpyrrolidone, blasting agents such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum and/or materials by which to produce a depot effect, such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may consist of several layers.

Drag6es may be produced accordingly by coating cores manufactured in analogy to tablet manufacture using agents generally applied to drag6e coating, for example, polyvinylpyrrolidone or shellac, Arabic gum, talcum, titanium dioxide, or sugar. The coating of the dragee may also consist of several layers in which the adjuvants mentioned in the paragraph on tablets can be used.

Solutions or suspensions containing the active agent of the invention may additionally contain flavour-enhancing substances such as saccharin, cyclamate or sugar, or aromatic substances such as vanillin or orange extract.

They may also contain suspension-supporting adjuvants such as sodium carboxymethyl cellulose, or preservatives 20 such as p-hydroxybenzoates. Capsules containing active 9999 substances may be produced, for example, by mixing the active substance with an inert substrate such as lactose or sorbit and encapsulating such mixture in gelatin capsules.

'25 Appropriate suppositories may be made by mixing the 9e.

active substance with the suitable substrates, such as neutral fats or polyethylene glycol and their derivatives.

9 9 The 11ip-substituted benzaldoxime-estra-4,9-dienes of the invention are antigestagenic substances that combine, if compared with RU 486, superior in-vivo acting potential (cf. table 2) with a significantly reduced antigluco-

I

corticoid activity, which has been proved by the reduced bonding to glucocortinoid receptors (cf. table 1).

Table 1 Receptor bonding of selected substances listed in Examples 1 and 2 Compound acc. to Example Relative molar bonding affinity (RBA) for the glucocorticoid receptor (dexamethasone=100%) (J914) (J900)

C.

9 9*Vr

C

.54 *0*W 9O**

S..

S.

SO C i.

15 compared with RU 486 (mifepristone) ZK 98299 (onapristone) 73 66 685 39 This combination of properties of the antigestagens according to the invention promises superior inhibition 25 of progesterone while at the same time reducing antiglucocorticoid activity. This advantage is of particular relevance for indications that require excellent compatibility because of the duration of treatment.

During the menstrual cycle, uterine weight is decisively influenced by the circulating oestrogen. Reduced uterine weights reflect an inhibition of this oestrogenic function. The inhibition of uterine weight during the menstrual cycle determined in guinea pigs is superior to RU 486 and points to (indirect) anti-oestrogenic properties of the compounds according to the invention.

The respective effects promise the exertion of a particularly favourable influence on pathologically modified tissues in which oestrogens stimulate growth (endometriotic focuses, myomas, mammary and genital carcinomas, benign prostatic hypertrophy).

*0 *a 0 ooo 0 0009 a Table 2 Early abortive effect of RU 486 and J 914 (Example 1) and J 900 (Example 2) in the rat after subcutaneous application from the 5th to 7th day of pregnancy (dose 0.2 ml/animal/day in benzylbenzoate/castor oil [1 4 v/v]) Group Dose complete gravid- ED 50 substance (mg/animal/ ity inhibition+ (mg/animal/ day) N* /N day) vehicle -0/25 0 RU 486 3.0 5/5 100 2/5 40 1.1 0.3 0/5 0 J 900 1.0 9/10 90 0.6 0.3 0/5 0 J 914 3.0 5/5 100 7/10 70 0.6 0.3 1/5 0.1 0/6 0 empty uteri N number of inseminated females N* number of females not pregnant graphic determination i The following examples explain the invention.

Examples 180 mg of lip-[4-(hydroximinomethyl)phenyl]-17p-methoxy- 17a-methoxymethyl-estra-4,9-diene-3-on are acetylated in ml of acetic anhydride/pyridine After adding water, the batch is three times extracted with acetic ester. The organic phase is washed with dilute hydrochloric acid and water, dried above sodium sulfate, and concentrated by evapol <ior. under reduced pressure. The yield is 172 mg of duct that is purified by preparative thin-layer l r natography using silica gel

PF

2 4 5+ 3 66 and a toluene/acetone solvent system at a concentration of 4:1.

15 Yield: 115 mg of 11p-[4-(acetyloximinomethyl)phenyl]-17 methoxy-17a-methoxymethyl-estra-4,9-diene-3-on. The product crystallizes from acetic ester.

Melting point: 115 120 0 C (acetic ester) aD 2180 (CHC1 3 IR spectrum in KBr 1754 (OAc); 1654 1602 (phenyl) UV spectrum in MeOH: Xmax 271 nm s 28 157 .max 297 nm s 26 369 1H-NMR spectrum in CDC1 3 ppm] 0.511 3H, H-18); 2.227 3H, OCOCH3); 3.247 3H, 17P-OCH 3 3.408 (s, 13H, 17a-CH 2

OCH

3 3.386, 3.431, 3.544, 3.580 2H,

CH

2 0CH 3 4.399 1H, J=7.2 Hz, H-11a); 5.785 1H, 7.242, 7.266, 7.618, 7.647 4H, AA'BB' system of aromatics protons); 8.315 1H, CH=NOAc) MS m/e: 446 C 2 8 H3 2

NO

4 M CH 2 0CH 3 17 Example 2 0.3 ml of chloroethyl formate are dripped into 210 mg of 11p-[4-(hydroximinomethyl)phenyl]-17p-methoxy-17amethoxymethyl-estra-4,9-diene-3-on in 5 ml of pyridine while cooling with water. A white sediment forms. The batch is watered after 30 minutes, which results in a solution in which a white sediment settles down that is filtered off by suction and washed with water. Yield after drying: 133 mg. The aqueous phase is extracted with chloroform, washed with dilute hydrochloric acid and water, dried, and concentrated by evaporation under reduced pressure. Yield: 66 mg. Both solids are united and purified by preparative thin-layer chromatography using silica gel PF 245 366 and a toluene/acetone solvent system at a concentration of 4:1.

S.0 Yield: 150 mg of ll-[4-(ethoxycarbonyloximinomethyl)- ,phenyl]-17p-methoxy-17a-methoxymethyl-estra-4,9 d -3on which are recrystallized from acetone/hexanE.

Melting point: 137 148 0

C

aD 2040 (CHC1 3 UV spectrum in MeOH: Xmax 270 nm 8 27 094 Xmax 297 nm 8 25 604 1 H-NMR spectrum in CDC1 3 ppm]: 0.507 3H, H-18); 1.383 3H, J=7.0 Hz, OCH 2

CH

3 3.246 3H, 17p-

OCH

3 3.410 3H, 17a-CH20CH 3 3.39 3.56 2H, 0. C20OCH) 4.35 1H, J=7.0 Hz, H-lla); 5.784 1H, 7.23, 7.26, 7.61, 7.64 4H, AA'BB' system of aromatics protons); 8.303 1H, CE=NR) MS m/e: 431.24701 C 2 8

H

3 2

NO

3 M+ C 2

H

5

OCOOH

Example 3 190 mg of 11-[4-(hydroximinomethyl)phenyl]-17p-methoxy- 17a-methoxymethyl-estra-4,9-diene-3-on are suspended in ml of toluene. 0.5 ml of phenyl isocyanate and 1 ml of triethyl amine are added subsequently. The batch is agitated at room temperature for 3 hours and refluxed for 2 hours. The white sediment is filtered off by suction, and the solvent concentrated by evaporation under reduced pressure. Thus 310 mg of a light brown solid are obtained which is purified by preparative thin-layer chromatography using silica gel PF 2 4 5 3 66 and a toluene/ acetone solvent system at a concentration of 9:1.

mg of 17p-methoxy-17a-methoxymethyl-llp-{4-[(phenylamino-carbonyl)oximinomethyl)]phenyl)-estra-4,9- 15 diene-3-one are isolated.

Melting point: 241 246 0 C (acetone) .D 1780 (CHC1 3 UV spectrum in MeOH: Xkax 238 nm s 29 444 Smax 300 nm S 29 649 1H-NMR spectrum in CDC13 ppm] 0.474 3H, H-18); 3.245 3H, 173-OCH 3 3.405 3H, 17a-CH20CH 3 3.406 3.545 2H, ABX system, 17a-CH 2 0CH 3 4.413 (d, 1H, J=6.8 Hz, H-11a); 5.797 1H, 7.264 aromatic), 7.272, 7.293, 7.548, 7.575 4H, AA'BB' system of aromatics protons); 8.0 1H, CH=N-) MS m/e: 431.24249 C 2 8 H3 3

NO

3 M+ C 6 HsCNO Example 4 708 mg of 11-[4-(hydroximinomethyl)phenyl]-17p-methoxy- 17a-methoxymethyl-estra-4,9-diene-3-on are dissolved in ml of toluene. 1.5 ml of ethyl isocyanate and 3 ml of triethyl amine are added subsequently. The batch is agitated at room temperature for 6 hours and allowed to stand overnight. Then 20 ml of aqueous ammonium solution are added, the phases are separated, extracted with toluene, washed in water, aqueous ammonium solution, and water, dried above sodium sulfate and concentrated by evaporation under reduced pressure. Thus 800 mg of a bright yellow solid are obtained which is purified by preparative thin-layer chromatography using silica gel

PF

2 5 4 3 66 and a toluene/acetone solvent system at a concentration of 9:1.

610 mg of 11p-{4-[(ethylaminocarbonyl)oximinomethyl)]phenyl}-17p-methoxy-17a-methoxymethyl-estra-4,9-diene-3on are isolated.

Melting point: 142 147 0 C photodecomposition 15 (ether/acetone /hexane) 1H-NMR spectrum in CDC1 3 ppm]: 0.522 3H, H-18); 1.241 3H, J=7.5 Hz, NHCH 2 CH3); 3.253 3H, 17p- OCH3) 3.415 3H, 17a-CH 2

OCH

3 3.366- 3.574 4H, ABX system, 17a-CH 2

OCH

3

NHCH

2

CH

3 4.410 1H, J=7.2 Hz, H-lla); 5.790 1H, 6.238 1H, NHCO), 7.258, 7.286, 7.561, 7.589 4H, AA'BB' system of 'aromatics protons); 8.294 1H, CH=N-) 25 Example 500 mg of 11- (hydroximinomethyl) phenyl] -17p-methoxy- 17a-methoxymethyl-estra-4,9-diene-3-on are agitated subject to inert gas for 2.5 hours in 4 ml of propionic acid anhydride/ pyridine 1:1 The mixture is poured into iced water, and the sticky substance is extracted with chloroform. The organic phase is washed with dilute hydrochloric acid and water, dried above sodium sulfate, and concentrated by evaporation under reduced pressure.

The bright yellow foam is purified using chromatography and recrystallized from acetic ester. YJ',i.d: 306 mg of 11 P-[4-(propionyloximinomethyl) phenyl]-17p-methoxy-17amethoxymethyl-estra-4,9-diene-3-on.

Melting point: 110 114 0 C (acetic ester) 1H-NMR spectrum in CDC13 ppm] 0.515 3H, H-18); 1.241 3H, J=7.6 Hz, OCOCH 2

CH

3 3.253 3H, 17p-

OCH

3 3.415 3H, 17a-CH 2

OC

3 3.4 3.6 2H, ABX system, 17a-CH 2

OCH

3 4.128 1H, J=7.2 Hz, H-11a); 5.790 1H, 7.244, 7.271, 7.627, 7.655 4H, AA'BB' system of aromatics protons); 8.322 1H, CH=N-) Example 6 15 An etherial diazomethane solution is added while cooling with ice to 170 mg of 11-[4-(hydroximinomethyl)phenyl]- 17p-methoxy-17a-methoxymethyl-estra-4,9-diene-3-on until the mixture takes on a slight yellow colouring. The batch is agitated for 2 hours at 5°C, and dilute sodium 20 hydroxide solution is added. Then the mixture is extracted with ether, washed neutrally, and dried above sodium sulfate. The organic phase is evaporated under 'reduced pressure. The yellow resin is purified by preparative thin-layer chromatography using silica gel PF2 54 +366 and a toluene/acetone solvent system at a concentration of 4:1.

Yield: 110 mg of 11- [4-(methoximinomethyl)phenyl]-17phydroxy-17a-methoxymethyl-estra-4,9-diene-3-on in the form of colourless lamellae.

Melting point: 83 890C a, 1970 (CHC1 3

I

IR spectrum in CHC1 3 (cm- 1 1700 (C=NOCH 3 1649 1590 (aromatic) UV spectrum in MeOH: max 275 nm s 23 098 kmax 300 nm s 22 872 1 H-NMR spectrum in CDCl 3 ppm] 0.529 3H, H-18) 3.247 3H, 17P-OCH3); 3.408 3H, 17a-CH 2

OCH

3 3.39 3.598 2H, ABX system, 17a-CH 2

OCH

3 4.381 1H, Hz, H-1a); 5.773 1H, 7.173, 7.201, 7.463, 7.491 4H, AA BB' system of aromatics protons); 8.023 1H, CHphenyl) Example 7 A filtered mixture of 2 ml of benzoyl chloride and 3 ml of pyridine is added to 500 mg of 11p-[4-(hydroximinomethyl)phenyl]-17p-methoxy-17a-methoxymethyl-estra-4,9- 'diene-3-on. After 2 hours, the mixture is stirred into 150 ml of iced water. The steroid precipitates as a sticky substance. 5 ml of hydrochloric acid are added, S 20 and the mixture is taken up in acetic ester. The phases are separated, the organic phase is washed in aqueous bicarbonate solution and water, dried above sodium sulfate, filtered off, and evaporated under reduced pressure. The yellow oil (1.57 g) is liberated from non- 25 polar products using chromatography on 40 g of silica gel and a toluene/acetic ester gradient. The main fraction (0.7 g) is purified by preparative thin-layer chromatography using silica gel 60 PF 2 54 3 6 6 and a chloroform/ acetone solvent system. 410 mg of a colourless foam is obtained that is recrystallized from methanol.

Yield: 263 mg of lp-[4-(benzoyloximinomethyl)phenyl]-17p -methoxy-17a-methoxymethyl-estra-4,9-diene-3-on as colourless foam.

Melting point: 115 122 0 C (methanol) aD 2160 (CHC1 3 UV spectrum in MeOH: Xmax 279 nm 8 33 720 Xmax 299 nm s 30 120 1H-NMR spectrum in CDC1 3 ppm]: 0.527 3H, H-18); 3.253 3H, 17-OCH 3 3.415 3H, 17a-CH 2

OCH

3 3.403 3.598 2H, ABX system, 17a-CH20CH 3 4.416 (d, 1H, J=7.2 Hz, H-11a); 5.792 1H, 7.299 7.615 5H, aromatics protons, COphenyl); 7.701, 7.729, 8.111, 8.140 4H, AA'EB' system of aromatics protons); 8.520 1H, CHphenyl) Example 8 *i 15 Measurement of bonding affinity for receptors Receptor bonding affinity was determined by competitive bonding of a specifically binding 3H labelled hormone (tracer) and the compound to be tested to receptors in the cytosol from anima' target organs. It was tried to 20 obtain receptor saturation and a balanced reaction. The following incubation conditions were selected: Glucocorticoid receptor: thymus cytosol of the adrenalectomized rat, thymi kept at -300C, buffer: TED. Tracer: 3H-dexamethasone, 20 nM; reference substance: 25 dexamethasone.

After an incubation period of 18 hours at 0 4 0 C, bonded and free steroid was separated by mixing in active carbon/ dextrane centrifuging off and measuring the bonded 3H activity in the supernatant.

The IC 50 for the compound to be tested and for the reference substance were determined from measurements in series of concentrations. The quotient of both values (x 100%) is the relative molar bonding affinity.

Example 9 Inhibition -f early gravidity in the rat: Female rats are mated in the pro-oestrus. If semen is found in the vaginal smear on the next day, this day is counted as day 1 of the gravidity. Treatment with the test substance or vehicle is applied on d5 d7, autopsy is carried out on d9. The substances are injected subcutaneously in 0.2 ml of vehicle (benzyl benzoate/ castor oil 1 The rate of fully inhibited 44"* gravidities found in various groups can be seen from table 1. A superior inhibition capability of nidation was found for J 917 and J 900 as compared to RU 486.

*e oe *o *o 0 0* 00 *c 111--

Claims

1. llg3-benzaldoxime--estra-4,9-diene derivatives of the general formula I NOZ CH 2 -O-CH 3 S S S S 55 S S S 5555 where Z is -CQ--CH 3 -CO-O-C 2 H 5 -CO-NH-phenyl, -CO-NH-C 2 H 5 -CO-C 2 H 5 -CH 3 or CO-phenyl, as well as their pharmaceutically acceptable salts. S. S .5 S 05*@ o 50 S @5 S

2. Compounds according to Claim 1, namely

113- (acetoximinomethyl)phenyl] -17f3-methoxy-l7L- methoxymethyl-estra-4, 9-'diene-3 -on, lp- [(ethoxycarbonyl)oximinomethyllphenyl} -17p- methoxy-17ct-methoxymethyl-estra-4, 9-diene-3-on, l1-{4- [(ethylaminocarbonyl) oximinomethyll phenyl} -17f3- methoxy-j 7a-methoxymethyl-estra-4, 9-diene-3-on, 17p-methoxy-17a-methoxymethyl-llp- [(phenylamino- carbonyl) oximinomethyl] phenyl} -estra-4, 9-diene-3-on, .00. V 0 0. 11f3- 4- (propionyloximinomethyl) phenyli -17f3-methoxy-l7L -methoxymethyl-estra-4, 9-diene-3 -on, lpj-[4- (methyloximinomethyl)phenyl] -17j-hydroxy-17x- methoxymethyl-estra-4, 9-diene--3-on, and ii3- (benzoyloximinomethyl)phenyll -l71-hydroxy-l7ae- methoxymethyl-estra-4, 9-diene-3-on. 3. Methods for producing the compounds according to Claim 1 and their pharmaceutically acceptable salts, characterized in that a compound of the general formula II NOH 15 is esterified or etherified in a generally known way and, if required, converted into a salt. 4. Pharmaceutical compositions, characterized in that tchey contain at least one compound according to claims 1 to 2 in association with one or more pharmaceutically acceptable carriers. a 9* 3029W/PT 26 A method for the treatment of diseases associated with pathologically modified tissues in which oestrogens stimulate growth which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least one compound according to either of claims 1 or 2 optionally in association with one or more pharmaceutically acceptable carriers. 6. A method according to Claim 5 which is a method for the treatment of endometriotic focuses, myomas, mammary and genital carcinomas, and benign prostatic hypertrophy. 7. Compounds of the formula methods for their manufacture or pharamaceutical compositions or methods of treatment-involving/containing them, substantially as hereinbefore described with reference to the Examples. DATED this 18th day of August 1994. JENAPHARM GMBH By Its Patent Attorneys DAVIES COLLISON CAVE *eoe ABSTRACT This invention relates to new 11-benzaldoxime-estra-diene derivatives of the general formula I NOZ CH 2 -O-CH 3 I I o 00 *0 and their pharmaceutically acceptable salts, a method for their production, and pharmaceuticals containing such compounds. The compounds described show strong antigestagenic effects combined with reduced glucocorticoid activity. D a a a a -J