The invention relates to new compounds of general formula I(see Original Patent), their production and pharmaceutical preparations that contain these compounds.The compounds according to the invention are preferably used for female birth control and for HRT.

Description of the Invention

The invention relates to selective progesterone receptor modulators (SPRM) that can be used for treating gynecological disorders, especially for hormonal female contraception or in hormone replacement therapy.

Progesterone is secreted in large amounts from the ovary or the placenta during the cycle and in pregnancy. By interaction with estrogens, progesterone produces cyclic changes of the mucous membrane of the uterus in the menstrual cycle. In pregnancy, progesterone controls the relaxation of the myometrium and preserves the function of the decidual tissue.

Under the influence of elevated progesterone levels after ovulation, the mucous membrane of the uterus is converted into a state that allows the nidation of an embryo (blastocyst).

In a subtle way, progesterone is involved in the control of ovulation processes. It is known that progesterone has antiovulatory properties in connection with estrogens. The latter result from an inhibition of the hypophyseal gonadotropin secretion, which is a requirement for the maturation of a follicle and its ovulation. In contrast, it is evident that the comparatively low progesterone secretion of the maturing follicle plays an active role for the preparation and triggering of ovulation. In this connection, hypophyseal mechanisms (time-limited so-called positive feedback of progesterone on gonadotropin secretion) play a significant role (D. Loutradie, Human Reproduction 6, 1991, 1238-1240).

In addition, it is known that progesterone exerts a decisive influence on the endometrium. The endometrial proliferation is inhibited by the suppression of the estrogen-mediated mitosis in the uterus tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).

Hormonal contraception can be considered as a combination that consists of antiovulatory strategy associated with the replacement of the deficient endogenic hormones. The conventional hormonal contraception consists in simulating the woman's natural cycle by a combination that consists of gestagens and estrogens by withdrawal bleeding being induced in a 28-day rhythm. Apart from its effectiveness, this method is distinguished by other advantages that can be seen in a reduction of the carcinogenic risk, especially ovarian or endometrial cancer, or its positive influence on the cardiovascular system.

A drawback of the conventional hormonal contraception is associated with the administration of relatively high doses of estrogens (i.a., ethinylestradiol, EE), which are essential for regular bleeding behavior. Estrogens, especially ethinylestradiol, significantly influence certain liver functions, such as, e.g., the synthesis of transport proteins CBG, SHBG, TBG, angiotensinogen, and in addition various functions that play a role in the physiology of blood-clotting as well as lipoproteins (HDL, LDL).

The strong estrogenic action of EE in the liver, but also the natural estrogens during pregnancy, are expressed, i.a., in an increased thromoembolic risk. Also, without the pathophysiological bases to recognize thromboembolic complications in particular, it can be assumed that, in this connection, hepatic estrogen actions have a decisive role.

Selective progesterone receptor modulators, also named mesoprogestins, are a new class of progesterone receptor (PR)-ligands, which show both an agonistic action and an antagonistic action on the progesterone receptor in vivo.

This results in a neutralization of the antiovulatory effectiveness that is present both in pure PR-agonists and in pure PR-antagonists [Slayden, O. D., Chwalisz, K., and Brenner, R. M. Reversible Suppression of Menstruation with Progesterone Antagonists in Rhesus Macaques. Hum Reprod 16: 1562-1574, 2001, Elger, W.; Bartley, J.; Schneider, B.; Kaufmann, G.; Schubert, G.; Chwalisz, K. Endocrine Pharmacological Characterization of Progesterone Antagonists and Progesterone Receptor Modulators with Respect to PR-Agonistic and Antagonistic Activity. Steroids 65, 713-723 (2000)]. Deficient or unreliable inhibitory effects on the ovulation bring up questions on antifertile effectiveness of corresponding mesoprogestins.

Another feature of the mesoprogestins is the reduced or deficient potential of the compounds to trigger an abortion compared to the compound RU 38 468 that acts almost exclusively as an antigestagen.

Chemical compounds of the structure shown below, in which R can be a hydrogen atom or an alkyl group and R.sup.1 can be a hydrogen atom, an alkyl group or aryl group or an optionally substituted acyl function, are known as mesoprogestins -- see Original Patent.

WO 01/44267 describes new 11.beta.-phenylestradiene derivatives with fluoroalkyl groups in the aromatic side chain and production thereof. The compounds or the pharmaceutical preparations that contain these compounds are antihormonally effective and are therefore suitable for the treatment of diseases that are unfavorably influenced by cortisol or by corticoids, for the reduction of secreted cortisol, for stimulation of lactation, for treating dysmenorrhea and myomas, for treating Cushing's disease and for cervical maturation, for improving cognitive performance, for treating endometriosis or for hormone replacement therapy (HRT).

WO99/45023 relates to S-substituted 11.beta.-benzaldoxim-estra-4,9-diene-carboxylic acid-thiol ester. The compounds have antigestagenic properties while at the same time having an antigluocorticoidal action that is significantly more reduced in comparison to that of RU 468.

In EP 909764, 11.beta.-benzaldoxime-9.alpha.,10.alpha.-epoxy-estr-4-ene derivatives with high binding affinity to the progesterone receptor in the case of low glucocorticoid receptor affinity are described.

DE 4332283 and U.S. Pat. No. 5,693,628 relate to 11-benzaldoxim-estra-4,9-diene derivatives of general formula -- see Original Patent.

The compounds 4-[17.beta.-hydroxy-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde-1-(E)-ox- ime and 4-[17.beta.-hydroxy-17.alpha.-methyl-3-oxoestra-4,9-dien-11.beta.-- yl]benzaldehyde-1-(E)-oxime are not mentioned explicitly.

The disclosed compounds are distinguished by a strong antigestagenic action with reduced glucocorticoidal activity.

In un-prepublished application DE 102 1034, 17.alpha.-fluoroalkyl-11.beta.-benzaldoxime steroids of general formula -- see Original Patent.

The object of this invention is to make available compounds for female contraception that combine known advantages of conventional contraception and additional advantages. The contraceptive methods that can be carried out with the compounds according to the invention preferably will not require the addition of exogenic estrogens, however. In conventional contraceptives, the doses of EE used to achieve a reliable suppression of the ovarian function and to preserve a menstrual bleeding pattern are essential. The compounds according to the invention are to be distinguished by omitting or by reducing the dose of the estrogen components by a lower thromboembolic side-effect potential. It is to be possible to induce an amenorrhea by the compounds. At the same time, a stimulation of the mammary glands is to be avoided. Especially advantageous compounds are to be able to suppress both estrogenic and gestagenic effects in the endometrium. The compounds according to the invention are to inhibit the ovulation and to preserve the bone substance in the absence of estrogens; it is in the postmenopausal woman or is premenopausal after suppression of ovarian estrogen secretion.

The object is achieved according to this invention by the preparation of new 11.beta.-benzaldoxime-estra-4,9-diene derivatives of general formula I -- see Original Patent.

In addition, this invention comprises the new substances as pharmaceutical active ingredients, their production, their therapeutic use and the pharmaceutical dispensing forms that contain the new substances.

The compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts can be used for the production of a pharmaceutical agent for use in female birth control as well as in female hormone replacement therapy (HRT).

For HRT, the compounds according to the invention can be used alone or associated with a natural estrogen (e.g., estradiol, its esters, estrone, estrone sulfate, estriol and prodrugs of these estrogens).

For the formation of pharmaceutically compatible salts of the compounds of general formula I according to the invention, i.a., hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid are considered as inorganic acids, and, i.a., acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid are considered as organic acids.

The compounds are distinguished by a mild androgenic and simultaneously improved antigonadotropic action. For the structurally closest compounds, as they are known from the above-mentioned prior art, no androgenic action was previously described. The substances of general formula I according to the invention represent compounds, moreover, that have an improved agonistic activity on the progesterone receptor compared to known compounds.

Biological Characterization of the Compounds According to the Invention

The substances of general formula I according to the invention were tested in the following models:

Receptor Binding Tests

Measurement of the Receptor Binding Affinity:

The receptor binding affinity was determined by competitive binding of a specifically binding .sup.3H-labeled hormone (tracer) and the compound to be tested on receptors in the cytosol from animal target organs. In this case, receptor saturation and reaction equilibrium were sought.

The tracers and increasing concentrations of the compound to be tested (competitor) were co-incubated with the receptor-containing cytosol fraction at 0-4.degree. C. over 18 hours. After separation of the unbonded tracer with carbon-dextran suspension, the receptor-bonded tracer portion was measured for each concentration, and the IC.sub.50 was determined from the concentration sequence. As a quotient of the IC.sub.50 values of the reference substance and the compound to be tested (.times.100%), the relative molar binding affinity (RBA) was calculated (RBA of the reference substance=100%).

For the individual receptor types, the following incubation conditions were selected:

Progesterone Receptor:

Uterus cytosol of the estradiol-primed rabbit; homogenized in TED buffer (20 mmol of Tris/HCl, pH 7.4; 1 mmol of ethylenediamine tetraacetate, 2 mmol of dithiothreitol) with 250 mmol of saccharose; stored at -30.degree. C. Tracer: .sup.3H-ORG 2058, 5 nmol; reference substance: progesterone.

Glucocorticoid Receptor:

Thymus cytosol of the adrenalectomized rat, thymi stored at -30.degree. C.; buffer: TED. Tracer: .sup.3H-Dexamethasone, 20 nmol; reference substance: dexamethasone.

Androgen Receptor:

Prostate cytosol of the castrated rat; prostates stored at -30.degree. C.; buffer: TED with 10% glycerol as well as 2 .mu.mol of triamcinolone acetonide. Tracer: .sup.3H-metribolone 4 nmol; reference substances: metribolone (RU 1881) or 5.alpha.-dihydrotestosterone.

Evaluation of Antifertile Effects of the Substances in the Perinidation Phase of Rats

The determination of the progesterone-antagonistic activities was carried out on adult female rats in the nidation-inhibiting test.

The inhibition of the progesterone receptor leads to strong antifertile effects in the very early pregnancy of rats. Partial PR-agonistic properties of substances do not weaken the negative actions on pregnancy in this phase of the reproduction process (nidation) (Elger, W.; Bartley, J.; Schneider, B.; Kaufmann, G.; Schubert, G.; Chwalisz, K. Endocrine Pharmacological Characterization of Progesterone Antagonists and Progesterone Receptor Modulators with Respect to PR-Agonistic and Antagonistic Activity, Steroids 65, 713-723 (2000)). Unlike pure PR-antagonists, the substances according to the invention have no or have greatly reduced inhibiting effects on the pregnancy in terms of reduced or eliminated capacity to induce labor.

The principle of the test is described as follows: progesterone preserves pregnancy in all stages. An early-abortive action can accordingly be expected from competitive progesterone antagonists.

Female rats (Schoe strain: WIST Tierzucht GmbH Schonwalde) with a weight of 180-200 g were subjected daily to a cycle control and paired up in proestrus. The beginning of pregnancy was determined by detecting sperm in the vaginal smear on the same day (=day 1 of pregnancy=d1 p.c.).

From the 5.sup.th-7.sup.th day of pregnancy, the test substances were injected subcutaneously daily. On the 9.sup.th day, vaginal smears were taken, then the animals were autopsied and the uteri were prepared.

The degeneration of implants and pathological, hemorrhagic and otherwise abnormal nidation sites were counted as abortions and are shown in Table 2 (see Original Patent).

The results of these studies show that mesoprogestins according to the invention have PR-antagonistic properties.

Antiluteolysis Test/Ovulation-Inhibiting Test on Cyclic Guinea Pigs

Testing of the substances on progesterone-agonistic or progesterone-antagonistic activity was carried out in the antiluteolysis test on adult female guinea pigs after subcutaneous administration.

The principle of the test is represented as follows: The degeneration of the corpus luteum in the non-fertile cycle is carried out in guinea pigs by prostaglandins (PGF.sub.2.alpha.), which the uterus releases. In pregnancy, the corpora lutea persist since the embryo inhibits the prostaglandin secretion of the uterus [Elger, W.; Bartley, J.; Schneider, B.; Kaufmann, G.; Schubert, G.; Chwalisz, K. Endocrine Pharmacological Characterization of Progesterone Antagonists and Progesterone Receptor Modulators with Respect to PR-Agonistic and Antagonistic Activity. Steroids 65, 713-723 (2000)]. In the cycle, the progesterone stimulates the secretion of PGF2.alpha. of the uterus. Pure PR antagonists inhibit this function completely (inhibition of luteolysis). This test arrangement makes it possible to detect the inhibition of the uterine prostaglandin release as an antiluteolytic action by progesterone content determinations in the serum between days d0; d6/d7/d8 and d10-d18. At the same time, the ovulation inhibition can be determined by histological evaluation of the corpora lutea in the ovary (new corpora lutea=ovulation).

Female guinea pigs (Schoe strain: DH, Tierzucht GmbH Schonwalde) with a weight of 500 g were subcutaneously treated from day 10 to day 17 daily with test substances or comparison substances onapristone and RU 486 in the dose of 10 mg/animal/day. The substance vehicle benzyl benzoate/castor oil was administered to the control group. The administration volume was 0.2 ml/animal/day, and each group included 5 test animals.

On days 10, 12, 14, 16 and 18, blood samples were taken from the postorbital venous plexus to determine progesterone content. 24 hours after the last administration, the animals were autopsied. The results are shown in FIGS. 1 and 2 (see Original Patent).

Substances with affinity to PR and AR that inhibit the ovulation but not the degeneration of the corpora lutea are mesoprogestins according to the invention.

Determination of the Androgenic and Antigonadotropic Properties of the Substances in the Hershberger Test on Infantile Rats

The determination of the androgenic properties was carried out in the Hershberger test on infant male rats after subcutaneous administration over 7 days.

The principle of the test is represented as follows: the function and size of the accessory sexual glands (seminal vesicles and prostates) and the Musculus levator ani depend on the presence of androgens. A castration consequently results in the atrophy of these organs. If, after castration, an androgen (testosterone propionate) is substituted, the increase in the weight of the accessory glands can be considered to indicate that substances exert an androgenic activity.

Male infant animals (Mol strain: WIST, Tierzucht GmbH Schonwalde) with a weight of 40-50 g underwent orchiectomies (ORX). A control group remained uncastrated but underwent a sham operation (SHO). The vehicle of the test substances benzyl benzoate/castor oil was administered to control groups ORX and SHO (n/group=10 animals).

Testosterone propionate (standard) and the test substances were subcutaneously administered in the doses 0.1; 1.0 and 10 mg/animal/day, administration volumes 0.2 ml/animal/day.

24 hours after the 7.sup.th administration, the animals were autopsied. The results are shown in FIGS. 3, 4, 5 and 6 (see Original Patent).

Substances with an AR-agonistic and LH/FSH-reducing action in this assay and PR-agonistic and antagonistic properties are mesoprogestins according to the invention.

Determination of the Estrogenic and Osteoprotective Action of the Substances on Adult Rats

The tests on estrogenic and osteoprotective activity after subcutaneous administration over 28 days was carried out on female, 6-month-old rats (Shoe strain: WIST, Tierzucht GmbH Schonwalde). The animals were ovariectomized and equipped with osmotic pumps (Alzet) for continuous subcutaneous administration of test substances. The animals were autopsied on day 29.

To determine the estrogenic properties of substances, the uterus weight was determined. The bone density was determined by means of QCT (quantitative computer tomography) on the prepared tibia. The results are shown in FIGS. 7 and 8.

The results of these studies show that substances according to the invention have an osteoprotective action per se.

Determination of the Gestagenic Action of the Substances

Tests on gestagenic and antigestagenic activity were carried out on infant rabbits in the McPhail test.

The principle is represented as follows: by interaction of estrogens and progesterone, the endometrium is prepared for the implantation of the fertilized ovocytes. In this case, this results in completely characteristic changes in the endometrium, which can be clearly detected in rabbits. Estrogens produce a proliferation. The action of gestagens sets in only once the endometrium is proliferated. Gestagens produce a so-called transformatory conversion of the endometrium.

Infant rabbits (New Zealand white. Supplier: Harlan Winkelmann) with a weight of 700-900 g received 17.beta.-estradiolbenzoate (5 .mu.g/animal/day in 0.2 ml, s.c.) once daily as priming over 6 days (d1-d6). On test day d7, the administration of the test substances as well as the comparison substances progesterone and RU 486 began once daily over 7 days subcutaneously in benzyl benzoate/castor oil. A control group received one vehicle administration daily (benzyl benzoate/castor oil).

On day d14, the test was completed. First, blood samples were taken and then autopsies were carried out.

The replication of secretory structures of the endometrium typical of the gestagenic action is evaluated in the histological preparations according to the McPhail scale (stage 1-4; 0=no action, 4=full action).

The results are shown in FIGS. 9, 10, and 11 (see Original Patent).

Substances with an AR-agonistic action that weaken the action of progesterone in this assay but themselves trigger submaximal progesterone-analogous effects in the endometrium are mesoprogestins according to the invention.

Pharmaceutical Preparations and Indications

The compounds of general formula I represent a new type of mesoprogestins with both agonistic action on the progesterone receptor and improved antigonadotropic and mild androgenic action after peroral administration. As a result, previously impossible forms of hormone treatment are being developed.

This invention comprises the new substances as pharmaceutical active ingredients, their production, their therapeutic application and the pharmaceutical dispensing forms that contain the new substances.

The new mesoprogestins that are described here or their pharmaceutically acceptable salts can be used both without estrogens and with the addition of low-dose natural estrogens such as estradiol or their esters for the production of pharmaceutical agents that can be used in female birth control, in female hormone replacement therapy and for the treatment of gynecological diseases such as endometriosis, uterus myomatoses, dysfunctional bleeding and dysmenorrhea. In this connection, the estrogens can also be used in the form of their sulfamates. For the production and the special pharmacological properties of the sulfamates, see J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998).

The new progesterone receptor modulators are suitable by their high antiovulatory activity for a preferably estrogen-free or estrogen-dose-reduced contraception in women. The bleeding control is taken over by the mesoprogestin/gestagen components of the compounds according to the invention in contrast to conventional contraceptive agents. The purpose of the treatment is to induce an amenorrhea. The estrogen component in these preparations has the task of avoiding an estrogen deficit. As a result, the compounds according to the invention must not be combined with EE, but rather can preferably be added without estrogens or in combination with small doses of natural estrogens (e.g., estradiol, its esters, estrone, estrone sulfate, estriol and prodrugs of these estrogens).

By the natural cycle or under the hormonal contraception with a combined contraceptive agent (estrogen and gestagen treatment), a constant rise and fall of the female hormone condition is created. A significant increase in the risk of developing breast cancer, ovarian or endometrial carcinoma may be associated therewith [Coutinho, E. M. and Segal, S. Is Menstruation Obsolete?, Oxford University Press (1999)]. Classic gestagens stimulate the breast tissue of women [Isaksson, E.; von Schoultz, E.; Odlind, V., et al. Effects of Oral Contraceptives on Breast Epithelial Proliferation. Breast Cancer Res Treat 65: 163-169 (2001)].

The spectrum of hormonal properties of the substances according to the invention inhibits, however, the proliferation in the breast. Androgens have a significantly inhibiting effect on the proliferation of the mammary glands. Accordingly, the substances according to the invention have special advantages in this respect.

The use of the substances according to the invention for the production of pharmaceutical agents for use as a contraceptive agent thus makes possible a completely new concept of contraception, in which the risk of breast cancer is significantly limited.

In addition, in premenopausal women, the condition of a reversible amenorrhea can develop without the negative signs of an estrogen deficiency, since a basal estrogen secretion is also often maintained in the case of inhibited ovulation based on the dose. An estrogen-free or estrogen-dose-reduced contraception method in turn results in that the known side effects, such as thromboembolic complications, can be significantly reduced.

The substances according to the invention or their pharmaceutically compatible salts can also be used as single components. The use of low-dose, preferably natural estrogens, such as estradiol and its esters, results in a relaxation of the ovaries and the endometrium, which contributes to a reduction of undesirable proliferation appearances in the above-mentioned tissues.

Compared to conventional hormonal HRT products, the absence of any bleeding is an important feature. In addition, the advantageous effect of ovarian androgens on the CNS and metabolic functions is substituted by the substances according to the invention via their androgenic activity. Unlike gestagens, the compounds according to the invention do not stimulate the glandular tissue of the breast.

The special advantage of the compounds according to the invention relative to the treatment of gynecological diseases such as endometriosis, uterus myomatoses, dysfunctional bleeding and dysmenorrhea lies in their elevated antifertile action in comparison to compounds that do not have any androgenic activity. By the increased antiovulatory activity of the compounds according to the invention, pregnancies under the treatment of gynecological diseases with mesoprogestins are ruled out.

The compounds of general formula I according to the invention and their acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients at least one or more of the compounds of general formula I according to the invention or their acid addition salts, optionally in combination with other pharmacologically active substances. The production of the pharmaceutical agent is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.

As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmann's Enzyklopadie der technischen Chemie [Ullmann's Encyclopedia of Technical Chemistry], 4, 1953, 1-39; J. Pharm. Sciences, 52, 1963, 918 ff; issued by Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm Ind. 2, 1961, 72 ff; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor K G. Aulendorf in Wurttemberg 1971.

The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, in that the active ingredient is processed with the vehicles, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, dyes, etc., that are commonly used in galenicals and converted into the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15.sup.th Ed. Mack Publishing Company, East Pennsylvania (1980).

The preferred preparations consist in a dispensing form that is suitable for oral administration. Those dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.

The compounds of the general formula according to the invention or the pharmaceutical compositions that contain at least one of the compounds according to the invention are preferably administered orally.

Corresponding tablets can be obtained, for example, by mixing active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosives such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxylpolymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores, which are produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example polyvinyl pyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the shell of the coated tablet can also consist of several layers, whereby the adjuvants that are mentioned above in the tablets can be used.

Solutions or suspensions with the compounds of general formula I according to the invention can contain in addition flavor-improving agents such as saccharin, cyclamate or sugar, as well as, e.g., flavoring substances such as vanilla or orange extract.

In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose, or preservatives, such as p-hydroxy-benzoates.

The capsules that contain compounds of general formula I can be produced, for example, by the compound of general formula I being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.

Dosage

The amount of the compounds to be administered fluctuates within a wide range and can cover any effective amount.

Based on the effect to be achieved and the type of administration, the amount of compound to be administered can encompass a range of 0.01 to 50 mg. In humans, a recommended daily dose lies in the range of 0.05 to 10 mg.

Suitable dosages for the compounds according to the invention are from 0.1 to 10 mg.

The compounds according to the invention are administered continuously, preferably daily to once weekly.

The compounds according to the invention are suitable for vaginal, intrauterine and subcutaneous administrations in suitable vehicle systems (elastomers). From case to case, this dispensing form allows lower dosages than those indicated above.

The invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and/or vehicles.

The invention also comprises pharmaceutical compositions that contain one of the pharmaceutically active compounds according to the invention or a mixture of the latter or a pharmaceutically compatible salt as well as pharmaceutically compatible adjuvants and vehicles.

The compounds of general formula I according to the invention can be produced as described below:

Access to the 11.beta.-benzaldoxime-estra-4,9-diene derivatives of general formula I according to the invention is carried out via the 3,3-dimethoxy-estra-5(10),9(11)-dien-17-one [Pierdet, A.; Vignau, M. FR 5183 (1966)], which is converted with H.sub.2O.sub.2 in the presence of hexafluoroacetone into 3,3-dimethoxy-5.alpha.,10.alpha.-epoxiestr-9(11)-en-17-one [Costerousse, G.; Teutsch, G.; EP 5100 (1979); Teutsch, G.; Ojasoo, T.; Raynaud, J. P.: J. Steroid Biochem. 31, 1988, 549-565]. The introduction of the 11.beta.-benzaldehyde grouping is carried out by Grignard reaction with the corresponding bromobenzaldehyde acetal. After functionalization at C-17, the 11.beta.-benzaldehyde acetal is hydrolyzed and then oximized (see formula diagram 1):
 

Claim 1 of 24 Claims

1. A compound of formula I -- see Original Patent.

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