KR0175687B1 - 11-benzaldoximeestradiene-derivates a process for their preparation and pharmaceutical compositions containing them. - Google Patents

Abstract

The present invention relates to 11-benzaldoxime-estra-diene derivatives of formula (I) and pharmaceutically acceptable salts thereof, methods for their preparation and pharmaceuticals containing such compounds.

The above compounds show a strong antigestagen effect with reduced glucocorticoid activity.

Description

11-Benzaldoxime-estra-diene derivatives, preparation method thereof and medicament containing same

Figure 1 shows the antigestagen treatment effects on cyclic uterine compression of guinea pigs compared to the therapeutic effects of J867 and RU486,

2 shows the antiglucocorticoid effect provided by J867 in the ZR75 / AGP-763 cell line of human breast compared to the effect of RU486,

3 shows the results of comparing the antiglucocorticoid effects of J867 and RU486 on rat liver cancer cells using the TAT model.

The present invention relates to a 11-benz aldoxime-estra-diene derivative, a method for preparing the same, and a medicament containing the same.

11β-substituted phenyl estra-triene is known. European Patent Publication No. 057 115 describes a process for the preparation of 11β-aryl-17α-propynylestra-4,9-diene, and German Patent Publication No. 3 504 421 describes 11β- (4-formyl phenyl). A method of reacting esttra-4,9-dien-3-one with hydroxylamine is described. Both 11β-formylphenylene moiety and 3-keto group are oxime according to the method recited. In addition, syn and anti isomers are formed at C-3. The effects of the compounds described above are not yet known.

Progesterone is released during menstruation, and during pregnancy, in large quantities in the ovaries and placenta. The importance of its control has not been made clear in nearly every way.

It is known that progesterone, along with estrogen, periodically changes the uterine mucosa during the menstrual cycle and during pregnancy. After ovulation, the concentration of progesterone is increased to make the uterine mucosa suitable for fetal (blastocyst) inclusion conditions. The protection of tissue in which the fetus grows also depends on progesterone.

During pregnancy, the work of the uterine muscles changes dramatically. In the non-pregnant state, the response of the uterine muscles in the pregnant state to hypertonic hormonal and mechanical stimuli is strongly reduced or absent. At this time, there is no doubt that progesterone acts principally, despite the fact that their response is high even at certain stages of pregnancy, for example, at high blood progesterone levels just before delivery.

Very high progesterone concentrations are also reflected by other conventional processes during pregnancy. An example of this is the composition of the mammary gland up to just before the powder and the obstruction of the cervix.

Progesterone obscures the ovulation process. Administration of high concentrations of progesterone is known to exhibit ovulation inhibitory properties. This is due to the inhibition of anterior pituitary gonadotropin secretion which is essential for follicle maturation and its ovulation. On the other hand, however, it can be seen that a relatively small amount of progesterone secreted by mature follicles acts as an active part in ovulation preparation and induction. In this respect, the anterior pituitary mechanism (temporary, so-called positive feedback of progesterone for gonadotropin secretion) is considered to be of great importance. Loutradie, D .; Human Reproduction 6, 1991, 1238-1240.

The agonists of progesterone in mature follicles and corpus luteum have not been analyzed very clearly. As a result, it is assumed that there are both stimulating and inhibitory effects on the endocrine function of the follicles and corpus luteum.

In addition, progesterone and progesterone receptors can be assumed to be of significant importance for physiological processes. Progesterone receptors have been found in endometritis lesions as well as in the uterus, breast and CNS (meningioma). The role of these receptors in relation to the growth characteristics of these etiologically related tissues is not necessarily dependent on blood progesterone concentrations. RU 486 = Materials characterized as progesterone antagonists, such as Mifepristone (Defe-O 057 115) and ZK 98299 = Onapristone (DE-OS-35 04 421), can vary widely, even if blood progesterone concentrations are negligible. It tends to cause a change in action.

In this respect, the transcriptional effects of progesterone receptors not filled with progesterone appear to be alterable (Chwalisz, K. et al., Endocrinology, 129, 317-322, 1991).

The effects of progesterone on reproductive and other tissues are caused by interaction with progesterone receptors. In the cell, progesterone binds to its receptor with high affinity. This changes the receptor protein, i.e. the structure changes, the two receptor units dimerize to form one complex, and degrade the protein (HSP 90) to expose the DNA binding site of the receptor and to hormone-responsive DNA elements. Combine. Eventually, transcription of certain genes is regulated. Gronemeyer, H. et al., J. Steroid Biochem. Molec. Biol. 41, 3-8, 1992].

The effects of progesterone or progesterone antagonists do not depend only on their blood concentration. Receptor concentrations in cells are also strongly regulated. Estrogens promote the synthesis of progesterone receptors in most tissues. Progesterone inhibits the synthesis of estrogen receptors and progesterone receptors. These interactions between estrogen and gestagen may explain why gestagen and antigestagen can affect estrogen-dependent processes without being bound by the estrogen receptor. These relationships naturally are of considerable importance for the therapeutic application of antigestagens. These substances are suitable for the female reproductive process, for example, to prevent post-ovulation implantation, or to increase the responsiveness of the uterus to prostaglandins and oxytocins during subsequent pregnancy or to direct action on metrutin insertion and cervical softening (maturation). Seems to be.

Antigestagens inhibit ovulation in various species of apes. The mechanism of this effect has not been elucidated yet. Among the hypotheses discussed are the hypothesis of suppression of gonadotropin secretion and the ovarian mechanism hypothesis based on the fact that progesterone in the ovary interferes with para- and self-cleaning action.

Antigestogens can modulate or attenuate the effects of estrogens, although most of them can increase estrogen receptor concentrations without showing estrogen receptor affinity at cytoplasmic concentrations. Similar effects on endometritis lesions or cancerous tissues, including estrogen and progesterone receptors, anticipate desirable effects on pathological symptoms. Certain advantages associated with having a desirable effect on pathological symptoms, such as endometritis, can be obtained when suppressed ovulation compensates for the inhibitory effect of antigestagen action in tissues. The stimulatory effect on the hormonal products of the ovaries and their pathologically modified tissues will also be reduced by inhibiting ovulation. In severe cases of endometritis, it will usually be desirable to suppress ovulation so that tissues in the reproductive organs to be constantly reconstituted are reversible.

Methods have been discussed related to contraception in which antigestagen therapy inhibits ovulation and subsequent gestagen therapy changes the secretion of the endometrium. Antigestagen and gestagen treatment days and untreatment days result in a 28-day cycle with regular withdrawal bleeding (Baulieu, E. E., Advances in Contraception 7, 345-51, 1991).

Antigestagens can have different hormonal and antihormonal properties. Antiglucocorticoid properties are associated with certain treatments. They are undesirable for therapeutic applications with the main purpose of progesterone receptor inhibition, which can cause undesirable side effects when applied at the dosages required for these treatments, which can prevent or stop treatment of therapeutic sensitization doses. Because you have to. In the case of treatment with antigestagens, in particular in the treatment of symptoms requiring weeks or months of treatment, partial or complete reduction of antiglucocorticoid properties is an important prerequisite.

It is an object of the present invention to provide 11-benzaldoxime-estra-diene derivatives of the general formula (I) and pharmaceutically acceptable salts thereof as well as methods for preparing them.

In the above formula,

R ¹ is a hydrogen atom or an alkyl moiety having 1 to 6 carbon atoms,

R ² is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, an acyl moiety or residue having 1 to 10 carbon atoms -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom or 1 carbon atom Alkyl, aryl, aralkyl or alkylaryl residues of from 10 to 10;

R ³ is a hydrogen atom, alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, residues-(CH ₂ ) n -CH ₂ X [where n is 0, 1 or 2, and X is fluorine, chlorine , Bromine or iodine atom, cyano, azide or rodano group, residues OR ⁵ or SR ⁵ , wherein R ⁵ is a hydrogen atom, alkyl having 1 to 10 carbon atoms, aryl, aralkyl or alkylaryl moiety or having 1 to carbon atoms 10 is an acyl residue of 10], residue OR ⁵ (where R ^{5 is} as defined above), residue-(CH ₂ ) o-CH = CH (CH ₂ ) pR ⁶ , where o is 0, 1, 2 Or 3, p is 0, 1 or 2, R ⁶ is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, a hydroxy group or an alkyl group having 1 to 10 carbon atoms, a hydroxyl group , an alkoxy or acyloxy group having 1 to 10 carbon atoms) or a residue - (CH ₂₎ qC≡CR ⁷ (wherein, q is 0, 1 or 2, R ⁷ is a hydrogen atom, a fluorine, a salt Is a bromine or iodine atom, an alkyl, aryl, aralkyl or alkylaryl moiety having 1 to 10 carbon atoms or an acyl moiety having 1 to 10 carbon atoms, and Z is a hydrogen atom, alkyl having 1 to 10 carbon atoms, aryl, aralkyl or Alkylaryl residues, acyl residues of 1 to 10 carbon atoms, residues -CONHR ⁴ or -COOR ⁴ (wherein R ⁴ is a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl residue having 1 to 10 carbon atoms) or an alkali metal or It is an alkaline earth metal atom.

Another object of the present invention is to provide a medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Preferred

R ¹ is a methyl or ethyl group,

R ² is a hydrogen atom, an alkyl group of 1 to 10 carbon atoms, an acyl moiety or residue of 1 to 10 carbon atoms, or residues -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom, alkyl or aryl moiety of 1 to 10 carbon atoms Is,

R ³ is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, residues-(CH ² ) n -CH ² X [where n is 0, 1 to 2, X is fluorine, chlorine , Bromine or iodine atom, cyano, azide or rodano group, residue OR ⁵ or SR ⁵ , wherein R ⁵ is an alkyl residue of 1 to 6 carbon atoms or an acyl residue of 1 to 6 carbon atoms; ⁵ , where R ⁵ is a hydrogen atom, an alkyl moiety of 1 to 10 carbon atoms or an acyl moiety of 1 to 10 carbon atoms, residue-(CH ₂ ) o-CH = CH (CH ₂ ) pR ⁶ , wherein o is 0, 1, 2 or 3, p is 0, 1 or 2, R ⁶ is a hydrogen atom, an alkoxy or acyloxy group having 1 to 10 carbon atoms, residue-(CH ₂ ) qC≡CR ⁷ where q is 0, 1 or 2, R ⁷ is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl residue having 1 to 10 carbon atoms or an acyl residue having 1 to 10 carbon atoms,

Z is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms, an acyl residue having 1 to 10 carbon atoms, the residue -CONHR ⁴ or -COOR ⁴ (wherein R ⁴ is a hydrogen atom or an alkyl residue having 1 to 10 carbon atoms), or an alkali Compound that is a metal or alkaline earth metal atom.

Especially preferred

R ² is an alkyl group having 1 to 6 carbon atoms, an acyl moiety or residue -CONHR ⁴ or -COOR ⁴ (wherein R ⁴ is a hydrogen atom, an alkyl or aryl moiety having 1 to 6 carbon atoms),

R ³ is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, residues- (CH ₂ ) n -CH ₂ X [where n is 0, 1 or 2, X is a fluorine, chlorine, bromine or iodine atom, cyano , An azide or rodano group, residue OR ⁵ or SR ⁵ , wherein R ⁵ is an alkyl moiety of 1 to 6 carbon atoms or an acyl moiety of 1 to 6 carbon atoms, and residue R ⁵ , wherein R ⁵ is carbon Alkyl residues of 1 to 6 or acyl residues of 1 to 6 carbon atoms, residues-(CH ₂ ) o-CH = CH (CH ₂ ) pR ⁶ , wherein o is 0, 1, 2 or 3, and p is 0, 1 or 2, R ⁶ is an alkyl group having 1 to 6 carbon atoms, an alkoxy or acyloxy group having 1 to 6 carbon atoms, or a residue-(CH ₂ ) qC≡CR ⁷ , wherein q is 0, 1 or 2, R ⁷ is an alkyl residue of 1 to 6 carbon atoms or an acyl residue of 1 to 6 carbon atoms,

Z is an alkyl moiety having 1 to 6 carbon atoms, an acyl moiety having 1 to 6 carbon atoms, residues -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl or acyl moiety having 1 to 6 carbon atoms.

Most desirable

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-ethoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-n-propoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-i-propoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-ethoxymethyl-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α- (3-hydroxyprop-1-yn-yl) -estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α- (3-hydroxyprop-1-yn-yl) -estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-Z- (3-hydroxypropenyl) -estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-Z- (3-hydroxypropenyl) -estra-4,9-dien-3-one,

17α-chloromethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-estra-4,9-dien-3-one,

17α-chloromethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one,

17α-cyanomethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-estra-4,9-dien-3-one,

17α-cyanomethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one,

17α-azidemethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one,

11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methylthiomethyl-estra-4,9-dien-3-one,

11β- [4- (methyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (methyloxyiminomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β-4- (ethoxycarbonyl) oximinomethyl] phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β-4- (ethylaminocarbonyl) oximinomethyl) phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

17β-methoxy-17α-methoxymethyl-11β-4-[(phenylaminocarbonyl) oximinomethyl] phenyl-estra-4,9-dien-3-one and

11β- [4- (hydroxyiminomethyl) phenyl] -17β-ethoxy-17α-ethoxymethyl-estra-4,9-dien-3-one.

The invention also reacts a compound of formula (II) with a compound of formula (IIa), wherein the compound of formula (IIa) is optionally present in the form of the compound or from ) Is removed under selected reaction conditions, and if present, esterified or etherified of hydroxyl amine groups and optionally chlorided, resulting in compounds of formula (I) and pharmaceutical It relates to a process for preparing acceptable salts thereof.

In the above formula,

R ¹ , R ² and R ³ are as defined above,

Y is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms, an acyl residue having 1 to 10 carbon atoms, or a residue -CONHR ⁴ or -COOR ⁴ (wherein R ⁴ is a hydrogen atom, alkyl having 1 to 10 carbon atoms, aryl, aralkyl Or alkylaryl residues).

It is preferable to make the compound of General formula (II) react with the compound of General formula (IIa) when it adds in equimolar amount.

When esterification, etherification or urethane formation is desired and when the R ² or Z substituent is a hydroxyl group, the compounds of formula (I) are acylating agents such as acid anhydrides or acid chlorides in the presence of a base, preferably pyridine. Esterification using a generally known method using; Etherification with methyl iodide in the presence of a base, preferably potassium tert-butanolate; The urethane can be formed by reacting with alkyl or aryl isocyanate in an inert solvent, preferably toluene, or with carbamoylchloride in the presence of a base, preferably triethylamine.

The parent compound of formula (II) is prepared from 5α, 10α-epoxide of formula (III):

[Nedelec Bull. Soc. chim. France (1970), 2548.

The introduction of the phenyl moiety to the 11β position while forming the Δ9 (10), 5α hydroxy structure of the following general formula (IV) was carried out at p-bromobenzaldehyde ketal, preferably p-bro, at a temperature of 0 to 30 ° C. Mobenzaldehyde dimethyl ketal and Cu (I) salt catalyzed Grignard reaction (Tetrahedron Letters 1979, 2051).

The-(CH ₂ ) nCH ₂ X group reacts with trimethyl sulfonium iodide and potassium tert-butanolate in dimethyl sulfoxide [Hubner et al., J. prakt. Chem. 314, 667 (1972); Arzneim. Forsch. 30, 401 (1973), followed by ring opening using nucleophiles such as halides and pseudohalogenides, alcoholates and mercaptide [Ponsold et al .; Z. Chem. 11, 106 (1971)] through the spiroepoxide of the general formula (V).

The resulting 17α-CH ₂ X compound of alvinyl formula (VI) is preferably acid hydrolyzed with toluene-p-sulfonic acid in acetone to decompose aldehydes of formula (II) wherein R ² is a hydrogen atom (see Or Tetrasch et al. (DE 2801416) or etherification of free hydroxyl groups with alkyl halides in the presence of potassium tert-butanolate, followed by conversion to 5α, 17β diethers (Kasch et al .; DD). 290 893), followed by acid hydrolysis, preferably with toluene-p-sulfonic acid, in acetone to convert aldehydes of formula (III) wherein R ² is an alkyl moiety, preferably a methyl moiety.

-(CH ₂ ) o-CH = CH (CH ₂ ) pR ⁶ residues react ketone (IV) with propyn-1-ol-tetrahydropyranyl ether and potassium tert-butanolate to produce 17α- (3-hydride Roxy-1-propynyl) -17β-hydroxy compound (VII) is obtained, followed by acid hydrolysis under the conditions specified above to convert R ² to aldehyde (II), a hydrogen atom, or to convert 5α, 17β diether Formed and then hydrolyzed according to the method described above followed by acid hydrolysis to give aldehyde (II) wherein R ² is alkyl residues, or using a deactivation catalyst such as 10% Pd / barium sulfate in the presence of an amine By hydration in a generally known reaction to convert to 17α- (3-hydroxypropenyl) -17β-hydroxy compound and then also to acid hydrolysis and then to aldehyde (II).

-(CH ₂ ) qC≡CR ⁷ residues react ketone (IV) with alcohol or ammonia with acetylene, propene or higher homologues in the presence of alkaline metals (e.g. lithium, sodium or potassium), or ether (e.g. It introduces by a well-known method by reacting with butyl lithium in (tetrahydrofuran). Acid hydrolysis of these compounds yields 17α-C≡CR ⁷ -substituted aldehyde (II).

The compounds of formula (I) produced according to the invention are optionally converted into acid addition salts, preferably salts of physiologically miscible acids. Examples of common physiologically compatible inorganic and organic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that may be used include those described in Fortschritte der Arzneimittelforschung, vol. 10, pp. 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966 and Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977).

Acid addition salts are usually prepared by free base or a solution thereof in an organic solvent such as lower alcohols (e.g., methanol, ethanol, n-propanol or isopropanol) or lower ketones (e.g. acetone, methyl ethyl ketone or methyl isobutyl ketone). Or by reaction with the respective acid or its solution in ether (e.g. diethyl ether, tetrahydrofuran or dioxane). Compositions of the solvents described above can be used to enhance crystallization. In addition, physiologically miscible hydrous solutions of acid addition salts of compounds according to formula (I) may be prepared in the form of hydrous acidic solutions.

Acid addition salts of compounds of general formula (I) can be converted into the free base, for example, by known methods using alkali or ion exchangers. Other salts can be obtained by reacting these free bases with inorganic or organic acids, especially acids suitable for forming pharmaceutically acceptable salts. Salts such as those described above or else of such novel compounds, such as picrates, can be used to purify the free base, which free base is converted and the salt is separated and the base is released again from the salt.

Another object of the present invention is to provide pharmaceuticals designed for oral, rectal, subcutaneous, intravenous or intramuscular administration which, in addition to the usual substrates and diluents, contain a compound of formula (I) or an acid addition salt thereof as an active ingredient. have.

The medicaments of the present invention are prepared in other suitable dosages according to the desired mode of administration by known methods using conventional solid or liquid substrates or diluents and conventional adjuvants used in pharmaceutical engineering. Preferred formulations are in a form suitable for oral administration, for example in the form of tablets, film tablets, dragees, capsules, pills, powders, solutions, suspensions or depots.

In addition, parenteral formulations such as injection solutions are also contemplated. Suppositories are another form of application.

Tablets may contain, for example, an active ingredient in an inert diluent (e.g., dextrose, sugar, sorbitol, mannite, polyvinylpyrrolidone), blasting agent (e.g. corn starch or alginic acid), binder (e.g. starch or By internal mixing with known auxiliaries such as gelatin), lubricants (e.g. magnesium stearate or talc) and / or substances which provide a storage effect (e.g. carboxy polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate) Can be obtained. Purification may consist of multiple layers.

Dragees are prepared by coating the cores prepared in a similar manner to the preparation of tablets using agents commonly applied to dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugars. It can manufacture. Dragee coatings may also consist of several layers in which an adjuvant as mentioned in the above paragraphs for tablets may be used.

Liquids or suspensions containing the active agents of the present invention may further contain flavor-enhancing substances such as saccharin, cyclate 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 such as p-hydroxybenzoate. Capsules containing the active ingredient can be prepared, for example, by mixing the active ingredient with an inert base such as lactose or sorbitol and encapsulating the mixture in gelatin capsules.

Suitable suppositories can be prepared by mixing the active ingredient with a suitable substrate, such as natural lipids or polyethylene glycols and derivatives thereof.

The 11β-substituted benzaldoxime-estra-4,9-diene of the present invention has the same activity against the progesterone receptor and better in vivo effect when compared with RU 486 (mifepristone) (Table 1). (See FIG. 1 and Table 2), while at the same time reduced binding capacity to the glucocortinoid receptor (see Table 1) and enzyme induction inhibition in cell lines reduced by 1/10 fold (see FIG. 2 and Antigestagogenic material with significantly reduced antiglucocorticoid activity as demonstrated by FIG. 3).

Selected antigestagen agents of the present invention significantly reduce uterine compression during ovulation period of guinea pigs at doses where RU 486 increases uterine compression when compared with control animals.

The combined properties of the antigestagen agents according to the invention ensure good inhibition of progesterone while at the same time reducing antiglucocorticoid activity.

This advantage is particularly suitable for conditions requiring very good miscibility due to continuous treatment. During the menstrual cycle, uterine compression is critically affected by the circulation of estrogens. Reduced uterine compression reflects the inhibition of this estrogenic action. Inhibition of uterine compression during the menstrual cycle, measured in guinea pigs, is superior to RU 486 and indirectly exhibits the antiestrogenic properties of the compounds according to the invention. Each of these effects has a particularly desirable effect on pathologically modified tissues that estrogen stimulates growth (endometritis lesions, myomas, breast and genital cancers, benign prostatic hyperplasia).

+ Womb of the cavity

N number of females fertilized

N Number of females who are not pregnant

++ graph detection

High doses (6 mg / 24 hours) of RU 486 reduce uterine compression in treated animals. However, low doses of the above substances only slightly increase uterine compression. Treatment of All Doses (1,3 and 6mg / 24 Hours) J867 inhibits uterine compression to a statistically significant degree.

In this cell line, dexamethasone induces the chloroamphenicolacetyl transferase gene (CAT). This induction is inhibited by antiglucocorticoid substances. Surprisingly, J867 inhibits CAT with less intensity over a broader concentration range compared to RU 486 (Mifepristone).

In rat liver cancer cells, dexamethasone stimulates tyrosine amino transferase enzyme (TAT). This effect is inhibited by antiglucocorticoid activity. J867 shows a much weaker antiglucocorticoid effect than RU 486.

The following examples are intended to illustrate the present invention.

EXAMPLE

Example 1

434 mg of 11β- (4-formylphenyl) -17β-methoxy-17α-methoxy-methyl-estra-4,9-dien-one were dissolved in 8 ml of pyridine at room temperature, 65 mg of hydroxylamine hydrochloride was added, The batch is stirred at 25 ° C. Another 5 mg of hydroxylamine hydrochloride is added after 2 hours. After 15 minutes, the solution is diluted with water, 1N aqueous hydrochloric acid is added and extracted with chloroform. The organic phase is washed with dilute HCl and water and dried over sodium sulfate and potassium carbonate. The solvent is evaporated under reduced pressure. 420 mg of crude product are obtained. After adding acetone, the crystals are precipitated, then filtered off with suction and recrystallized from isopropanol / CHCl.

Yield: 305 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

[Preparation of parent compound]

[Step A]

50 g of 4-bromobenzaldehyde and 30 ml of o-triethylformate are stirred in a solution of 60 ml of methanol and 0.8 ml of thionyl chloride for 5 hours at room temperature. Thereafter, 0.2 ml of thionyl chloride is further added. After 30 minutes, the batch is poured into aqueous bicarbonate solution, extracted with chloroform, washed with aqueous bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation under reduced pressure. 68 g of 4-bromobenzaldehyde dimethylketal are obtained in the form of a colorless oil.

0.2 ml of dibromomethane is added to a solution of 2.3 g of magnesium in 20 ml of dry THF using argon as an inert gas. When the reaction is initiated, 21.96 g of 4-bromobenzaldehyde dimethyl ketal in 70 ml of dry THF is added dropwise in such a way that the temperature does not rise above 40 ° C. After the total amount has been added, the batch is stirred at 30 ° C. for 2 hours and then cooled to −10 ° C. 511 mg of CuCl are added. Continue stirring at −30 ° C. for at least 15 minutes. Then, a solution of 6 g of 3,3-dimethoxy-5α, 10α-epoxy-estr-9,11-ene-17-one in 30 ml of dry THF is added dropwise. Warm up the batch to room temperature. The Grignard solution is decomposed using an aqueous ammonium chloride solution. The product is separated by extraction using acetic acid ester. The organic phase is neutralized washed and dried over sodium sulfate. After distilling off the solvent under reduced pressure, 19.7 g of crude product are obtained. Chromatography with toluene / acetic acid ester gradient using 300 g of silica gel and 20 g of aluminum oxide gave 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -5α-hydroxy-estre-9-ene-. 7.38 g of 17-one is obtained in the form of a yellow foam.

[Step B]

10.38 g of trimethyl sulfonium iodide and 7.64 g (fraction) of potassium tert-butanolate were dissolved in 85 ml of dimethyl sulfoxide using argon as an inert gas, and 3,3-dimethoxy-11β- [4- (dimethoxymethyl ) Phenyl] -5β-hydroxy-estr-9-ene-17-one in a solution of 7.38 g. After 1.5 hours, the mixture was cooled to 0 to 5 ° C., and an aqueous ammonium chloride solution was added thereto. The viscous precipitate is extracted with CH ₂ Cl ₂ , neutralized, washed, dried over sodium sulphate, the solvent is evaporated and separated in the form of a brown resin.

Yield: 8.63 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17β-spiro-1 ', 2'-oxirane-estr-9-ene-5α-ol.

[Step C]

3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17β-spiro-1 ', 2'-oxirane-ester-9- dissolved in 20 ml of 3N sodium methylate solution in 20 ml of methanol It is added to a solution of 8.63 g of en-5α-ol and refluxed for 2-3 hours. The solvent is evaporated under reduced pressure and the residue is neutralized washed by dissolving in CH ₂ Cl ₂ . The solution is dried over sodium sulfate and evaporated under reduced pressure.

Yield: 8.74 g of crude product in the form of a brown foam. Chromatography with toluene / acetic acid ester gradient using 260 g of silica gel and 90 g of aluminum oxide gave 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-methoxymethyl-ester-9-ene 1.92 g of −5α, 17β-diol are obtained.

[Step D]

8.65 g of potassium tert-butanolate was added to 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-methoxymethyl-ester-9-ene-5α in 120 ml of toluene in the presence of an inert gas. To a solution of 1.92 g of, 17β-diol. The suspension is stirred for 5 minutes at room temperature. Then, 6.35 ml of methyl iodide in 6 ml of toluene is added dropwise in such a way that the temperature does not rise above 40 ° C. After 1 hour 20 ml of water and 20 ml of acetic acid ester are added and the phases are separated. The aqueous phase is extracted with acetic acid ester. The organic phase is neutralized washed, dried over sodium sulfate and evaporated under reduced pressure.

Yield: 3,3-dimethoxy-11β- [4- (3,3-dimethoxymethyl) phenyl] -17α-methoxymethyl-ester-9-ene-5α, 17β-dimethyl ether in the form of a yellow foam 1.55 g.

[Step E]

1.55 g of 3,3-dimethoxy-11β- [4- (3,3-dimethoxymethyl) phenyl] -17α-methoxymethyl-estr-9-ene-5α, 17β-dimethyl ether in 12.6 ml of acetone Dissolve and add 1.3 ml of water. 158 mg of 4-toluenesulfonic acid are added in the presence of an inert gas. The batch is stirred for 40 minutes at room temperature. The crystal pulp is suction filtered and washed with acetone and crystallized with CH ₂ Cl ₂ / acetone.

Yield: 0.55 g of colorless crystals.

Recrystallization from CH ₂ Cl ₂ / acetone yields 440 mg of 11β- [4- (formylphenyl)]-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

Example 2

217 mg of 11β- (4- (formylphenyl))-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one and 4 mg of methoxyamine hydrochloride in 4 ml of pyridine are stirred at room temperature. After 1 hour an additional 5.2 mg of methoxyamine hydrochloride is added. 10 ml of water and 10 ml of acetic acid ester are added, the phases are separated and the aqueous phase is reextracted, the organic phase is washed with 10 ml of dilute HCl, neutralized with distilled water, dried and evaporated under reduced pressure. 241 mg of crude product in the form of a resin is obtained. Preparative thin layer chromatography using silica gel 60PF _{254 + 366} and a toluene / acetone solvent system with a concentration ratio of 4: 1 gave 188 mg of product in the form of a foam.

11β- (4- (methoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in the colorless lamellar form by recrystallization from acetone / hexane Is obtained.

Example 3

180 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in 5 ml of acetic anhydride / pyridine [1: 1) Acetylate for 12 hours. After addition of water, the medium is extracted three times with acetic acid ester. The organic phase is washed with dilute hydrochloric acid and water, dried over sodium sulfate and concentrated by evaporation under reduced pressure. 172 mg of crude product are obtained, which are purified by preparative thin layer chromatography using silica gel PF _{245 + 366} and a toluene / acetone solvent system with a 4: 1 concentration ratio.

Yield: 115 mg of 11β- [4- (acetyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one. The product is crystallized from acetic acid ester.

Example 4

0.3 ml of chloroethyl formate were cooled down with water, and 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-diene- in 5 ml of pyridine. Add dropwise to a solution of 210 mg of 3-one. White precipitate is formed. After 30 minutes, the batch is added with water to obtain a solution of white precipitate precipitated, which is suction filtered 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 combined and purified by preparative thin layer chromatography using silica gel 60 PF _{245 + 366} and a toluene / acetone solvent system with a 4: 1 concentration ratio.

Yield: 150 mg of 11β-4- (ethoxycarbonyl) oximinomethyl] phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one recrystallized from acetone / hexane.

Example 5

A solution of 244 mg of 11β- (4-formylphenyl) -17β-hydroxy-17α-chloromethyl-estra-4,9-dien-3-one in 4 ml of pyridine and 32.3 mg of hydroxylamine hydrochloride is stirred at room temperature. After 1 hour, 6.9 mg of hydroxylamine hydrochloride is further added. 10 ml of water and 10 ml of acetic acid ester are added, the phases are separated and the aqueous phase is extracted again, the organic phase is washed with 10 ml of dilute HCl, neutralized and washed with distilled water, dried and evaporated under reduced pressure.

183 mg of crude product in the form of a yellow resin is obtained. 17α-chloromethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β in the form of a foam by preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and a toluene / acetone solvent system with a 4: 1 concentration ratio. 87.7 mg of -hydroxy-estra-4,9-dien-3-one are obtained.

[Preparation of parent compound]

[Step F]

16.6 ml of concentrated HCl was added to 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17β-spiro-1 ', 2'-oxirane-estra-9- in 84 ml of dimethyl formamide at 0 ° C. Slowly dropwise addition of 4.12 g of en-5α-ol (prepared according to Example 1, step B). After 1 hour, 420 ml of water was added and stirred to form a white precipitate. The pH of the mixture is adjusted to 6 using aqueous bicarbonate solution and the precipitate is filtered off with suction and dried. Yield of the crude product: 3.38 g of ocher crystals.

It was purified by column chromatography on silica gel 60 90 g using toluene / acetic acid ester gradient to form 17α-chloromethyl-11β- (4-formylphenyl) -17β-hydroxy-estra-4,9-diene- in crystalline form. 1.16 g of 3-one are obtained.

Example 6

136 mg of 11β- (4-formylphenyl) -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one was dissolved in 2.2 ml of pyridine at room temperature, followed by 18 mg of hydroxylamine hydrochloride. And batch is stirred at 25 ° C. After 1.5 h, additional 4 mg of hydroxyl amine hydrochloride is added. After 15 minutes, the solution is diluted with water and extracted with chloroform by addition of 1N aqueous HCl. The organic phase is washed with dilute HCl and water and dried over sodium sulfate and potassium carbonate. The solvent is evaporated under reduced pressure.

Yield: 146 mg of crude product.

This was purified by preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and a toluene / acetone solvent system having a concentration ratio of 4: 1, to obtain 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α. 110 mg of -methoxymethyl-estra-4,9-dien-3-one are obtained.

[Preparation of parent compound]

[Step G]

860 mg of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17β-methoxymethyl-estra-9ene-5α, 17β-diol (prepared according to Example C step C) acetone Dissolve in 80 ml. After adding 7.7 ml of water and 430 mg of 4-toluene sulfonic acid, the batch is refluxed for 1.5 hours and concentrated by evaporation under reduced pressure. The residue is dissolved in chloroform and adjusted to pH 8 with 8 ml of dilute ammonia. Separate phases. The organic phase is neutralized washed, dried over sodium sulfate and evaporated under reduced pressure.

590 mg of 11β- (formylphenyl) -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one-1 are obtained as crude product which is recrystallized from acetic acid ester.

Example 7

480 mg of 17α-ethoxymethyl-11β- (4-formylphenyl) -17β-methoxy-estra-4,9-dien-3-one was dissolved in 6 ml of pyridine at room temperature, followed by addition of 74 mg of hydroxylamine hydrochloride. , The batch is stirred at 25 ° C. After 30 minutes, 8.5 mg of hydroxylamine hydrochloride is further added. After 15 minutes, the solution is diluted with water and 1N aqueous HCl is added and extracted with chloroform. The organic phase is washed with dilute HCl and water and dried over sodium sulfate and potassium carbonate. The solvent is evaporated under reduced pressure.

Yield: 410 mg of crude product.

This was preparative thin layer chromatography using silica gel 60 PF _{254 + 366} followed by 17α-ethoxymethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-diene 230 mg of 3-one is obtained.

[Preparation of parent compound]

[Step H]

5.33 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17β-spiro-1 ', 2'-oxirane-estre-9-ene-5α-ol (of Example 1 Is prepared according to step B) in 5 ml of ethanol and 25 ml of 1.5 N sodium ethylate solution is added and the batch is refluxed for 1 hour. The solvent is evaporated under reduced pressure and the residue is neutralized washed by dissolving in CH ₂ Cl ₂ . The solution is dried over sodium sulfate and evaporated under reduced pressure.

5.85 g of crude product in the form of a brown foam are obtained. Chromatography on silica gel using toluene / acetic acid ester gradient to 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-ethoxy methyl-ester-9-ene-5α, 17β -1.14 g of diol is obtained.

[Step I]

5.14 g of potassium tert-butanolate was used as argon as a protective gas, and 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-ethoxymethyl-estr-9-ene in 70 ml of toluene was used. To a solution of 1.14 g of −5α, 17β-diol. After 15 minutes, a mixture of 3.8 ml of methyl iodide in 4 ml of toluene is added dropwise. After 2 hours, 20 ml of water and 20 ml of acetic acid ester are added to stop the reaction. The organic phase is washed twice with water, dried over sodium sulfate and evaporated under reduced pressure.

Yield of the crude product: 3,3-dimethoxy-11β- [4- (3,3-dimethoxymethyl) phenyl] -17α-ethoxymethyl-17β-methoxy-estr-9-ene-5α-ol 1.14 g.

[Step I]

116 mg of 4-toluene sulfonic acid and 1 ml of water were prepared using 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-ethoxymethyl-17β-methoxy-est in 10 ml of acetone using a protective gas. To a solution of 1.14 g of le-9-ene-5α-ol. After 30 minutes, the batch is diluted with water and extracted twice with acetic acid ester. The organic phase is washed and dried over sodium sulfate. After evaporation of the solvent, 900 mg of 17α-ethoxymethyl-11β- (4-formylphenyl) -methoxy-estra-4,9-dien-3-one remains as a yellow foam. Chromatography on silica gel 60 using toluene / acetic acid ester gradient yields 480 mg of yellow crystals.

Example 8

4.4 ml of pyridine at room temperature with 244 mg of 11β- (4-formylphenyl) -17β-hydroxy-17α- (3-hydroxy-prop-1-yn-yl) -estra-4,9-dien-3-one at room temperature After dissolving in, 35.5 mg of hydroxylamine hydrochloride is added and the batch is stirred at 25 ° C. After 30 minutes, further 4.8 mg of hydroxylamine hydrochloride is added. After 15 minutes, the solution is diluted with water, extracted by dissolving in acetic acid ester and stirring with 1N aqueous HCl. The organic phase is washed with water and dried over sodium sulfate and potassium carbonate. The solvent is evaporated under reduced pressure.

Yield: 216 mg of crude product.

This was subjected to preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and toluene / acetone having a concentration ratio of 4: 1 as a solvent system, followed by 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy- 192 mg of 17α- (3-hydroxyprop-1-yn-yl) -estra-4,9-dien-3-one are obtained as colorless foams.

[Preparation of parent compound]

[Step K]

12 ml of 15% n-butyllithium in hexane is added dropwise to a solution of 3 ml of prop-in-yl-3-hydroxytetrahydropyranyl ether in 27 ml of dry THF at −5 ° C. After 15 minutes, 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -5α-hydroxy-estr-9-en-17-one in 16 ml of dry THF (Step B of Example 1) A solution of 1.2 g) is added dropwise to the solution. The batch is stirred for 30 minutes at room temperature. The reaction mixture is poured into 150 ml of ice water and extracted with acetic acid ester. The organic phase is neutralized washed, dried over sodium sulfate and evaporated under reduced pressure.

4.23 g of brown oil are obtained, which are purified by chromatography on silica gel 60 using toluene / acetic acid ester gradient. 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -7α- (3-tetrahydropyranyloxy-prop-1-yn-yl) -estr-9ene- in foam form 422 mg of 5α, 17β-diol are obtained.

[Step L]

3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α- (3-tetrahydropyranyloxyprop-1-yn-yl) -ester-9-ene-5α, 17β- 540 mg of diol is stirred with 100 mg of 4-toluene-sulfonic acid in 40 ml of acetone at room temperature for 2 hours. The batch is then evaporated to 10 ml and concentrated, aqueous sodium bicarbonate solution is added and extracted with acetic acid ester. The organic phase is neutralized washed, dried over sodium sulphate and evaporated under reduced pressure.

Yield of crude product: 330 mg.

It was purified by preparative thin layer chromatography on silica gel 60 PF _{254 + 366} to give 11β- (4-formylphenyl) -17β-hydroxy-17α- (3-hydroxy-prop-1-yn-yl) -estra- 310 mg of 4,9-dien-3-one are obtained. Recrystallization from acetone gives white crystals.

Example 9

190 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are suspended in 10 ml of toluene. 0.5 ml of phenyl isocyanate and 1 ml of triethylamine are added sequentially. The batch is stirred at room temperature for 3 hours and refluxed for 2 hours. The white precipitate is filtered off with suction and the solvent is concentrated by evaporation under reduced pressure. This gave 310 mg of a light brown solid, which was purified by preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and a toluene / acetone solvent system with a 9: 1 concentration ratio.

65 mg of 17β-methoxy-17α-methoxymethyl-11β- [4-[(phenylamino-carbonyl) oximinomethyl] phenyl] -estra-4,9-dien-3-one are isolated.

Example 10

125 mg of 17α-ethoxymethyl-11β- (4-formylphenyl) -17β-hydroxy-estra-4,9-dien-3-one was dissolved in 2 ml of pyridine at room temperature, followed by 20.2 mg of hydroxylamine hydrochloride. And batch is stirred at 25 ° C. After 50 minutes, the solution is diluted with water and acetic acid ester is added to separate the phases. The organic phase is washed with dilute HCl and water and dried over sodium sulfate. The solvent is evaporated under reduced pressure.

127 mg of crude product in the form of a pale yellow foam are obtained. This was preparative thin layer chromatography on silica gel 60 PF _{254 + 366} followed by 17α-ethoxymethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-estra-4,9-diene-3 62 mg of -one are obtained in the form of a colorless foam.

[Preparation of parent compound]

[Step M]

340 mg of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] -17α-ethoxymethyl-estra-9-ene-5α, 17β-diol (prepared according to step H of Example 7) Dissolve in 2.5 ml of acetone. 0.25 ml of water and 35 mg of 4-toluene sulfonic acid are added. After 1 hour, the batch is diluted with 10 ml of water and 10 ml of acetic acid ester is added. Separate phases. The aqueous phase is reextracted twice, the organic solution is washed and dried over sodium sulfate. After evaporation of the solvent, 300 mg of yellow crystals are obtained.

Preparative thin layer chromatography on silica gel 60 PF _{254 + 366} using toluene / acetone with a 9: 1 concentration ratio, followed by 17α-ethoxymethyl-11β- (4-formylmethyl) -17β-hydroxy-estra-4 200 mg of 9-dien-3-one are obtained.

Example 11

[Measure binding affinity for receptors]

Receptor binding substitutions are measured in particular by competitive binding of the compounds to be tested against binding ³ H labeled hormones (trackers) and receptors in the cytosol of animal target organs. It was intended to carry out receptor saturation and equilibrium reactions. Select the following culture conditions.

Progesterone receptor: uterine cytosol of rabbit injected estradiol maintained at −30 ° C. in TED buffer containing Sacrose 250 mM (20 mM Tris / HCl, pH 7.4; 1 mM ethylene diamine tetra acetate, 2 mM dithiotracetol) , Tracer: ³ H-ORG 2058, 5mM; Reference material: Progesterone.

Glucocorticoid Receptor: Thymic cytosol of adrenal excised rats, thymic maintained at −30 ° C., buffer: TED, tracer: ³ H-dexamethasone, 20 nM: reference material: dexamethason.

Estrogen Receptor: Uterine cytosol of immature rabbits maintained at −30 ° C. in TED buffer containing Saccharose 250 mM. Tracer: ³ H-ethynyl estradiol, ³ nM; For reference: 17β-estradiol.

After 18 hours of incubation at 0-4 ° C., the bound steroid and the free steroid are mixed in activated carbon / dextran (1% / 0.1%), centrifuged and separated by measuring bound ³ H activity in the supernatant. do.

IC ₅₀ of the compound to be tested and the reference material are detected by measuring in a series of concentrations. The exponent (x100%) of the two values represents the relative molar binding affinity.

Example 12

[Inhibition of Early Pregnancy in Rats]

Female rats are mated to mating season. If semen is found on the genital application sample the next day, it is counted as the first day of pregnancy (= dl). Treat with test substance or vehicle on days 5-7 and inspect on day 9. The material is injected subcutaneously in 0.2 ml of vehicle (benzoyl benzoate / castor oil 1 + 4). Complete pregnancy inhibition rates found in various groups are shown in Table 1. It was found that the anti-imaging performance for J867 was superior to RU 486.

Example 13

[Treatment of Female Guinea Peaks Using Antigestagen]

The indicated doses are administered using a treatment of subcutaneous osmotic pumps (Type 2 ML1 / ALZET) of mature female guinea pigs with cycles (test results) of 10 to 18 days. Vehicle: propylene glycol 2.0 ml / 24 hour.

Example 14

[Antiglucocorticoid Effect of J867 in ZR 75 / AGP-763 Cell Line of Human Breast]

Cell culture experiments are performed in RPMI 1640 added 10% fetal calf serum (FCS) using an incubator cabinet containing 95% air and 5% CO ₂ at 37 ° C. The cells are scattered in a 60 mm Petri dish. The adherent cell medium is replaced with a medium containing 5% FCS [treated with dextran coated carbon (DCC)]. CAT was induced by addition of dexamethasone at a concentration of 10 ⁷ M in ethanol (0.2%; v / v). Stimulator cells are harvested after 16 hours by generating cell extracts using cytolysis buffer. CAT is measured using a Boehringer ELISA according to the teaching for quantitative CAT measurement of infected cells.

Example 15

[Antiglucocorticoid Effect of J867 in Liver Cancer Cells of Rat Using TAT Model]

Cell cultures are treated in DMEM under essentially the same conditions as in Example 14. Cells are scattered on a 24 grid for experiment. The material is added to adherent liver cancer cells in 0.2% (v / v) ethanol for 16 hours. The cells are carefully harvested using a scraper and the ultrasonic extracts are used to obtain cell extracts and then the TAT is measured according to Diamondstone.

Claims (23)

11-Benzaldoxime-estra-4,9-diene derivatives of formula (I) and pharmaceutically acceptable salts thereof. Wherein R ¹ is a hydrogen atom or an alkyl moiety having 1 to 6 carbon atoms, R ² is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, an acyl moiety or residue having 1 to 10 carbon atoms- CONHR ⁴ or —COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl moiety having 1 to 10 carbon atoms, R ³ is a hydrogen atom, alkyl, aryl having 1 to 10 carbon atoms, Aralkyl or alkylaryl groups, residues-(CH ₂ ) n -CH ₂ X [where n is 0, 1 or 2, and X is fluorine, chlorine, bromine or iodine atom, cyano, azide or rodano group , residue oR is ⁵ or SR ⁵ (where R ⁵ is an acyl moiety of a hydrogen atom, a C 1 -C 10 alkyl, aryl, aralkyl or alkylaryl moiety or 1 to 10 carbon atoms of), residue oR ⁵ (wherein, R ⁵ is as defined above, residue — (CH ₂ ) o —CH═CH (CH ₂ ) pR ⁶ where o is 0, 1, 2 or Is 3, p is 0, 1 or 2, R ⁶ is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, a hydroxyl group or an alkoxy or acyloxy group having 1 to 10 carbon atoms ) Or residues-(CH ₂ ) qC≡CR ⁷ where q is 0, 1 or 2, R ⁷ is a hydrogen atom, fluorine, chlorine, bromine or iodine atom, alkyl of 1 to 10 carbon atoms, aryl, aralkyl Or an alkylaryl moiety or an acyl moiety of 1 to 10 carbon atoms, Z is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl moiety of 1 to 10 carbon atoms, an acyl moiety of 1 to 10 carbon atoms, residue -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl moiety having 1 to 10 carbon atoms or an alkali metal or alkaline earth metal atom. The compound of claim 1, wherein R ¹ is a methyl or ethyl group. 3. The compound of claim 1, wherein R ² is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an acyl moiety or residue having 1 to 10 carbon atoms, or a residue -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom, or Alkyl or aryl moiety having 1 to 10 carbon atoms. 4. The compound of claim 3, wherein R ² is an alkyl group having 1 to 6 carbon atoms, an acyl moiety having 1 to 6 carbon atoms, or a residue —CONHR ⁴ or —COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl or aryl having 1 to 6 carbon atoms. Residues). The compound of claim 1, wherein R ³ is a hydrogen atom. The compound of claim 1, wherein R ³ is an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms. The compound of claim 6, wherein R ³ is an alkyl group having 1 to 10 carbon atoms. The compound of claim 6, wherein R ³ is an alkyl group having 1 to 6 carbon atoms. The compound of claim 1, wherein R ³ is the residue-(CH ₂ ) n -CH ₂ X [where n is 0, 1 or 2 and X is fluorine, chlorine, bromine or iodine atom, cyano, azide or rhoda No group, residue OR ⁵ or SR ⁵ , wherein R ⁵ is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms or an acyl residue having 1 to 10 carbon atoms. 10. The compound of claim 9, wherein R ³ is the residue-(CH ₂ ) n-CH ₂ X [where n is 0, 1 or 2 and X is a fluorine, chlorine, bromine or iodine atom, cyano, azide or rhoda) No group, residue OR ⁵ or SR ⁵ , wherein R ⁵ is an alkyl residue of 1 to 6 carbon atoms or an acyl residue of 1 to 6 carbon atoms. The compound of claim 1, wherein R ³ is residue OR ⁵ , wherein R ⁵ is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms, or an acyl residue having 1 to 10 carbon atoms. The compound of claim 11, wherein R ³ is residue OR ⁵ , wherein R ⁵ is an alkyl residue of 1 to 6 carbon atoms or an acyl residue of 1 to 6 carbon atoms. The compound of claim 1, wherein R ³ is the residue-(CH ₂ ) o-CH = CH (CH ₂ ) pR ⁶ , wherein o is 0, 1, 2 or 3, p is 0, 1 or 2, and R is ⁶ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a hydroxyl group or an alkoxy or acyloxy group having 1 to 10 carbon atoms. The compound of claim 13, wherein R ³ is residues — (CH ₂ ) o —CH═CH (CH ₂ ) pR ⁶ , wherein o is 0, 1, 2 or 3, p is 0, 1 or 2, and R ⁶ is an alkyl group having 1 to 6 carbon atoms or an alkoxy or acyloxy group having 1 to 6 carbon atoms. The compound of claim 1, wherein R ³ is the residue-(CH ₂ ) qC≡CR ⁷ where q is 0, 1 or 2, and R ⁷ is a hydrogen atom, fluorine, chlorine, bromine or iodine atom, 1 to 10 carbon atoms Or an alkyl residue of C1 or an acyl residue of 1 to 10 carbon atoms. The compound of claim 15, wherein R ³ is residues — (CH ₂ ) qC≡CR ⁷ where q is 0, 1 or 2 and R ⁷ is an alkyl residue having 1 to 6 carbon atoms or an acyl residue residue having 1 to 6 carbon atoms. Compound). The compound of claim 1, wherein Z is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms, an acyl residue having 1 to 10 carbon atoms, or a residue -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom or alkyl having 1 to 10 carbon atoms Residues). The compound of claim 17, wherein Z is an alkyl moiety having 1 to 6 carbon atoms, an acyl moiety having 1 to 6 carbon atoms, or a residue -CONHR ⁴ or -COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl or aryl moiety having 1 to 6 carbon atoms. Phosphorus Compound The compound of claim 1, wherein Z is an alkali metal or alkaline earth metal atom. The compound of claim 1, wherein 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- (hydroxy Loximinomethyl) phenyl] -17β-hydroxy-17α-ethoxymethyl-estra-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α -n-propoxymethyl-estra-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-i-propoxymethyl-estra-4, 9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- (Hydroxyxinomethyl) phenyl] -17β-methoxy-17α-ethoxymethyl-estra-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy -17α- (3-hydroxyprop-1-yn-yl) -estra-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α -(3-hydroxyprop-1-yne) -S La-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-17α-Z- (3-hydroxypropenyl) -estra-4,9- Dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-Z- (3-hydroxypropenyl) -estra-4,9-dien-3-one, 17α-chloromethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-estra-4,9-dien-3-one, 17α-chloromethyl-11β- [4- (hydroxyimino Methyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one, 17α-cyanomethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-hydroxy-estra-4 , 9-dien-3-one, 17α-cyanomethyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one, 17α-azide Methyl-11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one, 11β- [4- (hydroxyiminomethyl) phenyl] -17β-meth Oxy-17α-methylthiomethyl-estra-4,9-dien-3-one, 11β- [4- (methyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- (methyloximinomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra -4,9-dien-3-one, 11β-4- (ethoxycarbonyl) oximinomethyl] phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β-4-[(ethylaminocarbonyl) oximinomethyl] phenyl-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 17β-methoxy-17α-methoxymethyl -11β-4-[(phenylaminocarbonyl) oximinomethyl] phenyl-estra-4,9-dien-3-one and 11β- [4- (hydroxyiminomethyl) phenyl] -17β-ethoxy-17α -Ethoxymethyl-estra-4,9-dien-3-one. Reacting a compound of formula (II) with a compound of formula (IIa), wherein the compound of formula (IIa) is present in the form of the compound or from which the compound of formula (IIa) is released under selected reaction conditions A process for preparing the compounds according to claim 1 and pharmaceutically acceptable salts thereof, characterized by esterifying or etherifying hydroxyl amine groups which may be present if present. Wherein R ¹ is a hydrogen atom or an alkyl moiety having 1 to 6 carbon atoms, R ² is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, an acyl moiety or residue having 1 to 10 carbon atoms- CONHR ⁴ or —COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl, aryl, aralkyl or alkylaryl moiety having 1 to 10 carbon atoms, R ³ is a hydrogen atom, alkyl, aryl having 1 to 10 carbon atoms, Aralkyl or alkylaryl groups, residues-(CH ₂ ) n -CH ₂ X [where n is 0, 1 or 2, X is a hydrogen atom, alkyl having 1 to 10 carbon atoms, aryl, aralkyl or alkylaryl residues , Fluorine, chlorine, bromine or iodine atom, cyano, azide or rodano group, residues OR ⁵ or SR ⁵ where R ⁵ is a hydrogen atom, alkyl having 1 to 10 carbon atoms, aryl, aralkyl or alkylaryl residues or having a carbon number of 1 is the acyl residue of 1 to 10), residue oR ⁵ (wherein, R ⁵ is As shown) defined by the residues _{- (CH 2) o-CH} = CH (CH 2) pR 6 ( where, o is 0, 1, 2 or 3, p is 0, 1 or 2, R ⁶ is hydrogen Is an atom, an alkyl, aryl, aralkyl or alkylaryl group having 1 to 10 carbon atoms, a hydroxy group or an alkoxy or acyloxy group having 1 to 10 carbon atoms, or a residue-(CH ₂ ) qC≡CR ⁷ where q is 0, 1 or 2, R ⁷ is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl, aryl, aralkyl or alkylaryl moiety having 1 to 10 carbon atoms or an acyl moiety having 1 to 10 carbon atoms; Is a hydrogen atom, an alkyl residue having 1 to 10 carbon atoms, an acyl residue having 1 to 10 carbon atoms, or residues -CONHR ⁴ or -COOR ⁴ (wherein R ⁴ is a hydrogen atom or alkyl, aryl, aralkyl or Alkylaryl residues). The method according to claim 21, wherein the compound of formula (II) is reacted with the compound of formula (IIa) in an equimolar amount. A pharmaceutical composition useful as an antigestagen agent characterized in that it contains as an active ingredient at least one compound according to any one of claims 1 to 20.