EP1636249A1

EP1636249A1 - Target-oriented chemotherapy for treating tumors of the sexual organs

Info

Publication number: EP1636249A1
Application number: EP04733542A
Authority: EP
Inventors: Heinz Förster
Original assignee: TRIN GmbH
Current assignee: TRIN GmbH
Priority date: 2003-05-30
Filing date: 2004-05-18
Publication date: 2006-03-22
Also published as: CN1835964A; US20070099876A1; RU2005141057A; DE10324496A1; RU2320669C2; IL172298A0; JP2006526002A; ZA200509698B; CA2531319A1; AU2004242908A1; WO2004106358A1; KR20060024784A

Abstract

The invention relates to dialkyltriazene-supporting estrogens and antiestrogens that are suited for use as chemotherapeutic drugs for treating carcinomas of the sexual organs of humans and animals.

Description

Targeted chemotherapy of tumors of the sexual organs

The present invention relates to novel compounds based on estrogens and anti-estrogens which are suitable as chemotherapeutic agents for combating tumors, processes for their preparation and their use for the treatment of diseases, in particular cancer.

The healthy cells, the cancer cells and the cells of the metastases of the sexual organs contain estrogen receptors (= cytoplasmic proteins), cf. "The nuclear receptor ligand-binding domain: structures and function" in Curr. Opin. Cell Biol. 10, 384-391 (1998). That is why natural and synthetic female sex hormones (oestrogens) and their antagonists (antiostrogens) an affinity for the tissues of the sexual organs (breast, uterus, ovaries, prostate); the OH groups of the sex hormones have the ability to bind to the estrogen receptors.

The estrogen receptors accumulate in the cancer cells of tumors of the sexual organs, e.g. in mammary tumors and their metastases, particularly strongly (E. v. Angerer, The estrogen receptor as a target for rational drug design, pages 5, 49 and 137, Springer-Verlag, Heidelberg 1995). Attempts have previously been made to use the estrogen receptors as targets for active substances, for example by the natural female sex hormone estradiol or the synthetic diethylstilbestrol with an active group, e.g. associated with a nitrogen mustard function and hoped that the estrogenic base molecule would transport the active group into the tumor and this could then destroy it (G. Leclercq, Brest Cancer - Experimental and Clinical Aspects, 287-293, Pergamon, Oxford 1980; H. Hamacher, Potential Antineoplastika m, Arch. Pharm. 311, 184-195, Verlag Chemie, Weinheim 1978). However, all such attempts have failed (E. v. Angerer, loc. Cit, 155).

In order to develop active substances against tumors of the human sexual organs, you need an animal model that is very close to human tumors so that really meaningful test results can be obtained. The known "Huggins tumors" (C. Huggins et al., Rapid induction of mammary carcinoma in the rat and the influence of hormones, J. Exper. Med. 109, 25 (1959)) are easy to generate and easy to combat, e.g. through endocrine manipulations and the usual chemotherapy (eg with Endoxan® = cyclophosphamide monohydrate) The tumors produced by gasoline on female Wistar rats, on the other hand, take more time to induce and (like the human breast tumor) are only about 50% hormone-dependent; they can (like the human breast tumor) by chemotherapy drugs and other treatments of the Do not have a lasting impact on the state of the art. We found the animal model we were looking for in Wistar rats with breast tumors induced by benzidine.

Surprisingly, it has now been found that dialkyltriazenyl group-carrying estrogens and antiostrogens cause their regression after administration to rats with breast tumors. The therapy directed selectively at the breast tumor tissue does not lead to the side effects known from the prior art, e.g. Damage to the bone marrow and intestinal epithelium. Diall ylphenyltriazenes are known as general unselective cytostatic agents; see. Proc. Soc. Exper. Biol. Med. 90: 484 (1955); like alkylating agents (endoxane), they intervene in a targeted manner in the proliferation of all body cells.

Furthermore, 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-oestra-l, 3,5 (10) -trien-17-one is known as an intermediate for the preparation of a fluorine compound (exchange of triazenyl for fluorine) ; see. J. Org. Chem. 46 (12), 2520-2528 (1981).

The invention thus relates to oestrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, with the exception of 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-estra-1,3,5 ( 10) -trien- 17-one.

The terms “estrogens” and “antiostrogens” in the context of the invention encompass both natural and synthetic estrogenic or anti-estrogenic compounds. Suitable compounds which act as estrogen or anti-estrogen and whose substitution with dialkyltriazenyl groups leads to the compounds according to the invention are, in principle, all those in which the “receptor occupancy quotient” which is obtained with 10 mg / 1 test substance in the “detection of the competitive” described below Inhibition against 6,7-ditritium oestradiol at the estrogen receptor "is at most 0.9, preferably at most 0.7, in particular at most 0.3.

The term “core-substituted” in the sense of the invention refers to one or more aromatic rings of the basic estrogen and anti-estrogen bodies.

Without wishing to be bound by any particular theory, from today's perspective the success according to the invention can perhaps be explained as follows: The triazenyl groups can apparently form bonds with OH groups with estrogen receptors. In order to bring the active groups to the target, ie to the tumor tissue, the estrogen or anti-estrogen part of the molecule is used as a carrier, which gives the compounds according to the invention a hormone-like lend specificity. When they arrive in the cancer cells, they cause the cancer cells to oncolysis.

The incorporation of certain groups can impart some desired properties to the compounds according to the invention; for example, by incorporating hydrophilic groups, the degree of water solubility of the compounds can be controlled as desired within a wide range. As alkali or ammonium salts, the compounds according to the invention with hydrophilic groups are very readily soluble in water.

The advantages of the compounds according to the invention with hydrophilic groups include the fact that they can be accumulated in the cancer cells in the amounts necessary for the therapy due to an excess supply to the estrogen receptors and the excesses can be rapidly eliminated from the body. This minimizes toxic side effects.

Due to the hormone-like specificity of the compounds according to the invention, relatively low application rates are sufficient.

According to the invention, estrogen and anti-estrogen derivatives can be used as carriers, for example from the substance groups of steroids, stilbenes, hexestrols, phenyl-l, 2-bis (2,6-dichloro-phenyl) -l, 2- bis (ethyleneaminoethanes), triphenylethylenes, phenylbenzofurans, phenylbenzothiophenes , which are substituted in the 3-position by a benzoyl group, 4,5-bis-phenyl-imidazoles, 2,3-diarylpiperazines, 4,5-phenyl-2-imidazolines. Some carrier types are discussed below as examples.

Compounds according to the invention include e.g. Steroid triazenes of the formula

woπn R ¹ 1 hydrogen, N = N-NR, 7 ^/ A ^A τR.7 ^/ B ^Ü , 0 (GR "R ^s CO ₂ H, C0 ₂ H or S0 ₃ H R ³ hydrogen, N = N-NR ^{/ A} R ^7B , 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, C0 ₂ H or S0 ₃ H,

R ⁴ and R ⁶ independently of one another hydrogen, 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, (CR ⁸ R ⁹ ) _n C0 ₂ H or

C ₆ H ₄ OCH ₂ C0 ₂ H and R ⁴ also (CH ₂ ) ι ₀ CON (CC ₄ alkyl) ₂ , R ^{5 is} hydrogen or OH,

R ^7A and R ^{7B are} independently alkyl,

R ⁸ and R ⁹ independently of one another are hydrogen, methyl or ethyl, X CO, CHOH or C (OH) -C≡CH and n is an integer from 1 to 10 with the proviso that only one of the radicals

R ¹ to R ^{3 stands} for N = N-NR ^7A R ^7B ,

and their salts, solvates and solvates of these salts.

These steroid triazenes I can e.g. by diazotization of amino derivatives of the formula

wherein one of the radicals R ¹ to R ^{3 is} NH ₂ and the remaining symbols R ¹ to R ⁶ and X have the meanings given in the legend for formula I, or their salts and by reaction of the resulting diazonium salts of the formula

[RN ₂ ] ⁺ T (IH)

wherein R stands for the formula II, in which one of the radicals R ¹ to R ³ (N ₂ ) ⁺ , the other variables have the meanings given in the legend to formula II and Y ^"stands for an acid anion, with dialkylamines and, if appropriate obtained by releasing the acids from the salts obtained.

If, for example, 2-amino-3-carboxymethoxy-estradiol is used as the starting material, the course of the reaction can be represented by the following formula 1:

The aminosteroids used as starting compounds are either known or can be found in

Analogy to known manufacturing methods.

Examples of aminosteroids II include e.g.

1-amino-3-oxyacetic acid estradiol,

2-amino-3-oxyacetic acid-estradiol,

4-amino-3-oxyacetic acid estradiol, l-amino-3-oxyacetic acid estrone,

2-amino-3-oxyacetic acid-oestrone

4-amino-3-oxyacetic acid estrone,

1-amino-3-methoxy-estradiol,

2-amino-3-methoxy-estradiol, 4-amino-3-methoxy-estradiol,

1-amino-3-methoxy-estrone,

2-amino-3-methoxy-estrone,

4-amino-3-methoxy-estrone,

1-amino-3-oxyacetic acid estriol, 2-amino-3-oxyacetic acid estriol,

4-amino-3-oxyacetic acid estriol,

1 - amino-3-oxyacetic acid-ethynyl estradiol,

2-amino-3-oxyacetic acid-ethinyl estradiol,

4-amino-3-oxyacetic acid-ethynyl estradiol, 2-amino-4-sulfonic acid estradiol,

4-amino-2-sulfonic acid-estradiol,

2-amino-4-sulfonic acid estrone and

4-amino-2-sulfonic acid-estrone.

If the OH group in the estrone is replaced by a triazenyl group (cf. Example 11), then a potent cancer chemotherapeutic agent is obtained which has a very good effect at low doses against the breast cancer of the rat. It can be concluded from this that the triazenyl group can surprisingly replace the essential OH group as an adhesive group on the estrogen receptor. If one wishes to use the maximum binding properties of the OH group (or its ethers) on the estrogen receptor for the antitumor effect, the triazenyl group is preferably introduced into the 2- or 4-position according to the invention.

As already mentioned above, it may be desirable to provide the compounds according to the invention with hydrophilic groups in order to increase their water solubility. Sulfonate and carboxylate groups as well as -Ce residues bearing such groups are preferred as hydrophilic groups. Even though there are fundamentally many positions for an additional substitution, substitutions on the aromatic ring can be carried out particularly easily - for example by nuclear sulfonation or by etherification of phenolic hydroxyl groups.

When it comes to the place of substitution, one can be guided by the knowledge that estrone, estradiol or ethynyl estradiol is also a strong one

Have affinity for the estrogen receptor if there are large substituents in positions 2, 4, 7 and 11 (PW Jungblut et al., Hormone receptors, colloquium of the Society for Physiological Chemistry from 05.-08.04.1967 in Mosbach / Baden; M. Görlich, Arch. Geschwulstforschung 37/2, 161-170 (1971)). These positions are therefore ideal for substitutions.

For example, in the 3-position a carboxyalkoxy radical, e.g. a carboxymethoxy radical as a solubilizing group [(prodrug) as a salt]. If the triazenyl group is in one of the positions 2 or 4, the second position (4 or 2) can carry a solubilizing group, e.g. the salt of a carboxyalkoxy or sulfonic acid residue. Positions 7 and 11 are available for further substituents and can, for example, carry additional solubilizing groups (e.g. carboxyalkoxy radicals); one has the possibility, if necessary, of achieving desired selectivities by carrying out substituents.

Compounds in which the phenolic OH group is etherified act as a prodrug, ie it is to be expected that a 3-position carboxymethoxy residue will adhere to the estrogen receptor preserved; see. eg Mestranol, see E. Mutschier, drug effects, textbook of pharmacology and toxicology, page 368, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1997. Since it is only important in the case of the manufacture of chemotherapeutics in the present case that the active substance binds to the estrogen receptor, it does not matter whether the carrier is an estrogen or an anti-estrogen.

The estrogenic steroids are an example of how highly specific and highly effective active ingredients can be synthesized from estrogens that bind optimally to the estrogen receptor by introducing a dialkyltriazenyl group. Furthermore, it must be assumed that such active substances are effective against all carcinomas of the sexual organs that contain estrogen receptors (uterus, ovaries, prostate) due to their binding to the estrogen receptor.

Stilbene: cancer chemotherapy drugs derived from stilbenes. Diethylstilbestrol and hexestrol Other compounds according to the invention are e.g. Ice and trans stilbenes and hexestroles of the formula

where R is hydrogen, methyl or ethyl,

R ^{1 is} hydrogen, chlorine, methyl, ethyl, CH ₂ C0 ₂ H, CH (CH ₃ ) C0 ₂ H, OCH ₂ C0 ₂ H,

OCH (CH ₃ ) C0 ₂ H or S0 ₃ H,

R 'OH, OCH ₃ , OCH ₂ CO ₂ H, OCH (CH ₃ ) CO ₂ H or N = N-NR ^7A R ^7B , R ^; Hydrogen, chlorine, preferably in the 6-position, or N = N-NR ^7A R ^7B , R 'is hydrogen, methyl, ethyl, CH ₂ C0 ₂ H or CH (CH ₃ ) C0 ₂ H and

R ^7A and R ⁷⁵ independently of one another are alkyl with the proviso that either R ² or R ^{3 is} N = N-NR ^7A R ^7B , and the broken bonds indicate that the compounds comprise both ethane and ethylene derivatives,

and their salts, solvates and solvates of these salts. These compounds VI can be obtained, for example, by diazotizing amino derivatives of the formula

wherein

R ^{3 is} hydrogen or NH ₂ and

R ^{4 is} hydrogen, methyl, ethyl, CH ₂ C0 ₂ H or CH (CH ₃ ) C0 ₂ H with the proviso that either R ² or R ^{3 is} NH ₂ , and R, R ¹ , R ² , R ^7A , R ⁷² and the interrupted bonds have the meanings given in the legend to formula VI,

or their salts and

by reacting the resulting diazonium salts of the formula

[R ⁵ -N ₂ ] ⁺ Y ^" (VTJJ)

in which R ⁵ represents formula VII, in which one of the two radicals R ² or R ³ denotes (N ₂ ) ⁺ , the other variables have the meanings given in the legend to formula VH and Y ^"represents an acid anion, with a dialkylamine and, if appropriate, release of the acids from the salts obtained.

If you use e.g. 3,3'-diamino-diethylstilbestrol (H. Hamacher, Potential Antineoplastika HI, Arch. Pharm. 311, 184-195, Weinheim 1978) as a starting material, the course of the reaction can be represented by the following formula scheme 2:

(IX) (X) By further reaction of 3,3'-di (dialkyltriazenyl) diethylstilbestrol with 1 or 2 equivalents of an alkylating agent of the formula

R ⁶ - Y (XI)

embedded image in which

R ° Ci- -Al yl, CH ₂ C0 ₂ CH ₃ or CH (CH ₃ ) C0 ₂ CH ₃ and Y are a leaving group for alkylating agents, the corresponding alkylation products can be obtained; see the following formula 3:

If R ⁶ in the above formula 3 is, for example, CH ₂ CO ₂ CH ₃ , then the disodium salt can be obtained from the bis-ester by alkaline hydrolysis, for example with NaOH (formula scheme 4):

Other compounds of the invention are e.g. Triphenylethylene derivatives of the formula

wherein

R is hydrogen, chlorine, chloromethyl or ethyl,

R ¹ OCH ₂ C0 ₂ H or OCH (CH ₃ ) C0 ₂ H, R and R independently of one another hydrogen, S0 ₃ H or N = N-NR 7A-Rn7B

R ³ and R ⁵ independently of one another are hydrogen, OH, OCH ₃ , OCH ₂ CO ₂ H, OCH (CH ₃ ) CO ₂ H or N = N-NR ^7A R ^7B and

R ^7A and R ^7B independently of one another alkyl 7m ^' t, with the proviso that only one of the radicals R ² to R ^{5 stands} for = N-NR ^7A R ^7B ,

and their salts, solvates and solvates of these salts.

The compounds XVI according to the invention can be obtained, for example, by diazotizing amino derivatives of the formula

embedded image in which

R ² and R ^{4 are} independently hydrogen, NH ₂ or S0 ₃ H, R ³ and R ^{5 are} independently hydrogen, NH ₂ , OH, OCH ₃ , OCH ₂ C0 ₂ H or

0CH (CH ₃ ) C0 ₂ H and R and R ^{1 have} the meanings given in the legend to formula XVI with the proviso that only one of the radicals R ² to R ^{5 is} NH ₂ ,

or their salts and by reacting the resulting diazonium salts of the formula

[R ° -N ₂ r Y ^" (XVII)

wherein R ^{6 is} the formula XVIa, in which one of the radicals R ² to R ^{5 is} ( ₂ ) ⁺ and the other variables have the meanings given in the legend to formula XVIa, and Y ^"is an acid anion, with a dialkylamine and optionally releasing the acids from the salts obtained.

If one uses as the starting product e.g. the amino compound XVIII, the course of the reaction can be represented by the following formula 5:

(XVI left) (XIX) By alkaline hydrolysis of the methyl ester XLX, the sodium salt XX can be obtained according to reaction scheme 6:

(XIX) (XX)

In the manner shown by way of example above, cancer chemotherapeutic agents can be produced from any oestrophilic compounds by introducing the triazenyl group, e.g .:

Tr = N = N-NR ^7A R ^7B sb = -CH ₂ C0 ₂ Na, -CH (CH ₃ ) C0 ₂ Na

The arrows indicate preferred positions for triazenyl (Tr) and solubilizing groups (sb).

The invention thus furthermore relates to a process for the preparation of estrogens and anti-estrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, after which at least one dialkyltriazenyl substituent is introduced into one or more aromatic rings of an estrogenic or anti-estrogenic compound, the process for Preparation of the 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-oestra-l, 3,5 (10) -trien-17-one is excluded. Physiologically acceptable salts are preferred as salts in the context of the invention.

Physiologically acceptable salts, primarily physiologically acceptable salts of the compounds I, II, VI, VE, XVI and XVIa, include salts of conventional bases, such as, for example, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts , derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, tris-hydroxyethylamine, dicyclohexylamine, dimethylaminoethanol, procaine, diberizylamine, N-methylmorphylamine, dihydroamine Arginine, lysine, ethylenediamine and methylpiperidine.

In the context of the invention, solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water. Alkyl per se and "alkyl" and "alk" in dialkylamine and carboxyalkoxy stand for a linear or branched alkyl radical with usually 1 to 6, 1 to 4 or 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl , tert-butyl, n-pentyl and n-hexyl.

Diazotizations are known; see. e.g. Organikum, 10th edition, VEB German Publishing House of Sciences, Berlin 1971, 580-600.

Acid anions in the sense of the invention are above all the anions of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Leaving groups for alkylating agents in the sense of the invention include e.g. Chloride, bromide and sulfate.

The invention further relates to estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group for the treatment of diseases. The invention furthermore relates to the use of estrogens and anti-estrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group for combating tumors of the sexual organs in humans and animals. The invention further relates to a method for combating tumors of the sexual organs in humans and animals by applying a sufficient amount of at least one compound from the series of estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group.

Another object of the invention is the use of estrogens and anti-estrogens, which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, for the production of medicaments for combating tumors of the sexual organs in humans and animals.

The invention further relates to medicaments which contain at least one compound from the series of estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, if appropriate together with one or more pharmacologically acceptable auxiliaries or excipients, and their use in relation to the foregoing mentioned purposes.

The compounds according to the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.

The active ingredient can be administered in suitable administration forms for these administration routes.

Known application forms which deliver the active ingredient quickly and / or modified, such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, for example, inhalation pharmaceutical forms (including powder inhalers, nebulizers), nasal drops / solutions, sprays are suitable; lingual, sublingual or buccal too applying tablets or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the administration forms mentioned in a manner known per se. This can be done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) ) or taste and / or smell.

In general, it is recommended to administer amounts of about 1 to 20 mg / kg, preferably about 2.5 to 10 mg / kg body weight in the case of parenteral administration, in order to achieve effective results. In the case of oral administration, the amount is approximately 1 to 70 mg / kg, preferably approximately 1 to 30 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the upper limit mentioned must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

Generation of test tumors

20 female Wistar rats are treated with benzidine. The first dose of benzidine is 150 mg / kg; the doses are then reduced to 100 mg / kg weekly. Doses of 75 mg / kg follow at 14-day intervals. This results in a total dose of 1.225 g / kg. A total of 29 breast cancers develop. The average life expectancy of the Wistar rats treated with benzidine was 325 days. After the first tumor (approx. 0.5 g) has formed, no more benzidine is given. Then breast cancer grows relatively quickly. The tumor size is determined by palpation; experienced experimenters can feel it down to 0.1 g. Tumors from 0.5 g are used for the experiments.

Evidence of competitive inhibition against 6.7-ditritium estradiol on the estrogen receptor by compounds according to the invention

6,7-Ditritium estradiol with a specific activity of 0.5 Ci / mmol is used in the experiments.

Tissue sections with a thickness of 0.7 mm and a surface area of 0.5 cm ^{2 are} made from rat uterine and breast cancer tissue using a tissue cutter. The carcinoma should have a minimum weight of 1.5 g for tissue sections.

Treated tissue sections: Tissue sections from uterine and breast carcinoma are treated in physiological saline with concentrations of 5, 10, 15, 20, 35 and 50 mg / 1 compound according to the invention. Then all tissue sections are washed and incubated again for 1 hour in physiological saline solution which contains 10 ^"9 mol / 1 6.7-ditritium estradiol = physiological concentration.

Control: Tissue sections as above but untreated are incubated with physiological saline for 1 hour.

After incubation, all tissue sections are washed and placed in 4% formol. They are then dried, weighed and burned. The ash is dissolved in scintillation fluid and the activity is determined in a liquid scintillation counter. The number of flashes of light per mg of ash dry matter in a defined time interval is a measure of the amount of 6,7-ditritium-estradiol taken up and thus an indirect measure of the number of estrogen receptors which have been replaced by the compound according to the invention. For the purposes of this invention, we call the ratio of the number of light flashes obtained from rats treated according to the invention to the number of light flashes obtained from untreated rats "receptor occupancy quotient" (meaning: occupied by estradiol). The lower the ratio, the stronger it is Compound according to the invention occupies the estrogen receptors; the estradiol used in the test can only prove the receptors (unoccupied by the compound according to the invention). It is in the nature of the tissues examined that the number of estrogen receptors per tissue section fluctuates within certain limits. For example, the number of estrogen receptors in adjacent tissue sections of a breast tumor (due to the different density of the tumor tissue) may differ. It is therefore advisable to examine 3 samples each and calculate the mean.

If the amount of compound according to the invention selected for the experiment is relatively high, the receptors which can be occupied by the compounds according to the invention are occupied at the first application rate and an increase no longer has any significant effect.

Qualitative detection of the cytotoxic effect of compounds according to the invention on breast tumor cells

This thymidine test makes it easy to check tumor growth: if thymidine is no longer incorporated into the cell, tumor growth has stopped.

Untreated rats treated with the compound according to the invention are fed with tritiated thymidine.

The autoradiogram shows a large number of marked cells in the tumor tissue of the untreated control group. The cells marked by tritium can be recognized by many black dots in the autoradiogram (strong silver excretion on the photo plate). These points are a sign of the strong growth of cancer cells and the associated incorporation of the nucleoside thymidine.

Small tumors slowly disappear in the rats treated with the compound according to the invention, while necrosis occurs in large tumors.

Breast carcinomas of rats which are treated with 20 mg / kg / day of a compound according to the invention for 20 days show no more thymidine incorporation after feeding with tritiated thymidine in the autoradiogram, i.e. the growth of cancer cells has at least stopped.

Unless stated otherwise, the percentages in the following examples are percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume. Examples

Examples for the preparation of the starting compounds (marked with "A" and preparation examples

All preparations were examined for purity by thin layer chromatography (Kieselgel 60 F 254, Merck, Darmstadt). NMR spectra of all self-produced starting compounds and all compounds according to the invention have been recorded; they agree with the postulated structures.

I. steroids

Reaction scheme of the reactions carried out:

The nitrated estrones, estradiols and the amino compounds produced therefrom used as starting products are either known or can be prepared analogously to known processes (cf. St. Kraychy, Am. Soc. 81, 1702 (1959)).

Example AI: Preparation of 2- and 4-nitroestrone

16.48 ml of conc. Are slowly added to a solution of 40 g of estrone in 1000 ml of glacial acetic acid at 35 to 40 ° C. with stirring. Added dropwise nitric acid. Allow to stir for 24 hours. 4-nitroestrone precipitates pale yellow crystalline, is filtered off and recrystallized from ethanol. Yield: 9 g of 4-nitroestrone; Mp 270 ° C.

4000 ml of water are added to the filtrate, the precipitated crude product is filtered off with suction and dried (yield: 45 g). The cleaning is carried out by column chromatography over aluminum oxide (Woelm), AKT.St.1 acid. The crude product is dissolved in 300 ml of hot benzene (max. 15 g) and slowly pipetted onto the prepared glass column (height 120 cm, diameter 4.5 cm) applied. Then elute with benzene under DC control. The solution is concentrated and the remaining 2-nitroestrone is isolated.

Yield (from 3 columns): 25 g of 2-nitroestrone; Mp 180 ° C.

Example A2: 2-nitro-3-methoxyestrone

480 ml of dimethyl sulfate are added dropwise at 35 ° C. in the course of 6 hours under a nitrogen atmosphere to a solution of 16 g of 2-nitroestrone from example A1, 750 ml of ethanol and 750 ml of 10% aqueous potassium hydroxide solution. Care is taken to ensure that the solution remains alkaline; if necessary, 45% aqueous potassium hydroxide solution is added dropwise. The mixture is stirred until the solution remains light yellow and alkaline. The solution is then cooled to about 5 ° C., the precipitated product is filtered off with suction and washed with dilute aqueous potassium hydroxide solution and water, dried and recrystallized from ethanol / toluene (1: 1). Yield 15.7 g; Mp 154 ° C.

Example A3: 3-methoxy-4-nitroestrone

The title compound is prepared from the compound of Example AI analogously to Example A2. Yield 2.1 g; Mp 259 ° C. Example A4: 2-amino-3-methoxyestrone

A solution of 5 g of 2-nitro-3-methoxyestrone from Example A2, 4 g of sodium thiosulfate, 800 ml of acetone and 160 ml of 0.5N sodium hydroxide solution is heated under reflux for 35 minutes, a solution of 3.2 g of sodium thiosulfate in 160 ml of 0.5 N sodium hydroxide solution was added and the resulting solution was heated under reflux for 50 minutes. Then 400 ml of water are added and the acetone is removed under reduced pressure. The suspension obtained is cooled and the crystals are suction filtered, washed with water, dried and recrystallized from methanol. Yield 4.2 g; Mp 155 ° C,

Example A5: 3-methoxy-4-aminoestrone

The title compound is produced from the compound of Example A3 in the same way as Example A4. Yield 0.6 g; Mp 183 ° C.

Example A6: 2-Ammo-3-methoxyestrole

A mixture of 1 g of 2-amino-3-methoxyestrone from Example A4, 200 ml of methanol and 0.44 g of sodium borohydride is stirred at 40 to 50 ° C under TLC control until the reaction is complete (14 hours). Then 4 ml of glacial acetic acid are added and the methanol is removed under reduced pressure. The residue is dissolved hot in dilute hydrochloric acid, the title compound is precipitated with sodium hydroxide solution, the suspension is cooled and the product which has precipitated is filtered off with suction and dried. Yield 0.6 g; Mp 160 ° C.

Example A7: 3-methoxy-4-aminoestrole

The title compound is prepared from the compound of Example A5 analogously to Example A6. Yield 0.4 g; Mp 176 ° C.

Example 8: 2- (1,1-dimethyltriazenyl) -3-methoxyestrone

At 0 to 4 ° C, a solution of 0.55 g of sodium nitrite in 3 ml of water to a solution of 2.3 g of 2-amino-3-methoxyestrone from Example A4, 160 ml of water and 1.2 ml of conc. Dropped (37%) hydrochloric acid. The diazonium salt solution obtained is then rapidly introduced at 0 to 4 ° C. into a solution of 0.95 g of sodium carbonate, 1 ml of 40% aqueous dimethylamine solution and 40 ml of water. After stirring for 1 hour, the solid product is filtered off, dried and recrystallized from a little toluene. Yield 1.5 g; Mp 168 ° C.

Example 9: 3-methoxy-4- (l, 1-dimethyltriazenyl) estrone

The title compound is prepared from the compound of Example A5 analogously to Example 8. Yield 1.5 g; Mp 142 ° C.

Example 10: 2- (1, 1-dimethyltriazenyl) -3-methoxyestrole

The title compound is prepared from the compound of Example A6 analogously to Example 8. Yield 3 g; Mp 135 ° C.

Example 11: 3 - (1, 1-Dimethyltriazenyl) estrone

To a solution of 2.7 g of 3-amino estrone, 40 ml of water and 2 ml of conc. Hydrochloric acid (37%), a solution of 0.7 g of sodium nitrite and 10 ml of water is added dropwise at 0 to 4 ° C. The diazonium salt solution obtained is then introduced into a solution of 1.2 g of sodium carbonate, 1.2 ml of 40% aqueous dimethylamine solution and 20 ml of water. After stirring for 1 hour, the title compound is filtered off, dried and recrystallized from a little ligroin. Yield: 2g; Mp: 168 ° C.

Example 12: 3 - (1, 1-Dimethyltriazenyl) estrole

0.44 g of sodium borohydride are added to a solution of 1 g of 3- (l, l-dimethylttiazenyl) estrone from Example 11 in 200 ml of methanol. The solution is stirred at 40 to 50 ° C under TLC until the reaction is complete (14 hours). After adding 4 ml of glacial acetic acid, the methanol is removed under reduced pressure. The residue is triturated with water, the title compound is suction filtered and dried. Yield: 1 g; Mp: 138 ° C.

E. Stilbene

The stilbenes of the examples were prepared by Wittig olefmation (G. Wittig, Angew. Chem. 68, 505). In the synthesis of the Nittostilbenes by Wittig olefination, it was found for the first time that, when changing from para to ortho-substituted benzaldehydes, Wittig olefination gives increasing proportions of cis-stilbene. If the ethyl acetate group is ortho to the aldehyde group, 100% cis-stilbene is formed.

The cis content obviously depends on the type and size of the substituent on the benzene nucleus of the aldehyde.

The compounds used as starting products are either known or can be prepared analogously to known processes.

Reaction scheme of the reactions carried out:

R - Br HO

cis / trans = 50/50 A17

R = CH ₂ C0 ₂ C ₂ H ₅ , CH (CH ₃ ) C0 ₂ C ₂ H ₅

Zn / H ⁺ Zn / H ⁺ Na ₂ S 9H _z O

R = CH ₂ CO ₂ C ₂ H ₅ ; R = CH ₂ CO ₂ Me; Me = H, Na, C ₂ H ₅ or HN (CH ₂ CH ₂ OH) ₃

Example AI 3: (4-nitrobenzyl) -tτiphenylphosphomum chloride

[0 ₂ NC ₆ H ₄ -CH ₂ -P ⁺ Ph ₃ ] Cr

A solution of 263 g (1 mol) triphenylphosphine, 172 g (1 mol) 4-nitrobenzyl chloride and toluene is stirred for 15 hours at the boiling point. The reaction mixture is cooled, the crystals are suction filtered and washed with toluene. Yield: 344 g; Mp 280 ° C Example A14: (2-formylphenoxy) ethyl acetate

At 50 ° C., 167 g (1 mol) of ethyl bromoacetate are added to a solution of 122 g (1 mol) of 2-hydroxybenzaldehyde, 1 mol of sodium methylate (in methanolic solution) and 1.5 l of acetonitrile, and the solution is stirred for 7 hours stirred at 70 ° C. Then the reaction solution is dipped into 2 liters of ice water. The oil which separates out is extracted with 500 ml of dichloromethane, the organic phase is dried over sodium sulfate and the dichloromethane is distilled off. The remaining oil crystallizes. Yield: 180 g; Mp 48 ° C.

Example A15: (4-formylphenoxy) ethyl acetate

The compound is prepared analogously to Example A14 from 4-hydroxybenzaldehyde. Yield: 195 g; Mp 43 ° C.

Example AI 6: {2 - [(Z) -2- (4-nitrophenyl) ethenyl] phenoxy} ethyl acetate

At 0 to 5 ° C, 218 g of phosphonium salt from Example A13 and 0.5 mol of sodium methylate solution are added in portions (after each decolorization) to a solution of 104 g (0.5 mol) of aldehyde from Example A14 and 750 ml of ethanol. After decolorization of the The reaction solution is separated from the undissolved. The filtrate is freed from the solvent and the residue is rubbed with 400 ml of phosphoric acid tis (dimethylamide). At 0 ° C, triphenylphosphine oxide precipitates out of the solution and is suctioned off. After adding 2 l of ice water to the filtrate, the oil which precipitates is extracted with 3 l of benzene, the solvent is removed, the residue is stirred with 500 ml of isopropanol and, after cooling, the crystalline product is filtered off with suction. Yield: 105 g of pure cis compound; Mp 70 ° C

Example A17: {2 - [(E) - and {2 - [(Z) -2- (4-nitrophenyl) ethenyl] phenoxy} acetic acid, ethyl ester

E shape Z shape

At 0 to 5 ° C, 218 g of phosphonium salt from Example A13 and 0.5 mol of sodium methylate solution are added in portions (after each decolorization) to a solution of 104 g (0.5 mol) of aldehyde from Example AI 5 and 750 ml of ethanol. After the reaction solution has been decolorized, the precipitated crystals are filtered off with suction and recrystallized from ethanol. It is the pure trans connection. Yield: 51 g; Mp 118 ° C.

To isolate the cis part, the procedure is as described in Example AI 6. Yield: 48 g; Mp 59 ° C.

Example AI 8: Sodium 2 - [(E) - and -2 - [(Z) -2- (4-nitrophenyl) ethenyl] benzenesulfonate

E-shape ^{Z "shape}

0.4 mol of sodium methylate (in methanolic solution) is added to a solution of 83.2 g (0.4 mol) of sodium benzaldehyde 2-sulfonate in 500 ml of methanol. A solution of 173 g of phosphonium salt from Example A13 and 400 ml of methanol is added to the resulting solution at 0 ° C. with stirring dripped. After the reaction solution has been decolorized, the solvent is distilled off, the residue is suspended in 300 ml of water and suction filtered with cold suction. The solid product is slurried with 1 1 of diethyl ether, filtered off with suction, air-dried and then boiled with 1.3 1 of nitromethane and suctioned off from the insoluble residue (trans compound). The cis compound crystallizes on cooling.

Yield cis-compound: 53 g; Mp 247 ° C (from nittomethane). Yield trans compound: 20 g; Mp 323 ° C.

Example AI 9: Sodium 2 - [(E) -2- (4-aminophenyl) ethenyl] benzene sulfonate

A solution of 17.5 g of Na ₂ S ^' 9H 0 and 20 ml of water is added to a solution of 16 g of cis-nitro compound of Example AI 8 in 60 ml of ethanol at 80 ° C. and stirred for 1 hour. The solvent is then distilled off and the residue is recrystallized from nittomethane. Yield: 13 g; Mp> 360 ° C.

Example A20: {2 - [(Z) -2- (4-aminophenyl) ethenyl] phenoxy} ethyl acetate

A solution of 16 g of ammonium chloride in 60 ml of water is slowly added dropwise at a maximum of 30 ° C. with stirring to a mixture of 65.4 g (0.2 mol) of nitro compound from Example A16, 800 ml of acetone and 200 g of zinc dust. Then stirring is continued for 20 hours. The zinc is then suction filtered and washed with 1 liter of hot acetone. The acetone solutions are concentrated. The residue is concentrated in 800 ml of water and 25 ml. Dissolved hydrochloric acid and immediately extracted twice with ethyl acetate. Then quickly becomes weakly alkaline with sodium hydroxide solution provided and immediately extracted again with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off. Yield: 55 g, brown oil. The raw product is processed further.

Example A21: {2 - [(E) -4- (4-aminophenyl) ethenyl] phenoxy} acetic acid ethyl ester

The title compound is prepared analogously to Example A20 from the trans-nitrostilbene of Example AI 7.

Yield: 45 g, yellow crystals; Mp 118 ° C.

Example A22: {2 - [(Z) -4- (4-aminophenyl) ethenyl] phenoxy} acetic acid ethyl ester

The title compound is prepared analogously to Example A20 from the cis-nitrostilbene of Example A17.

Yield: 35 g, yellow oil.

Example 23: [4 - ((Z) -2- {4 - [(1E) -3, 3 -dimethyl-1-triazenyl] phenyl} ethenyl) phenoxy] ethyl acetate

In a 50 ° C hot mixture of 80 ml of water, 600 ml of ethanol and 60 ml of conc. Hydrochloric acid 71 g of cis-aminostilbene from Example A22 are introduced quickly; the mixture is stirred vigorously and quickly cooled to 0 ° C. Then a solution of 18 g of sodium nitrite and 70 ml of water is run in immediately and the mixture is stirred at 0 ° C. for one hour. This solution is then rapidly run into a mixture of 80 g of 40% aqueous dimethylamine solution, 120 g of sodium carbonate and 1 liter of water with vigorous stirring at 0.degree. The mixture is stirred at room temperature for 1 hour, the reaction product is suctioned off, dried and further processed as a crude product. Yield: 63 g.

Example 24: [4 - ((E) -2- {4 - [(IE) -3,3-dimethyl-1-triazenyl] phenyl} ethenyl) phenoxy] acetic acid ethyl ester

The title compound is prepared analogously to Example 23 from 0.033 mol of the trans-aminostilbene from Example A21. Yield: 7 g, mp 113 ° C.

Example 25: [2 - ((E) -2- {4 - [(lZ) -3,3-dimethyl-l-ttiazenyl] phenyl} ethenyl) phenoxy] acetic acid, ethyl ester

The title compound is prepared analogously to Example 23 from 0.2 mol of the cis-aminostilbene from Example A20. The pale yellow oil is processed as a raw product. Yield: 55 g.

Example 26: Sodium [2 - ((Z) -2- {4 - [(IE) -3,3-dimethyl-l-ttiazenyl] phenyl} ethenyl) phenoxy] acetate

50 g of 10% sodium hydroxide solution are run in to a boiling solution of 35.3 g of the triazenyl stilbene ester from Example 25 and 850 ml of ethanol and the mixture is heated under reflux for a further 20 minutes. Then 300 ml of water and 350 ml of a saturated aqueous saline solution are added. The title compound precipitates, is filtered off, dried and recrystallized from acetonitrile. Yield: 33 g, beige; Mp 72 ° C.

Example 27: Sodium [4 - ((Z) -2- {4 - [(1Z) -3,3-dimethyl-l-triazenyl] phenyl} ethenyl) phenoxy] acetate

50 g of 10% sodium hydroxide solution are run into a boiling solution of 35.3 g of the trans-triazenyl stilbene ester from Example 24 and 850 ml of ethanol and the mixture is heated under reflux for a further 20 minutes. 300 ml of water are then added, and the sodium salt which has precipitated is filtered off with suction. Yield: 30 g.

Example 28: [4 - ((Z) -2- {4 - [(lZ) -3,3-dimethyl-l-triazenyl] phenyl} ethenyl) phenoxy] acetic acid

5 g of the compound from Example 27 are dissolved in a mixture of 250 ml of tris (dimethylamide) phosphoric acid and 250 ml of water while hot. The mixture is then allowed to cool to 40 ° C. and is suctioned off. The filtrate is cooled to 30 ° C. and 60 ml of glacial acetic acid are added. With further cooling, 50 ml of ice water and 30 ml of glacial acetic acid are immediately added. After 10 minutes, the title compound is suctioned off. Yield: 3 g; Mp 170 ° C. Example 29: Triethanolammonium- [4 - ((Z) -2- {4 - [(1Z) -3,3-dimethyl-l-triazenyl] phenyl} ethenyl) phenoxyj acetate

The compound from Example 28 is given as a 10% aqueous solution in the form of the triethanolamine salt for biological testing.

Example 30: sodium 2 - ((Z) -2- {4 - [(IE) -3,3-dimethyl-l-ttiazenyl] phenyl} ethenyl) benzene sulfonate dihydrate

To a solution of 15 g of cis-aminostilbene from Example A19, 10 ml of water and 24 ml of conc. Hydrochloric acid is added dropwise at 0 ° C. to a solution of 3.5 g of sodium cutite and 5 ml of water, the mixture is left to stir for 10 minutes and the resulting diazonium salt solution is quickly dipped into a solution of 30 g of sodium carbonate, 60 ml of water and 7 g of 40% aqueous dimethylamine solution. The mixture is stirred for 40 minutes, the crystalline reaction product is filtered off and recrystallized from acetonitrile. Yield: 17 g.

St. Triphenylethylene Derivatives Reaction Scheme:

Etherspaltυng

Wittig reaction

Example A31: 1 - [bromo- (4-methylphenyl) methyl] -4-methylbenzene

Hydrogen bromide is introduced into a suspension of 100 g of bis (4-methoxyphenyl) carbinol and 46 g of calcium chloride in 1.7 l of benzene until it is saturated. The resulting salt is filtered off and the filtrate is concentrated. Yield: 98 g

Example A32: [bis (4-methoxyphenyl) methyl] -tiphenylphosphonium bromide

The title compound is prepared from the bromide of Example A31 analogously to Example AI 3. Yield: 99 g. Example A33: 1- [2,2-bis (4-methoxyphenyl) vinyl] -4-nitrobenzene

The title compound is prepared from the phosphonium salt of Example A32 and 4-nittobenzaldehyde analogously to Example A17. Yield: 14 g

Example A34: 4- [1- (4-hydroxyphenyl) -2- (4-nitrophenyl) vinyl] phenol

380 g of conc. Are added to a mixture of 150 g of the compound of Example A33 and 300 ml of Pyridm. Dropped hydrochloric acid. Then the reaction solution is heated to 150 ° C. for 3 hours. It is then poured onto 2 l of ice water, made significantly acidic with hydrochloric acid and the title compound is filtered off with suction, washed with water and dried. Yield: 110g. Example A35: {4- [1- [4- (2-Ethoxy-2-oxoethoxy) phenyl] -2- (4-nitrophenyl) vinyl] phenoxy} acetic acid, ethyl ester

The title compound is prepared from the phenol of Example A34 analogously to Example A14. Yield: 14 g.

Example A36: {4- [1- [4- (2-Ethoxy-2-oxoethoxy) phenyl] -2- (4-aminophenyl) vinyl] phenoxy} acetic acid ethyl ester

The title compound is prepared from the nitro compound of example A35 analogously to example A20.

Yield: 13 g.

Example A37: Dinattium- (4- {2- (4-aminophenyl) -1- [4- (2-oxido-2-oxoethoxy) phenyl] vinyl} phenoxy) acetate

A mixture of 13 g of the ester from Example A35, 20 ml of water and 5.3 g of potassium hydroxide is heated under reflux for 5 hours. The alcohol formed is then removed, the crystalline residue is triturated with 50 ml of water, suction filtered and dried. Yield: 10 g.

Example 38: Disodium- (4- {2- {4 - [(IE) -3,3-dimethyl-l-ttiazenylj-phenyl} -l- [4- (2-oxido-2-oxoethoxy) phenyl ] -vinyl} phenoxy) acetate

To a mixture of 10 g of disodium salt of Example A37, 2 g of sodium hydroxide, 1.7 g of sodium nitrite and 50 ml of water is added dropwise at 0 to 5 ° C, a solution of 100 ml of water, 130 ml of dimethylformamide and 16 ml of conc. Hydrochloric acid. The resulting aqueous diazonium salt solution is introduced at 0 to 5 ° C. into a solution of 23 g of sodium carbonate, 14 ml of aqueous 40% dimethylamine solution and 50 ml of water. Then the mixture is evaporated to dryness. The residue is dissolved in the necessary amount of water and 100 ml of saturated aqueous sodium chloride solution are added. The title compound, which crystallizes out, is filtered off with suction and dried. Yield: 5.7 g.

Claims

claims:

1. Estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, with the exception of 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-oestral, 3,5 (10) -triene- 17-one.

2. estrogens and antiostrogens according to claim 1, characterized in that the substances derivatives from the group of steroids, stilbenes, hexestoles, phenyl-l, 2-bis (2,6-dichlorophenyl) -l, 2-bis (ethyleneaminoethane ), Triphenylethylenes, phenylbenzofurans, phenylbenzothiophenes, 4,5-bis-phenyl-imidazoles, 2,3-diarylpiperazines, 4,5-phenyl-2-imidazolines.

3. estrogens and antiostrogens according to claim 1 or 2 of the formula

where R ^{1 is} hydrogen, N = N-NR ^7A R ^7B , 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, C0 ₂ H or S0 ₃ H,

R ² OH, OCH ₃ , N = N-NR ^7A R ^7B or 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, R ³ hydrogen, N = N-NR ^7A R ^7B , 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, C0 ₂ H or SO ₃ H, R ⁴ and R ⁶ independently of one another hydrogen, 0 (CR ⁸ R ⁹ ) _n C0 ₂ H, (CR ⁸ R ⁹ ) _n C0 ₂ H or C ₆ H ₄ θCH ₂ C0 ₂ H and R ⁴ also (CH ₂ ) ₁₀ CON (C ₁ -C ₄ alkyl) ₂ ,

R ^{5 is} hydrogen or OH,

R ^7A and R ⁷⁸ independently of one another are alkyl,

R ⁸ and R ⁹ independently of one another are hydrogen, methyl or ethyl, X CO, CHOH or C (OH) -C≡CH and n is an integer from 1 to 10 with the proviso that only one of the radicals R ¹ to

R ³ stands for N = N-NR ^7A R ^7B , and their salts, solvates and solvates of these salts.

4. estrogens and antiostrogens according to claim 1 or 2 of the formula embedded image in which

R is hydrogen, methyl or ethyl,

R ^{1 is} hydrogen, chlorine, methyl, ethyl, CH ₂ C0 ₂ H, CH (CH ₃ ) C0 ₂ H, OCH ₂ C0 ₂ H, OCH (CH ₃ ) C0 ₂ H or S0 ₃ H,

R ² OH, OCH ₃ , OCH ₂ C0 ₂ H, OCH (CH ₃ ) C0 ₂ H or N = N-NR ^7A R ^7B ,

R ^{3 is} hydrogen, chlorine, preferably in the 6-position, or N = N-NR ^7A R ^7B ,

R ^{4 is} hydrogen, methyl, ethyl, CH ₂ C0 ₂ H or CH (CH ₃ ) C0 ₂ H and

R ^7A and R ⁷⁸ independently of one another are alkyl with the proviso that either R ² or R ^{3 is} N = N-NR ^7A R ^7B ,

and the broken bonds indicate that the compounds include both ethane and ethylene derivatives,

and their salts, solvates and solvates of these salts.

5. estrogens and antiostrogens according to claim 1 or 2 of the formula

where R is hydrogen, chlorine, chloromethyl or ethyl,

R ¹ OCH ₂ C0 ₂ H or OCH (CH ₃ ) C0 ₂ H,

R ² and R ^{4 are} independently hydrogen, S0 ₃ H or N = N-NR ^7A R ^7B , R ³ and R ^{5 are} independently hydrogen, OH, OCH ₃ , OCH ₂ C0 ₂ H, OCH (CH ₃ ) C0 ₂ H orN = N-NR ^7A R ^7B and R ^7A and R ™ independently of one another alkyl with the proviso that only one of the radicals R ² to R ^{5 is} N = N-NR ^7A R ^7B , and their salts, solvates and solvates of these salts.

6. estrogens and antiostrogens according to claim 1, characterized in that the substances are derivatives of the formula

(XXII) are.

7. A process for the preparation of the compounds according to claims 1 to 6, according to which at least one dialkyl tiazenyl substituent is introduced into one or more aromatic rings of an estrogenic or anti-estrogenic compound. Estrogens and antiostrogens, which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, for the treatment of diseases.

8. Use of the compounds according to claim 7 for combating tumors of the sexual organs in humans and animals.

9. A method for combating tumors of the sexual organs in humans and animals by applying a sufficient amount of at least one of the compounds according to claim 7.

10. Use of the compounds according to claim 7 for the manufacture of medicaments for combating tumors of the sexual organs in humans and animals.

11. Medicaments containing at least one compound according to claim 7 - optionally together with one or more pharmacologically acceptable auxiliaries or carriers.

12. Use of the medicament according to claim 11 for the purposes mentioned in claims 8 to 10.