RU2137777C1 - DERIVATIVES OF 11β-BENZALDOXIME-ESTRA-4,9-DIENE, METHOD OF THEIR SYNTHESIS, PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes new derivatives of 11β-benzaldoxime-estradiene of the general formula (I) 11β where values

Description

 The invention relates to new derivatives of 11-benzaldoxime-estra-4-9-diene, a method for their preparation and medicines containing these compounds.

 11β-Substituted phenyl estratrienes are already known. The preparation of 11β-aryl-17α-propionyl-estra-4,9-dienes has already been described, for example, in European patent 057115; the interaction of 11β- (4-formylphenyl) -estra-4,9-dien-3-ones with hydroxylamines is already described in German Patent No. 3504421. In this method, both the 11β-formyl-phenyl group and also the 3-keto group are oxidized. In addition, syn- and anti-isomers are formed at position C-3. The action of the described compounds is still unknown.

 Progesterone in large quantities is secreted by the ovary and placenta during the cycle and during pregnancy. Its regulatory significance is allegedly not clarified in all aspects.

 It is guaranteed that progesterone, when interacting with estrogens, causes cyclic changes in the uterine mucosa in the menstrual cycle and during pregnancy. Under the influence of an increased level of progesterone after ovulation, the uterine mucosa is transferred to a state that allows implantation of an embryo (blastocyst). Preservation of tissues in which the growing embryo “expands” also depends on progesterone.

 During pregnancy, a "dramatic" change in the muscular function of the uterus occurs. The uterus muscle during pregnancy reacts very weakly or does not at all respond to hormonal and mechanical irritations that cause pain outside pregnancy. There is no doubt that in this case, progesterone plays a key role, although in some phases of pregnancy, for example, immediately before childbirth, there is a high reactionary readiness with an extremely high level of progesterone in the blood.

 Other typical pregnancy processes are also associated with very high progesterone levels. Examples of this are the structure of the mammary glands and a solid obstruction of the uterine throat up to a point near the term of labor.

 Progesterone subtly takes part in the management of ovulation processes. It is known that progesterone in high doses has antivulatory properties. They arise from the suppression of the pituitary secretion of gonadotropin, a prerequisite for the maturation of the follicle and its ovulation. On the other hand, it is known that the relatively insignificant release of progesterone by the ripening follicle plays an active role in the preparation and induction of ovulation. At the same time, pituitary mechanisms (time limited by the so-called “positive feedback” of progesterone with gonadotropin secretion) play, as you know, an important role (Loutradie, D .; Human Reproduction 6, 1991, 1238 - 1240).

 Less well analyzed are the functions of progesterone in a ripening follicle and in the corpus luteum, the existence of which there is no doubt. In the final analysis, it is also necessary to assume stimulating and suppressing effects on the endocrine function of the follicle and corpus luteum.

 The significant role of progesterone and progesterone receptors in pathophysiological processes should also be considered. Progesterone receptors are found in foci of endometriosis, but also in tumors of the uterus, mammary gland, and ZNS (meningeoma). The role of these receptors for the growth process of these pathologically relative tissues is not necessarily related to the presence of progesterone levels in the blood. It turned out that substances that are characterized as progesterone antagonists, RU 486 = Mifepristone (European patent 0057115) and ZK 98299 = Onapriston (laid out description of the invention to the unapproved patent application of Germany 3504421), in these tissues cause profound functional changes also when blood there is a negligible, which can be neglected, the level of progesterone.

 It is possible that, due to antagonists, changes in the transcriptional actions of the non-progesterone receptor occupied by the non-progesterone play an important role (Chwalisz, K. et al., Endocrinology, 129, 317 - 322, 1991).

 The action of progesterone in the tissues of the genital organs and in other tissues is carried out due to the interaction with the progesterone receptor. In a cell, progesterone binds to its receptor with high affinity. Thus, changes in the receptor protein are caused: conformational changes; dimerization of 2 receptor units into a complex; exposure of receptor DNA binding sites by removal due to protein dissociation (HSP 90); binding of hormone-responsible DNA elements. Finally, transcription of certain genes is regulated (Gronemeyer, H. et al., J. Steroid. Biochem. Molec. Biol. 41, 3-8, 1992).

 The action of progesterone or progesterone antagonists depends not only on their concentration in the blood. The concentration of receptors in the cell is also highly regulated. Estrogens stimulate the synthesis of progesterone receptors in most tissues. Progesterone suppresses the synthesis of estrogen receptors and the synthesis of a new own receptor. There are probably these and other interactive relationships between estrogens and gestagens that can explain why gestagens and antigestagens can influence estrogen-dependent processes without binding to an estrogen receptor. These relationships, of course, are of great importance for the therapeutic use of antigestagens. These substances are suitable for targeted participation in reproduction processes in women, for example, after ovulation, to inhibit nidation, in later pregnancy, to increase the uterus's reactivity for prostaglandins and oxytocin, or to achieve opening and softening ("maturation") of the cervix.

 Antigestagens in various higher species of primates suppress ovulation. The mechanism of this action is clearly unclear. Along with suppressing the secretion of gonadotropin, ovarian mechanisms are also discussed due to a violation of the para- and autocrine functions of progesterone in the ovary.

 Antigestagens have the ability to modulate or attenuate the effects of estrogens, although they themselves predominantly have no means for estrogen receptor in the cytoplasmic region and although they can cause an increase in estrogen receptor concentration. From the corresponding effects in the endometrial foci, respectively, in the tumor tissues, which are equipped with estrogen and progesterone receptors, a favorable effect on the disease states can be expected. Particular advantages for a beneficial effect on painful conditions such as endometriosis can occur when ovulation suppression is added to the suppressive effects of antigestagen due to the action in the tissue. With the suppression of ovulation, part of the ovarian hormone production would also disappear, and thus the stimulating effect on pathologically altered tissue, which disappears with this part, would also disappear. In the presence of severe endometriosis, it would be desirable to suppress ovulation, and the tissue of the genital tract, usually located constantly in remodeling, can be reversibly restored to a calm state.

 For contraception, a method is also discussed in which antigestagen treatment suppresses ovulation, and secretory transformation of the endometrium is induced by subsequent progestogen treatment, so that approximately 28-day cycle follows with days of treatment with antigestagens and gestagens and days in which treatment is not performed bleeding (Baulieu, EE, Advances in Contraception 7, 345-51, 1991).

 Antigestagens can have various hormonal and antihormonal properties. Especially therapeutically relevant antiglucocorticoid properties. For therapeutic applications in which the goal of therapy is to suppress progesterone receptors, they are negative, since at therapeutically necessary dosages they cause unwanted side effects, prevent the introduction of a therapeutically rational dose, or may harm the treatment. A partial or complete decrease in antiglucocorticoid properties is an important prerequisite for therapy with antigestagens, especially for those indications that require treatment lasting for weeks or months.

Другой задачей изобретения является получение лекарственных средств, которые содержат соединение общей формулы I или его фармацевтически приемлемую соль.The objective of the present invention is to obtain new derivatives of 11β-benzaldoxymester-4,9-diene of General formula I and their pharmaceutically acceptable salts, as well as the development of a method for their preparation

Another object of the invention is to provide drugs that contain a compound of general formula I or a pharmaceutically acceptable salt thereof.

где R¹ обозначает атом водорода или алкильный остаток с 1 - 6 C-атомами;
R² обозначает атом водорода; алкильную, арильную, аралкильную или алкиларильную группу с 1 - 10 C-атомами; ацильный остаток с 1 - 10 C-атомами или остаток -CONHR⁴ или -COOR⁴,
причем R⁴ обозначает атом водорода, алкильный, арильный, аралкильный или алкиларильный остаток с 1 - 10 C-атомами;
R³ обозначает атом водорода; алькильную, арильную, аралкильную или алкиларильную группу с 1 - 10 C-атомами; остаток - (CH₂)_n-CH₂X, причем n = 0, 1 или 2, X обозначает атом фтора, хлора, брома или иода, циано-, азидо- или роданогруппу, остаток OR⁵ или SR⁵,
причем R⁵ обозначает атом водорода, алкильный, арильный, аралкильный или алкиларильный остаток с 1 - 10 C-атомами или ацильный остаток с 1 - 10 C-атомами;
остаток OR⁵, причем R⁵ имеет вышеуказанное значение;
остаток -(CH₂)_o-CH=CH(CH₂)_p-R⁶, причем o = 0, 1, 2 или 3 и p = 0, 1 или 2 и R⁶ обозначает атом водорода, алькильную, арильную, аралкильную или алкиларильную группу с 1 - 10 C-атомами, гидроксильную группу, алкоксильную группу или ацилоксигруппу с 1 - 10 C-атомами;
остаток -(CH₂)_qC ≡ CR⁷, причем q = 0, 1 или 2 и R⁷ обозначает атом водорода, атом фтора, хлора, брома или иода, алкильный, арильный, аралкильный или алкиларильный остаток с 1 - 10 C-атомами или ацильный остаток с 1 - 10 C-атомами;
Z обозначает атом водорода, алкильный, арильный, аралкильный или алкиларильный остаток с 1 - 10 C-атомами, ацильный остаток с 1 - 10 C-атомами, остаток - CONHR⁴ или -COOR⁴, причем R⁴ обозначает атом водорода, алкильный, арильный, аралкильный или алкиларильный остаток с 1-10 C-атомами;
или атом щелочного или щелочно-земельного металла.In the general formula I

where R ¹ denotes a hydrogen atom or an alkyl residue with 1 to 6 C-atoms;
R ² represents a hydrogen atom; an alkyl, aryl, aralkyl or alkylaryl group with 1 to 10 C atoms; an acyl residue with 1 to 10 C atoms or the residue —CONHR ⁴ or —COOR ⁴ ,
moreover, R ⁴ denotes a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl residue with 1 to 10 C-atoms;
R ³ represents a hydrogen atom; an alkyl, aryl, aralkyl or alkylaryl group with 1 to 10 C atoms; the remainder is (CH ₂ ) _n -CH ₂ X, wherein n = 0, 1 or 2, X is a fluorine, chlorine, bromine or iodine atom, a cyano, azido or rhodano group, the remainder is OR ⁵ or SR ⁵ ,
wherein R ⁵ represents a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl residue with 1 to 10 C atoms or an acyl residue with 1 to 10 C atoms;
the remainder of OR ⁵ , with R ⁵ having the above meaning;
the residue is (CH ₂ ) _o —CH = CH (CH ₂ ) _p —R ⁶ , wherein o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R ⁶ represents a hydrogen atom, an alkyl, aryl, aralkyl or an alkylaryl group with 1 to 10 C atoms, a hydroxyl group, an alkoxy group or an acyloxy group with 1 to 10 C atoms;
the remainder is (CH ₂ ) _q C ≡ CR ⁷ , with q = 0, 1 or 2 and R ⁷ denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl, aryl, aralkyl or alkylaryl residue with 1 to 10 C- atoms or an acyl residue with 1 to 10 C-atoms;
Z is a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl residue with 1 to 10 C atoms, an acyl residue with 1 to 10 C atoms, the residue is CONHR ⁴ or —COOR ⁴ , wherein R ⁴ is a hydrogen atom, alkyl, aryl , an aralkyl or alkylaryl residue with 1-10 C atoms;
or an alkali or alkaline earth metal atom.

Compounds in which are preferred:
R ¹ represents a methyl or ethyl group;
R ² denotes a hydrogen atom, an alkyl group with 1-10 C atoms, an acyl residue with 1-10 C atoms or a residue —CONHR ⁴ or —COOR ⁴ , wherein R ⁴ denotes a hydrogen atom, an alkyl or aryl residue with 1-10 carbon atoms;
R ³ represents a hydrogen atom; an alkyl, aryl, aralkyl or alkylaryl group with 1-10 C-atoms;
R ³ denotes the residue - / CH ₂ / _n -CH ₂ X, wherein n = 0, 1 or 2, X denotes a fluorine, chlorine, bromine or iodine atom, a cyano, azido or rhodano group, the remainder of OR ⁵ or SR ⁵ , moreover
R ⁵ denotes an alkyl residue with 1-6 C atoms or an acyl residue with 1-6 C atoms;
the residue is OR ⁵ , wherein R ⁵ is a hydrogen atom, an alkyl residue with 1-10 C atoms or an acyl residue with 1-10 C atoms;
the residue is / CH ₂ / _o —CH = CH / CH ₂ / _p —R ⁶ , wherein o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R ⁶ represents a hydrogen atom, an alkyl group with 1- 10 C atoms, a hydroxyl group, an alkoxyl group or an acyloxy group with 1-10 C atoms; or
the remainder is (CH ₂ ) _q C ≡ CR ⁷ , with q = 0, 1 or 2 and R ⁷ denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl residue with 1-10 C-atoms or an acyl residue with 1 -10 C atoms; and Z is a hydrogen atom; an alkyl residue with 1-10 C atoms; an acyl residue with 1-10 C atoms; the residue is —CONHR ⁴ or —COOR ⁴ , wherein R ⁴ is a hydrogen atom or an alkyl residue with 1-10 C atoms; or an alkali or alkaline earth metal atom. Particularly preferred compounds in which:
R ² is an alkyl group with 1-6 C atoms, an acyl residue with 1-6 C atoms or a —CONHR ⁴ or COOR ⁴ residue, wherein R ⁴ is a hydrogen atom, an alkyl or aryl residue with 1-6 C atoms;
R ³ denotes a hydrogen atom or an alkyl group with 1-6 C-atoms; the remainder is / CH ₂ / _n -CH ₂ X, wherein n = 0, 1 or 2, X is a fluorine, chlorine, bromine or iodine atom, a cyano, azodio or rhodano group, the remainder is OR ⁵ or SR ⁵ , wherein R ⁵ denotes an alkyl residue with 1-6 C-atoms or an acyl residue with 1-6 C-atoms; the residue is OR ⁵ , wherein R ⁵ is alkyl with 1-6 C atoms or an acyl residue with 1-6 C atoms;
the residue is / CH ₂ / _o —CH = CH / CH ₂ / _p —R ⁶ , with o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R ⁶ is an alkyl group with 1-6 C- atoms, an alkoxy group or an acyloxy group with 1-6 C-atoms; or the residue is (CH ₂ ) _q C ≡ CR ⁷ , wherein q = 0, 1 or 2 and R ⁷ is an alkyl residue with 1-6 C atoms or an acyl residue with 1-6 C atoms; and
Z represents an alkyl residue with 1-6 C atoms, an acyl residue with 1-6 C atoms, the residue —CONHR ⁴ or —COOR ⁴ , wherein R ⁴ represents a hydrogen atom, an alkyl or aryl residue with 1-6 C atoms.

Most preferred:
11β- [4- / hydroxyminomethyl / phenyl] - 17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxyminomethyl / phenyl] - 17β-hydroxy-17α-ethoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxyminomethyl / phenyl] - 17β-hydroxy-17α-n-propoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxyminomethyl / phenyl] - 17β-hydroxy-17α-isopropoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxyminomethyl / phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxyminomethyl / phenyl] - 17β-methoxy-17α-ethoxymethyl-estra-4,9-dien-3-one;
11β- [4- / hydroxymininomethyl / phenyl] - 17β-hydroxy-17α- / 3-hydroxyprop-1-in-yl / -estra-4,9-dien-3-one;
11β- [4- / hydroxymininomethyl / phenyl] - 17β-methoxy-17α- / 3-hydroxyprop-1-in-yl / -estra-4,9-dien-3-one;
11β- [4- (hydroxymininomethyl / phenyl] - 17β-hydroxy-17α-Z- / 3-hydroxypropenyl / estra-4,9-dien-3-one;
11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-17α-Z- [3-hydroxypropenyl] -estra-4,9-dien-3-one;
17α-chloromethyl-11β- [4- (hydroxymininomethyl) phenyl] 17β-hydroxy-estra-4,9-dien-3-one;
17α-chloromethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one;
17α-cyanomethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-hydroxy-estra-4,9-dien-3-one;
17α-cyanomethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one;
17α-azidomethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one;
11β- [4- (hydroxymininomethyl) phenyl] - 17β-methoxy-17α-methylthiomethyl-estra-4,9-dien-3-one;
11β- [4- (methyloxymininomethyl) phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- [4- / acetoxyximinomethyl-phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- [4- (methyloxymininomethyl) phenyl] - 17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- {4 - [(ethoxycarbonyl) oxymininomethyl] phenyl} - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one;
11β- {4 - [(ethylaminocarbonyl / oxymininomethyl] phenyl} - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one;
17β-methoxy-17α-methoxymethyl - 11β- [4 - {(phenylaminocarbonyl / oxymininomethyl} phenyl] estra-4,9-dien-3-one; and
11β- [4- (hydroxyminomethyl / phenyl] - 17β-ethoxy 17α-ethoxymethyl-estra-4,9-dien-3-one.

где R¹, R² и R³ имеют вышеуказанное значение;
вводят во взаимодействие с соединением общей формулы IIa
NH₂ - O - Y
где Y обозначает атом водорода, алкильный остаток с 1-10 C-атомами, ацильный остаток с 1-10 C-атомами или остаток - CONHR⁴ или COOR⁴,
причем R⁴ обозначает атом водорода, алкильный, арильный, аралкильный или алкиларильный остаток с 1-10 C-атомами;
и причем соединение общей формулы IIa в случае необходимости находится в форме такого соединения или из которой соединение общей формулы IIa высвобождается при выбранных реакционных условиях.The invention further relates to a process for preparing compounds according to general formula I and their pharmaceutically acceptable salts, which is characterized in that the compound of general formula II

where R ¹ , R ² and R ³ have the above meaning;
enter into interaction with the compound of General formula IIa
NH ₂ - O - Y
where Y denotes a hydrogen atom, an alkyl residue with 1-10 C-atoms, an acyl residue with 1-10 C-atoms or a residue - CONHR ⁴ or COOR ⁴ ,
moreover, R ⁴ denotes a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl residue with 1-10 C-atoms;
and wherein the compound of general formula IIa is optionally in the form of such a compound or from which a compound of general formula IIa is released under the selected reaction conditions.

 If necessary, the existing hydroxylamine group is esterified to an ester or ether group and, if necessary, the resulting compound is converted into a salt.

 It is preferable to react compounds of general formula II with compounds of general formula IIa, in which the compounds are used in equimolar amounts.

If desired, according to esterification to an ester, esterification to an ether or formation of urethane of compounds of the general formula I, the R ² - or Z-substituent of which is a hydroxyl group, the esterification to the ester can be carried out by itself in a known manner using alkylating agents, such as acid anhydrides or acid chlorides, in the presence of bases, preferably pyridine; etherification with ether can be carried out with methyl iodide in the presence of bases, preferably potassium tert-butylate, or the formation of urethane can be carried out by reacting with alkyl or aryl isocyanates in inert solvents, preferably toluene, or by reacting with carbamoyl chlorides in the presence of bases, preferably triethylamine.

(см., например, Nedelec Bull. Soc. Chim. France (1970), 2548).The starting compound of general formula II is prepared starting from 5α, 10α-epoxide of formula III

(see, for example, Nedelec Bull. Soc. Chim. France (1970), 2548).

The introduction of the phenyl residue at the 11β position during the formation of the Δ9 (10), 5α-hydroxy structure of formula IV is achieved by the copper salt catalyzed - / 1 / Grignard reaction [Tetrahedron Letters, 1979, 2051] with p-bromobenzaldehyde ketal, preferably p-bromobenzaldehyde dimethyl ketal, at temperatures 0 - 30 ^o C.

Введение группировки -/CH₂/_nCH₂X осуществляют само по себе известным путем через спиро-эпоксид формулы /V/ путем взаимодействия с триметилсульфонийиодидом и трет-бутилатом калия в диметилсульфоксиде [Hubner и др., J. prakt. Chem, 314, 667 (1972); Arzneim. Forsch, 30, 401 (1973)] и

и последующим раскрытием кольца с помощью нуклеофилов, как галогениды и псевдогалогениды, алкоголяты и меркаптиды [Ponsold и др., Z. Chem, 11, 106/1971/]. Образующиеся при этом 17α-CH₂X-соединения формулы VI

можно либо путем кислотного гидролиза, предпочтительно с помощью п-толуолсульфокислоты в ацетоне [Teutsch и др., патент ФРГ 2801416], расщеплять до альдегидов общей формулы II с R² в значении атома водорода, либо путем этерификации до простых эфиров свободных гидроксильных групп с помощью алкилгалогенидов в присутствии трет-бутилата калия сначала переводят простые 5α,17β-диэфиры /Kasch и др., патент ГДР 290893/, которые затем путем кислотного гидролиза, предпочтительно с помощью п-толуолсульфокислоты в ацетоне, превращают в альдегиды общей формулы /II/ с R² в значении алкильных остатков предпочтительно метильного остатка.

The introduction of the group - / CH ₂ / _n CH ₂ X is carried out by itself in a known manner through a spiro epoxide of the formula / V / by reaction with trimethylsulfonium iodide and potassium tert-butylate in dimethyl sulfoxide [Hubner et al., J. prakt. Chem, 314, 667 (1972); Arzneim. Forsch, 30, 401 (1973)] and

and subsequent ring opening with nucleophiles, such as halides and pseudo-halides, alcoholates and mercaptides [Ponsold et al., Z. Chem, 11, 106/1971 /]. The resulting 17α-CH ₂ X-compounds of formula VI

it is possible either by acid hydrolysis, preferably with p-toluenesulfonic acid in acetone [Teutsch et al., German patent 2801416], to be broken down to aldehydes of the general formula II with R ² as a hydrogen atom, or by esterification to ethers of free hydroxyl groups with alkyl halides in the presence of potassium tert-butylate are first converted to 5α, 17β-diesters / Kasch et al., GDR patent 290893 /, which are then converted by acid hydrolysis, preferably with p-toluenesulfonic acid in acetone, to aldehydes of the general formula / II / c R ² the meaning of alkyl residues, preferably a methyl residue.

которые либо путем кислотного гидролиза при вышеуказанных условиях можно гидролизовать до альдегидов типа II с R² в значении атома водорода, либо путем образования простого 5α,17β-диэфира по вышеуказанному способу и последующего кислотного гидролиза можно гидролизовать до альдегидов типа II с R² в значении алкильного остатка, либо, однако, само по себе известной реакции с дезактированными катализаторами, как 10%-ный палладий-на-сульфате бария, в присутствии амина можно гидрировать до 17α- /3-гидроксипропенил/- 17β- гидрокси-соединений, которые путем кислотного гидролиза также переводят в альдегиды типа II.The introduction of residues - / CH ₂ / _o CH = CH / CH ₂ / _p R ^{6 is} carried out by reacting a ketone of the formula / IV / with simple propin-1-ol-tetrahydropyranyl ether and potassium tert-butylate to obtain 17α- / 3-hydroxy- 1-propinyl / -17β-hydroxy compounds of formula VII

which, either by acid hydrolysis under the above conditions, can be hydrolyzed to type II aldehydes with R ² in the value of a hydrogen atom, or by the formation of a simple 5α, 17β-diester according to the above method and subsequent acid hydrolysis, it can be hydrolyzed to type II aldehydes with R ² in the value of alkyl of the residue, or, however, of the per se known reaction with deactivated catalysts, such as 10% palladium barium sulfate, in the presence of an amine, it is possible to hydrogenate up to 17α- / 3-hydroxypropenyl / - 17β-hydroxy compounds, which acidic hydrolysis it is also converted to aldehydes of type II.

The introduction of residues - (CH ₂ ) _q C ≡ CR ^{7 is} carried out in a known manner by reacting a ketone of formula IV with acetylene, propine or higher homologues in the presence of alkali metals such as lithium, sodium or potassium, in combination with alcohol or ammonia, or, however, using butyllithium in ethers like tetrahydrofuran. Acid hydrolysis of these compounds leads to 17α-C ≡ CR ⁷ -substituted aldehydes of type II.

 If necessary, the compound of general formula I obtained according to the invention is converted to an acid addition salt, preferably a physiologically acceptable acid salt. Common physiologically acceptable inorganic and organic acids are, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, oxalic, maleic, fumaric, lactic, tartaric, malic, citric, salicylic, adipic and benzoic acids. Other acids used are described, for example, in Fortschritte der Arzneimittelforschund, v. 10, p. 224-225, Birkhauser Verlag, Basel und Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, p. 1-5 (1977).

 Addition addition salts are prepared, as a rule, in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example in a lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, or in a lower ketone as acetone, methyl ethyl ketone or methyl isobutyl ketone, or in ether, as diethyl ether, tetrahydrofuran or dioxane. For better crystal separation, mixtures of these solvents can also be used. Moreover, physiologically acceptable aqueous solutions of the acid addition salts of the compounds of formula I in an aqueous acidic solution can be prepared.

 The acid addition salts of the compounds of the general formula I can be converted into free bases in a manner known per se, for example using alkalis or ion exchangers. From free bases by reaction with inorganic or organic acids, in particular those which are suitable for the preparation of therapeutically applicable salts, other salts can be obtained. These and also other salts of the new compound, such as picrate, can also serve to purify free bases by converting the free base into a salt, separating it and releasing the base again from the salt.

 The subject of the present invention is also medicines for oral, rectal, subcutaneous, intravenous or intramuscular administration, which, along with the usual carriers or diluents, contain a compound of general formula I or an acid addition salt thereof as a biologically active substance.

 The medicaments of the invention are prepared in a manner known per se using conventional solid or liquid carriers or diluents and excipients commonly used in pharmaceutical technology, according to the desired application, with a suitable dosage. Preferred compositions are in a form of administration which is suitable for oral administration. Such uses are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions, or prolonged forms.

 It goes without saying that parenteral compositions such as injectable solutions are also taken into account. Further, as compositions should be mentioned, for example, also candles.

 Appropriate tablets can be obtained, for example, by mixing the biologically active substance with known auxiliary substances, for example, inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone; fillers such as corn starch or alginic acid; binders like starch or gelatin; lubricants such as magnesium stearate or talc and / or agents to achieve a prolonged effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of several layers.

 Accordingly, dragees can be obtained by coating nuclei (cores) prepared in the same way as tablets using means commonly used to coat dragees, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the dragee shell may consist of several layers, and the aforementioned excipients in the case of tablets may be used.

 Solutions or suspensions with the biologically active substance according to the invention may additionally contain taste-improving agents, such as saccharin, cyclamate or sugar, as well as, for example, flavoring agents, such as vanillin or orange extract. In addition, they may contain adjuvants for suspension, such as sodium carboxymethyl cellulose, or preservatives, such as p-hydroxybenzoate. Capsules containing biologically active substances can be prepared, for example, by the fact that the biologically active substance is mixed with an inert carrier, such as milk sugar or sorbitol, and encapsulated in gelatin capsules.

 Suitable candles can be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol, respectively, their derivatives.

 The 11β-substituted benzaldoxime-estra-4,9-dienes according to the invention are anti-gestagen active substances which, with the same activity as RU 486 (Mifepristone) with respect to the progesterone receptor (see table 1), respectively, with superior action in vivo (see Fig. 1 and table 2) have a distinctly lower antiglucocorticoid activity compared to RU 486, which is detected by reduced glucocorticoid receptor binding (see table 1), as well as by a ten-fold reduction in enzyme induction in cell lines (see Fig. 2 and 3).

 The antigestagens selected according to the invention [J 687] in the case of guinea pigs in the cycle also lead to statically significantly lower uterine weights at dosages in which RU 486, compared to the control, increases the uterine weight.

 This combination of properties allows us to expect from the inventive antigestagens excellent suppression of inhibition of progesterone, while reducing antiglucocorticoid activity. This advantage is particularly relevant for indications which, due to their duration of use, require particularly good acceptability. In a cycle, the weight of the uterus is decisively determined by circulating estrogens. Reduced uterine weights show a suppression of this estrogen function. Established, superior to RU 486 suppression of uterine weight in the guinea pig cycle is an indication / indirect / of the antiestrogenic properties of the compounds according to the invention. The corresponding effects should be expected to have a particularly beneficial effect on pathologically altered tissues in which estrogens contribute to growth impulses (foci of endometriosis, fibroids, genital carcinomas and breast carcinomas, benign prostatic hypertrophy).

 In FIG. 1 shows the effect of anti-gestagen treatment of cyclic guinea pigs on the weight of the uterus when comparing J 867 with RU 486.

 High doses of RU 486 [6 mg / 24 hours] reduce the uterus weight of the treated animals. Low dosages of this substance, in contrast, lead to a slight increase in uterine weight. All tested dosages of J 867 [1.3, respectively, 6 mg / 24 hours], in contrast, statistically significantly suppress the weight of the uterus.

 In FIG. 2 shows the antiglucocorticoid effect of J 867 in the human breast cell line ZR 75 / AGP-763 compared to RU 486.

 Dexamethasone in this cell line induces the chloramphenicolacetyltransferase (CAT) gene. This induction is suppressed by antiglucocorticoid substances. J 867 unexpectedly in a wide concentration range suppresses CAT less strongly than RU 486 (Mifepristone).

 In FIG. 3 shows the antiglucocorticoid effect of J 867 in the TAT model in the case of rat hepatoma cells compared to RU 486.

 In rat hepatoma cells, Dexamethasone stimulates the tyrosine amino transferase (TAT) enzyme. This action is suppressed by antiglucocorticoid activity. J 867, accordingly, acts distinctly antiglucocorticoid weaker than RU 486.

 Example 1

434 mg of 11β- / 4-formylphenyl / - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is dissolved in 8 ml of pyridine at room temperature and mixed with 65 mg of hydroxylamine hydrochloride and stirred at 25 ^o C. After 2 hours, the following 5 mg of hydroxylamine hydrochloride was added and the solution was diluted with water after 15 minutes, mixed with 1N. aqueous hydrochloric acid and extracted with chloroform, the organic phase is washed with dilute HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated off under reduced pressure. 420 mg of crude product are obtained. After the addition of acetone, crystals are separated which are suctioned off and recrystallized from a mixture of isopropanol with CH ₂ Cl ₂ .

 305 mg of 11β- [4- (hydroxyminomethyl / phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is obtained.

Mp: 118 ^° C upon decomposition.

(α) _D = +197 ^o / CHCl ₃ /.

IR spectrum in CHCl ₃ / cm ^-1 /: 3575, 3300 / OH /, 1705 / C = NOH /; 1649 / C = CC = CC = O /; 1599 / phenyl /.

/; 3,393 /с, 3H,

/; 3,441-3,598 /м., 2H, ABX - система

/; 4,381 /д. , 1H, J = 6,9 Гц, H-11α/; 5,788 /с., 1H, H-4/; 7,187 - 7,487 /м. , 4H, AA'BB'-система ароматических протонов/; 8,05 /с., 1H, OH/; 8,097 /с., 1H,

/.UV spectrum in methanol:
λ _max = 264 nm, ε = 20366,
λ _max = 299 nm, ε = 20228,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.533 / s, 1H, H-18 /; 3.252 / s, 3H

/; 3.393 / s, 3H,

/; 3,441-3,598 / m., 2H, ABX - system

/; 4.381 / d. , 1H, J = 6.9 Hz, H-11α /; 5.788 / s, 1H, H-4 /; 7.187 - 7.487 / m. , 4H, AA'BB'-system of aromatic protons /; 8.05 / s, 1H, OH /; 8.097 / s, 1H,

/.

Mass spectrum m / e: 449.25509; C ₂₉ H ₃₅ NO ₄ M ⁺ .

 Obtaining the starting compound.

 Stage A.

 50 g of 4-Bromobenzaldehyde and 30 ml of o-formic acid triethyl ester in 60 ml of methanol, together with 0.8 ml of thionyl chloride, are stirred for 5 hours at room temperature. Then 0.2 ml of thionyl chloride was added again and after 30 minutes it was poured into an aqueous bicarbonate solution and extracted with chloroform, washed with an aqueous bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure to obtain 68 g of 4-bromobenzaldehyde dimethyl ketal as a colorless oil.

To 2.3 g of magnesium in 20 ml of anhydrous THF in an argon atmosphere, 0.2 ml of dibromomethane is added as a protective gas, and after the start of the reaction, 21.96 g of 4-bromobenzaldehyde dimethyl ketal is added dropwise in 70 ml of anhydrous THF so that the temperature does not exceed 40 ^o C. Upon completion of the addition, the mixture is further stirred for 2 hours at 30 ^° C., then cooled to -10 ^° C. and mixed with 511 mg of CuCl. Stirring was continued for 15 minutes at -30 ^° C and then a solution of 6 g of 3,3-dimethoxy-5α, 10α-epoxy-estr-9/11 / en-17-one in 30 ml of anhydrous THF was added dropwise. It is allowed to warm to room temperature and the Grignard solution is decomposed with an aqueous solution of ammonium chloride. The product was isolated by extraction with ethyl acetate, the organic phase was washed until neutral and dried over sodium sulfate. After distilling off the solvent under reduced pressure, 19.7 g of a crude product are isolated.

 Chromatography on 300 g of silica gel and 20 g of alumina using a toluene / ethyl acetate gradient gives 7.38 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] -5α-hydroxy-estr-9-en-17 It is in the form of a yellow foam.

 Stage B.

7.38 g of 3,3-Dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 5α-hydroxy-estr-9-en-17-one is dissolved in 85 ml of dimethyl sulfoxide and mixed with 10 as a protective gas in the atmosphere of argon , 38 g of trimethyl sulfonium iodide and in portions with 7.64 potassium tert-butylate. After 1.5 hours, it was cooled to 0-5 ^° C. and mixed with an aqueous solution of ammonium chloride. The evolving adhesive product is extracted with methylene chloride, washed until neutral, dried over sodium sulfate and, after evaporation of the solvent, is isolated in the form of a brown gum. Yield: 8.63 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] - 17β-spiro-1 ', 2'-oxiran-est-9-en-5α-ol.

 Stage B.

 8.63 g of 3,3-Dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 17β-spiro-1 ', 2'-oxiran-estr-9-en-5α-ol is dissolved in 20 ml of methanol and mixed with 20 ml 3n. sodium methoxide solution and refluxed for 2-3 hours. The solvent was evaporated under reduced pressure, the residue was taken up in methylene chloride, washed until neutral, the solution was dried over sodium sulfate and evaporated under reduced pressure.

 8.74 g of crude product are obtained in the form of a brown foam. Chromatography on 260 g of silica gel and 90 g of alumina using a toluene / ethyl acetate gradient gives 1.92 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 17α-methoxymethyl-est-9- en-5α, 17β-diol.

 Stage G.

To 1.92 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] -17α-methoxymethyl-est-9-en-5α, 17β-diol in 120 ml of toluene in an inert gas atmosphere is added 8, 65 g of potassium tert-butylate. The suspension is stirred for 5 minutes at room temperature and 6.35 ml of methyl iodide in 6 ml of toluene are added dropwise so that the temperature does not rise above 40 ^° C. After 1 hour, 20 ml of water and 20 ml of ethyl acetate are added, the phases are separated and the aqueous phase is further extracted with ethyl acetate. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

 1.55 g of simple 3,3-dimethoxy-11β- [4- / 3,3-dimethoxymethyl / phenyl] - 17α-methoxymethyl-estr-9-en-5α, 17β-dimethyl ether are obtained in the form of a yellow foam.

 Stage D.

 1.55 g of simple 3,3-dimethoxy-11β- [4- / 3,3-dimethoxymethyl / phenyl] - 17α-methoxymethyl-estr-9-en-5α, 17β-dimethyl ether is dissolved in 12.6 ml of acetone and mixed with 1.3 ml of water. 158 mg of 4-toluenesulfonic acid are added under a protective gas atmosphere. It is stirred for 40 minutes at room temperature and the slurry of the crystals is sucked off, washed with acetone and crystallized from a mixture of methylene chloride with acetone.

 Yield = 0.55 g of colorless crystals.

 A new recrystallization from a mixture of methylene chloride with acetone gives 440 mg of 11β- [4-formylphenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

Mp = 233-240 ^o C.

(α) _D = +189 ^o / CHCl ³ /.

IR spectrum in CHCl ₃ / cm ^-1 /: 1710 / CHO /; 1660 / C = CC = C = O /; 1610 / phenyl /.

/; 3,38 /с. , 3H,

/; 4,40 /д., 1H, J = 7,2 Гц, H-11α/; 5,78 /с. , 1H, Н-4/; 7,28-7,93 /м., 4H, AA'BB-система ароматических протонов/; 9,95 /с., 1H,

/.UV spectrum in methanol:
λ _max = 262 nm, ε = 10775,
λ _max = 299 nm, ε = 13999.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.48 / s, 3H, H-18 /; 3.25 / s, 3H,

/; 3.38 / s , 3H,

/; 4.40 / d, 1H, J = 7.2 Hz, H-11α /; 5.78 / s , 1H, H-4 /; 7.28-7.93 / m, 4H, AA'BB-system of aromatic protons /; 9.95 / s, 1H,

/.

Mass spectrum m / e: 434.24771; C ₂₈ H ₃₄ O ₄ M ⁺ .

 Example 2

217 mg of 11β- / 4-Formylphenyl / - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in 4 ml of pyridine together with 40 mg of methoxyamine hydrochloride is stirred at room temperature. After an hour, a further 5.2 g of methoxyamine dihydrochloride was added. 10 ml of water and ethyl acetate are added, the phases are separated, the aqueous phase
additionally extracted, the organic phase is washed with 10 ml of diluted HCl and washed with distilled water until neutral, dried and evaporated under reduced pressure. 241 mg of crude product are obtained in the form of a gum. Preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} when eluting with a mixture of toluene with acetone / 4: 1 / gives 188 mg of the product as a foam.

 Recrystallization from a mixture of acetone with hexane gives 11β- [4- (methoxyminomethyl / phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in the form of colorless leaves.

Mp = 83-89 ^o C.

(α) _D = +197 ^o (chloroform).

IR spectrum in CHCl ₃ / cm ^-1 /: 1700 / C = NOCH ₃ /; 1649 / C = CC = CC = O /; 1590 (aromatic).

/; 3,408 /с. , 3H,

/; 3,39-3,598 /м., 2H, ABХ-система,

/; 4,381 /д. , 1H, J = 7,5 Гц, H-11α/; 5,773 /с., 1H, H-4/; 7,173, 7,201, 7,463, 7,491 /м., 4H, AA'BB'-система ароматических протонов/; 8,023 /с., 1H,

фенил/.UV spectrum in methanol:
λ _max = 275 nm, ε = 23098,
λ _max = 300 nm, ε = 22872,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.529 / s, 3H, H-18 /; 3.247 / s, 3H,

/; 3.408 / s , 3H,

/; 3.39-3.598 / m., 2H, ABX system,

/; 4.381 / d. , 1H, J = 7.5 Hz, H-11α /; 5.773 / s, 1H, H-4 /; 7.173, 7.201, 7.463, 7.491 (m, 4H, AA'BB'-system of aromatic protons); 8.023 / s, 1H,

phenyl/.

Mass spectrum m / e: 463.26950; C ₂₉ H ₃₇ NO ₄ M ⁺ .

 Example 3

180 mg of 11β- [4- / Hydroximinomethyl / phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is acetylated for 12 hours in 5 ml of a mixture of acetic anhydride and pyridine / 1: 1 /. After the addition of water, it was extracted three times with ethyl acetate, the organic phase was washed with dilute HCl and water, dried over sodium sulfate and evaporated under reduced pressure. Get 172 mg of crude product, which is purified by preparative thin layer chromatography on silica gel PF _{254 + 366} by elution with a mixture of toluene with acetone / 4: 1 /.

 Yield: 115 mg 11β- [4- (acetyloxyiminomethyl / phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-4-one. The purified product is crystallized from ethyl acetate.

Mp = 115-120 ^o C / ethyl acetate /.

(α) _D = +218 ^o / CHCl ₃ /.

/; 3,247 /с. , 3H,

/; 3,408 /с., 3H,

/; 3,386, 3,431, 3,544, 3,580 /м., 2H,

/; 4,399 /д., 1H, J = 7,2 Гц, H-11α/; 5,785 /с. , 1H, H-4/; 7,242, 7,266, 7,618, 7,647 /м., 4H, AA'BB'-система ароматических протонов/; 8,315 /с., 1H,

/.UV spectrum in methanol:
λ _max = 271 nm, ε = 28157,
λ _max = 297 nm, ε = 26369,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.511 / s, 3H, H-18 /; 2.227 / s, 3H,

/; 3.247 / s , 3H,

/; 3.408 / s, 3H,

/; 3.386, 3.431, 3.544, 3.580 / m, 2H,

/; 4.399 / d, 1H, J = 7.2 Hz, H-11α /; 5.785 / s , 1H, H-4 /; 7.242, 7.266, 7.618, 7.647 (m, 4H, AA'BB'-system of aromatic protons); 8.315 / s, 1H,

/.

Mass spectrum m / e: 491.26971; C ₃₀ H ₃₇ NO ₅ M ⁺ .

 Example 4

0.3 mg of ethyl chloroformate are added dropwise to 210 mg of 11β- [4- (hydroxymininomethyl-phenyl] - 17β-methoxy-17α-methoxymethylestra-4,9-dien-3-one in 5 ml of pyridine under cooling with water. A white precipitate forms. After 30 minutes, they are mixed with water, a solution is formed, then a white precipitate precipitates, which is filtered off with suction and washed with water. The yield after drying is 133 mg. The aqueous phase is extracted with chloroform, washed with dilute HCl and water, dried and concentrated under reduced pressure. Yield = 66 mg. Both solid phases are combined and by preparative chromatography on silica gel 60 PF _{254 + 366 is} purified by elution with a mixture of toluene with acetone / 4: 1 /.

 150 mg of 11β- {4 - [(ethoxycarbonyl / oxyiminomethyl] - phenyl} - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is obtained, which is recrystallized from a mixture of acetone and hexane.

Mp = 137 - 148 ^o C / decomposition /.

(α) _D = + 204 ^o / CHCl ₃ /.

/; 3,246 /с., 3H,

/; 3,410 /с., 3H,

/; 3,39 - 3,56 /м., 2H,

/; 4,35 /д., 1H, J = 7,0 Гц, H-11α/; 5,784 /с., 1H, H-4/; 7,23, 7,26, 7,61, 7,64 /м., 4H, AA'BB'-система ароматических протонов/; 8,303 /с., 1H,

/.UV spectrum in methanol:
λ _max = 270 nm, ε = 27094,
λ _max = 297 nm, ε = 25604,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.507 / s, 3H, H-18 /; 1.383 / t, 3H, J = 7.0 Hz,

/; 3.246 / s, 3H,

/; 3.410 / s., 3H,

/; 3.39 - 3.56 / m, 2H,

/; 4.35 / d, 1H, J = 7.0 Hz, H-11α /; 5.784 / s, 1H, H-4 /; 7.23, 7.26, 7.61, 7.64 (m, 4H, AA'BB'-system of aromatic protons); 8.303 / s, 1H,

/.

Mass spectrum m / e: 431.24701; C ₂₈ H ₃₃ NO ₃ M ⁺ - C ₂ H ₅ OCOOH.

 Example 5

 244 mg of 11β- / 4-Formylphenyl / - 17β-hydroxy-17α-chloromethyl-estra-4,9-dien-3-one in 4 ml of pyridine together with 32.2 mg of hydroxylamine hydrochloride are stirred at room temperature. After an hour, the following 6.9 mg of hydroxylamine hydrochloride was added. Then, 10 ml of water and ethyl acetate are added, the phases are separated, the aqueous phase is further extracted, the organic phase is washed with 10 ml of diluted HCl and distilled water until neutral, dried and evaporated under reduced pressure.

183 g of crude product are obtained in the form of a yellow gum. Preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} when using a mixture of solvents of toluene with acetone / 4: 1 / gives 87.7 mg of 17α-chloromethyl-11β- [4- / hydroxyminomethyl / -phenyl] - 17β- hydroxy-estra-4 , 9-dien-3-one in the form of a foam.

(α) _D = + 185 ^° / CHCl ₃ /.

/; 4,428 /д., 1H, J = 6,9 Гц, H-11α/; 5,807 /с. , 1H, H-4/; 7,185, 7,212, 7,482, 7,509 /м., 4H, AA'BB'-система ароматических протонов/; 8,05 /с., 1H, OH/; 8,104 /с., 1H,

фенил/.UV spectrum in methanol:
λ _max = 264 nm, ε = 20797,
λ _max = 299 nm, ε = 20439,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.607 / s, 3H, H-18 /; 3.628, 3.664, 3.824, 3.861 / m. , 2H, ABX system

/; 4.428 / d, 1H, J = 6.9 Hz, H-11α /; 5,807 / s , 1H, H-4 /; 7.185, 7.212, 7.482, 7.509 / m, 4H, AA'BB'-system of aromatic protons /; 8.05 / s, 1H, OH /; 8.104 / s, 1H,

phenyl/.

Mass spectrum m / e: 439.19070; C ₂₆ H ₃₀ ClNO ₃ M ⁺ .

 Obtaining the starting compound.

To 4.12 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 17β-spiro-1 ', 2'-oxiran-est-9-en-5α-ol / was obtained according to example 1, stage B / 84 ml of dimethylformamide at 0 ^° C. are added dropwise 16.6 ml of concentrated HCl. After an hour, they are mixed in 420 ml of water, and a flocculent precipitate forms. Using an aqueous solution of bicarbonate, pH 6 is adjusted, the precipitate is suctioned off and dried.

 Crude yield: 3.38 g of ocher-colored crystals, which are purified by column chromatography on 90 g of silica gel 60 using a toluene / ethyl acetate gradient. Yield: 1.16 g of 17α-chloromethyl-11β- [4-formylphenyl / - 17β-hydroxy-estra-4,9-dien-3-one in the form of crystals.

T. pl. = 205 - 208 ^o C / acetone with hexane /.

(α) _D = +161 ^o / CHCl ₃ /.

IR spectrum in CHCl ₃ / cm ^-1 /; 3600 / OH /; 1695 / CHO /; 1650 / C = CC = CC = C /; 1590 / phenyl /.

/.UV spectrum in methanol:
λ _max = 262 nm, ε = 19993,
λ _max = 297 nm, ε = 22755.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.583 / s, 3H, H-18 /; 3.30 / s, 1H, OH /; 3.63 - 3.85 / m, 2H, ABX system CH ₂ Cl /; 4.45 / d, 1H, J = 7.0 Hz, H-11α /; 5.809 / s, 1H, H-4 /; 7.355, 7.282, 7.799, 7.826 (m, 4H, AA'BB'-system of aromatic protons); 9.977 / s, 1H,

/.

Mass spectrum m / e: 424.18280; C ₂₈ H ₂₉ ClO ₃ M ⁺ .

 Example 6

136 mg of 11β- / 4-Formylphenyl / - 17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one at room temperature is dissolved in 2.2 ml of pyridine and mixed with 18 mg of hydroxylamine hydrochloride and stirred at 25 ^o C. After 1.5 hours, the next 4 mg of hydroxylamine hydrochloride was added and the solution was diluted with water after 15 minutes, mixed with 1N. aqueous HCl and extracted with chloroform, the organic phase is washed with dilute HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated off under reduced pressure.

Obtain 146 mg of crude product, which is purified by preparative thin layer chromatography on silica gel 60 PF _{254 + 366} using a mixture of solvents toluene-acetone / 4: 1 /.

 110 mg of 11β- [4- (hydroxyminomethyl) phenyl] - 17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one is obtained.

Mp = 104 ^o upon decomposition / isopropanol /.

(α) _D = + 195 ^o / CHCl ₃ /.

/; 3,206, 3,237, 3,552, 3,582 /м., 2H, ABX-система

/; 4,384 /д. , 1H, J = 7,2 Гц, H- 11α /; 5,784 /с., 1H, H-4/; 7,179, 7,206, 7,456, 7,483 /м., 4H, AA'BB'-система
ароматических протонов/; 7,9 /с., 1H, OH/; 8,088 /с., 1H,

/.UV spectrum in methanol:
λ _max = 263 nm, ε = 21170,
λ _max = 299 nm, ε = 20188.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.517 / s, 1H, H-18 /; 3.418 / s, 3H,

/; 3.206, 3.237, 3.552, 3.582 / m., 2H, ABX system

/; 4.384 / d. , 1H, J = 7.2 Hz, H-11α /; 5.784 / s, 1H, H-4 /; 7.179, 7.206, 7.456, 7.483 / m., 4H, AA'BB'-system
aromatic protons /; 7.9 / s, 1H, OH /; 8.088 / s, 1H,

/.

Mass spectrum m / e: 435.24289; C ₂₇ H ₃₃ NO ₄ M ⁺ .

 Obtaining the starting compound.

 Stage J.

 860 mg of 3,3-dimethoxy-11β- [4- (dimethoxymethyl / phenyl] - 17α-methoxymethyl-estra-9-en-5α, 17β-diol / was prepared according to Example 1, step B / was dissolved in 80 ml of acetone. After adding 7.7 ml of water and 430 ml of 4-toluenesulfonic acid, it was refluxed for another 1.5 hours and concentrated under reduced pressure, the residue was treated with chloroform, pH 8 was adjusted with 8 ml of diluted ammonia, and the phases were separated. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

 590 mg of 11β- [4-formylphenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one is obtained in the form of a crude product, which is recrystallized from ethyl acetate.

Mp = 195 - 205 ^o C (ethyl acetate).

(α) _D = + 209 ^o / chloroform /.

IR spectrum in CHCl ₃ / cm ^-1 /: 3590 / OH /; 1710 / CHO /; 1660 / C = CC = CC = O /; 1605 / aromatic /.

/; 3,417 /с., 3H,

/; 4,446 /д., 1H, J = 6,9 Гц, H- 11α/; 5,797 /с., 1H, H-4/; 7,360 7,386, 7,786, 7,813 /м., 4H, AA'BB'-система ароматических протонов/; 9,970 /с., 1H,

/.UV spectrum in methanol:
λ _max = 263 nm, ε = 20683,
λ _max = 298 nm, ε = 20749,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.509 / s, 3H, H-18 /; 2.666 (s, 1H, OH); 3.196, 3.226, 3.550, 3.580 / m., 2H, ABX system

/; 3.417 / s, 3H,

/; 4.446 / d, 1H, J = 6.9 Hz, H-11α /; 5.797 / s, 1H, H-4 /; 7.360, 7.386, 7.786, 7.813 (m, 4H, AA'BB'-system of aromatic protons); 9.970 / s, 1H,

/.

Mass spectrum m / e: 420.23300; C ₂₇ H ₃₂ O ₄ M ⁺ .

 Example 7

480 mg of 17α-ethoxymethyl-11β- / 4-formylphenyl / -17β-methoxy-estra-4,9-dien-3-one is dissolved in 6 ml of pyridine at room temperature, mixed with 74 mg of hydroxylamine hydrochloride and stirred at 25 ^o C. After 30 minutes, the following 8.5 mg of hydroxylamine hydrochloride was added and the solution was diluted with water after 15 minutes, mixed with 1N. aqueous HCl and extracted with methylene chloride, the organic phase is washed with dilute HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated off under reduced pressure.

410 mg of crude product is obtained, which by preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} gives 230 mg of 17α-ethoxymethyl-11β- [4- / hydroxyminomethyl / phenyl] - 17β-methoxy-estra-4,9-diene-3 It is in the form of a yellow foam.

(α) _D = + 200 ^o / CHCl ₃ /.

/; 3,252, /с., 3H, 17β-OCH₃/; 3,423 - 3,623 /м., 2H, ABX-система,

/; 4,355 /д., 1H, J = 7,2 Гц, H-11α/; 5,783 /с., 1H, H-4/; 7,191, 7,219, 7,460, 7,488 /м., 4H, AA'BB'-система ароматических протонов/; 8,097 /с., 1H,

/.UV spectrum in methanol:
λ _max = 264 nm, ε = 20366,
λ _max = 299 nm, ε = 20228.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.533 / s, 1H, H-18 /; 1.267 / t, 3H, J = 6.9 Hz,

/; 3.252, (s., 3H, 17β-OCH ₃ ); 3.423 - 3.623 / m., 2H, ABX system,

/; 4.355 / d, 1H, J = 7.2 Hz, H-11α /; 5.783 / s, 1H, H-4 /; 7.191, 7.219, 7.460, 7.488 (m, 4H, AA'BB'-system of aromatic protons); 8.097 / s, 1H,

/.

Mass spectrum m / e: 463.27069; C ₂₉ H ₃₇ NO ₄ M ⁺ .

 Obtaining the starting compound.

 Stage Z.

 5.33 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 17β-spiro-1 ', 2'-oxiran-estr-9-en-5α-ol / obtained according to example 1, stage B / dissolved in 5 ml of ethanol, mixed in 25 ml of 1.5N. sodium methylate solution and refluxed for 1 hour. The solvent was evaporated under reduced pressure, the residue was taken up in methylene chloride, washed until neutral, the solution was dried over sodium sulfate and evaporated under reduced pressure.

 5.85 g of crude product are obtained in the form of a brown foam. Chromatography on silica gel using a toluene / ethyl acetate gradient gave 1.14 g of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] -17α-ethoxymethyl-estr-9-en-5α, 17β-diol.

 Stage I.

 To 1.14 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl / phenyl] - 17α-ethoxymethyl-estr-9-en-5α, 17β-diol in 70 ml of toluene under argon atmosphere, is added as a protective gas 5.14 g of potassium tert-butylate. After 15 minutes, a mixture of 3.8 ml of methyl iodide in 4 ml of toluene was added dropwise. After 2 hours, the reaction was stopped by adding 20 ml of water and 20 ml of ethyl acetate. The organic phase is washed twice with water, dried over sodium sulfate and evaporated under reduced pressure.

 Crude yield: 1.14 g of 3,3-dimethoxy-11β- [4- / 3,3-dimethoxymethyl / phenyl] -17α-ethoxymethyl-17β-methoxy-estr-9-en-5α-ol.

 Stage K.

 To 1.14 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl / phenyl] - 17α-ethoxymethyl-17β-methoxy-estr-9-en-5α-ol in 10 ml of acetone in an inert gas atmosphere, 1 ml of water and 116 mg of 4-toluenesulfonic acid. After 30 minutes, diluted with water, extracted twice with ethyl acetate, the organic solution was washed and dried over sodium sulfate. After evaporation of the solvent, 900 mg of 17α-ethoxymethyl-11β- / 4-formylphenyl / - 17β-methoxy-estra-4,9-dien-3-one remained in the form of a yellow foam. Chromatography on silica gel 60 using a toluene / ethyl acetate gradient gave 480 mg of yellow crystals.

 Example 8

244 mg of 11β- / 4-Formylphenyl / - 17β-hydroxy-17α- / 3-hydroxyprop-1-in-yl / -estra-4,9-dien-3-one is dissolved in room temperature 4.5 ml of pyridine and mixed with 35.5 mg of hydroxylamine hydrochloride and stirred at 25 ^° C. After 30 minutes, the next 4.8 mg of hydroxyl amine hydrochloride was added and after 15 minutes the solution was diluted with water, treated with ethyl acetate, shaken with 1N. aqueous hydrochloric acid, the organic phase is washed with water, dried over sodium sulfate and potassium carbonate, and the solvent is evaporated off under reduced pressure.

216 g of crude product are obtained which, after preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} using a solvent mixture of toluene / acetone [4: 1], gives 192 mg of 11β- [4- / hydroxyminomethyl / phenyl] - 17β- hydroxy-17α- / 3-hydroxyprop-1-in-yl / -extra-4,9-dien-3-one as a colorless foam.

Mp = 171-179 ^o C / ether /.

(α) _D = + 82 ^° / dioxane /.

UV spectrum in methanol:
λ _max = 264 nm, ε = 21495,
λ _max = 299 nm, ε = 20236.
Mass spectrum m / e: 445.22369; C ₂₈ H ₃₁ NO ₄ M ⁺ .

 Obtaining the starting compound.

 Stage L.

12 ml of 15% n-butyllithium in hexane are added dropwise to 3 ml of prop-1-yn-yl-3-hydroxytetrahydropyranyl ether in 27 ml of anhydrous THF at -5 ^° C. After 15 minutes, 1.2 g of 3,3-dimethyl-11β- [4- / dimethoxymethyl / phenyl] -5α-hydroxyestr-9-en-17-one was added dropwise to this solution, prepared according to Example 1, step B / in 16 ml of anhydrous THF. It is stirred for 30 minutes at room temperature, the reaction solution is poured into 150 ml of ice water and extracted with ethyl acetate. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

 4.23 g of a brown oil are obtained, which is purified by chromatography on silica gel 60 using a toluene / ethyl acetate gradient. 422 mg of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl] - 17α- / 3-tetrahydropyranyloxyprop-1-yn-yl / -estr-9-en-5α, 17β-diol is obtained in the form of a foam.

 Stage M.

 540 mg 3,3-Dimethoxy-11β- [4- (dimethoxymethyl / phenyl] - 17α- / 3-tetrahydropyranyl-prop-1-in-yl / -estr-9-en-5α, 17β-diol in 40 ml acetone together with 100 mg of 4-toluenesulfonic acid is stirred for 2 hours at room temperature. It is then concentrated to a volume of 10 ml, mixed with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

Crude yield: 330 mg. Purification by preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} gives 310 mg of 11β- / 4-formylphenyl / - 17β-hydroxy-17α- / 3-hydroxyprop-1-in-yl / -estra-4,9-diene-3 -it. Recrystallization from acetone gives white crystals.

Mp = 225-231 ^o C.

(α) _D = +59 ^o / chloroform /.

/; 4,497 /д., 1H, J = 7,2 Гц, H- 11α ; 5,810 /с,. 1H, H-4/; 7,353, 7,380, 7,797, 7,824 /м., 4H, AA'BB'-система ароматических протонов/; 9,974 /c., 1H,

/.UV spectrum in methanol:
λ _max = 302 nm, ε = 23608,
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.496 / s.,
3H, H-18 /; 4.375 / s, 2H,

/; 4.497 / d, 1H, J = 7.2 Hz, H-11α; 5.810 / s 1H, H-4 /; 7.353, 7.380, 7.797, 7.824 (m, 4H, AA'BB'-system of aromatic protons); 9.974 / s., 1H,

/.

Mass spectrum m / e: 430.21460; C ₂₈ H ₃₀ O ₄ M ⁺ .

 Example 9

190 mg of 11β- [4- [Hydroximinomethyl] phenyl] - 17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is suspended in 10 ml of toluene. 0.5 ml of phenylisocyanate and 1 ml of triethylamine are successively added. It is stirred for 3 hours at room temperature, refluxed for 2 hours, a white precipitate is suctioned off and the solvent is concentrated under reduced pressure. 310 mg of a light brown solid are obtained, which is purified by preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} using a toluene / acetone solvent mixture [9: 1]. 65 mg of 17β-methoxy-17α-methoxymethyl-11β- [4- {/ phenylaminocarbonyl / oxyminomethyl} phenyl] estra-4,9-dien-3-one are isolated.

Mp 241 - 246 ^o C / acetone /.

(α) _D = + 178 ^o / CHCl ₃ /.

/; 3,405 /с, . 3H,

/; 3,406-3,545 /м., 2H, ABX-система

/; 4,13 /д., J = 6,8 Гц, 1H, H-11α/; 5,797 /с., 1H, H-4/; 7,264 /м., 5H, ароматические/; 7,272, 7,293, 7,548, 7,575 /м., 4H, AA'BB'- система ароматических протонов/; 8,0 /с., 1H,

/.UV spectrum in methanol:
λ _max = 238 nm, ε = 29444,
λ _max = 300 nm, ε = 29649.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.474 / s, 3H, H-18 /; 3.245 / s, 3H,

/; 3.405 / s,. 3H,

/; 3.406-3.545 / m., 2H, ABX system

/; 4.13 / d, J = 6.8 Hz, 1H, H-11α /; 5.797 / s, 1H, H-4 /; 7.264 (m, 5H, aromatic); 7.272, 7.293, 7.548, 7.575 / m, 4H, AA'BB'-system of aromatic protons /; 8.0 / s, 1H,

/.

Mass spectrum m / e: 431.24249; C ₂₈ H ₃₃ NO ₃ M ⁺ - C ₆ H ₅ CNO + H ₂ O.

 Example 10

125 mg of 17α-Ethoxymethyl-11β- / 4-formylphenyl / -17β-hydroxy-estra-4,9-dien-3-one is dissolved in 2 ml of pyridine at room temperature, mixed with 20.2 mg of hydroxylamine hydrochloride and stirred at 25 ^o C. After 50 minutes, the solution was diluted with water, mixed with ethyl acetate and the phases were separated. The organic phase was washed with dilute HCl and water, dried over sodium sulfate and the solvent was evaporated under reduced pressure.

127 mg of the crude product are obtained in the form of a light yellow foam which, after preparative thin-layer chromatography on silica gel 60 PF _{254 + 366,} gives 62 mg of 17α-ethoxymethyl-11β- [4- / hydroxyminomethyl / phenyl] - 17β-hydroxy-estra-4 , 9-dien-3-one in the form of a colorless foam.

(α) _D = + 226 ^o / CHCl ₃ /.

/; 3,228-3,609 /м., 4H, 2хCH₂/; 4,381 /д., 1H, J = 7,2 Гц, H-11α/; 5,781 /с., 1H, H-4/; 7,181, 7,209, 7,459, 7,486 /м., 4H, AA'BB'-система ароматических протонов/; 8,098 /с., 1H,

/.UV spectrum in methanol:
λ _max = 265 nm, ε = 22696,
λ _max = 299 nm, ε = 21960.
¹ H-NMR spectrum in CDCl ₃ / δ, ppm /: 0.520 / s, 1H, H-18 /; 1.249 / t, 3H, J = 7.2 Hz,

/; 3.228-3.609 / m, 4H, 2xCH ₂ /; 4.381 / d, 1H, J = 7.2 Hz, H-11α /; 5.781 / s, 1H, H-4 /; 7.181, 7.209, 7.459, 7.486 / m, 4H, AA'BB'-system of aromatic protons /; 8.098 / s, 1H,

/.

Mass spectrum m / e: 449.25540; C ₂₈ H ₃₅ NO ₄ M ⁺ .

 Obtaining the starting compound.

 Stage N.

 3240 mg of 3,3-dimethoxy-11β- [4- / dimethoxymethyl / phenyl] - 17α-ethoxymethyl-estr-9-en-5α, 17β-diol [obtained according to example 7, stage 3] is dissolved in 2.5 ml acetone, mixed with 0.25 ml of water and 35 mg of 4-toluene sulfonic acid. After 1 hour, dilute with 10 ml of water and add 10 ml of ethyl acetate. The phases are separated, the aqueous phase is extracted twice more, the organic solution is washed and dried over sodium sulfate. After evaporation of the solvent, 300 mg of yellowish crystals remain.

By preparative thin-layer chromatography on silica gel 60 PF _{254 + 366} , eluting with a mixture of toluene and acetone / 9: 1 /, 200 mg of 17α-ethoxymethyl-11β- / 4-formylphenyl / - 17β-hydroxy-estra-4,9- dien-3-one in the form of yellowish crystals.

Mp = 144 - 150 ^o C / acetone with hexane /.

(α) _D = + 171 ^o / CHCl ₃ /.

/; 3,321 - 3,613 /м., 4H, 2 х CH₂/; 4,447 /д., 1H, J = 6,9 Гц, H-11α/; 5,799 /с., 1H, H-4/; 7,361, 7,388, 7,788, 7,816 /м., 4H, AA'BB'-система ароматических протонов/; 9,972 /с., 1H,

/.UV spectrum in methanol:
λ _max = 263 nm, ε = 17842,
λ _max = 299 nm, ε = 20083.
¹ H-NMR spectrum of CDCl ₃ / δ, ppm /: 0.512 / s, 1H, H-18 /; 1.249 / t., 3H, ΣJ = 4.6 Hz,

/; 3.321-3.613 / m, 4H, 2 x CH ₂ /; 4.447 / d, 1H, J = 6.9 Hz, H-11α /; 5.799 / s, 1H, H-4 /; 7.361, 7.388, 7.788, 7.816 (m, 4H, AA'BB'-system of aromatic protons); 9.972 / s, 1H,

/.

 Example 11. Measurement of the binding affinity of the receptor.

The binding affinity of the receptor is determined by competitive binding of the specifically binding ³ H-labeled hormone / labeled substance / and the test compound to receptors in the cytosol from animal target organs. At the same time, they strive for saturation of the receptor and reaction equilibrium. The following incubation conditions are selected: Progesterone receptor: cytosol from the uterus of a rabbit primed [geprimten] estradiol, stored at -30 ^° C, in a TED buffer [20 mol TRIS / HCl, pH 7.4; 1 mmol of ethylenediaminetetraacetate; 2 mM dithiothreitol with 250 mM sucrose. Labeled substance: ³ H-ORG 2058.6 nM; standard substance: progesterone.

Glucocorticoid receptor: rat thymus cytosol with adrenal gland removed; the thymus is stored at -30 ^o C; buffer: TED. Labeled substance: ³ H-Dexamethasone, 20 nM; standard substance: Dexamethiazone. Estrogen receptor: cytosol from the uterus of an immature rabbit, stored at -30 ^o C, in a TED buffer with 250 mm sucrose. Labeled substance: ³ H-ethinyl estradiol, 3 nM; standard substance: 17β-estradiol.

After an incubation time of 18 hours at 0-4 ^° C., the bound and free steroid are separated by using activated carbon with dextran [1% / 0.1%], centrifuging and measuring the bound ³ H activity in the supernatant.

From measurements in a series of concentrations, 1C ₅₀ is determined for the test compound and for the standard substance and as a quotient of both values (x100%), the relative molar binding affinity for binding is obtained.

 Example 12. The suppression of early pregnancy in rats.

 Female rats mate in Prooestrus. If sperm is found in a vaginal smear on the next day, this day is considered as day 1 / = d.1 / pregnancy. Treatment with a test substance or an indifferent drug base is carried out on days 5 to 7, autopsy is performed on day 9. The substances are injected subcutaneously in 0.2 ml of excipient [benzyl benzoate / castor oil = 1 + 4]. The number of fully suppressed pregnancies in different groups is shown in Table 1. For J 867, suppression of nidation superior to factor 3 RU 486 was established.

 Example 13. Anti-gestagen treatment (treatment) of female guinea pigs.

 Treatment of adult female guinea pigs on days 10-18 of the cycle (autopsy). The introduction of these doses through subcutaneous osmotic superchargers / ALZET type 2 MLI /; indifferent drug base: 2.0 ml propylene glycol / 24 hours.

 Example 14. Antiglucocorticoid effect of J867 in the human breast cancer cell line ZR 75 / AGP-763.

Experiments with cell cultures were performed in R PM1 1640 mixed with 10% fetal calf serum (FKS) in an incubator with 95% air and 5% CO ₂ at 37 ^° C. For experiments, cells were seeded in 60 mm diameter Petri dishes. The medium of confluent cells is replaced with medium with 5% FKS [treated with dextran-coated charcoal / DCC /]. For CAT induction, Dexamethasone is added at a concentration of 10 ^-7 M in ethanol / 0.2%; by volume. Harvesting of stimulated cells is carried out after 16 hours by preparing an extract from the cells using a cell lysis buffer. CAT determination was performed using a Boehringer ELISA as described for the quantitative CAT determination of transfected cells.

 Example 15. Antiglucocorticoid effect of J867 in the TAT model in rat hepatoma cells.

 Cell cultivation is carried out in DMEM, ceteris paribus as in example 14. Inoculation of cells for experiments is carried out on plates with 24 holes. The substance is added to the confluent hepatoma cells in 0.2% / vol / ethanol in 16 hours. After carefully harvesting the cells with a cell scraper and obtaining the cell extract by ultrasound, the Diamondstone TAT enzyme is determined.

 Additional examples of compounds.

 Attachment 1.

 1. 11β- [4- (hydroxymininomethyl) phenyl] - 17β-methoxy-17α- (i-propoxymethyl) -estra-4,9-dien-3-one.

920 mg (2 mmol) 11β- [4- (formylphenyl] - 17β-methoxy-17α- (i-propoxymethyl) -estra-4,9-dien-3-one is dissolved in 20 ml of pyridine and reacted with 345 mg hydroxylammonium sulfate for 2 hours at room temperature, then added dropwise into ice water, the precipitate is filtered off with suction, washed with water and dried.940 mg of the crude product are purified by preparative thin-layer chromatography on silica gel PF _{254 + 366 HM} (MERC AG) with a toluene / acetone 4: 1 solvent mixture and recrystallized from acetone / hexane to give 458 mg of colorless crystals.

Melting point: 143 ^o C (decomposition) (acetone / hexane).

(α) _D = +199 ^° (CHCl ₃ ).

); 4,37 (d, 1H, J = 6,9 Гц, H-11α); 5,79 (S, 1H, H-4); 7,21 и 7,48 (dd, 4H, J = 8,1 Гц, ароматические протоны); 7,99 (S, 1H, NOH), 8,10 (S, 1H,

). ¹ H-NMR [CDCl ₃ ; TMS] (α, nnm): 0.54 (S, 3H, H-18); 1.22 [t, 6H, CH (CH ₃ ) ₂ ], 3.26 (S, 3H, OCH ₃ ), 3.43 and 3.61 (dd, 2H, J = 10.5 Hz,

); 4.37 (d, 1H, J = 6.9 Hz, H-11α); 5.79 (S, 1H, H-4); 7.21 and 7.48 (dd, 4H, J = 8.1 Hz, aromatic protons); 7.99 (S, 1H, NOH); 8.10 (S, 1H,

)

 Obtaining the starting compound.

 Stage A.

3.0 and 3,3-dimethoxy-11β {[4- (1,1-dimethoxy) methyl] phenyl} - 17 (S) -spiro-oxiranyl-estr-9-en-5α-ol are added in 25 ml of dimethyl sulfoxide in interaction with 2.3 g of sodium isopropanolate at 80 ^o C for 3 hours. It is poured into 1.5 L of ice water, the precipitate is suctioned off, dissolved in ethyl acetate, dried with sodium sulfate, filtered and the solution is concentrated in vacuo. 3.15 g (94.5% of theory) of 3,3-dimethoxy-11β {[4- (1,1-dimethoxy) methyl] phenyl} -17α- (i-propoxymethyl) -estr-9-ene are obtained -5α, 17β-diol.

 Stage B.

3.15 g of 3,3-dimethoxy-11β {[4- (1,1-dimethoxy) methyl] phenyl} - 17α- (i-propoxymethyl) -estr-9-en-5α, 17β-diol is dissolved in 100 ml toluene, enter into interaction with 8.12 g (72.4 mmol) of potassium tert-butanolate and then with 4.98 ml of methyl iodide at 25-30 ^o C for 75 minutes. After adding water, the phases are separated, the organic phase is further extracted with ethyl acetate, the combined organic phases are washed with water, dried on sodium sulfate and evaporated in vacuo. 3.77 g of 3,3-dimethoxy-11β- {[4- (1,1-dimethoxy) methyl] phenyl} -17α- (i-propoxymethyl) -17β-methoxy-estr-9-en-5α- are obtained ol as a light brown oil.

 Stage C.

3.77 g of 3,3-dimethoxy-11β- {[4- (1,1-dimethoxy) methyl] phenyl} - 17α- (i-propoxymethyl) - 17β-methoxy-est-9-en-5α-ol are dissolved in 50 ml of tert-butyl methyl ether, mixed with 5 ml of water and stirred at room temperature for 3 hours with 350 mg of p-TsOH. Concentrate in vacuo to half volume and leave solution
at night in the refrigerator. The solution was taken up in CH ₂ Cl ₂ , neutralized by the addition of an aqueous bicarbonate solution, washed with water and dried on sodium sulfate. The solvent was evaporated in vacuo.

2.77 g (76.9% of theory) of 11β- [4- (formylphenyl] - 17β-methoxy-17α- (i-propoxymethyl) -estra-4,9-dien-3-one are obtained as a brown foam. the product was purified by silica gel chromatography (0.06-0.2 mm MERC AG) with a toluene / acetone solvent mixture, 1.44 g was isolated, which precipitated from Ch ₂ Cl ₂ with tert-butyl methyl ether to give 1.3 g (60 , 7% of theory).

Melting point: 122-129 ^° C (CH ₂ Cl ₂ / tert-butyl methyl ether).

α _D = +173 ^o (CHCl ₃ ).

] , 3,25 (s, 3H, OCH₃), 3,44 и 3,58 (dd, 2H , J = 10,4 Гц,

); 3,6 [m, 1H, OCH(CH₃)₂], 4,42 (d, 1H, J = 7,3 Гц, H-11α); 5,79 (s, 1H, H-4); 7,37 и 7,78 (dd, 4H, J = 8,1 Гц, ароматические протоны); 9,99 (S, 1H,

). ¹ H-NMR [CDCl ₃ ; TMS] (δ, nnm): 0.50 (s, 3H, H-18); 1.22 [t, 6H, J = 11.6 Hz,

], 3.25 (s, 3H, OCH ₃ ), 3.44 and 3.58 (dd, 2H, J = 10.4 Hz,

); 3.6 [m, 1H, OCH (CH ₃ ) ₂ ], 4.42 (d, 1H, J = 7.3 Hz, H-11α); 5.79 (s, 1H, H-4); 7.37 and 7.78 (dd, 4H, J = 8.1 Hz, aromatic protons); 9.99 (S, 1H,

)

 2. 11β- [4- (hydroxymininomethyl) phenyl] - 17β-hydroxy-17α-ethyl-thiomethyl-estra-4,9-dien-3-one.

450 mg of 11β- [4- (formylphenyl)] - 17β- hydroxy-17α- (ethylthiomethyl) - estra-4,9-dien-3-one is dissolved in 5 ml of pyridine and reacted with 172 mg of hydroxylammonium sulfate for 2 hours at room temperature. Drop in ice water, the precipitate is suctioned off, washed with water and dried. The crude product is purified by preparative thin-layer chromatography on silica gel PF _{254 + 366 HM} (MERC AG) with a solvent mixture of toluene / acetone 4: 1 and recrystallized from acetone. 185 mg of colorless crystals are obtained.

Melting point: 132-137 ^o C (acetone).

α _D = +165 ^o (CHCl ₃ ).

]; 2,61 (d, 2H, J = 7,5 Гц,

), 2,71 и 2,92 (dd, 2H, J = 12,9 Гц,

); 2,90 (S, 1H, OH); 4,42 (d, 1H, J = 7,2 Гц, H-11α); 5,79 (S, 1H, H-4); 7,20 и 7,49 (dd, 4H, J = 8,4 Гц), ароматические протоны); 7,93 (s, 1H, NOH), 8,10 (s, 1H,

). ¹ H-NMR: [CDCl ₃ ; TMS] (δ, nnm): 0.56 (s, 3H, H-18); 1.29 [t, 3H, J = 7.2 Hz,

]; 2.61 (d, 2H, J = 7.5 Hz,

), 2.71 and 2.92 (dd, 2H, J = 12.9 Hz,

); 2.90 (S, 1H, OH); 4.42 (d, 1H, J = 7.2 Hz, H-11α); 5.79 (S, 1H, H-4); 7.20 and 7.49 (dd, 4H, J = 8.4 Hz), aromatic protons); 7.93 (s, 1H, NOH), 8.10 (s, 1H,

)

 Obtaining the starting compound.

 Stage A.

992 mg of 3,3-dimethoxy-11β- {[4- (1,1-dimethoxy) methyl] phenyl} - 17 (S) -spirooxyranyl-estr-9-en-5α-ol in 7 ml of dimethyl sulfoxide is reacted with 3.36 g (4 mmol) of sodium thiomethanolate at 80 ^° C. for 2 hours. It is poured into an aqueous solution of NH ₄ Cl, the precipitate is suctioned off, and 1.5 g of a wet yellow crude product are obtained. est-9-en-5α, 17β-diol.

 Stage B.

1.5 g of 3,3-dimethoxy-11β- {[4- (1,1-dimethoxy) methyl] phenyl} - 17α- (i-ethylthiomethyl) -estr-9-en-5α, 17β-diol is dissolved in acetone and stirred at room temperature for 3 hours with 180 mg of p-TsOH. By adding an aqueous bicarbonate solution, a precipitate precipitates, which is filtered off with suction and dried. The crude product is purified by preparative thin-layer chromatography on silica gel (PF _{254 + 366 HM} MERC AG) with a solvent mixture of toluene / acetone 4: 1. 460 mg of 11β- [4- (formylphenyl)} - 17β-hydroxy-17α- (ethylthiomethyl) -estra-4,9-dien-3-one is obtained, which is recrystallized from acetone.

Melting point: 180-182 ^o C (acetone).

α _D = +160 ^o (CHCl ₃ ).

] ; 2,61 (d, 2H, J = 7,5 Гц,

), 2,71 и 2,96 (dd, 2H, J = 12,9 Гц,

); 2,87 (s, 1H, OH); 4,45 (d, 1H, J = 6,5 Гц, H-11α); 5,80 (s, 1H, H-4); 7,38 и 7,81 (dd, 4H, J = 8,4 Гц, ароматические протоны); 9,98 (s, 1H,

). ¹ H-NMR: [CDCl ₃ ; TMS] (δ, nnm): 0.54 (s, 3H, H-18); 1.29 [t, 3H, J = 7.2 Hz,

]; 2.61 (d, 2H, J = 7.5 Hz,

), 2.71 and 2.96 (dd, 2H, J = 12.9 Hz,

); 2.87 (s, 1H, OH); 4.45 (d, 1H, J = 6.5 Hz, H-11α); 5.80 (s, 1H, H-4); 7.38 and 7.81 (dd, 4H, J = 8.4 Hz, aromatic protons); 9.98 (s, 1H,

)

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

500 mg of 11β- [4- (formylphenyl] -17β- hydroxy-17α- (i-propoxymethyl) -estra-4,9-dien-3-one in 20 ml of pyridine is reacted with 65 mg of hydroxylamine hydrochloride for 2 hours at poured into ice-cold water, suctioned off, washed the precipitate until neutral, water and dried in air Light brown foam was purified by preparative thin-layer chromatography on silica gel PF _{254 + 366 HM} (MERC AG) with a solvent mixture of toluene / acetone 4: 1 and Recrystallized from ether to give 266 mg of colorless crystals.

Melting point: 192-196 ^o C (ether).

α _D = + 215 ^o (CHCl ₃ ).

], 3,02 (s, 1H, OH), 3,22 и 3,59 (dd, 2H, J=9,3 Гц,

); 3,62 (m, 1H,

); 4,38 (d, 1H, J=6,6 Гц, H-11α); 5,79 (s, 1H, H-4); 7,20 и 7,47 (dd, 4H, J=8,4 Гц, ароматические протоны); 8,08 (s, 1H, OH), 8,10 (s, 1H,

). ¹ H-NMR [CDCl ₃ ); TMS] (δ, nnm): 0.52 (s, 3H, H-18); 1.21 [q, 6H, Σ J = 9.6 Hz,

], 3.02 (s, 1H, OH), 3.22 and 3.59 (dd, 2H, J = 9.3 Hz,

); 3.62 (m, 1H,

); 4.38 (d, 1H, J = 6.6 Hz, H-11α); 5.79 (s, 1H, H-4); 7.20 and 7.47 (dd, 4H, J = 8.4 Hz, aromatic protons); 8.08 (s, 1H, OH), 8.10 (s, 1H,

)

 Obtaining the starting compound.

 Stage A.

3.0 g (6.04 mmol) of 3,3-dimethoxy-11β {[4 (1,1-dimethoxy) methyl] phenyl} -17 (S) -spirooxyranyl-est-9-en-5α-ol 25 ml of dimethyl sulfoxide are reacted with 2.3 g (4 mmol) of sodium isopropanolate at 80 ^° C. for 3 hours. It is poured into 1.5 L of ice water, the precipitate is suctioned off, dissolved in ethyl acetate, dried with sodium sulfate, filtered and the solution is concentrated in vacuo. 3.15 g (94.5% of theory) of 3,3-dimethoxy-11β {[4 (1,1-dimethoxy) methyl] phenyl} - 17α- (i-propoxymethyl) -estr-9-en-5α are obtained , 17β-diol.

 Stage B.

3.0 g of 3,3-dimethoxy-11β {[4- (1,1-dimethoxy) methyl] phenyl} - 17α- (i-propoxymethyl) -estr-9-ene 5α, 17β-diol is dissolved in 30 ml of tert of butyl methyl ether, mixed with 5 ml of water and stirred at room temperature for 3 hours with 250 mg of p-TsOH. It is concentrated in vacuo to half the volume, taken up in CH ₂ Cl ₂ , neutralized by the addition of an aqueous bicarbonate solution, washed with water, dried over sodium sulfate. The solvent was evaporated in vacuo. 2.77 g (76.9% of theory) of 11β- [4- (formylphenyl)] - 17β-hydroxy-17α- (i-propoxymethyl) estra-4,9-diene are obtained as a brown foam. The crude product is purified by silica gel chromatography (0.06-0.2 mm MERC AG) with a toluene / acetone solvent mixture. 1.44 g of purified crude product are obtained, which are precipitated from CH ₂ Cl ₂ with tertiary butyl methyl ether. 1.3 g (60.7% of theory) are isolated.

Melting point: 122 ^o C (decomposition) (tert-butyl methyl ether / hexane).

α _D = + 186 ^o (CHCl ₃ ).

], 2,84 (s, 1H, OH), 3,22 и 3,59 (dd, 2H, J=9,3 Гц,

); 3,62 (m, 1H,

); 4,45 (d, 1H, J=6,6 Гц, H-11α); 5,80 (s, 1H, H-4); 7,37 и 7,80 (dd, 4H, J=8,4 Гц, ароматические протоны); 9,97 (s, 1H, CH=O). ¹ H-NMR: [CDCl ₃ ; TMS] (δ, nnm): 0.51 (s, 3H, H-18); 1.22 [d, 6H, Σ J = 9.9 Hz,

], 2.84 (s, 1H, OH), 3.22 and 3.59 (dd, 2H, J = 9.3 Hz,

); 3.62 (m, 1H,

); 4.45 (d, 1H, J = 6.6 Hz, H-11α); 5.80 (s, 1H, H-4); 7.37 and 7.80 (dd, 4H, J = 8.4 Hz, aromatic protons); 9.97 (s, 1H, CH = O).

 4. 17α-azidomethyl-11β- [4- (hydroxymininomethyl) phenyl] - 17β-hydroxy-estra-4,9-3-one.

800 mg (1.85 mmol) of 17α-azidomethyl-11β- [4 (formylphenyl)] - 17β-hydroxy-estra-4,9-dien-3-one is dissolved in 22 ml of pyridine and reacted with 245 mg of hydroxylamine hydrosulfate 2 hours at room temperature. A clear solution was added dropwise into ice water, the precipitate was suctioned off, washed with water and dried. Yield 827 mg. Preparative thin-layer chromatography on silica gel PF _{254 + 366 HM} (MERC AG) with a solvent mixture of toluene / acetone 3: 1 gives 649 mg of a colorless oil,
which is recrystallized from tert-butyl methyl ether. 458 mg of colorless crystals are obtained.

Melting point: 145 - 151 ^o C and again 193 - 200 ^o C (methyl tert-butyl ether).

a _D = -212 ^o (MeOH).

); 4,43 (d, 1H, J=6,3 Гц, H-11α); 4,74 (s, 1H, 17β OH); 5,68 (s, 1H, H-4); 7,24 и 7,51 (dd, 4H, J=8,1 Гц, ароматические протоны); 8,09 (s, 1H,

), 11,2 (s, 1H, NOH).IR [(KBr) cm ^-1 ]: 1643 and 1657 (C = CC = CC = O); 2099 (N ₃ );
UV [MeOH]:
λ _max 209 nm ε = 23692, logε = 4.37;
λ _max 265 nm ε = 21765, logε = 4.33;
λ _max 299 nm ε = 21389, logε = 4.33;
¹ H-NMR: [DMSO; TMS] (δ, nnm): 0.43 (s, 3H, H-18); 3.08 and 3.40 (dd, 2H, J = 12.6 Hz,

); 4.43 (d, 1H, J = 6.3 Hz, H-11α); 4.74 (s, 1H, 17β OH); 5.68 (s, 1H, H-4); 7.24 and 7.51 (dd, 4H, J = 8.1 Hz, aromatic protons); 8.09 (s, 1H,

), 11.2 (s, 1H, NOH).

 Obtaining the starting compound.

 1 g (2.02 mmol) of 3,3-dimethoxy-11β [4- (1,1-dimethoxy) methyl] phenyl} -17 (S) -spiro-1 ', 2', - oxiranyl-9-ene -5α-ol is suspended in 70 ml of ethylene glycol and heated for 3 hours with 1.008 g (15.5 mmol) of sodium azide in a boiling water bath. Dropped in 600 ml of ice-cold water, sucked off, washed with water and suction dried in air. Yield 1.08 g (100% of theory) 17α-azidomethyl-3,3-dimethoxy-11β- {[4 (1,1-dimethoxy) methyl] phenyl} -estr-9-en-5α, 17β-diol .

 1.08 mg of this compound is dissolved as a crude product in 20 ml of acetone and 2 ml of water, mixed with 258 mg of p-toluenesulfonic acid and stirred for 5 hours at room temperature. It is then neutralized with diluted ammonia, whereupon the crude product is precipitated, which is filtered off with suction. Yield: 909 mg of 17α-azidomethyl-11β- [4- (formylphenyl)] - 17β-hydroxy-estra-4,9-dien-3-one. Recrystallization from acetone and a small amount of methylene chloride gives colorless crystals.

Melting point: 197 - 205 ^o C (acetone).

α _D = + 156 ^o (CHCl ₃ ).

IR (KBr) [cm ^-1 ]: 1648 (C = CC = CC = O); 1712 (CHO), 2100 (N ₃ ).

); 4,48 (d, 1H, J=7,2 Гц, H-11α); 5,81 (s, 1H, H-4); 7,37 и 7,82 (dd, 4H, J=8,4 Гц, ароматические протоны); 9,98 (s, 1H,

).UV [MeOH]:
λ _max 203 nm ε = 21143, logε = 4.32;
λ _max 263 nm ε = 18338, logε = 4.26;
λ _max 299 nm ε = 20712, logε = 4.32;
¹ H-NMR: [CDCl ₃ ; TMS] (δ, nnm): 0.53 (s, 3H, H-18); 2.04 (s, 1H, OH); 3.31 and 3.60 (dd, 2H, J = 12.3 Hz,

); 4.48 (d, 1H, J = 7.2 Hz, H-11α); 5.81 (s, 1H, H-4); 7.37 and 7.82 (dd, 4H, J = 8.4 Hz, aromatic protons); 9.98 (s, 1H,

)

 5. 11β- [4- (hydroxymininomethyl) phenyl] - 17β-hydroxy-estra-4,9-dien-3-one.

115 mg of 11β- [4- (formylphenyl)] - 17β-hydroxy-estra-4,9-dien-3-one is dissolved in 2 ml of pyridine and reacted with 22.5 mg of hydroxylaminohydrochloride at 23 ^° C. After 2 hours diluted with ice water, the precipitate is suctioned off, washed with water and dried. 99.4 mg are obtained. 11β- [4- (hydroxymininomethyl) phenyl] - 17β- hydroxy-estra-4,9-dien-3-one, which is purified by preparative thin-layer chromatography on silica gel PF _{254 + 366, is} recrystallized from methanol.

Melting point: 150 - 153 ^o C (MeOH).

). ¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.42 (s, 3H, H-18); 3.68 (t, 1H, H-17α); 4.38 (d, J = 6.9 Hz, 1H, H-11α); 5.79 (s, 1H, H-4); 7.20, 7.22, 7.48, 7.51 (m, 4H, A, A ', B, B' - system of aromatic protons); 7.78 (s, 1H, OH), 8.11 (s, 1H,

)

 6. 11β- [4- (hydroxymininomethyl) phenyl] - 17β-hydroxy-17α-methyl-estra-4,9-dien-3-one.

428 mg of 11β- (4-formylphenyl)] - 17β-hydroxy-17α-methyl-estra-4,9-dien-3-one is dissolved in 2 ml of pyridine and reacted in parts with 148 mg of hydroxylamine hydrochloride at 23 ^o C. 2 hours diluted with ice water, the precipitate is suctioned off, washed with water and dried. 368 mg of 11β- [4- (hydroxyminomethyl) phenyl] - 17β-hydroxy-17α-methyl-estra-4,9-dien-3-one is obtained. Preparative thin-layer chromatography on silica gel PF _{254 + 366} with toluene / acetone 4: 1 gives a white foam, which recrystallizes from methyl tert-butyl ether.

Melting point: 154 - 160 ^o C [(CH ₃ ) ₃ OCH ₃ ].

α _D = + 224 ^o (CHCl ₃ ).

IR spectrum in CDCl ₃ [cm ^-1 ]: 3375 (OH), 3284 (bound OH), 1650 (C = CC = CC = O); 1600 phenyl.

); 8,11 (s, 1H,

).UV Spectrum (MeOH):
λ _max = 264 nm, ε = 19111,
λ _max = 299 nm, ε = 18912.
¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.53 (s, 3H, H-18); 1.20 (s, 9H, tert-butyl group of recrystallization agent); 1.27 (s, 3H, 17α-CH ₃ ); 3.22 (s, 3H, (CH ₃ ) ₃ OCH ₃ ); 4.42 (d, J = 6.9 Hz, 1H, H-11α); 5.79 (s, 1H, H-4); 7.19, 7.22, 7.48, 7.51 (m, 4H, A, A ', B, B'— aromatic proton system); 7.79 (s, 1H,

); 8.11 (s, 1H,

)

 Obtaining the starting compound.

To a Grignard solution (obtained from 2.43 mg of magnesium and 6.4 ml of methyl iodide in 25 ml of methyl tert-butyl ether), a solution of 5.69 g of 11β {[4-dimethoxymethyl] phenyl} -3,3- is added dropwise at room temperature. dimethoxy-5α-hydroxy-estr-9-en-17one in 30 ml of terahydrofuran. It is stirred for 2 hours at 40 ^° C., decomposed at room temperature with an aqueous solution of ammonium chloride, the phases are separated, the aqueous phase is further extracted and the organic phases are combined dried over sodium sulfate and evaporated under reduced pressure. Obtain 4.7 g of the product in the form of a yellow foam, which is purified by chromatography on silica gel (0.23 - 0.5 mm) with a gradient of toluene / acetic ether. Yield: 1.3 g of 11β- [4-dimethoxymethyl) phenyl] -3,3-dimethoxy-17α-methyl-est-9-en-5α, 17β-diol.

 The crude product is dissolved in 3.5 ml of acetone, mixed with 0.35 ml of water and 74 mg of p-toluenesulfonic acid and stirred at room temperature for 30 minutes. The initial mixture was diluted with ethyl acetate and water, the phases were separated and the organic phase was dried over sodium sulfate. 1.07 g of 11β- (4-formylphenyl) -17β-hydroxy-17α-methyl-estra-4,9-dien-3-one is obtained as yellow crystals, which are purified by chromatography.

Melting point: 160 - 164 ^o C (acetone).

IR (in MeOH) [cm ^-1 ]: 3605 (OH); 1704 (CHO); 1657 (C = CC = CC = O); 1603 (phenyl).

); 2,18 (ацетон); 4,48 (d, J = 7,2 Гц, 1H, H-11α); 5,80 (s, 1H, H-4); 7,38 (d, 2H, J = 8,1 Гц ароматические протоны) 7,81 (s, 2H, J = 6,6 Гц ароматические протоны); 9,98 (s, 1H,

). ¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.50 (s, 3H, H-18); 1.28 (s, 3H,

); 2.18 (acetone); 4.48 (d, J = 7.2 Hz, 1H, H-11α); 5.80 (s, 1H, H-4); 7.38 (d, 2H, J = 8.1 Hz aromatic protons) 7.81 (s, 2H, J = 6.6 Hz aromatic protons); 9.98 (s, 1H,

)

 7. 17β-acetoxy-11β- [4- (hydroxyminomethyl) phenyl] estra-4,9-dien-3-one.

450 mg of 17β-acetoxy-11β- (4-formylphenyl)] -estra-4,9-dien-3-one is dissolved in 5.7 ml of pyridine and reacted with 74.7 mg of hydroxylamine hydrochloride at 21 ^° C. After 40 minutes diluted with ice water, the precipitate is suctioned off, washed with water and dried. 450 mg of 17β-acetoxy-11β- [4- (hydroxymininomethyl) phenyl] estra-4,9-dien-3-one are obtained. The crude product is purified by preparative thin-layer chromatography on silica gel PF _{254 + 366} and recrystallized from acetone.

Melting point: 130-135 ^o C (acetone).

α _D = +202 ^o (CHCl ₃ ).

IR spectrum in CDCl ₃ [cm ^-1 ]: 3575 (OH); 1711 (OCOCH ₃ ); 1656 (C = CC = CC = O); 1605 (phenyl).

).UV Spectrum (MeOH):
λ _max = 264 nm, ε = 20698,
λ _max = 299 nm, ε = 20569.
¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.47 (s, 3H, H-18); 2.03 (s, 3H, COCH ₃ ); 4.35 (d, J = 6.9 Hz, 1H, H-11α); 4.63 (t, J = 9.3 Hz, 1H, H-17α); 5.79 (s, 1H, H-4); 7.20, 7.49 (d, J = 8.4 Hz, 2H, aromatic protons); 7.64 (s, 1H, OH); 8.11 (s, 1H,

)

 Obtaining the starting compound.

 Stage 1

To a Grignard solution (obtained from 1.6 mg of magnesium and 17.7 g of 4-bromobenzaldehyde-neopentyl ketal in 100 ml of tetrahydrofuran), 426 mg of CuCl are added at -20 ^° C, stirred for an additional 10 minutes and 5 g of 3,3-dimethoxy- are added dropwise. 5α, 10α-epoxy-estr-9-en-17-one in 25 ml of anhydrous tetrahydrofuran. Heated to 0 ^o C, further stirred for 1.5 hours and decomposed with an aqueous solution of ammonium chloride. After adding ethyl acetate, the phases are separated. The organic phase is washed with an aqueous solution of ammonium chloride and water, dried over sodium sulfate and evaporated under reduced pressure. Light syrup is purified on silica gel with a gradient of toluene / ethyl acetate. 3.24 g of crude product are obtained. Recrystallization from methyl tert-butyl ether / hexane gave 3,3-dimethoxy-11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] - 5α-hydroxy-ext-9- en-17-he is like colorless crystals.

Melting point: 194-202 ^o C.

α _D = +64 ^o (CHCl ₃ ).

IR spectrum (CHCl ₃ ): 1732 cm ^-1 (C = O).

неопентилкеталя); 3,20 и 3,33 (2s, по 3H,

); 3,63 - 3,79 (q, 4H,

кеталя); 4,30 (d, J = 6,9 Гц, 1H, H-11α); 4,66 (s, 1H, OH); 5,35 (s, 1H,

); 7,24 (d, 2H, J = 7,8 Гц, ароматические протоны); 7,41 (s, 2H, J = 8,1 Гц, ароматические протоны). ¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.46 (s, 3H, H-18); 0.80 and 1.31 (2s, 3H each,

neopentyl ketal); 3.20 and 3.33 (2s, 3H each,

); 3.63 - 3.79 (q, 4H,

ketal); 4.30 (d, J = 6.9 Hz, 1H, H-11α); 4.66 (s, 1H, OH); 5.35 (s, 1H,

); 7.24 (d, 2H, J = 7.8 Hz, aromatic protons); 7.41 (s, 2H, J = 8.1 Hz, aromatic protons).

 Stage 2

2.1 g of 3,3-dimethoxy-11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -5α-hydroxy-est-9-en-17-one is dissolved in 25 ml of methanol / tetrahydrofuran and restore at 23 ^o C using 303 mg of sodium borohydride. After 45 minutes, it is mixed with water and the aqueous phase is extracted several times with methylene chloride. The organic phase is dried and evaporated under reduced pressure. The crude product is dissolved in 25 ml of acetone, stirred for 8 hours at room temperature with 2 ml of water and 283 mg of p-toluenesulfonic acid. Then pour water and the precipitate is sucked off. Purification of the crude product is carried out by chromatography with a gradient of toluene / acetone on silica gel. 1.1 g of 11β- (4-formylphenyl) -17β-hydroxy-estra-4,9-dien-3-one are obtained.

Melting point: 197-200 ^o C (acetone).

α _D = +225 ^o (CHCl ₃ ).

IR (CHCl ₃ ) [cm ^-1 ]: 3404-3502 (OH); 1707 (CH = O); 1658 (C = CC = CC = O); 1603 (phenyl).

).UV Spectrum (MeOH):
λ _max = 263 nm, ε = 14756,
λ _max = 299 nm, ε = 17015.
¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.40 (s, 3H, H-18); 3.68 (t, J = 9 Hz, 1H, H-17α); 4.44 (d, J = 7.2 Hz, 1H, H-11α); 5.80 (s, 1H, H-4); 7.38 (d, 2H, J = 9.8 Hz, 2H, aromatic protons); 7.82 (d, 2H, J = 8.4 Hz, aromatic protons); 9.98 (s, 1H,

)

 Stage 3.

 437 mg of 11β- (4-formylphenyl)] - 17β-hydroxy-estra-4,9-dien-3-one is acetylated with 6 ml of 1: 1 acetanhydride / pyridine at room temperature for 3 hours. The crude product is precipitated by the addition of ice water, which is purified by recrystallization from acetone. 226 mg of 17β-acetoxy-11β- (4-formylphenyl) -estra-4,9-dien-3-one is obtained.

Melting point: 188-191 ^o C (acetone).

α _D = +202 ^o (CHCl ₃ ).

; 1658 (C=C-C=C-C=O); 1604 (фенил).IR spectrum in CDCl ₃ [cm ^-1 ]: 1725 (OCOCH ₃ ); 1671

; 1658 (C = CC = CC = O); 1604 (phenyl).

).UV Spectrum (MeOH):
λ _max = 261 nm, ε = 19289,
λ _max = 298 nm, ε = 22303.
¹ H-NMR spectrum in CDCl ₃ (δ, nnm): 0.44 (s, 3H, H-18); 2.04 (s, 3H, CHCO ₃ ); 4.40 (d, J = 6.9 Hz, 1H, H-11α); 4.63 (t, J = 8.1 Hz, 1H, H-17α); 5.80 (s, 1H, H-4); 7.37 (d, J = 8.1 Hz, 2H, aromatic protons); 7.8 (d, J = 8.1 Hz, 2H, aromatic protons); 9.98 (s, 1H,

)

 8. 11β- [4- (hydroxymininomethyl) phenyl)] - 17β-ethoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

127 mg of 11β- (4-formylphenyl) -17β-ethoxy-17α-methoxymethyl-estra-4,9-dien-3-one at room temperature under argon protection is mixed in 2 ml of pyridine with 21.7 mg of hydroxylamine hydrochloride and stirred for 1 hour at 25 ^o C. For processing, the reaction solution is stirred in ice water. The precipitated white precipitate is suctioned off and washed with water until neutral. The crude product is purified by preparative thin-layer chromatography on silica gel PF _{254 + 366} with a mixture of toluene / acetone. 95 mg of 11β- [4- (hydroxyminomethyl) phenyl)] - 17β-ethoxy-17α-methoxymethyl-estra-4,9-dien-3-one are obtained.

Melting point: 192-197 ^o C (hexane).

α _D = +213 ^o (chloroform).

Infrared spectrum (CHCl ₃ ) [cm ^-1 ]: 3380 (bound, OH); 1650 (C = CC = CC = O); 1597 (aromatics).

); 3,40 (s, 3H, OCH₃); 3,36-3,58 (m, 2x2H,

); 4,38 (d, 1H, J = 6,9 Гц, 11α); 5,78 (s, 1H, H-4); 7,21 (d, 2H, J = 8,4 Гц, ароматические протоны); 7,45 (d, 2H, J = 8,4 Гц, ароматические протоны) J = 5,8 (s, 1H, OH); 8,10 (1,1H,

).UV Spectrum (MeOH):
λ _max = 264 nm, ε = 23170,
λ _max = 299 nm, ε = 22847.
¹ H-NMR spectrum in CDCl ₃ (δ, nmm): 0.54 (s, 3H, H-18); 1.11 (t, 3H,

); 3.40 (s, 3H, OCH ₃ ); 3.36-3.58 (m, 2x2H,

); 4.38 (d, 1H, J = 6.9 Hz, 11α); 5.78 (s, 1H, H-4); 7.21 (d, 2H, J = 8.4 Hz, aromatic protons); 7.45 (d, 2H, J = 8.4 Hz, aromatic protons) J = 5.8 (s, 1H, OH); 8.10 (1.1H,

)

 Obtaining the starting compound.

 Stage 1

 250 mg of sodium and 250 mg of naphthalene are mixed in anhydrous tetrahydrofuran while protecting with argon, until a thick green suspension forms. A solution of 1.56 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl)] -17α-methoxymethyl-estr-9-en-5α, 17β-diol in 10 ml of anhydrous tetrahydrofuran is added dropwise in it so that the green color remained constant. Then 3 ml of ethyl iodide are added dropwise in 5 ml of anhydrous tetrahydrofuran, the solution decolorizing. It was further stirred for 12 hours at room temperature, 3 ml of methanol was added and stirred for another 10 minutes. After adding water and ethyl acetate, the phases are separated, the organic phase is washed to a neutral state, dried over sodium sulfate and evaporated under reduced pressure. 2.47 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl)] 17β-ethoxy-17α-methoxymethyl-estr-9-en-5α-ol are obtained as a crude product.

 Stage 2

2.47 g of 3,3-dimethoxy-11β- [4- (dimethoxymethyl) phenyl)] -17β-ethoxy-17α-methoxymethyl-estr-9-en-5α-ol is stirred for 50 minutes at room temperature in 6 ml of acetone and 0.6 ml of water with 130 mg of p-toluenesulfonic acid. Then it is poured into 50 ml of chloroform / water 1: 1, the phases are separated, the aqueous phase is further extracted, the organic phase is washed to a neutral state and dried over sodium sulfate. After the solvent was distilled off, 2.1 g of a light brown oil remained. Preparative thin-layer chromatography on silica gel PF _{254 + 366} with a toluene / acetone mixture gives 388 mg of 11β- (4-formylphenyl)] - 17β-ethoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

 Additional examples on the composition.

 Appendix 2

 The composition of the pharmaceutical formulation.

 Example R1.

10.0 mg 11β- [4- (hydroxyminomethyl) phenyl)] - 17β- methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,
125 mg lactose,
60 mg of corn starch,
2.5 mg poly-N-vinylpyrrolidone,
2.0 mg aerosil,
0.5 mg magnesium stearate,
200 mg total weight of the tablet, which is obtained in the usual way on a tablet press. Moreover, it is also possible the active substance according to the invention, respectively, with a half of the above additives to compress separately a tablet with a notch.

 Example R2

20.0 mg 11β- [4- (hydroxyminomethyl) phenyl)] 17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one,
150 mg dextrose
75 mg alginic acid
2.5 mg poly-N-vinylpyrrolidone,
6.0 mg gelatin
0.5 mg magnesium stearate,
254 total weight of the tablet, which is obtained in the usual way on a tablet press. Moreover, it is also possible to compress the active substance according to the invention, respectively, with half of the above additives separately into a notched tablet.

Claims (16)

1. Derivatives of 11β-benzaldoxime-estra-4,9-diene of the general formula I

where R ¹ is CH ₃ ,
R ² is a hydrogen atom, alkyl, C ₁ -C ₁₀ , an acyl residue C ₁ -C ₁₀ , or a CONHR ⁴ residue, where R ⁴ is an aryl residue such as phenyl;
R ³ is a hydrogen atom, C ₁ -C ₁₀ alkyl, the residue is (CH ₂ ) _n -CH ₂ -X, where X is an azido group, a halogen atom, n = 0, ... 1, or OR ⁵ , where R ⁵ is hydrogen atom, alkyl C ₁ -C ₁₀ ; or SR ⁵ , where R ⁵ is C ₁ -C ₁₀ alkyl;
or R ³ is the residue (CH ₂ ) _O — C = CH (CH ₂ ) _p - R ⁶ , where 0 = 1, p = 0.1, and R ⁶ is a hydrogen atom;
or R ³ is the residue (CH ₂ ) _q -C = CR ⁷ , where q = 1.2, R ⁷ is a hydrogen atom;
Z is a hydrogen atom, C ₁ -C ₁₀ alkyl, an acyl residue, C ₁ -C ₁₀ . 2. Compounds according to claim 1, characterized in that R ¹ is methyl or ethyl. 3. The compounds of claims. 1 and 2, characterized in that R ² is a hydrogen atom, a C ₁ -C ₁₀ alkyl, an acyl residue C ₁ -C ₁₀ or a residue CONHR ⁴ , where R ⁴ is phenyl. 4. The compounds of claims. 1-3, characterized in that R ² is alkyl C ₁ -C ₆ , acyl C ₁ -C ₆ or the residue CONHR ⁴ , where R ⁴ is a hydrogen atom. 5. The compounds of claims. 1-4, characterized in that R ³ is a hydrogen atom. 6. The compounds of claims. 1-4, characterized in that R ³ is alkyl C ₁ -C ₁₀ . 7. The compounds of claims. 1-6, characterized in that R ³ is alkyl C ₁ -C ₆ . 8. The compounds of claims. 1-7, characterized in that R ³ is the residue - (CH ₂ ) _n -CH ₂ X, where n = 0, 1, X is a chlorine atom, an azido group, the residue is OR ⁵ , where R ⁵ is a hydrogen atom, alkyl C ₁ -C ₁₀ , or SR ⁵ , where R ⁵ is C ₁ -C ₁₀ alkyl. 9. The compounds of claims. 1-8, characterized in that R ³ is the remainder of OR ⁵ , where R ⁵ is a hydrogen atom, alkyl C ₁ -C ₁₀ . 10. The compounds of claims. 1-9, characterized in that R ³ - residue - (CH ₂ ) _o -CH = CH (CH ₂ ) _p - R ⁶ , where 0 = 1, p = 0, 1, R ⁶ is a hydrogen atom. 11. The compounds of claims. 1-10, characterized in that R ³ is the residue (CH ₂ ) _q C = CR ⁷ , where q = 1, 2, R ⁷ is a hydrogen atom. 12. The compounds of claims. 1-11, characterized in that Z is a hydrogen atom, an alkyl C ₁ -C ₁₀ , an acyl residue C ₁ -C ₁₀ .  13. The compounds of claims. 1-12, namely: 11β- [4- (hydroxyminomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one; 11β- [4- (hydroxymininomethyl) phenyl] -17β-hydroxy-17α-ethoxymethyl-estra-4,9-dien-3-one; 11β- [4- (hydroxymininomethyl) phenyl] -17β-hydroxy-17α-isoproproxymethyl-estra-4,9-dien-3-one; 11β- [4- (hydroxymininomethyl-phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one; 11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-17α-ethoxymethyl -estra, 4,9-dien-3-one; 11β- [4- (hydroxymininomethyl) phenyl] -17β-hydroxy-17α- (3-hydroxyprop-1-in-yl) -estra-4,9-diene -3-one; 11β- [4- (hydroxyminomethyl) phenyl] -17β-methoxy-17α- (3-hydroxyprop-1-in-yl) estra, 4,9-dien-3-one; 17α-chloromethyl- 11β- [4- (hydroxymininomethyl) phenyl] -17β-hydroxy-estra-4,9-dien-3-one; 17α-chloromethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy estra- 4,9-dien-3-one; 17α-azidomethyl-11β- [4- (hydroxymininomethyl) phenyl] -17β-methoxy-estra-4,9-dien-3-one; 11 β- [4- (hydroxymininomethyl) 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- (acetoxyximinomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one; 11β- {4- [ethoxycarbonyl) oxyminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 17β-methoxy-17α-methoxymethyl-11β- {4- [phenylaminocarbonyl) oxymininomethyl] phenyl } -estra-4,9-dien-3-one and 11β- [4- (hydroxymininomethyl) phenyl] -17β-ethoxy-17α-ethoxymethyl-estra-4,9-dien-3-one. 14. A method of producing compounds according to claim 1, characterized in that the compound of general formula II

where R ¹ , R ² , R ³ have the meanings indicated in paragraph 1, are reacted with a compound of the general formula IIa:
H ₂ NOY,
where Y - has the meanings indicated in paragraph 1 for Z, and the compound of general formula IIa, if necessary, is used in the form of such a compound from which the compound of general formula IIa is released under the selected reaction conditions, and if necessary, the existing hydroxylamine group is esterified to complex or simple ether.  15. The method according to p. 14, characterized in that the compounds of general formula II and general formula IIa are reacted in equimolar amounts.  16. A pharmaceutical composition having antigestagenic and antiglucocorticoid action, characterized in that it contains at least one compound according to any one of paragraphs. 1-13.

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