UA78062C2 - 9?-substituted estratrienes as estrogens of selective action - Google Patents

Abstract

The invention relates to novel -substituted estratrienes of general formula (I) -wherein R3, R7, R7`, R13, R16, R17 and R17' have the designations cited in the description, and R9 represents a linear-chain or branched-chain, optionally partially or fully halogenated alkenyl radical comprising between 2 and 6 carbon atoms, or an ethinyl radical or a prop-1-inyl radical - as pharmaceutical active ingredients which have, in vitro, a higher affinity to estrogen receptor preparations of the rat prostate than to estrogen receptor preparation of the rat uterus, and, in vivo, preferably a preferential action on the ovary compared to the uterus. The invention also relates to the production of said estratrienes, to the therapeutic application thereof and to pharmaceutical forms of administration containing the novel compounds. The invention further relates to the use of said compounds for treating illnesses and states related to estrogen deficiency. (1)

Description

Description of the invention

The present invention relates to new compounds as pharmaceutical active substances, which have a higher affinity to estrogen receptors in preparations from the rat prostate compared to the affinity to estrogen receptors in preparations from the rat uterus and whose action is mainly directed to the ovary, and not on the uterus, the preparation of such compounds, their therapeutic use and pharmaceutical dosage forms containing these new compounds.

Similar chemical compounds are steroidal estrogens of a new type with a selective action in relation to 70 specific tissues.

The effectiveness of estrogens in the treatment of symptoms caused by hormonal insufficiency, such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapy to prevent bone loss in peri- and postmenopausal women is a confirmed and generally accepted fact | Ogadu and etc., App. IPIEGP May 117, 1992, pp. 1016-1037). Likewise, 19 literary sources confirm the fact that estrogen replacement therapy in women in the postmenopausal period or in women with ovarian dysfunction caused by other causes can reduce the risk of cardiovascular diseases in comparison with women who did not undergo estrogen therapy (Ogadu et al., see above).

In traditional estrogen or hormone replacement therapy (HRT), natural estrogens such as estradiol and conjugated estrogens from horse urine are used either individually or in combination with an appropriate progestogen. Derivatives obtained by esterification can also be used instead of natural estrogens, such as, for example, 17 p-estradiol valerate.

Since estrogens used in hormone replacement therapy have a stimulating effect on the endometrium, which increases the risk of endometrial cancer |Napar 5., At. in). Bangs Supesoi!. 166, 1992, pp. 1986-19921, combined preparations based on estrogen/gestagen are mainly used. Although the progestogen component in such a combination prevents hypertrophy of the endometrium, the use of such a combination containing progestagen is associated with the possibility of unwanted intermittent bleeding.

A new alternative to combined estrogen/gestagen-based drugs are estrogens with selective action (hereinafter, selective estrogens). Until now, the term selective estrogens refers to compounds that, due to their partial anti-uterotrophic (ie, anti-estrogenic) effect, similar to conventional estrogens, affect the brain, bone tissue and vascular system, while not showing a proliferative effect on the (Ce) endometrium.

One of the classes of substances that partially correspond to the set of properties that a selective estrogen should have, are the so-called "selective estrogen receptor modulators" (SMERs)

IK.E. Kashytap, N.O. Vguapi; OMAR 8(9), 1995, pp. 531-539). At the same time, we are talking about partial agonists of estrogen receptors, which belong to the subtype of estrogen receptor-alpha "EC". However, similar substances are ineffective in the treatment of acute attacks of such painful conditions that appear in the postmenopausal period, such as hot flashes. As an example of one of the SMERs, we can name raloxifene, which was recently approved for use in such an indication as osteoporosis. "in U Izayavka SE-A 19906159) new compounds proposed in it as pharmaceutical active substances are described, which sho! ip migo have a higher affinity for estrogen receptors in preparations from the prostate gland of the rat and whose action ip mimo is mainly directed at the ovary and not at the uterus, the preparation of such compounds, their therapeutic 1" use and pharmaceutical dosage forms containing these new compounds . These compounds are 16 4- and 16p-hydroxyester-1,3,5(10)-trienes, which may have any other substituents on the steroid skeleton, and

B-, C-, and/or O-rings may have one or more additional double bonds. -I For the treatment of reproductive disorders (fertility) in women, the cause of which in many cases is ovarian dysfunction due to surgical intervention, drug therapy or other factors, so thanks to the use of new selective estrogens, new promising possibilities for therapy also open up. o IVF fertility treatment is a method that has proven itself and has been widely practiced for more than 20 years. Numerous methods of treating infertility due to ovarian dysfunction are also known

Me. with the help of exogenous gonadotropins. At the same time, it is assumed that thanks to the introduction into the body

Gonadotropins, such as follicle-stimulating hormone (FSH), will achieve the necessary stimulation of the ovaries, which will ensure the maturation of healthy follicles.

The follicle is a structural component of the ovary and performs two functions: it is the location of oocytes dv | thus creates the conditions and opportunity for their growth and maturation. Folliculogenesis includes the period of ovarian follicle development starting from the primordial stage and ending with the antral follicle stage, which

F; gradually formed, that is, the final stage before ovulation. Only the antral follicle, which has reached the optimal degree of development, can ensure the release of a mature egg from the ovary (i.e., ovulation).

In patients with infertility due to ovarian dysfunction (the cause of which is polycystic ovary syndrome (PCOS)), the maturation of follicles is disturbed, which is associated with both hormonal and ovulatory disorders and underdevelopment of eggs. In these cases, the number of primary and secondary follicles is approximately two times greater than their number in a normally functioning ovary. bupesoi Zy, igmeu 37, 1982, pp. 59-77|.

According to some data, the early stages of folliculogenesis (which affect the stages of follicle development from 65 primordial to antral) do not depend on gonadotropins. However, to date, there is no unequivocal evidence of how great the influence of known paracrine and autocrine factors is on the early stage of folliculogenesis (|EiYimip et al., Moi. SeiYi Epadoshypoiyudu 13, 1999, p. 1035-1048; MesManu et al., doshgp Kerhod.

Eepie Z, irri. 54, 1999, pp. 3-161.

Gonadotropins, such as FSH, are involved in the maturation of follicles mainly in the final stages of folliculogenesis, that is, in the development from an early antral follicle to a mature follicle capable of ovulation.

Infertility of ip mimo and ip mygo is treated mainly with the help of gonadotropins (FSH and antiestrogens)

YiMUine and others, associate professor. Sp. Epdoshypoi. Meyer. 81, 1996, pp. 3821-3824). In the treatment of intrauterine infertility, oocytes are obtained from antral follicles that are in the preovulatory stage in order to ensure the possibility of their intrauterine maturation before the formation of an egg capable of fertilization. After fertilization and/or completion of the stage of pre-embryonic development, one to three embryos are implanted in the woman's uterus.

Treatment with exogenous gonadotropins in many respects is associated with numerous risks and side effects. The greatest risk is the danger of excessive stimulation of the ovaries, which in particularly severe cases can be a serious threat to life (ovarian hyperstimulation syndrome (OHSS)). Side effects should include, not least, significant costs associated with infertility treatment, which 7/5 married couples have to bear. Gonadotropin treatment is also associated with such negative side effects as weight gain, bloating, nausea, vomiting, and a previously unknown long-term ("delayed") risk of cancer.

One of the possible approaches, which would allow to avoid the indicated disadvantages and risks, is to initiate ip past the maturation of the follicles and stimulate their growth in infertility due to ovarian dysfunction with the help of appropriate active substances before starting treatment with exogenous gonadotropins.

Estrogen receptor-beta (EC-B)

A few years ago, a second subtype of estrogen receptors was discovered, which was designated as estrogen receptor-beta (EK-B) | Kyireg et al., Rgos. May Asai. All together. 93, 1996, pp. 5925-5930; Mozzei!tap, biiketa,

March Ietseg5 392, 1996, pp. 49-53; Tgetbriau et al., Moiesshag EEEpadoshypoirsdu 11, 1997, pp. 353-365).

The nature of expression of EK-B receptors differs from that of EKa receptors (Kiireg et al., Epdoshypoiodu 138, sch dv 1996, p. 863-870). So, in particular, EC-B receptors prevail over receptors in the rat prostate gland

EC, while in the uterus of the rat, the opposite pattern is observed: the superiority of EC receptors over EKV receptors. In o); the highest concentrations of EKV receptor mRNA were detected in the ovaries |Soizve et al., Epdoshypoiodu 138, 1997, p. 4612-4613).

The list of other organs and systems of the body with a relatively high level of expression of EKV receptors includes

Bone tissue (Opoe U. et al., Epdoshypoisdu 138, 1997, pp. 4509-4512), vascular system |Kedivieg T.S.,

Adatez M.K., Associate Professor Z(egoii. Moies. Visi. 64, 1998, p. 187-191), genitourinary tract IKiireg (.).M. ii etc., ke,

Epdoshypoiyusdu 138, 1997, p.863-870), gastrointestinal tract |Satrrei-Tporzop, VVKS 240, 1997, "from p.478-483), as well as the testicle |Mozzei!tapp 5. and others, Rerv. I enNege 392, 1996, pp. 49-53), including spermatids

IZPpydgie et al., Z(egoidz 63, 1998, pp. 498-504)|. A similar distribution of receptors in tissues indicates that estrogens regulate the functions of organs through EKV receptors. The functional role of ECV receptors in this regard is also confirmed by studies on EC fu-knockout (ECKO-), respectively, on ECV-knockout (VECKO-) mice: in ECKO-mice after ovariectomy, a decrease in bone mass is observed, which can be prevented due to estrogen substitution |Kitgo et al., Abvigasi OK7-4, Epdosgipe Zosieiu Meeiiipd Mem Ogieapv, « 1998). In the same way, estradiol inhibits the proliferation of cells of the middle lining of blood vessels and smooth muscle cells in the blood vessels of female ECKO mice (Aiani M.O. et al., Mayte Meadisipe Z, 1997, p. 545-548). Approximately this protective effect of estradiol is realized in ECKO-mice through receptors of EC Dr. The functional focus of both EC receptors is different; and ECD was confirmed by successful experiments on ECKO and DVEKKO mice. According to the obtained results, EC receptors play an important role in the uterus of adults, in mammary gland tissue, in the negative regulation of gonadotropin activity, while EC receptors are mainly involved in processes related to the physiology of the ovaries, such as folliculogenesis and ovulation (Soizve et al., Epdosgipe Kemiemuv 20, 1999, p. 358-417). (ee) Observations carried out on VEKKO mice indicate the fact that ECD receptors perform a certain function in the prostate gland and bladder: in male mice of an older age, symptoms of hyperplasia of the prostate gland and bladder are detected (Ikgede U.N. and etc., Rhos. Mai. Asad. Zsi. 95, 1998, (22) 50 p. 15677-156821. In addition, in females (Irayp O.V. and others, Rhos. Mai. Asai. Zsi. 90, 1993 , pp. 11162-11166)

Kz and in male ECKO-mice |Nezz V.A. et al., Maiige 390, 1997, pp. 509-512), as well as in female VEKKO mice (Kgede ..N.,

Rgos. May Asad All together. 95, 1998, p. 15677-15682| disorders of the reproductive function, i.e. infertility, are detected. These observations confirm the important role of estrogens, which they play in the preservation of the function of the oocyte and ovaries, as well as in the preservation of reproductive capacity.

The selective effect of estrogens on specific target organs can be ensured by taking into account the different distribution of both (F) subtypes of EC receptors in tissues, respectively, in organs due to the use of ligands specific for

GI in relation to one of the subtypes of the indicated receptors. Substances with a predominant focus of action on

EKr-receptors, and not on EKo-receptors, revealed in the experiment of ip migo from binding to receptors, described in Kiireg et al. authors (Kiireg et al., Epaoshipoiyudu 138, 1996, pp. 863-870). As for the selective effect of ligands, specific for the corresponding subtype of estrogen receptors, on estrogen-sensitive parameters of ip mimo, to date, there are no specific data on this effect.

Taking into account the above, the present invention was based on the task of obtaining compounds that would have selectivity in relation to binding to estrogen receptors in preparations from B5 of the rat prostate gland and uterus. When creating the invention, it was assumed that these compounds should show a higher affinity to estrogen receptors in preparations from the rat prostate compared to the affinity to estrogen receptors in preparations from the rat uterus. Further, it was assumed that compounds specific to ECR receptors should immediately initiate an action in the testicle that contributes to the development and preservation of fertility. At the same time, such compounds had to have a selective effect, mainly aimed at the ovaries, and not at the uterus. In addition, when creating the invention, it was assumed that the compounds proposed in it should have a certain protective effect to prevent the reduction of bone mass caused by hormonal insufficiency, which is superior in comparison with the action that stimulates the uterus.

In addition, when creating the invention, it was intended to propose such a relationship between the chemical structure and its characteristic action, which would allow obtaining compounds with the above-described set of pharmacological 7/0 properties. In accordance with the invention, the compounds proposed in it, in case of infertility due to ovarian dysfunction, should actively contribute to the improvement of reproductive function by their effect on the ovaries, while at the same time reducing the effect on the uterus.

This problem is solved in accordance with the invention with the help of the proposed 9-substituted ester-1,3,5(10)-triene derivatives of the general formula I c re od 9; I AV but what

Кк 0х in which the residues VU, 7, 7, VU, VZ, Vb, v and VT independently of each other have the following values:

BZ means a hydrogen atom or a group BZ, where ch 25 BZ is a straight-chain or branched, saturated or unsaturated hydrocarbon residue, (o) which contains up to 6 carbon atoms, a trifluoromethyl group, an aryl, heteroaryl or aralkyl residue or an aryl or heteroaryl residue substituted methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano group, halogen (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C. dalalkyl)amino- or di (C. dalalkyl)amino group, where both alkyl groups are identical or different, di(aralkyl)uamino group, where both aralkyl groups are identical or different, carboxyl, carboxyalkoxy group, C oracyl or C. odacyloxy group, acyl residue SOKU, where KU is o a straight-chain or branched, saturated or up to three-fold unsaturated, partially or fully halogenated hydrocarbon residue containing up to 10 carbon atoms, or

B "8 represents the group B2950»5., where 229 represents the group B?B22M, in which

In 822, independently of each other, mean a hydrogen atom, C. a alkyl residue, a C(O)B2U group, in which 223 is a straight-chain or branched, saturated or up to three-fold unsaturated, partially or "fully halogenated hydrocarbon residue containing up to 10 carbon atoms, cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl group, Su5cycloalkylalkyl residue with 3-7 carbon atoms in - with a cycloalkyl fragment and with an alkyl fragment containing up to 8 carbon atoms, or in» aryl, heteroaryl or an aralkyl residue, or an aryl or heteroaryl residue, substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano group, - halogen (fluorine, chlorine, bromine, iodine), hydroxy-, co-amino -, mono(C.alkyl)amino- or di(C.alkyl)amino group, where both alkyl groups are identical or different, o di(aralkyl)amino group, where both aralkyl groups are

F 20 identical or different, carboxyl, carboxyalkoxy group, C. oracyl or C..20 g» acyloxy group, or together with the M-atom mean a polymethyleneimino group with 4-6 atoms or a carbon morpholino group, 29 V'/yev" each independently of each other means a hydrogen atom or a halogen atom, KU represents

HF) a straight-chain or branched alkenyl or alkynyl residue with 2-6 carbon atoms, which may be partially or fully fluorinated, or an ethynyl or prop-1-ynyl residue,

BZ represents a metal group or an ethyl group, and B5 represents a hydroxy group or a group of B190-, K20505- or ОС(ОБ2, where B8, 829 23 each has the value specified when revealing the values of the radical B,

BB each independently means a hydrogen atom or a halogen atom. "8 in each case can be in the u- or b-position.

According to one of the variants of implementation of the invention, the preferred ones include gonatriene derivatives, where Viv bo means a hydrogen atom, KZ is a vinyl, ethynyl or prop-1-ynyl group, B 15 means a hydroxy group,

and VT in" each means a hydrogen atom.

The following combinations of substitution schemes with halogen atoms, preferably fluorine, near the C atom in positions 7 and 17 are preferred: either 7-mono 7-di, and B17 and 17 each mean hydrogen, or 17-mono 17-di and B' and 27 each means hydrogen, as well as 7-mono/17-mono, 7-mono/17-di, 7-di/17-mono, 7-di/17-di. In monofluorosubstituted compounds, position 7 is preferred, respectively position 178.

According to another embodiment of the invention, compounds where 279 is a group are preferred

В'8О- or К29850».-О-, while В Z и 229 each has the value specified when revealing the values of the KZ radical.

Preferred according to the present invention include the following compounds: 9o-vinyl ester-1,3,5(10)-trien-3,1bo-diol, U-allyl ester-1,3,5(10)-trien-3, 16 u -diol, 18a-homo-9o-vinyl ester-1,3,5(10)-trien-3,16u-diol, 18a-homo-9Uu-allylester-1,3,5(10)-trien-3, 16 -diol,

3-Methoxy-9o-vinyl ester-1,3,5(10)-trien-16u-ol, Ux-allyl-3-methoxyestra-1,3,5(10)-trien-16u-ol, 18a-homo- 3-methoxy-9o-vinyl ester-1,3,5(10)-trien-16b4u-ol, 75 8va-homo-Uu-allyl-3-methoxyestra-1,3,5(10)-trien-16o-ol , 9-(22'-difluorovinyl)estra-1,3,5(10)-triene-3, 16 o-diol, 9oa-(2,2-difluorovinyl)-3-methoxyestra-1,3,5(10 )-trien-16u-ol, 1α-hydroxy-Za-vinyl ester-1,3,5(10)-trien-3-ylsulfamate, 9o-allyl-1bu-hydroxyester-1,3,5(10)-triene -3-ylsulfamate, 18a-homo-16bo-hydroxy-9Uu-vinyl ester-1,3,5(10)-trien-3-ylsulfamate, 18a-homo-9u-allyl-1bo-hydroxyester-1,3,5 (10)-trien-3-ylsulfamate,

U9o-vinyl ester-1,3,5(10)-triene-3,16u-diyldisulfamate, U9u-allylester-1,3,5(10)-triene-3,16u-diyldisulfamate, 18a-homo-9u-vinylester- 1,3,5(10)-triene-3,16u-dyldisulfamate, 18a-homo-Uu-allylestra-1,3,5(10)-triene-3,16u-dyldisulfamate, sc dv bo-hydroxy-Uo -vinyl ester-1,3,5(10)-trien-3-yl-(M-acetyl)sulfamate,

C9o-allyl-1bu-hydroxyester-1,3,5(10)-trien-3-yl-(M-acetyl)sulfamate, o 18a-homo-16bu-hydroxy-9Uu-vinylester-1,3,5(10 )-trien-3-yl-(M-acetyl)sulfamate, 18α-homo-9y-allyl-1bu-hydroxyestra-1,3,5(10)-trien-3-yl-(M-acetyl)sulfamate,

39o-(prop-(2)-enyl)estra-1,3,5(10)-triene-3,16 y-diol, Uy-(n-propyl)estra-1,3,5(10)-triene -3,16 y-diol, c 9oe-ethynylestra-1,3,5(10)-triene-3,1b y-diol, Uu-vinyl ester-1,3,5(10)-triene-3,16y- diol diacetate, Ge 18a-homo-9u-vinyl ester-1,3,5(10)-trien-3,16 y-diol diacetate, 1bu-valeroyloxy-9Uu-vinyl ester-1,3,5(10)-trien-3- ol, 16u-acetoxy-9Uu-vinyl ester-1,3,5(10)-trien-3-ol, 18a-homo-16bu-acetoxy-ZU9u-vinyl ester-1,3,5(10)-trien-3- ol, oh

To-fluoro-9o-vinyl ester-1,3,5(10)-triene-3,16u-diol, 7o-fluoro-9o-allylester-1,3,5(10)-triene-3,16u-diol , (ee) 17B-fluoro-9o-vinyl ester-1,3,5(10)-triene-3,16.-diol, 17 D-fluoro-Uu-allyl ester-1,3,5(10)-triene- 3,1vo-diol, chn 18a-homo-7o-fluoro-9o-vinyl ester-1,3,5(10)-triene-3,16-diol, 18a-homo-7o-fluoro-9u-allylester-1, 3,5(10)-triene-3, 16-diol, 1va-homo-17 VD-fluoro-9o-vinyl ester-1,3,5(10)-triene-3,16b-diol, " 1va-homo- 17VD-fluoro-9Uo-allylester-1,3,5(10)-triene-3, 16-diol.

Other possible variants of the invention are presented in the dependent clauses of the claims. The hydrocarbon residue B'Z can be, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.

Alkoxy groups ОВ "З in compounds of the general formula I can contain 1-6 carbon atoms, respectively, methoxy-, ethoxy-, propoxy-, isopropoxy- and tert-butyloxy groups are preferred. - 395 As representatives of Su alkyl residues 221 Its 822 can be called methyl , ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl, etc. As representatives of straight-chain or branched hydrocarbon residues, which contain from 1 to a maximum of 10 carbon atoms, we can name, for example, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl, the predominant among them being methyl, ethyl, propyl and isopropyl. , -pentyl, -hexyl or -heptyl

GC group.

Su 15cycloalkylalkyl residue contains 3-7 carbon atoms in the cycloalkyl fragment, typical representatives are the above-mentioned cycloalkyl groups, the alkyl fragment of which contains up to 8 carbon atoms. Examples of C) 15-cycloalkylalkyl residue include cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl and other similar groups. (F) By aryl residue in the context of this description is meant a phenyl, 1- or 2-naphthyl residue,

The predominant GI is the phenyl residue.

The term "aryl" in all cases also includes a heteroaryl residue. Examples of heteroaryl residues are 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or

B-pyrimidinyl and 3- or 4-pyridazinyl.

Substituents that can be used in an aryl or heteroaryl residue include, for example, a metal, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano group, halogen (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C.alkyl)amino- or di(C.alkyl)amino group, in which both alkyl groups are identical or different, di(aralkyl)amino group, where both aralkyl groups are identical or different, carboxyl , a carboxyl alkoxy group, S. .»racyl or Su. oracyloxy group.

An aralkyl residue is a residue that contains 14, preferably 6-10, C atoms in the ring, and 1-8, preferably 1-4, C atoms in the alkyl chain. Accordingly, as aralkyl residues can be considered, for example, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl.

Alkyl groups, respectively, hydrocarbon residues can be partially or completely replaced by 1-5 halogen atoms, hydroxy groups or C. lalkoxy groups.

By Co valkenyl residue is primarily meant a vinyl or allylic residue. Under

C»o.valkynyl residue preferably means ethynyl or prop-1-ynyl residue.

Like Su. radical residues can be considered acetyl, propionyl, butyryl, valeroyl, isovaleroyl, pivaloyl, 76 hexanoyl, octyl, nonyl or decanoyl.

One or both hydroxyl groups near C-atoms C and 16 can be esterified with aliphatic, straight-chain or branched, saturated or unsaturated C). 1/ mono- or polycarboxylic acid or aromatic carboxylic acid. Monocarboxylic acids such as formic acid, acetic acid, propionic acid, /5 butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid can be considered as similar acceptable for esterification of carboxylic acids. , propionic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid and elaidic acid. Valerian acid or pivalic acid is preferred for esterification.

Dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, cork acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid or mesanoic acid, and aromatic carboxylic acids such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o0-, m- and p-toluic acid, hydrotropic acid, atropic acid, cinnamic acid, nicotinic acid or isonicotinic acid . Preferential esterification using benzoic acid.

The esters of 9o-substituted estratrienes proposed in the invention have many advantages as prodrugs in comparison with i) non-esterified active substances regarding the mode of their introduction into the body, the principle of their action, their effectiveness and the duration of their action.

First of all, the He sulfamates of 9y-substituted estratrienes proposed in the invention differ in their pharmacokinetic and pharmacodynamic advantages. Similar effects, but which are achieved with the use of other steroid sulfamates, have been described earlier (Oigp.

Ipmevi Ogodz 7, 1998, pp. 575-589). And Av

This specification discusses steroids based on a skeleton of 9 y-substituted estra-1,3,5(10)-trienes and so intended for the treatment of estrogen receptor-beta-mediated disorders and disease states as selective estrogens having ip myo selectivity in relation to their binding to estrogen receptors in preparations from the prostate gland and uterus of the rat and which show a predominant effect on the ovaries and not on the uterus. In addition, these compounds have a certain protective effect to prevent the decrease in bone mass caused by hormonal insufficiency. "

According to the invention, it has been found that 390-substituted estra-1,3,5(10)-trienes of the general formula are suitable as selective estrogens for the treatment of various disease states and disorders associated with a higher content of no) in the corresponding target or in the corresponding target organ of estrogen receptors-beta in comparison with the content of estrogen receptors-alpha in them.

The invention also relates to pharmaceutical preparations containing at least one compound of the general formula

Y (or its physiologically compatible additive salts with organic and inorganic acids), and the use of compounds of the general formula I for the preparation of appropriate medicinal products, primarily medicinal products intended for use in the following indications. Estrogens described in this application can be used as a single component in a pharmaceutical composition or in combination primarily with progestogens. Especially preferable is the combination of selective estrogens with selective in relation to EC receptors o, o antiestrogens, which have a selective effect in relation to the peripheral system, that is, which do not pass through

F 250 blood-brain barrier, as well as with selective modulators of estrogen receptors (SMER).

The compounds proposed in the invention with a selective effect on ECRD receptors can primarily be used for the preparation of drugs intended for the treatment of reproductive function disorders (fertility), for the prevention and therapy of prostate hyperplasia, for the prevention and treatment of mood swings in women and men, caused by hormonal insufficiency, as well as for use in hormone replacement therapy (HRT) in men and women.

GF) Therapeutic product containing estrogen and pure antiestrogen for simultaneous, sequential or separate use in selective estrogen therapy of ailments in the perimenopausal or postmenopausal period, described in (application EP-A 0346014).

The compounds proposed in the invention and pharmacological agents containing these compounds, due to their selective action 60 on the ovaries in comparison with the action on the uterus, are particularly suitable for the treatment of ovarian dysfunction caused by surgery, drug therapy or any other causes, such as female infertility, to stimulate folliculogenesis, to treat only to improve fertility, to improve the effectiveness of IVF in combination with IVF and to treat age-related ovarian disorders ("late fertility"), as well as for therapy for ovarian diseases, such as polycystic ovary syndrome, premature ovarian failure syndrome, and ovulation disorders.

Another possibility of using compounds of the general formula | is that they are used in combination with selective estrogen receptor modulators (SERs), such as raloxifene, namely: primarily in hormone replacement therapy (HRT) and for the treatment of gynecological disorders.

The compounds proposed in the invention are further suitable as a separate component for the treatment of ailments in the peri- and postmenopausal period, primarily such as hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy and mental disorders caused by hormone deficiency. Also, the specified compounds can be used for hormone replacement and for the therapy of disorders associated with hormonal insufficiency in 7/0 ovarian dysfunction caused by surgery, drug therapy or any other causes.

In addition, the compounds proposed in the invention can be used to prevent bone loss and osteoporosis caused by hormone deficiency, to prevent diseases of the cardiovascular system, primarily angiopathy, such as atherosclerosis, arterial hypertension, and to prevent neurodegenerative diseases caused by hormone deficiency, such as such as Alzheimer's disease, as well as hormone-related memory and learning disorders.

These compounds can be used further as an active substance in preparations intended for the treatment of inflammatory diseases and diseases of the immune system, primarily autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease and other inflammatory bowel diseases, 2o inflammatory skin diseases , such as psoriasis, as well as for the treatment of endometriosis. In addition, the compounds proposed in the invention are also effective against inflammatory diseases of the respiratory tract, lungs and bronchi, such as, for example, asthma.

The drug, which contains the specified compounds, is suitable for the therapy and prevention of diseases caused by estrogen deficiency in both women and men. high school

When prescribed to men, the compounds according to the invention can primarily be used for the therapy of bone mass reduction and osteoporosis caused by hormonal insufficiency, for the prevention of io) cardiovascular diseases, primarily angiopathy, such as atherosclerosis, arterial hypertension and for the prevention of neurodegenerative diseases caused by hormone deficiency, such as such as Alzheimer's disease, and hormone-related memory and learning disorders, as well as for the prevention and treatment of prostatic hyperplasia.

Another possibility of using these compounds is the prevention and therapy of age-related dysfunctions or diseases in men. Primarily, these compounds can be used to prevent and treat age-related decline in androgen secretion, such as testosterone and dihydroepiandrosterone (DHEA), as well as growth hormone. co

The drug containing the compounds of the invention can further be used for the treatment of inflammatory diseases and diseases of the immune system, primarily autoimmune diseases in men, such as, for example, rheumatoid arthritis, multiple sclerosis and Crohn's disease, as well as other inflammatory bowel diseases, as well as inflammatory diseases of the respiratory tract, lungs and bronchi.

The amount of the corresponding compound of the general formula I that is prescribed varies widely and is determined by the achievement of the required effect. Depending on the condition to be treated and the method of injection, this amount of the prescribed compound can be from 0.01 µg/kg to 100 µg/kg of body weight, preferably from

O,b4mcg/kg to mg/kg of body weight, per day. For humans, this corresponds to a daily dose of 0.8 μg to 8 g, mostly from 33.2 μg to 8 μg. According to the invention, one unified dose contains from 1.bmcg to 200mg of one or more compounds of the general formula I.

The compounds proposed in the invention and their acid addition salts are suitable for the preparation of pharmaceutical formulations and compositions. Pharmaceutical formulations, respectively, medicinal products contain as an active ingredient one or more compounds according to the invention or their acid-addition salts, if necessary, in a mixture with other pharmacological, respectively pharmaceutically effective substances. Medicinal products are manufactured according to known technology, using for this purpose usual, known auxiliary pharmaceutical substances, as well as other

Generally accepted carriers and diluents. me) How similar carriers and excipients can be considered, for example, those that are recommended or

Ge are indicated as auxiliary substances for use in pharmaceuticals, cosmetics and related fields in the following literary sources: |ШПИТапе ЕпсуКиорадие дег иеспизспеп SPpetiye, 1953, vol. 4, p. 1-39; dTsotsgpa! oh

Rpagtaseciisa! Zsiepsev, vol. 52, 1963, p. 918 et seq., N. M. Sleivsp-I ipaepulaid, NinevioPe iTig Rpagtalie pa apdgepgepde Sebrieie; React. Ipa., Mo2, 1961, p. 72 et seq.: Og. N.R. Riedieg, Gehikop deg Niizwiobe Tig

RNagtpagie, KoziteikK ipa apdgepgepade Sebieie, vid-vo Sapiog KO, Ashepaop ip Uuigschetrega 19711.

F; The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or transdermally. The compounds can also be implanted into tissue. Capsules, pills, tablets, dragees, etc. can be prescribed for oral use. Uniform doses together with the active substance may contain a pharmaceutically acceptable carrier, such as, for example, starch, sugar, sorbitol, gelatin, lubricants, silicic acid, talc, and others.

For parenteral administration, active substances can be dissolved or suspended in a suitable physiologically compatible diluent. As diluents in many cases, oils are used with or without the addition of a dissolution promoter, surfactant, suspending agent or emulsifier. Examples of oils used include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil.

The compounds can also be used in the form of injections or an implanted drug, the composition of which can be selected in such a way as to ensure the gradual release of the active substance, that is, to ensure a prolonged effect.

Implants can contain either inert materials such as biodegradable polymers or synthetic silicones such as silicone rubber. In addition, in the case of transdermal application, the active substances can, for example, be immersed in a patch.

To obtain intravaginal systems intended for local administration, which contain active compounds of the general formula I! (for example, vaginal rings) or intrauterine systems (for example, pessaries, 70 spirals, IUDs, MigepaF) various polymers are suitable, such as, for example, organosilicon polymers, ethylene vinyl acetate, polyethylene or polypropylene.

To achieve preferential bioavailability of the active substance, the compounds according to the invention can also be used for the formation of cyclodextrin clathrates. For this purpose, such compounds are subjected to interaction with f-, d- or y-cyclodextrin or their derivatives (PCT/ЕРОБ/02656).

According to the invention, compounds of the general formula | can also be "encapsulated" in liposomes.

The affinity of the new selective estrogens was studied in experiments on competitive binding on preparations of estrogen receptors from the prostate gland and uterus of the rat using ZN-estradiol as a ligand. For the preparation of prostatic cytosol preparations and for conducting an experiment on binding to estrogen receptors using prostatic cytosol, the method described in Testas and other authors was used | Gesvziasis 4). et al., Epdoshypoiodu 109, 1981, pp. 1287-1289).

For the preparation of preparations of rat uterine cytosol, as well as for carrying out experiments on binding to receptors using cytosol containing the EC receptor, the method described in 5iasK and Sogeki (Epaosgipoiosdu 117, 1985, pp. 2024-2032) was mainly used. , with some modifications described in

Eipptpapp M. and others. Sopigaseriiop 51, 1995, p. 45-52). Ge

The substances presented in this application have a higher affinity for estrogen receptors from the rat prostate compared to the affinity for estrogen receptors from the rat uterus. At the same time, they proceed from the fact that in the prostate gland of the rat, EKV receptors prevail over EC receptors, while in the uterus of the rat, the opposite picture is observed: the superiority of EC receptors over ECR receptors. The data presented below in Table 1 indicate that the ratio between the degree of binding to receptors from the prostate gland and the degree of binding to receptors from the uterus is qualitatively consistent with the relative affinity (BA) coefficient for human ECD receptors and rat EC receptors (according to Kyireg et al.,

Epdoshypoiodu 138, 1996, pp. 863-8701. at

Zhklragno | Structure: |People| People. GEKDK| VC BA); ren zero M

Py il SHYNY pod do 0 x pat " s Y is shchi --Й g. y - a : "v |zavsvnyk| SN v i mn nyn she VO Z vot ven tut I pa A Sa Kit tin u ty KY rya ll aKv a Kr tu ploti ryuh rus s er oyu | VP TWEN EV

Bey Me not her iy rn o i ZM yu kp i 00 y tyu u t Mi Zh liky NK

F) I them wai kkasdkh Mine ih Shchi i ik Vinyeiilei skh with VE before VKA sly yu we provin ninenimya poured out ili M they delonUnnYa; i news vv

Zo-vinyl ester-1,3,5(10)-17-3,16o-diol(2) 2,200

The target number was 00010218

The compounds 1, 2, 4 and 5 proposed in the invention show a higher affinity to estrogen receptors from the rat prostate compared to the affinity to estrogen receptors from the rat uterus.

In addition, in the course of ip mimo experiments conducted on test systems containing, respectively, receptors of the prostate gland and receptors of the uterus, it was possible to confirm the superiority of the first of them in terms of selective action in relation to the tissue. In a comparative study of substances with a higher affinity for estrogen 70 receptors from the prostate gland in relation to their effect on the ovaries and uterus, as well as on the pituitary gland, it was established that they show selectivity, mainly affecting the ovaries.

The effect that the compounds proposed in the invention have on uterine growth and ovulation (an indirect effect due to the influence of pituitary hormone secretion) was studied on adult female rats (weighing 220-250g). Test compounds were administered to animals four times over four days. The first dose was administered during metestrus. Five days after the administration of the last dose, the animals were killed, an autopsy was performed, and the number of oocytes in the tube was counted (analysis of the effect on ovulation), as well as the weight of the uterus was determined.

The obtained data indicate that estradiol, depending on the administered dose, inhibits ovulation and stimulates an increase in the weight of the uterus at EO»ko, which is equal to 0.004 mg/kg of body weight, while the compound 1 proposed in the invention when administered in a dose of up to 0 , 4mg/kg of body weight, does not affect ovulation and the weight of the uterus.

The compounds were tested ip mimo in hypophysectomized, young (not yet mature) female rats. Using this modified operative method, animals were injected with a SspKkN antagonist.

The purpose of such an experiment was to find out whether the applied substance stimulates the proliferation (maturation) of follicles in the ovary. The measured parameter is the mass of the ovary.

From the experimental animals, groups of five randomly selected individuals (weighing 40-50g) were formed in each group. The animals were kept in macrolon cages in rooms with an artificial climate under the conditions of the appropriate light regime (1 hour in the dark, 14 hours under normal lighting), while the animals had free access to standard food (altrumin) and acidified tap water. When administered subcutaneously, the tested compound, as well as the control substance (estradiol E2), was dissolved in a mixture of benzyl benzoate and castor oil (volume ratio 1:4). c zo In young female rats, on day 0, the pituitary gland was removed, and during the time period from the 1st to the 4th day, inclusive, they were injected subcutaneously (once daily) with estradiol, compound 1 proposed in the invention, compound 2, respectively, or only the solvent (castor oil /benzyl benzoate). With the help of the indicated modified method, cetrorelix at a dose of 0.5 mg/animal/day was administered to the animals simultaneously with compound 2, respectively, with the solvent and the control substance estradiol for all four days. In both cases, animals after 24 hours. after the administration of the last dose of COZ5, they were killed and the mass of their ovaries was determined. Cha

In hypophysectomized animals, which were injected subcutaneously with compound 1 at a dose of 0.5 mg/animal/day for 4 days, an increase in the mass of the ovary was observed, comparable to the effect of estradiol when it was administered in a dose

About 1 Tmg/animal/day. The solvent has no effect.

Thus, the compound 1 proposed in the invention has a selectivity of action, which is mainly aimed at the ovary, and not at the uterus and pituitary gland, and due to its stimulating effect on the follicles, it can be used exceptionally successfully for such a predominant indication, which is the female sterility.

In animals that were injected with compound 2 along with the SpEKH antagonist, this compound, already at a concentration of 0.1-0.1 mg/animal/day, had the same effect on the ovary as estradiol when it was used in a dose of 1 mg/animal/day. day (see Fig. 1). Even at a lower dosage (0.01, 0O,OZmg/animal/day) compound 2

It affects the ovary and allows you to eliminate the antagonistic effect of cetrorelix (see Fig. 2). -I Thus, the compound 2 proposed in the invention also has a noticeable positive effect in relation to the ovary, which is manifested in the stimulation of the maturation of follicles, which allows it to be used in the same way for the treatment of various disorders of the reproductive system in women or female infertility. o For the synthesis of the compounds proposed in the invention of the general formula | you can use primarily two

General approaches.

Me, According to one of them for modifications of some provisions of the steroid skeleton can be used in

Primarily 3,16-protected derivatives of ester-1,3,5(10)-triene-3,162-diols, and under certain conditions also free diols.

Another approach allows the use of appropriately modified estrone analogues, many of which can be obtained by known methods | see examples of similar synthesis methods. in addn. Spent Zos. RegkK. 1, 1973, p. 2095 for the C atom in position 9; Ziegoidv 54, 1989, p. 71 for the C atom in position 7), due to the movement (transposition) of the oxygen function (7. Spet., 1970, p. 221 | from C(17) to C(16), and such approach

Ф, allows changing the possibilities of obtaining the compounds proposed in the invention. ko In the case of 3-methyl ether, after the conversion of ketone into sulfonylhydrazone, in the simplest case by interaction with phenylsulfonylhydrazide, as a result of the destruction reaction, C(16)-C(17)olefin C2 is formed. in Spet. 10, 1970, p. 221 et seq.; Predv App. Spet., 1981, p. 1973 et seq.!) to which hypobromide is added by regio-/stereo-controlled synthesis. After reductive dihalogenation and removal of the protective group in C(3), 16B-alcohol is obtained, which can be converted into 1bu-epimer by known methods.

According to another variant of the introduction of a hydroxyl group near the C atom in position 16, hydroboration of the 16(17) double bond is carried out with sterically hindered boranes. It is known that this reaction leads to 65 the formation of oxygenated products in position 16 (Ipaiap dosgp. Spet. 9, 1971, p. 287-288). According to this interaction of estra-1,3,5(10),16-tetraenes, for example, with 9-borabicyclo|3.3.1|nonane after oxidation with alkaline hydrogen peroxide, 16bo-hydroxyestratrienes are obtained. Epimeric 16p-hydroxysteroids are formed in less significant quantities during this reaction. After cleavage of the 3-methoxy group, ester-1,3,5(10)-triene-3,16 o-diols are obtained.

Due to the inversion of the configuration near the C atom in position 16, for example, by the reaction of Mitsunobu (Zupipeviv 1, 1980), it is also possible to obtain 16p-hydroxyestratrienes.

Other possibilities of obtaining intermediate C(16)-C(17)olefins are also described in (application OE 19906159 AT).

Fluorine substituents are introduced by reactions of nucleophilic substitution of hydroxyl groups with fluoroamine reagents (Oga. Keasi. 21, 1974, p. 158-173)|. If the hydroxyl groups are previously converted into the corresponding tosylates, then in these cases fluorinated compounds are obtained by interaction with tetra-n-butylammonium fluoride (Choigp. Spet. Kev. 70. (M), 1979, pp. 4728-4755). It is also possible to obtain fluorinated compounds by the interaction of the corresponding alcohols with diethylaminosulfur trifluoride (TDAS) (05 3976691). Geminal difluoride compounds can be obtained, for example, by the reaction of carbonyl compounds with sulfur tetrafluoride (5 3413321| or with diethylaminosulfur trifluoride (TDAS) I (patent OB 3979691). For the synthesis of 9 y-substituted 17rD-fluoroester-1,3,5 (10)-triene-3,16-diols 17-oxoestra-1,3,5(10)-trienes are converted into 79.17,17-difluoroester-1,3,5(10)-trienes (05 39766911. Obtained in this way 17,17-difluoroester-1,3,5(10)-trienes will be converted into 17-fluoroester-1,3,5(10)-tetraenes by treatment with aluminum oxide (05 3413321). Another possibility of obtaining fluoroolefins is , that the corresponding ketones are reacted with diethylaminosulfur trifluoride (TDAS) in the presence of polar catalysts, such as fuming sulfuric acid (05 4212815).

The interaction of 17-fluoroester-1,3,5(10),16-tetraenes with boranes and subsequent oxidation with alkaline hydrogen peroxide yields 17B-fluoroester-1,3,5(10)-triene-16-choles (Ogo. Keasi. 13, 1963, pp. 1-54).

For the synthesis of the 9"e-alkenyl-, respectively 9o-alkynyl-substituted ester-1,3,5(10)-triene-3,16bodiols proposed in the invention, the protected in position C and 16 are first obtained

C,16-dihydroxyester-1,3,5(10)-trienes. Then, by interacting with trimethylsilylcyanide in the presence of lithium perchlorate, regio- and stereoselective 9 o-cyano grouping is introduced (Zupiei, 1992, p. 821-822). After removal of the protective groups, the 9u-cyano compound is first converted into the 9 5-formyl compound by reduction, (o) which is then converted into the 9 oF-alkenyl-, respectively

C9o-alkynyl-substituted compound.

The sulfamates of estratrienes proposed in the invention can be obtained according to known technology from the corresponding SM hydroxysteroids by esterification with sulfamoyl chlorides in the presence of the base |2. Spent 15, 1975, pp. 270-272; Z(egoiaz 61, 1996, p. 710-717). ish

As a result of the subsequent acylation of the sulfamate group, the av) (M-acyl) sulfamates proposed in the invention are obtained, for which positive pharmacokinetic properties have already been confirmed, see OEE 19540233 JSC. co

Regioselective esterification of polyhydroxylated steroids with M-substituted and M-unsubstituted /-|che sulfamoyl chlorides is carried out after partial protection of those hydroxyl groups that should not undergo esterification, that is, remain unesterified. As protective groups with selective reactivity suitable for this purpose, silyl ethers have proven themselves, since under the conditions of sulfamate formation, they "remain stable, and their repeated cleavage to regenerate the other hydroxyl group(s) still preserved in the molecule group(s) does not affect the sulfamate group ((egoidz 61, 1996, p. 710-717). - c The sulfamates proposed in the invention with one additional hydroxyl group in the molecule can also be obtained on the basis of hydroxysteroid ketones acceptable for such purposes. Initially, depending on the set and" purpose, one or more available hydroxyl groups are subjected to sulfamoylation. After that, the sulfamate groups, if necessary, can be converted using the necessary acyl chloride in the presence of a base into the corresponding (M-acyl)usulfamates. The resulting oxosulfamates or oxo(M-acyl)sulfamates due to - And the reduction will be converted into the corresponding hydroxysulfamates or hydroxy(M-acyl)sulfamates |Z(egoiaz 61, 1996, p tor. 710-717). It is advisable to use sodium borohydride and borane-dimethylsulfide bo complex as reducing agents. (ав) Below, the invention is explained in more detail by means of examples. o 50 Analogously to the construction of the 9a-vinyl group using reagents homologous to the reagents described in the examples, other compounds of the general formula can be obtained. that) Etherification of free hydroxyl groups to a simple and/or complex ether is carried out by methods well known to specialists.

Example 1

ZU9o-vinylester-1,3,5(10)-triene-3, 16u-diol o Stage 1

ZU9o-cyano-3-methoxyestra-1,3,5(10)-trien-16 y-yl acetate de To a suspension of 2.13 g (b49mmol) of 3-methoxyestra-1,3,5(10)-trien-16 (-yl acetate, 2.07 ml (16.54 mmol) of trimethylsilyl cyanide and 0.14 g of lithium perchlorate in 100 ml of methylene chloride, while stirring, add dropwise a solution of 2.21 g (9.7 mmol) of 2,3-dichloro-5,6-dicyano-1 . contains products chromatographed on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 6:11). In this way, 0.44 g (21965) of d9o-cyano-3-methoxyestra-1,3,5(10)- of trien-16 y-yl acetate.

Stage 2

Cyano-3-hydroxyester-1,3,5(10)-trien-16-butyl acetate

To a solution of 0.59 g (1.67 mmol) of 9a y-cyano-3-methoxyestra-1,3,5(10)-trien-16 y-yl acetate in 30 ml of acetonitrile, 7.51 g (50.1 mmol) is added with stirring in an argon atmosphere ) of sodium iodide and 8.87 ml (70.14 mmol) of trimethylenechlorosilane. After approximately 10 minutes at 60-702C, the reaction is complete. The reaction solution is poured into a sodium hydrosulfite solution and extracted with acetic acid ethyl ether. The organic phase is washed several times with water, dried over M950, and concentrated to dryness in a vacuum. The crude product is chromatographed on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 4:1). In this way, 70 0.43 g (7695) of the required product are obtained.

Stage C 3,160-dihydroxyester-1,3,5(10)-triene-9-carbonitrile 0.43g (1.27mmol) 9 "o-cyano-3-hydroxyester-1,3,5(10)-triene-1bu -yl acetate is stirred at room temperature for 2 hours with 1.0 g (7.24 mmol) of potassium carbonate in 40 ml of methanol (at a water content of 195). Then 72 methanol is distilled off in a vacuum and the organic residue is dissolved in methylene chloride. The organic phase is washed with water and concentrated. As a result, 3.5 g (9390) of 9Zo-cyanoester-1,3,5(10)-triene-3,16u-diol are obtained.

Stage 4 3,16bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde

A suspension of L1O0O0 mg (0.34 mmol) of 3,16 f-dihydroxyester-1,3,5(10)-triene-9-carbonitrile in 40 Oml of toluene 720 is cooled with stirring to a temperature of the order of -20 C. After adding O.Oml (1 .35 mmol) of diisobutylaluminum hydride suspension after about 10 minutes is mixed with sodium bicarbonate solution, filtered through celite and the precipitate on the filter (which is also the filter medium) is extracted with ethyl acetic acid. The combined organic phases are washed with water. After concentration of the solution in high vacuum, 84.bmg of a light yellow foamy substance is obtained. The amount of product contained in the mixture corresponds to a yield of about 5295 of theory, and without further chromatographic processing (o) the product is used in the next step.

Stage 5

ZU9o-vinyl ester-1,3,5(10)-trien-3, 16 u-diol c zo In an inert gas atmosphere, 3.1 g (7.9 μmole) of triphenylmethylphosphonium iodide and 0.24 g (vmmol) of sodium hydride (8095 paraffin oil) in 20 ml of DMSO are subjected to interaction in an ultrasonic bath at a temperature of the order of 5596. After 10 minutes, 8 mg (0.1 mmol, approximately boOdr) of 3,16o-dihydroxyester-1,3,5(10)-triene of 9-carbaldehyde and the reaction is continued for a few minutes at the same temperature of the order of 552C in an ultrasonic bath. After adding water, it is extracted with acetic acid ethyl ether. The collected organic phases are washed with water and the organic phase is concentrated in a vacuum. Their crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl ether in a ratio of 2:1) and subsequent recrystallization from chloroform.

Yield: 24mg (5095), melting point: 88-95260. "7"H-NMR (400MHz, DMSO-4dv, TMS): 9.00 (in, 3-OH); 6.98 (a, 9-86 Hz, H-1); 6.49 (da, 9U -8.6/2.7Hz, H-2); 40. vd (а, у0-2.7Hz, H-4); 6.25 (ad, 9-17.2/10.5Hz, -СНеСН» ); 5.00 (ad, 10.5/1.9Hz, -СНеСН»); 4.47 (a, 4.69Hz, 162-OH); C c 4.45 (aa, 17.2/1, 9Hz, -SNASN"); 4.24 (t, 168-H); 2.68 (t, H-6); 0.69 (c, H-18). y" Example 2

U9o-vinyl-1va-homoester-1,3,5(10)-triene-3,1bo-diol

Stage 1 -1 15 3,16o-bis(hydropyran-2-yl)oxy|-1b8a-homoester-1,3,5(10)-triene-9-carbonitrile 1.03g (2.2bmmol) 3.16o -bis((perhydropyran-2-yl)oxy)|-18a-homoestra-1,3,5(10)-triene, 48.2 mg (0.45 mmol) of lithium perchlorate and 0.71 ml (5.6 mmol) of trimethylsilyl cyanide placed in TOml of methylene chloride (molecular sieve) and cooled in an atmosphere of inert gas with stirring to a temperature of the order of -7020. Then 0.77 g (3.39 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dissolved in bbml, is added dropwise within 1 Th

Me. methylene chloride. After approximately 1 hour (warming to room temperature), the reaction solution is mixed with sodium bicarbonate solution and the reaction products are extracted with methylene chloride. The crude product obtained after the concentration of the organic phases is purified by chromatography. After chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 4:1), 0.74 g (6890 from dv theory) of the required product are obtained.

Stage 2

F) 3,16o-dihydroxy-18a-homoestra-1,3,5(10)-trien-9-carbaldehyde co 1.9g (2.7mmol) 3,16o-bis((perhydropyran-2-yl)oxy |-18α-homoester-1,3,5(10)-triene-9-carbonitrile is dissolved in 40 ml of toluene and mixed at room temperature in an inert gas atmosphere with 7.2 ml molar in toluene). After 30 minutes, during which the reaction continues, a mixture of 30 ml of methanol and 30 ml of dilute hydrochloric acid is added to the solution (the ratio of the components in the mixture is 1:1). Then the reaction solution is concentrated in a vacuum and the residue that is formed is dissolved in acetic acid ethyl ether. The obtained organic phase is extracted with water and washed with sodium bicarbonate solution. After drying the solution and concentrating in vacuo, 0.73g of 65 (8695 from theory) of yellow crystals are obtained.

Stage Z

C9o-vinyl-1a-homoester-1,3,5(10)-triene-3,1bo-diol

In an inert gas atmosphere, 13.7g (34.6mmol) of triphenylmethylphosphonium iodide and 1.0g (34.mmol) of sodium hydride (approximately 8095th in paraffin oil) in VOml of DMSO are subjected to interaction in an ultrasonic bath at a temperature of the order of 50 °C. 0.7 g (2.3 mmol) of 3,16o:-dihydroxy-18a-homoester-1,3,5(10)-triene-9-carbaldehyde, dissolved in 100 ml of DMSO, is added to the solution over 10 min, and the reaction is continued for the next 20 min in an ultrasonic bath. After adding water, it is extracted with ethyl acetic acid, the organic phase is washed, dried and concentrated. The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate in a ratio of 2:1) and crystallization from chloroform.

Yield: 0.59 g (8195 from theory) after chromatography, mp: 214-220260.

TN-NMR (400 MHz, DMSO-iv, TMS): 9.00 (in, 3-OH); 6.96 (4, uU-8.6Hz, H-1); 6.49 (aa, U-8.6/2.7Hz, H-2); 6.41 (a, yu-2, yIGhz, H-4); 6.29 (aa, 9-17.2/10.5Hz, -SNASN"); 5.00 (aa, 9u-10.5/1.9Hz6, -SNASN"); 4.48 (a, 9-4.7Hz, 160-OH); 4.43 (aa, 9-17.2/1.9Hz, -SNASN"; 4.18 (t, 168-H); 2.68 (t, H-6); 0.72 (i, 9- 6.8Hz, H-18a).

Example C 9a-(22-difluorovinyl)estra-1,3,5(10)-triene-3,16u-diol

Stage 1 3,16o-bis((perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile

As a result of the chemical transformation of 3,16β-bis(perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene, which is carried out similarly to example 1, stage 1, 3,16o-bis(( perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile.

Output: 5895 from the theory.

Stage 2 Ge 3,16bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde o

As a result of the chemical transformation of 3,1bo-bis((perhydropyran-2-yl)oxy|)estra-1,3,5(10)-triene-9-carbonitrile, which is carried out similarly / to example 1, stage 2, 3 is obtained ,1bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde.

Output: 8395 from theory. with

Stage C (Te) 9a-(22-difluorovinyl)estra-1,3,5(10)-triene-3,16u-diol

1.5 ml of dimethoxyethane (molecular o sieve), 0.3 ml of pentane and 0.1 ml (0.77 mmol) of diethyldifluoromethyl)phosphonate are placed in an inertized (that is, after purging with inert gas) flask and cooled to a temperature of the order of -15926. After adding 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 molar in pentane) and 0.14 g (0.3 mmol) of He

C,1bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde, dissolved in a mixture of 1.5 ml of dimethoxyethane and 0.3 ml of pentane. Next, the solution is heated under reflux until the exchange reaction is complete. After adding this solution to the cooled solution of ammonium chloride, it is extracted with ethyl acetic acid. "

The organic phase is concentrated under vacuum, the resulting residue is dissolved in 5 ml of methanol and mixed with Ob.5 ml 7-8

Hash of diluted hydrochloric acid (in a ratio of 1:1). Then ethyl acetic acid is added to the reaction solution, the organic phase is washed with sodium bicarbonate solution and concentrated under vacuum. The crude product obtained is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 2:1).

Yield: 22 mg (2195 from theory). -I TN-NMR (400MHz, DMSO-iv, TMS): 9.08 (in, 3-OH); 7.10 (4, 9U-8.6Hz, H-1); 6.51 (aa, U-8.6/2.3Hz, H-2); 6.41 (a, U-2.3Hz, H-4); 4.76 (aa, 9-25.4/10.9Hz, -CH-ACE"); 4.51 (a, 9U-4.69 Hz, 160-OH); 4.25 (t, 168-H); 2.68 (t, so H-6); 0.68 (in, H-18). (ав) Example 4 b 50 9o-(22-difluorovinyl)-18a-homoester-1,3,5(10)-triene-3,16o-diol

Stage 1

From 3,16bo-bis|(perhydropyran-2-yl)oxy|-18a-homoestra-1,3,5(10)-triene-9-carbonitrile

As a result of the chemical transformation of 3,16"-bis(perhydropyran-2-yl)oxy|-18a-homoestra-1,3,5(10)-triene, which is carried out similarly to example 1, stage 1, 99 3.16o is obtained -bis((perhydropyran-2-yl)oxy|-18a-homoestra-1,3,5(10)-triene-9-carbonitrile. gF) Yield: 589; from the theory. 7 Stage 2 3,16bo-dihydroxy-18a-homoester-1,3,5(10)-triene-9-carbaldehyde in As a result of the chemical transformation of 3,16bo-bis((perhydropyran-2-yl)oxy|-18a- homoester-1,3,5(10)-triene-9-carbonitrile, which is carried out similarly to example 1, stage 2, 3,16y-dihydroxy-18a-homoester-1,3,5(10)-triene-9 is obtained - carbaldehyde.

Output: 8795 from theory.

Stage C 65 9a-(22-difluorovinyl)-18a-homoester-1,3,5(10)-triene-3,16u-diol

As a result of the chemical transformation of 3,16 y-dihydroxy-18a-homoester-1,3,5(10)-triene-9-carbaldehyde, which is carried out under conditions and according to the methodology similar to stage 4 in example 1 and at the same molar ratios, 9a4-(2,2'-difluorovinyl)-18a-homoester-1,3,5(10)-triene-3,16u-diol is obtained.

The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 21) and crystallization from ethyl acetic acid.

Yield: 1295 from theory, melting point: 225-23226.

TN-NMR (400 MHz, DMSO-iv, TMS): 9.06 (in, 3-OH); 7.08 (4, 9U-8.6Hz, H-1); 6.50 (aa, U-8.6/2.7Hz, H-2); 6.41 (a, 9-2.7 Hz, H-4); 4.78 (aa, 9-21.5/14.8Hz, -CH-SE"); 4.47 (a, 9-4.50Gu, 160-OH); 4.18 (t, 168-H); 2.68 (t,

H-6); 0.72 (i, 9-6.8Hz, H-18a).

Example 5 17D-fluoro-9o-vinyl ester-1/3,5(10)-triene-3,16bu-diol

Stage 1 3,16bo-bis|(perhydropyran-2-yl)oxy1|-17B-fluoroester-1,3,5(10)-triene-9-carbonitrile

As a result of the chemical transformation of 3,16 o-bis(perhydropyran-2-yl)oxy)|-17 B-fluoroestra-1,3,5(10)-triene, which is carried out similarly to example 2, stage 1, is obtained

C,16bo-bis|(perhydropyran-2-yl)oxy|-17D-fluoroester-1,3,5(10)-triene-9-carbonitrile.

Output: 4595 from the theory.

Stage 2 3.16o-dihydroxy-17B-fluoroester-1.3,5(10)-triene-9-carbaldehyde

As a result of chemical transformation

C,16bo-bis|(perhydropyran-2-yl)oxy|-17D-fluoroestra-1,3,5(10)-triene-9-carbonitrile, which is carried out similarly to example 2, stage 2, obtains C,16bo -dihydroxy-17 D-fluoroester-1 /3,5(10)-triene-9-carbaldehyde.

Output: 8395 from theory. with

Stage C o 17B-fluoro-9o-vinyl ester-1,3,5(10)-triene-3, 16-diol

As a result of the chemical transformation of 3,16 o-dihydroxy-17 rD-fluoroester-1,3,5(10)-triene-9-carbaldehyde, which is carried out similarly to example 2, stage 3, 17 D-fluoro-9o-vinyl ester is obtained -1,3,5(10)-triene-3,162-diol.

The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 2:1) and crystallization from chloroform. (That)

Yield: 5195 from theory, melting point: 94-98260. 7TH-NMR (400 MHz, DMSO-iv, TMS): 9.02 (in, 3-OH); 6.97 (4.9-8.2Hz, H-1); 6.51 (aa, U-8.2/2.7GHz, H-2); and 6.42 (4.9-2.7Hz, H-4); 6.22 (aa, 9-17.2/10.5Hz, -CH-CH"); 5.09 (a, 9-5.5Hz, 160-OH); 5.01 (aa, 9-10.5/1.99Hz, with -SNASN"); 4.45 (aa, 9-17.2/1.9Hz, -СНА:СН»); 4.35 (aa, 9-55.1/4.7Hz, H-175); 4.11 (t, 168-H); 2.68 (t, H-6); 0.79 them (a, 9-1.9Hz, H-18).

Example 6 17,17-difluoro-9y-vinyl ester-1,3,5(10)-triene-3,1br-diol

Stage 1 "3,16o-bis|(perhydropyran-2-yl)oxy|-17,17-difluoroester-1,3,5(10)-triene-9-carbonitrile -sh s As a result of chemical transformation in" 3, 1bo-bis((perhydropyran-2-yl)oxy|-17,17-difluoroestra-1,3,5(10)-triene, which is carried out similarly to example 2, stage 1, 3,16o-bis|(perhydropyran -2-yl)oxy|-17,17-difluoroester-1,3,5(10)-triene-9-carbonitrile.

Output: 4695 from the theory. 7 Stage 2 (os) 3,16bo-dihydroxy-17,17-difluoroestra-1,3,5(10)-triene-9-carbaldehyde o As a result of chemical transformation 3,16bo-bis((perhydropyran-2-yl) oxy|-17,17-difluoroester-1,3,5(10)-triene-9-carbonitrile, which is carried out (22) similarly to example 2, stage 2, is obtained from 3,1bo-dihydroxy-17,17-difluoroester -1,3,5(10)-triene-9-carbaldehyde.

Output: 8895 from theory.

Stage C 17,17-difluoro-9y-vinyl ester-1,3,5(10)-triene-3, 16y-diol o As a result of chemical transformation of 3,16 fu-dihydroxy-17,17-difluoroester-1,3 ,5(10)-triene-9-carbaldehyde, which is carried out similarly to example 2, stage C, 17,17-difluoro-9o-vinyl ester-1,3,5(10)-triene-3,1b9-diol is obtained . The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/acetic acid ethyl ether in a ratio of 2:1) and crystallization from 60 chloroform.

Output: 7595 from theory. "NA-NMR (400MHz, SOS1z, TM): 7.08 (4.9-8.6Hz, H-1); 6.63 (aa, U-8.6/2.7Hz, H-2); 6.54 (y, 9-2.7 Hz,

H-4); 6.23 (aa, 9-17.2/110.5Hz, -CH-CH"); 5.08 (aa, 9U-10.5/11.9Hz, -SNASN"); 4.48 (yes, 9-17.2/11.9Hz, -SNASN"); 4.44 (t, 168-H); 2.79 (t, H-6); 0.95 (a, 9-1.9 Hz, H-18). because Example 7

U9o-(hex-1-enyl)estra-1,3,5(10)-triene-3,16bo-diol

Stage 1 3,16bo-bis|(perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile

As a result of the chemical transformation of 3,16"-bis((perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene, which is carried out similarly to example 2, stage 1, 3,16o-bis( (perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile.

Output: 6195 from the theory.

Stage 2 3,16bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde

As a result of the chemical transformation of 3,16bo-bis((perhydropyran-2-yl)oxy|)ester-1,3,5(10)-triene-9-carbonitrile, which is carried out similarly / to example 2, stage 2, 3 is obtained ,1b4y-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde.

Output: 8795 from theory.

Stage Z

U9o-(hex-1-enyl)estra-1,3,5(10)-triene-3,16bo-diol

8.68 g (20 mmol) of sodium pentyltriphenylphosphonium bromiduntamide are placed in an inerted flask (one tg contains 2.3 mm mol of pentyltriphenylphosphonium bromide), 0.2 g (0.67 mmol)

of 3,1bo-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde and ZOml of DMSO. Then the reaction mixture is processed in an ultrasonic bath at 602 for about 2 hours. After the completion of the exchange reaction, water is added to the solution, the crude product is isolated by extraction with ethyl acetic acid, the organic phase is washed with water and concentrated to dryness. The obtained crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a ratio of 1:1) and crystallization from ethyl acetate CM

Acids. at

Yield: 0.18g (7595 from theory) after chromatography, melting point: 166-16890. 7TH-NMR (400 MHz, DMSO-iv, TMS): 8.97 (in, 3-OH); 7.08 (4, 9U-8.6Hz, H-1); 6.49 (aa, U-8.6/2.7Hz, H-2); 6.41 (a, 9-2.7 Hz, H-4); 5.73 (a, 9-12.5Hz6, -SNASN-CH»-); 5.20 (and 9U-12.5/74Hz6, -SNASN-ASN"-); 4.48 (a, 9-47, 165-OH); 4.24 (t, 168-H); 2.66 (t, H-6); 0.68 (i, 9U-7.0Hz, СН3-СНе»-); 0.66 (in, H-18). with

Example 8 (se)

C9o-(but-1'-enyl)ester-1,3,5(10)-triene-3,16u-diol

Stage 1 o 3,16bo-bis|(perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile (ee)

As a result of the chemical transformation of 3,16"-bis((perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene, which is carried out similarly to example 2, stage 1, 3,16o-bis is obtained ((perhydropyran-2-yl)oxy|ester-1,3,5(10)-triene-9-carbonitrile.

Output: 5295 from the theory. "

Stage 2 3,16bo-dihydroxyestra-1,3,5(10)-triene-9-carbaldehyde - c As a result of chemical transformation into 3,16bo-bis((perhydropyran-2-yl)oxy|)estra-1, 3,5(10)-triene-9-carbonitrile, which is carried out similarly to example 2, stage 2, 3,1b4y-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde is obtained.

Output: 8795 from theory.

Stage C and C9o-(but-1'-enyl)estra-1,3,5(10)-triene-3,16u-diol (ee) 8.68 g (20 mmol) of sodium propyltriphenylphosphonium bromiducamide (in tg o contains 2.3 mmol of propyltriphenylphosphonium bromide), 0.2 g (0.67 mmol) of 3,16o-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde and ZOoml of DMSO. Then the reaction mixture for approx

Me, treated in an ultrasonic bath at 602 for 2 hours. After completion of the exchange reaction, water is added to the solution, the crude product is isolated by extraction with ethyl acetic acid, the organic phase is washed with water and concentrated to dryness. The crude product obtained is purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetic acid in a 1:1 ratio) and crystallization from ethyl acetic acid.

Yield: 0.16 g (7395 from theory) after chromatography, melting point: 140-14820. o TN-NMR (400 MHz, DMSO-iv, TMS): 8.98 (in, 3-OH); 7.09 (4, uU-8.6Hz, H-1); 6.49 (aa, U-8.6/2.7Hz, H-2); ime) 6.41 (a, 20-2.7 Hz, H-4); 5.70 (a, 9-12.5Hz, -"SNASN-SN"-); 5.19 (ac, 9U-12.5/7 4Hz, -SNASN-CH»-); 4.47 (a, - 4.7Hz, 165-OH); 4.24 (t, 168-H); 2.66 (t, H-6); 0.66 (from, H-18); 0.57 (9-7.2 Hz, СН3-СНео-).

Claims (23)

The formula of the invention 1. 9a-substituted derivatives of ester-1,3,5(10)-trienes of the general formula b5 vis vya 00 What else and what about | EE in" in which the residues ВЗ, 7, В", 89, ВЗ, В5 in и Вт have the following meanings independently of each other: ВЗ means a hydrogen atom or a ВЗ group, where ВЗ is a straight-chain or branched, saturated or unsaturated hydrocarbon residue , which contains up to 6 carbon atoms, a trifluoromethyl group, an aryl, heteroaryl or aralkyl residue, or an aryl or heteroaryl residue substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano group, halogen (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C.alkyl)amino- or di(C.alkyl)amino group, where both alkyl groups are identical or different, di(aralkyl)amino group, where both aralkyl groups are identical or different, carboxyl, carboxyloxy group, C.uracil or C.odacyloxy group, the acyl residue SOKU, where KU is a straight-chain or branched, saturated or up to three-fold unsaturated, partially or fully halogenated hydrocarbon residue, i which contains up to 10 carbon atoms, or B "8 represents the group B29505-, where 229 represents the group B?B22M, in which B and 822 independently of each other mean a hydrogen atom, C. 5 an alkyl residue, the group SIO)B2U, in which CH Зо 223 is a straight-chain or branched, saturated or up to three-fold unsaturated, partially or fully halogenated hydrocarbon residue containing up to 10 carbon atoms, a cyclopropyl, -butyl, o -pentyl, -hexyl or -heptyl group, Su. a residue with 3-7 carbon atoms in the cycloalkyl fragment and with an alkyl fragment containing up to 8 carbon atoms, or an aryl, d) a heteroaryl or aralkyl residue, an y- or an aryl or heteroaryl residue substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio -, methoxy-, ethoxy-, nitro-, cyano group, halogen (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C. alkyl)amino- or di(C. alkyl)amino group, where both alkyl groups are identical or different, di(aralkyl)uamino group, where both aralkyl groups are identical or different, carboxyl, " 20 carboxyloxy group, Sioracyl or C. oracyloxy group, or together with the M-atom means a polymethyleneimino group with 4-6 carbon atoms or a morpholino group, B and 87 each independently of each other means a hydrogen atom or a halogen atom, )" BZ is a straight-chain or branched alkenyl or alkynyl residue with 2-6 atoms carbon, which can be partially or completely fluorinated, or an ethynyl or prop-1-ynyl residue, BZ is a methyl group or an ethyl group, - B2'9 is a hydroxy group or a group B 190-, 2208505- or ОС(О)Б2З , where ВВ, т?9 and в?Z each have the value specified when revealing the values of the radical VU, ВВ each independently means a hydrogen atom or a halogen atom. at 2. Compounds of the general formula I according to claim 1, in which EZ means a hydrogen atom. b" 7o 3. Compounds of the general formula I according to claim 1 or 2, in which B means a hydrogen atom or a fluorine atom in the o-position, B? Kz represents a vinyl, ethynyl or prop-1-ynyl group, B 197 means a hydroxy group, and B!" means a hydrogen atom or a fluorine atom in the y-position. 4. Compounds of the general formula I according to claim 1 or 2, in which KB 15 means the group K'8-O- or K19505-0O-, where BB and v/z each have the value specified when revealing the values of the KZ radical. GF) 5. Estratrienes of the general formula | according to claim 1 or 2 from the group that includes: U9o-vinyl ester-1,3,5(10)-triene-3,16A-diol, o U9o-allylester-1,3,5(10)-triene-3, 16A-diol, 18a-homo-9u-vinylester-1,3,5(10)-trien-3, 16u-diol, bo 18a-homo-9u-allylestra-1,3,5(10)-trien- 3,1bo-diol, Z-methoxy-Zu-vinyl ester-1,3,5(10)-trien-16bu-ol, ZU9o-allyl-3-methoxyestra-1,3,5(10)-trien-16u- ol, 18a-homo-3-methoxy-9o-vinyl ester-1,3,5(10)-trien-16b4u-ol, 65 18a-homo-9u-allyl-3-methoxyestra-1,3,5(10) -trien-16u-ol, 9a-(22-difluorovinyl)estra-1,3,5(10)-trien-3,16u-diol, 9o-(22-difluorovinyl)-3-methoxyestra-1,3,5(10)-trien-16u-ol, 1bo-hydroxy-9Uo-vinyl ester-1,3,5(10)-trien-3-ylsulfamate . . -allyl ester-1,3,5(10)-triene-3,16o-dyldisulfamate, 18a-homo-9u-vinyl ester-1,3,5(10)-trien-3,16u-dyldisulfamate, then 18a-homo -9u-Allyl ester-1,3,5(10)-trien-3,16u-diyldisulfamate, 16be-hydroxy-Uu-vinyl ester-1,3,5(10)-trien-3-yl-(M-acetyl) sulfamate, U-allyl-1bu-hydroxyester-1,3,5(10)-trien-3-yl-(M-acetyl)sulfamate, 18a-homo-16u-hydroxy-9Uu-vinyl ester-1,3,5( 10)-trien-3-yl-(M-acetyl)sulfamate, 18a-homo-9y-allyl-1bu-hydroxyestra-1,3,5(10)-trien-3-yl-(M-acetyl)sulfamate, C9o-(prop-(2)-enyl)estra-1,3,5(10)-trien-3,16u-diol, C9o/-(n-propyl)estra-1,3,5(10)- triene-3,16u-diol, ZU9e-ethynyl ester-1,3,5(10)-triene-3,16b u-diol, U9o-vinyl ester a-1,3,5(10)-triene-3,16u-diol diacetate, 18a-homo-9u-vinyl ester-1,3,5(10)-triene-3,16u-diol diacetate, 16u-valeroyloxy-9u -vinyl ester-1,3,5(10)-trien-3-ol, 16u-acetoxy-9Uu-vinyl ester-1,3,5(10)-trien-3-ol, 1va-homo-16u-acetoxy-Zu -vinyl ester-1,3,5(10)-trien-3-ol, sc To fluoro-9u-vinyl ester-1,3,5(10)-trien-3, 16 u-diol, To-fluoro-9u- allyl ester-1,3,5(10)-triene-3,16 y-diol, o, 17B-fluoro-9o-vinyl ester-1,3,5(10)-triene-3,162-diol, 17B-fluoro-9o -allyl ester-1,3,5(10)-trien-3, 16-diol, 18a-homo-7o-fluoro-9o-vinyl ester-1,3,5(10)-trien-3,1b y-diol, c 18a-homo-7o-fluoro-9o-allylester-1,3,5(10)-trien-3, 16-diol, Ge) 1va-homo-17p-fluoro-9o-vinylester-1,3,5( 10)-triene-3,16b-diol, o 1va-homo-17VD-fluoro-9Uo-allylester-1,3,5(10)-triene-3, 16-diol. b. A pharmaceutical composition containing at least one compound according to any one of claims 1-5, as well as (2.0) a pharmaceutically acceptable carrier. chn 7. Application of compounds of the general formula I! according to any of claims 1-5 for obtaining the corresponding medicinal products. 8. Application according to claim 7 for the treatment of diseases and painful conditions caused by estrogen deficiency in women and men. "20 9. Application according to claim 7 for the treatment of ailments in the peri- and postmenopausal period. sw with 10. Application according to claim 7 for the treatment of female infertility. 11. Application according to claim 7 for the treatment of ip mimo female infertility. 1" 12. Application according to claim 7 for the therapy of ailments associated with hormonal insufficiency in ovarian dysfunction caused by surgical intervention, drug treatment or any other reasons. 13. Application according to claim 7 for hormone replacement therapy (GH3T). -AND 14. Application according to claim 13 in combination with selective estrogen receptor modulators (SMERs), for example raloxifene. co 15. Application according to claim 7 for the prevention and therapy of bone mass reduction caused by hormonal insufficiency. 16. Application according to claim 7 for prevention and therapy of osteoporosis. (2) 17. Application according to claim 7 for prevention and therapy of cardiovascular diseases. GE 18. Use according to claim 7 for the prevention and treatment of prostatic hyperplasia. 19. Application according to claim 18 in combination with anti-estrogens and selective estrogen receptor modulators (SMER) for the prevention and therapy of prostatic hyperplasia. 20. Application according to claim 7 for the treatment of diseases of the immune system. 21. Application according to claim 20 for the treatment of autoimmune diseases. (F, 22. Application according to claim 21 for the treatment of rheumatoid arthritis. GI 23. Application according to claim 21 for the treatment of multiple sclerosis. 60 b5