17-deoxy-1,3,5(10)-estratrien, methods of treatment, the method of synthesis alfa-mutilation, compounds, pharmaceutical composition

 

Describes the new anti-estrogenic compounds, which are applicable for the treatment of numerous disorders, in particular estrogenzawisimy violations. Preferred compounds are 1,3,5-estratriene the nucleus and substituted at position C-17 or position-11 molecular fragment, which makes these compounds are effective in blocking the binding of estrogen to its receptor. Particularly preferred compounds are 17-deoxy-1,3,5-estratriene. Also described therapeutic methods and pharmaceutical compositions. 12 c. and 9 C.p. f-crystals, 3 ill., table 2.

This invention relates in General to steroid hormones, and more specifically to new steroids that are suitable as anti-estrogenic agents. Additionally, the invention relates to methods for treating various diseases with the use of these new compounds, in particular conditions or diseases that are estrogenzawisimy, i.e. estrogeninduced or estrogenzawisimae, and to pharmaceutical compositions containing one or more of these new compounds.

Breast cancer is one of the most prevalent types of cancer, and epidemiological and clinical. This means that for the growth of such tumors breast cancer in premenopausal and postmenopausal periods in patients require estrogen. In women in postmenopausal period, which most often occurs in breast cancer, the concentration of estrone and estradiol in breast cancer are significantly higher than the levels of estrogen in the blood. Although the retention of estrogen in the breast tumors of high affinity binding proteins contributes to estrogen levels in tumors, the concentration of estrogen in the breast are higher than plasma levels in patients with breast cancer, regardless of whether their tumor-positive estrogen receptor (ER+) or negative (ER-). It is now known that the formation of in situ estrogen from biosynthetic precursors of estrogen in tumors is a major contributor to estrogen breast tumors.

Numerous other estrogenzawisimy States, disorders, and diseases were also identified, including, but not limited to, cancer of the ovaries, uterus and pancreas, galactorrhea syndrome of Makuna-Albright, dobrogicus what atrami, localized in the nucleus are sensitive to estrogen cells. This receptor contains garmonsway domain for binding of estrogen, the activation domains of transcription DNA-binding domain. The binding of the complex receptor-hormone meet with estrogen elements (ERE) in the DNA of target genes is essential for regulation of gene transcription.

Medicines which are competitive block the binding of estrogen to its receptor, called antiestrogens, is able to inhibit the stimulatory effects of this hormone on cell proliferation and, therefore, are useful in the clinical treatment of breast cancer. Clinically positive estrogen receptor tumors respond with a higher frequency on antiestrogens than tumors that do not have a significant level of receptors.

Antiestrogenic drugs are divided into two chemical classes: non-steroidal and steroidal. Nonsteroidal antiestrogen tamoxifen (Nolvadex®) used as an auxiliary treatment for breast cancer after chemotherapy or radiation therapy. However, tamoxifen exhibits estrogenic activity in reproductive tissues, leading to an increased risk receded itself as a partial agonist in the uterus.

Thus far, only little work has been done in the development of selective competitive antagonist of estrogen. Were synthesized several steroid an antiestrogen, which does not have estrogenic activity. Among them are ICI 164 384, ICI 182 780 and RU 58668. See, for example, Wakeling et al. J. Steroid Biochem. 31:645-653 (1988), which refers to the ICI 164 384; Wakeling et al. Cancer Res. 51:3867-3873 (1991), and Wakeling et al. J. Steroid Biochem. Molec. Biol. 37:771-774 (1990), which are in ICI 182 780; and Van de Velde et al. Ann. N. Y. Acad. Sci. 761:164-175 (1995), Van de Velde et al., Pathol. Biol. 42:30 (1994) and Nique et al., Drugs of the Future 20:362-366 (1995), which belong to RU 58668. Unfortunately, these drugs are not active when administered orally and must be injected intramuscularly in high doses. In addition, the production of these drugs is time-consuming and requires complex 14-16-stage synthesis with a very low overall yields. Potent antiestrogens that are active when administered orally, still have not been developed or put into mass production, although non-steroidal mixed agonist/antagonist "raloxifene" is now available.

Thus, this invention relates to new steroid agents that are extremely Echis and/or uterus. Thus, this invention represents a significant progress in this area, in particular, in the treatment of breast cancer and other diseases and conditions, which are enhanced by the presence of estrogen.

Importantly, a number of compounds of this invention are potent, active when orally administered agents, find timeselection pharmacology. That is, these compounds applicable as timeselection agonists/antagonists of estrogen, also called "selective receptor modulators estrogen or SERM". SERM produce favorable estrogenically effects in some respects, what is important in bone metabolism and lipids, although nevertheless act as antagonists of estrogen in the breast and/or the uterus. Profile SERM may differ from the profile of pure estrogen, such as 17-estradiol, which behaves as an estrogen agonist in all tissues, and from the profile of the pure antiestrogen, which shows the profile of the antagonist of estrogen in all types of fabrics.

The following references relate to one or more aspects of the present invention and as such may be of interest in ka is described derivatives of estradiol, substituted in position 17=CH-CH2HE has estradiol-like activity; U.S. patent No. 3536703, Colton et al., which describes antimicrobial derivatives of estradiol, substituted at position C-3-methoxy group in position C-17 different groups, including =C-CH2NR+3(where R denotes hydrogen or lower alkyl, or where two groups R form a cyclic structure); U.S. patent No. 3716530, Krubiner et al., which describes steroids containing different substituents at position C-17, including a derivative of estradiol, substituted at position C-17=CH-CH2X, where X denotes a halogen (applicable, as approved, as an intermediate product in the synthesis of compounds related to gestagenna means, and antifungal agents); Blickenstaff et al Steroids.. 46(4,5): 889-902 (1985), which refers to a derivative of estradiol having substituents in position 16 associated with steroid nucleus through a double bond, synthesized as part of the search for new anticancer agents; French patent No. 1453210, which describes analogs of estradiol, substituted in position 17-CH(CH3)-O-(CH2)2NR'r R", where R' and R" may be alkyl or aralkyl; French special patent for a medicinal VA-1,3,5(10)-triens; and Qian et al., J. Steroid Biochem. 29 (6):657-664 (1988), where the estimated correlation between the substitution in position 17 estradiol and possible antiestrogenic activity and described analogs of estradiol, substituted in position 17- (CH2)2-NR1R2where R1and R2denote methyl, ethyl, cyclopentyl, cyclohexyl or tetrahydropyranyl (none of these compounds were found, did not possess antiestrogenic activity).

In addition, the following references discuss timeselection antiestrogens, or SERM, and as such they may also be of interest in connection with this invention:

Grese et al., (1998), Synthesis and Pharmacology of Conformationally Restricted Raloxifen Analogues: Highly Potent Selective Estrogen Receptor Modulators, J. Med. Chem. 41:1272-1283; Bryant et al., (1998), Selective Estrogen Receptor Modulators: An alternative to Hormone Replacement Therapy, J. Soc. for.. Biol. and Medicine, pp. 45-52; Ke et al., (1998), Effects of CP-336156, a New Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus and Body Composition in Rat Models, Endocrinology 139 (4):2068-2076; Kauffman et al., (1997), Hypocholesterolemic Activity of Raloxifen (LY139481): Pharmacological Characterization as a Selective Estrogen Receptor Modulator, J. Pharmacol. Experimental Therap. 280(1):146-153. You can reference the U.S. patents numbers 5447941 issued Zuckerman, 5 510 370, issued

Hock, 5552416 issued Keohane, 5578613 issued by Bryant et al., 5578614 issued by Bryant et al., 5593987 issued by Cullinan et al of which relates to different applications timeselection of antiestrogens in particular, raloxifene.

However, none of the earlier publications, which are known to the authors of the present invention, is not described compounds disclosed here. As far as known to applicants, the compounds and methods of this invention are previously unknown and it is not perceived the same level of technology.

Thus, the primary objective of the present invention is directed to the aforementioned need in this area by providing new steroid compounds applicable as anti-estrogenic agents.

Another purpose of this invention is to provide new compounds that are anti-estrogenic and have low estrogenic activity, as this can be determined by the degree of inhibition and the degree of stimulation, respectively, induced by estradiol activity of alkaline phosphatase in Ishikawa cells of man.

An additional objective of this invention is the provision of such compounds, which essentially does not have estrogenic activity, as may be determined by the above test.

Another purpose of this invention is the provision of such compounds in the form of steroidal active agents having a core 1,3,5-estricta method for the treatment of an individual with a violation, which is estrogenzawisimy, i.e. estrogeninduced or astroenterology condition or disease, by introducing this individual a therapeutically effective amount of an antiestrogen compounds disclosed here, or its pharmaceutically acceptable salt.

The next objective of this invention is to provide pharmaceutical compositions for the treatment of an individual with a disorder that is estrogenzawisimy, and this composition contains a therapeutically effective amount of the new compounds disclosed here, or its pharmaceutically acceptable salt or a complex ester.

Additional objectives, advantages and new features of this invention will be presented in part in the description that follows, and will partly be obvious to specialists in this area when considering the following description, or may become clear when the practice of this invention.

In one embodiment, this invention relates to new compounds having anti-estrogenic activity and reduced estrogenic activity, as defined by the degree of inhibition and the degree of stimulation, respectively, estradiolcreamau alkaline catriena and substituted or position of the C-17, or at position C-11 molecular fragment, which makes these compounds are effective in the competitive blocking the binding of estrogen to its receptor. The most preferred compounds of them are 17-deoxy", i.e., compounds that do not contain oxygen atom linked directly with the C-17. Such compounds are described here, for example, the General structures of formula (I) and (III).

Examples of preferred anti-estrogenic compounds of this invention are the compounds of formula (I), formula (II) and formula (III):

In the formula (I),

R is selected from the group consisting of C and N, and, when R represents, is in the E or Z configuration;

r1 and r2 denote optional double bonds;

X denotes hydrocarbon, usually comprising at least one oxygen atom, sulfur atom and/or nitrogen atom in the form of-O-, -S-, -NH - or-N(alkyl)-optionally containing additional substituents and functional groups such as hydroxyl, oxo, alkoxy, amino, alkyl substituted amino, halogen, aryl, heteroaryl, heterocycle-alkyl or etc;

X' denotes hydrogen or hydrocarbon, usually comprising at least one oxygen atom, sulfur atom and/or atom of the functional group, or

X and X' can be associated with the formation of a heterocyclic structure containing one to four, usually two or three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur;

when r2 is present, R1denotes CR11R12where R11and R12represent hydrogen or lower alkyl, and when r2 is absent, R1denotes hydrogen, alkyl or halogen;

R2selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, aryl, alkaryl, -ONO2, -OR13and-SR13where R13denotes alkyl, acyl or aryl;

R3selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, alkenyl, aryl, alkaryl, cyano,

-OR13and-SR13where R13has the above meanings;

R4denotes hydrogen or lower alkyl;

R5selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, -CH2CH=CH2, -Cho, -NR14R15and

-(CH2)NR14R15where R14and R15may be the same or different and denote hydrogen or alkyl, or, together, form a five - or six-membered cycloalkyl group, optionally containing additional hetero 2NH2;

R7selected from the group consisting of hydrogen, halogen, -NO2, -Cho, -CH2CH=CH2, -NR16R17and-CH2NR16R17where R16and R17may be the same or different and denote hydrogen, alkyl or acetyl;

R8selected from the group consisting of hydrogen, hydroxyl, -OR18and-SR18where R16denotes alkyl, acyl or aryl;

R4denotes hydrogen or alkyl, provided that when R is N, R9is absent; and

R10denotes methyl or ethyl.

In another embodiment, this invention relates to new compounds having the structure of formula (II)

where r1, r2, R, R1, R3, R4, R5, R6, R7, R8, R9, R10X and X' have the above meanings; and

R13and R20independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, quinil, alkoxy and halogen, or R19and R20together form =o

In an additional embodiment, this invention relates to new compounds having the structure of formula (III)

where r2, R1-R8and R10have specified will voznikaet hydrocarbon, comprising at least one oxygen atom, sulfur atom and/or nitrogen atom in the form of-O-, -S-, -NH - or-N (alkyl)-optionally including additional substituents and functional groups such as hydroxyl, oxo, alkoxy, amino, alkyl substituted amino, halogen, aryl, heteroaryl, heteroseksualci etc;

R22denotes hydrogen or alkyl or, when m is O, R21and R22may be associated with the formation of five - or six-membered cyclic structure which may or may not be aromatic, containing 0-3 heteroatoms selected from the group consisting of N, O and S, and substituted by 0-4 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, -C(O)-alkyl, -C(O)-O-alkyl, -O-(CO)-alkyl, -C(O)-aryl, hydroxyl, carboxyl, halogen, nitrile, nitrate and fluorinated alkyl;

R23denotes hydrogen or lower alkyl; and

R24and R25represent both hydrogen or both methylene and connected to each other one covalent bond.

Assume that each of formulas (I), (II) and (III) includes pharmaceutically acceptable salts, esters, amides, prodrugs and other analogs and derivatives of the compounds shown.

In another variantarray media and antiestrogenic compound of the present invention, i.e., the agent that is anti-estrogenic, but has reduced estrogenic activity, as may be determined by the degree of inhibition and the degree of stimulation, respectively estradiol-induced alkaline phosphatase in Ishikawa cells of man. Preferred such compounds are steroids having a core 1,3,5-estratriene, which is 17-deoxy, and especially preferred compounds have a side chain - (CH2)m-chr21R22at position 17, as shown in structural formula (III), and m, R21and R22have the above values. Typically, these pharmaceutical compositions contain as active agent a compound defined by the structural formula (I), (II) or (III).

In an additional embodiment, the invention relates to methods of using these novel compounds as anti-estrogenic agents. New anti-estrogenic compounds are used in the treatment of individuals with disabilities who are estrogenzawisimy, i.e., conditions or diseases that are estrogeninduced or estrogenzawisimae. Important examples of such applications include the treatment of cancer of the breast, uterus, Yai the obligations and violations, which are not estrogenzawisimy, for example independent of estrogen on cancer and, in particular, diseases that are resistant to many drugs.

In another embodiment, this invention relates to methods of using compounds of this invention as timeselection antiestrogenic agents, i.e. as a "SERM", for the treatment or prevention of disorders of the breast, to increase bone mass and/or inhibiting bone loss, to lower serum cholesterol and so on

Fig.1 illustrates in graph form the effect of two typical compounds of this invention on trabecular bone density in a subject oophorectomy rats evaluated in example 42 of the present invention.

Fig.2 illustrates in graph form the effect of two typical compounds of this invention at levels of pyridinoline and deoxypyridinoline in urine undergone oophorectomy rats evaluated in example 42 of the present invention.

Fig.3 illustrates in graph form the effect of two typical compounds of this invention at levels of serum alkaline phosphatase in undergone oophorectomy rats evaluated in example 42 this image of the present invention, it should be noted, this invention is not limited to specific reagents or reaction conditions/ specific pharmaceutical carriers or specific schemes, which can, of course, vary. Also it should be clear that used in the description of the terminology is intended solely for the purpose of describing specific options and is not intended to be limiting.

It should be noted that, in the application description and the attached claims, the only form (the articles "a", "an" and "the") include plural forms unless the context makes clear otherwise. So, for example, reference to "an antiestrogen agent" includes a mixture of anti-estrogenic agents, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and etc.

In this description and in the claims that follow, will be given a number of terms that must be defined as having the following meanings:

The term "alkyl" used herein refers to a branched or unbranched hydrocarbon group of 1-24 carbon atoms, such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, isobutyl, tert-butyl, octyl, decyl, Tetra-decyl, hexadecyl, eicosyl, tetracosyl, etc. and Lnuu group of one to six carbon atoms, preferably one to four carbon atoms. The term "cycloalkyl" as applied here refers to cyclic hydrocarbon of 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "alkenyl" used herein refers to a branched or unbranched hydrocarbon group of 2-24 carbon atoms containing at least one double bond, such as ethynyl, n-propenyl, Isopropenyl, n-butenyl, Isobutanol, octanol, decenyl, tetradecanol, hexadecanol, eicosanol, tetracosane, etc. Preferred here alkeneamine groups contain 2-12 carbon atoms. The term "lower alkenyl" implies alkenylphenol a group of two to six carbon atoms, preferably two to four carbon atoms. The term "cycloalkenyl" means cyclic alkenylphenol a group of three to eight, preferably five to six carbon atoms.

The term "quinil" used here refers to a branched or unbranched hydrocarbon group of 2-24 carbon atoms containing at least one triple bond, such as ethinyl, n-PROPYNYL, Isopropenyl, n-butenyl, Isobutanol, octenyl, decenyl, etc. Preferred here alkenylsilanes carbon preferably two to four carbon atoms.

The term "alkylene", as used here, refers to difunctional branched or unbranched saturated hydrocarbon group of 1-24 carbon atoms, such as methylene, ethylene, n-propylene, n-butylene, n-hexylen, deciles, tetradecyl, hexadecyl, etc., the Term "lower alkylene" refers to alkalinous a group of one to six carbon atoms, preferably one to four carbon atoms.

The term "albaniles" used here refers to difunctional branched or unbranched hydrocarbon group of 2-24 carbon atoms containing at least one double bond, such as, ethenylene, n-propanole, n-butylen, n-hexarelin, etc., the Term "lower albaniles" refers to alkenylamine group of two to six carbon atoms, preferably two to four carbon atoms.

The term "alkoxy" as used here, means an alkyl group linked through one terminal ether linkage; that is, a group of "alkoxy" can be defined as-O-alkyl, where alkyl is mentioned above. The group "lower alkoxy" means an alkoxy group containing one to six, more preferably one to four carbon atoms.

The term "aryl" used herein and unless otherwise indicated, refers to aromatic groups containing 1-3 aromatic rings fused or linked, and either unsubstituted or substituted by 1 or more substituents typically selected from the group consisting of lower alkyl, lower alkoxy, halogen, etc., the Preferred aryl substituents contain 1 aromatic ring or 2 condensed or linked aromatic rings. The term "Allen" refers to difunctional aromatic species containing 1-3 aromatic rings substituted by 1 or more substituents described above. Preferred allenbyi substituents contain one aromatic ring (e.g., phenylene) or 2 condensed or linked aromatic rings (for example, biphenylene).

The term "aralkyl" refers to an aryl group with an alkyl substituent. The term "kalkeren" refers to Allenova group with alkyl Deputy.

The term "alkaryl" refers to an alkyl group which has aryl sleaterkinney" refers to five - or six-membered monocyclic structure or eight-odinnadtsatiletnego the bicyclic heterocycle. "Heterocyclic" alternates may or may not be aromatic, i.e. they can be either heteroaryl or Goethe rockleesmile. Each heterocycle consists of carbon atoms and one to three, usually one or two, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, usually nitrogen and/or oxygen.

The term "halo" or "halogen" is used here in its conventional sense to denote a substituent chlorine, bromine, fluorine or iodine. The terms "halogenated", "halogenoalkanes" or "halogenoalkanes" (or "halogenated alkyl", "halogenated of alkenyl" or "halogenated quinil") refer to alkyl, alkenylphenol or alkenylphenol group, respectively, in which at least one of the hydrogen atoms has been replaced by a halogen atom.

The term "hydrocarbon" is used in its conventional sense to denote a hydrocarbon group containing carbon and hydrogen, and may be aliphatic, alicyclic or aromatic or may contain a combination of aliphatic, alicyclic and/or aromatic portions of the molecule. Aliphatic and alicyclic hydrocarbon can be saturated or can contain one or more unsaturated bonds, usually downimage to be substituted by various substituents and functional groups, or may be modified they contain simple ester, thioester communication, -NH-, -NR-, -C(O)-, -C(O)-O - and/or other communications.

"Optional" or "optionally" means that the following may occur or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not occur. For example, the phrase "optionally substituted" means that the Deputy, which are not hydrogen may be present or absent, and thus, the description includes structures in which non-hydrogen Deputy is present, and structures in which non-hydrogen Deputy is absent. Similarly, the phrase "optionally present double bond indicated by the dashed line----in the chemical formula indicates that the double bond may be present or absent, and if it is absent, it indicates a simple relationship.

The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the onset of symptoms and/or their underlying cause and improvement or cure damage. For example, this method "electroscene, and treatment of disorders in individuals with clinical symptoms.

The terms "effective amount" or "pharmaceutically effective amount" or "effective antiestrogen number of" agent, disclosed by the present invention, to mean a nontoxic but sufficient amount of the agent required to achieve the desired prophylactic or therapeutic effect. As will be shown below, the exact required amount will vary from subject to subject, depending on the species, age and General condition of the subject, the severity of the condition to be treated, and a specific anti-estrogenic agent and the route of administration, etc. Therefore, it is impossible to define an exact "effective amount". However, an appropriate "effective" amount in each individual case may be determined by the person skilled in the art using only routine experimentation.

By "pharmaceutically acceptable carrier" refers to a material that is not biologically or otherwise undesirable, i.e., this material can be entered in the individual along with the selected antiestrogenic agent without inducing any undesirable biologist the composition, in which it is contained. Similarly, the "pharmaceutically acceptable salt or pharmaceutically acceptable ester of a new connection in the application there is a salt or a complex ether, which are not biologically or otherwise undesirable.

Under "antiestrogenic" as applied here implies a connection that tends inhibition in situ production of estrogen, such as estradiol, after the introduction of their individual is a mammal. Without claiming to be theoretical explanation, the inventors believe that the compounds of this invention are anti-estrogenic in nature due to the competitive blocking the binding of estrogen to its receptor, in particular, in the tissue of the mammary gland and uterus. Antiestrogenic activity can be evaluated by inhibition estradiolcreamei activity of alkaline phosphatase in Ishikawa cells of a person, for example, using procedures described in example 40 in the description.

Generally, a new antiestrogen agents inhibit stimulated 10-9M estradiol alkaline phosphatase activity by at least 30%, preferably at least about 45%, more preferably at measures being has no estrogenic activity", used here, mean a compound which has, approximately less than 5%, preferably approximately less than 2% of the estrogenic activity of estradiol (as may be determined, for example, using procedures described in example 40). The term "reduced estrogenic activity" refers to a connection that has 60% or less estrogenic activity of estradiol.

The term "translationy", as used here, refers to compounds of the present invention, which act as a SERM, i.e. they are antiestrogenic in reproductive tissues, in particular in the breast tissue and/or uterus, have a reduced estrogeno activity or no estrogenic activity in reproductive tissues, but make a favorable estrogenically effects in other respects, including, but not only, in relation to bone and lipid metabolism. That is, such compounds act as agonists of estrogen on bone metabolism and cholesterol.

In describing the location of groups and substituents will be used above numbering system to match the numbering cyclopentanophenanthrene kernel with the Convention used cyclopentanophenanthrene the kernel.

In these structures the use of solid and dashed lines to denote a specific conformation of the group also complies with the Convention refer to steroids IUPAC. The characters "" and "indicate the specific stereochemical configuration of the substituent at an asymmetric carbon atom in the chemical structure as drawn. So, ""denoted by a dashed line, indicates that this group is below the main plane of the drawn molecule, ""denoted by a solid line, indicates that this group in this position is above the main plane of this molecule as drawn.

In addition, five - and six-membered ring of the steroid molecule is often denoted a, b, C and D, as shown.

New connections:

New compounds are antiestrogenic agents that have anti-estrogenic activity, and reduced estrogenic activity, as may be determined by the degree of inhibition and the degree of stimulation, respectively estradiolcreamei activity of alkaline phosphatase in Ishikawa cells of man. The compounds of this invention of OneNote alkaline phosphatase at least 30%, and estrogenic activity of less than about 5% in relation to the stimulation of alkaline phosphatase activity 10-9M estradiol. Preferred compounds of this invention are 1,3,5-estratriene kernel and substituted or position of the C-17, or in position C-11 molecular group, which makes these compounds are effective in the competitive blocking the binding of estrogen to its receptor. Of these preferred compounds are 17-substituted, "17-deoxy-compounds, i.e., no oxygen atom linked directly to the position of the C-17. Particularly preferred compounds are 17-deoxy-1,3,5-estratriene that exhibit tissue-specific pharmacology, i.e., compounds that act as a SERM is by the manifestation of antagonism against estrogen in reproductive tissues, but make a favorable estrogenically effects elsewhere in the body, in particular in respect of the bone tissue metabolism and lipid metabolism.

Formula (I) represents the first group of compounds are examples of compounds of this invention:

in which r1 and r2 denote optional double bonds and R is selected from the group Costes R denotes With.

Other substituents, X, X' and R1-R10are defined as follows.

X denotes hydrocarbon, usually and preferably includes at least one oxygen atom, sulfur atom and/or nitrogen atom in the form of-O-, -S-, -NH - or-N(alkyl)-bond, preferably-N(lower alkyl)-connection, and optionally containing additional substituents and functional groups such as hydroxyl, oxo, alkoxy, amino, alkyl substituted amino, halogen, aryl, heteroaryl, heteroseksualci or so on, When there is r1, so this relationship with X via a double bond, preferred X-parts of the molecule are CH-Y and N-y When r1 is absent, so that the communication with X via a simple link, the preferred X-part of the molecule presents-Z-Y CH-Y1Y2or-NR26Y, where Y, Y1and Y2have the above specified values, Z is oxygen or sulfur and R26is hydrogen or lower alkyl. In the preferred structures described herein, r1 is absent.

X' denotes hydrogen or hydrocarbon, and if it means hydrocarbon, typically and preferably, it includes at least one oxygen atom, sulfur atom and/or nitrogen atom in the form of-O-, -S-, -NH - else against X. X and X' can be the same or they may be different. Alternatively, X and X' can be associated with the formation of heterocyclic rings, usually six to eight-membered geteroseksualbnogo ring containing one to three, preferably two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, preferably nitrogen and oxygen. Heterocytolysine group may, for example, have the structure-Z1-(CH2)n1-N(R27)-(CH2)n2-Z2- where n1 and n2 is 1 or 2 and are preferably, though not necessarily identical, R27denotes hydrogen or lower alkyl and Z1and Z2independently represent oxygen or sulphur.

Y denotes hydrogen, - (R28)n3-JR29R30or - (R31)n4-Z3-(R32)n5-[L-(R33)n6]n7-[Z4-(R34)n8]n9-JR29R30where R28, R31, R32, R33and R34denote alkylene or albaniles, usually alkylen, preferably lower alkylene, and Z3and Z4independently represent oxygen or sulphur. L represents-C(O)-, O, S, or-NR35- where R35denotes hydrogen or lower alkyl, or L may be five - or chesticles and their combinations, and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy (preferably lower alkyl, lower alkenyl, lower alkoxy, halogenated lower alkyl, halogenated lower alkenyl and halogenated lower alkoxy), carboxyl, hydroxy, amino, nitro, cyano, halogen, halogenated alkyl, alkenyl and alkoxy, and L can, optionally, be Allenby ring and, if arisen, it is preferably phenylene, halogen-substituted phenylene, (lower alkyl)substituted phenylene, (lower alkoxy)substituted phenylene or bifani-flax, more preferably phenylene, methoxsalen phenylene or izlesene phenylene (R33associated with any one of the carbon atoms of the ring). J denotes N or CH, n3 and n4 is 0 or 1, but necessarily equal to 1 when Y is associated with an atom of oxygen, sulfur or nitrogen, n5, n6, n7, n8 and n9 independently equal to 0 or 1 and R29and R30may be the same or different and independently selected from the group consisting of hydrogen, lower alkyl and halogenoalkane or, together, form a monocyclic or polycyclic Deputy, preferred is achet NR36, O or CH2, Q' represents oxo or CH2and i is 0 or 1. Y is optionally substituted at one or more available carbon atoms by halogen, oxo, hydroxyl, lower alkyl, lower alkoxy or lower halogenation, provided that when X represents 0-Y, and R stands for S, then Y is other than hydrogen, and when J corresponds to SN, then R29and R30together form J'.

Y1and Y2may be the same or different and are defined-Z-Y. Alternatively, Y1and Y" may be associated with the formation of heterocyclic rings, usually geteroseksualbnogo rings described in relation to X and X' above.

The identity of R1depends on the presence or absence of a double bond when r2. When r2 is present, so there is a double bond linking R1with the carbon atom in position 16 estratriene kernel, then R1represents CR11R12where R11and R12independently represent hydrogen or lower alkyl. A preferred group R1when present, r2 is CH2. When r2 is absent, so there is a simple relationship linking R1with the carbon atom at position 16, then R1represents Volpi, consisting of hydrogen, hydroxyl, alkyl, alkenyl (preferably lower alkyl and alkenyl), aryl, alkaryl, -ONO2, -OR13and-SR13where R13represents alkyl (preferably lower alkyl), lower acyl or aryl. Preferably, though not necessarily, R2is hydrogen.

R3selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, alkenyl, (preferably lower alkyl or alkenyl), aryl, alkaryl, -OR13and-SR13where R13has the values described previously. Preferred R3-substituents are hydrogen and lower alkyl.

R4denotes hydrogen or lower alkyl, preferably hydrogen.

R5selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, -CH2CH=CH2, -Cho, -NR14R15and -(CH2)NR14R15where R14and R15may be the same or different and denote hydrogen or lower alkyl or together form a five - or six-membered cycloalkyl group, optionally containing an additional heteroatom of nitrogen. Preferably, R5represents hydrogen, methoxy, -NR14R15or -(CH2)NR14R15where R, ostoja from hydrogen, alkyl, acyl (preferably lower alkyl or lower acyl), -C(O)-aryl, -C(O)-alkyl and-SO2NH2(sulpham). Preferred R6-substituents are hydrogen, sulpham, -C(O)-C6H5and-C(O)-tert-butyl, and especially preferred hydrogen and sulpham.

R7selected from the group consisting of hydrogen, halogen, -NO2, -Cho, -CH2CH=CH2, -NR16R17and -(CH2)NR16R17where R16and R17may be the same or different and denote hydrogen, lower alkyl or acetyl. Preferably, R7represents hydrogen.

R9selected from the group consisting of hydrogen, hydroxyl, -OR18and-SR18where R18denotes alkyl, acyl (preferably lower alkyl or lower acyl), or aryl. In preferred compounds, R8represents hydrogen.

R9denotes hydrogen or lower alkyl, provided that when R is N, R9no. When R3is present, it preferably represents hydrogen or methyl.

R10denotes methyl or ethyl, usually ethyl. Formula (II) represents the second group of compounds are examples of d is p>, R6, R7, R6, R9, R10X and X' have the above for formula (I) values; and

R19and R20independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, quinil, alkoxy (preferably lower alkyl, lower alkenyl, lower quinil and lower alkoxy, and halogen, or R19and R20together form = o

Preferred compounds of structural formulas (I) and (II) are compounds in which G1 is absent, R is a C, R3represents hydrogen or methyl, X represents-O-Y, or-S-Y -, Y represents -(CH2)m1-NR29R30OR -(CH2)m2-O-(CH2)m3-[L-(CH2)m4]n7-[O-(CH2)m5]n9-NR29R30where L denotes a phenylene, methoxsalen phenylene, izlesene phenylene, -NH-, -N(CH3)- or-O-, m1-m5 is 1, 2, 3 or 4, R29and R30denote hydrogen, lower alkyl, halogenated (preferably lower halogenated) or associated with education geteroseksualbnogo rings, such as ring, a certain J' previously, labeling together, for example, -CH2CH2-NH-CH2CH2-, -CH2CH2-O-CH2CH2- ,- (the nutrient compounds of structural formula (II), in particular, are compounds in which one of R19and R20represents hydrogen and the other represents hydroxyl, lower alkyl or lower quinil, or in which R19and R20together form =o

Formula (III) is the third group of compounds which are examples of the present invention

in which r2 and R1-R8and R10are as defined above in respect to formula (I) and (II) values, and the remaining substituents are as follows:

R21means hydrocarbon, usually and preferably includes at least one oxygen atom, sulfur atom and/or nitrogen atom in the form of-O-, -S-, -NH - or-N(alkyl) -, preferably-N(lower alkyl)-) linkage, and optionally including additional substituents and functional groups such as hydroxyl, oxo, alkoxy, amino, substituted amino, halogen, aryl, heteroaryl, heteroseksualci or so on a Typical R21the substituents represented by -(R28)n3-JR29R30and -(R31)n4-Z3-(R32)n5-[L-(R33)n6]n7- [Z4-(R34)n8]n9-JR29R30where R28,R29, R30, R31, R32, R332)m1-NR29R30and -(CH2)m2-O-(CH2)m3-[L-(CH2)m4]n7-[O-(CH2)m5]n9-NR29R30where L denotes a phenylene, methoxsalen phenylene, izlesene phenylene, -NH-, -N(CH3)- or-O-, m1-m5 is 1, 2, 3 or 4, R29and R30denote hydrogen, lower alkyl, halogenated (usually the lowest halogenated) or associated with education geteroseksualbnogo rings, as explained above, but preferably R29and R30represent lower alkyl, most preferably methyl or ethyl.

R22denotes hydrogen or alkyl or, when m is O, R21and R22may be associated with the formation of five - or six-membered cyclic structure which may or may not be aromatic and contains from 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted by from 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy (preferably lower alkyl, alkenyl, quinil and alkoxy), -C(O)-alkyl, -C(O)-O-alkyl, -O-(CO)-alkyl (preferably-C(O)-lower alkyl, -C(O)-O-lower alkyl and(CO)-lower alkyl), -C(O)-aryl, hydroxyl, carboxyl, halogen, nitrile, nitrate and f the em hydrogen or lower alkyl, usually hydrogen or methyl.

R24and R25represent both hydrogen, or represent both the methylene and connected to each other one covalent bond.

In addition, m is an integer in the range from 0 to 6, inclusive, preferably 1, 2, 3 or 4, and n is 0 or 1.

Preferred compounds of structural formula (I) have the following formula (Ia):

In structural formula (Ia) r2, R1-R8and R10have some respect to structural formula (I) values, the signature "m" is an integer in the range from 0 to 6 inclusive, preferably 1, 2, 3 or 4, the signature "p" is an integer in the range from 0 to 6 inclusive, preferably 1, 2, 3 or 4, R29and R30represent lower alkyl, preferably methyl or ethyl, or associated with education geteroseksualbnogo rings, signifying together, for example, -CH2CH2-NH-CH2CH2-, -CH2CH2-O-CH2CH2-, (CH2)4-, -(CH2)5or similar, and L denotes a five - or six-membered cyclic structure, which may or may not be aromatic, and optionally contains 1-4 heteroatoms selected from the group consisting of N, O and S, and the sludge, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy (preferably lower alkyl, lower alkenyl, lower alkoxy, halogenated lower alkyl, halogenated lower alkenyl and halogenated lower alkoxy), carboxyl, hydroxy, amino, nitro, cyano and halogen.

Especially preferred compounds encompassed by structural formula (I) are compounds having the following formula (Ib):

where m, p, R29and R30are defined in terms of the structure (Ia) above values, and Q1, Q2, Q3and Q4independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy (preferably lower alkoxy), alkyl (preferably lower alkyl), halogen, amino and (lower alkyl)-substituted amino.

Similarly, the preferred compounds of formula (II) have the following formula (IIA):

In the structure (IIA) r2, R1, R3-R8, R10, R19and R20are defined in respect of compounds of structure (II) values, and t, R, L, R29and R30are defined in terms of the structure (Ia).

Especially preferred soy
and R30have defined for structure (Ia) values and Q1, Q2, Q3, Q4have defined for compounds of structural formulas (Ib).

Preferred compounds of formula (III) have the structure (IIIa)

while particularly preferred compounds of formula (III) have the structure (IIIb), where all substituents are defined for compounds (Ia) and (Ib) values, respectively.

Thus, specialists in this field will be clear that the preferred compounds of this invention are 17-deoxy-1,3,5-estratriene with the fragment molecule

preferably

and most preferably

at position C-11 or the position of the C-17 and 17-deoxy-1,3,5-estratriene with the fragment molecule

preferably

and most preferably

present at C-17.

Important is that the new compounds of this invention in which R6prestame for the original antiestrogenic compounds, which are formed in vivo by hydrolysis of the group - SO2NH2at position C-3.

Examples of typical compounds of this invention include, but are not limited to, the following connections:

These compounds can be in the form of pharmaceutically acceptable salts, esters, amides, prodrugs and other derivatives or analogs, or they can be modified by the addition of one or more suitable functional groups to enhance selected biological properties. Such modifications are known in this field and include those modifications which increase biological penetration into a particular biological system, increase oral bioavailability, increase solubility, making it possible introduction by injection, etc.

Salts of these compounds can be obtained using the mill. arch, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). An acid additive salt is obtained from the free base (for example, compounds having a neutral-NH2or cyclic amino group) using conventional methods, including reaction with a suitable acid. Usually, the shape of the base compounds are dissolved in a polar organic solvent such as methanol or ethanol, and add the acid at a temperature from about 0°to about 100°C., preferably at ambient temperature. The obtained salt or precipitates, or can be removed from solution by addition of a less polar solvent. Suitable acid to produce an acid additive salts include both organic acids, e.g. acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc., and inorganic acids, niisato etc. An acid additive salt can be again converted into the free base by treatment with a suitable base. The preferred acid additive salts of these compounds are citrate, fumaric, succinate, benzoate and malonate salt.

Basic salts of acid parts of molecules that may be present (for example, groups of carboxylic acids), perform in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, trimethylamine, or etc.

Production of esters involves functionalization of hydroxyl and/or carboxyl groups that may be present. These esters are usually acetamidine derivatives of free alcohol groups, i.e., parts of molecules, which are produced from carboxylic acids of the formula RCOOH, where R is alkyl and preferably lower alkyl. Pharmaceutically acceptable esters can be obtained by methods known to experts in this field and/or described in the literature. Esters can be again converted into the free acid, if desired with the use of derivatives of these compounds are also within the knowledge of experts in this field and/or described in the relevant literature and guidelines.

Some of the new compounds are chiral in nature and, therefore, can be in enantiomerically pure form or in racemic mixtures. In some cases, i.e. in relation to some characteristic compounds illustrated here, the chirality is specified. In other cases it is not specified, and implied that this invention covers both isomere pure form shown compounds and their racemic or diastereomeric mixture. For example, the compounds of structural formula (III) shown as having two substituent at position 17 of the steroid nucleus, without specifying what the Deputy is 17and what is 17. It is assumed that every opportunity is covered by a General structure, i.e., R23can be a and -(CH2)n-chr21R22may beor R23may beand -(CH2)n-chr21R22may be and. In addition, some compounds are stereoisomers that are asymmetric in respect To the C=C-bond. In this case, as shown above in relation to the structures of formulas (I) and (II), the invention includes both of these structures, i.e., as "the treatment of many disorders; first of all, these compounds are suitable for treatment estrogenzawisimy violations, i.e., conditions or diseases that are estrogeninduced or estrogenzawisimae. These compounds are able to induce remission in breast cancer, including metastatic tumors. In addition, these compounds are applicable in the treatment of tumors of the ovaries, uterus and pancreas, as well as pathological conditions such as galactorrhea syndrome of Makuna-Albright, benign disease of the breast cancer and endometriosis. These compounds are also applicable for the treatment of certain conditions and disorders that are not estrogenzawisimy, for example, estrogenzawisimy of cancer, particularly cancers that are resistant to many drugs. The last advantage of these new compounds represents an important progress in this area, as the main problem affecting the effectiveness of the programs of chemotherapy lies in the evolution of cells, which upon exposure chemotherapeutic drug are becoming resistant to a variety of structurally unrelated drugs and therapeuticeducational pharmacology and act as a SERM. That is, these compounds are antagonists of estrogen in reproductive tissues, including breast tissue and/or uterus, causing at the same time, the emergence estrogenically effects elsewhere in the body, in particular in the metabolism of bone and lipid metabolism. A series of compounds of the present invention, in particular compounds defined by structural formula (III) shown here are timeselection antiestrogenic agents, as just explained. Other compounds within the scope and merits of the invention can also be timeselection pharmacology, and specialists in this field can perform common procedures not involving undue or excessive experimentation in order to determine the potential translatively connection.

Compounds applicable as SERM, can be used to treat all estrogenzawisimy violations discussed above, i.e., breast cancer, tumors of the ovaries, uterus and pancreas, galaktorei, syndrome Makuna-Albright, benign disease of the breast and endometriosis. Furthermore, the new compounds of this invention, which are timeselection on SNA, as described in U.S. patent No. 5447941 issued Zuckerman;

(2) to suppress dysfunctional uterine bleeding, as described in U.S. patent No. 5552416 issued Keohane;

(3) for inhibition of increase in weight or induction or facilitate weight loss, as described in U.S. patent No. 5578613 and 5578614 issued by Bryant et al.;

(4) for the suppression of disorders of the breast, such as gynecomastia, hypertrophy, politely, mastodinia/mastalgia, hyperprolactinemia and afibrinogenemia, cancer of the breast, as described in U.S. patent No. 5593987 issued by Cullinan et al.;

(5) for delay atrophy of the skin and vagina, as described in U.S. patent No. 5610167 issued Cullinan;

(6) for the inhibition of bone rarefaction (rarefication) and reducing serum cholesterol, as described in U.S. patent No. 5641790 issued Draper;

(7) to increase bone mass, as described in U.S. patent No. 5510370 issued Hock;

(8) for the treatment of osteoporosis, as described in U.S. patent No. 5646137 issued to Black et al.;

(9) for the suppression of CNS problems in postmenopausal women, as described in U.S. patent No. 5663184 issued by Bryant et al.; and

(10) to suppress dysgenesia (dysplasia) of the ovaries, delayed puberty, or sexual infantilism, as described in U.S. patent No. 5719165 issued by Dodge.

In addition to the new compounds described above, the invention further includes methods of applying some known compounds as anti-estrogenic agents, i.e. compounds which had previously been known that they are applicable only for purposes not related to treatment estrogenzawisimy violations. These compounds include

Antiestrogenic agents of this invention can be easily prepared in the form of pharmaceutical compositions comprising one or more of these compounds in combination with a pharmaceutically acceptable carrier. Cm. Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, PA: Mack Publishing Co., 1995), which describes a typical carriers and conventional methods of preparing pharmaceutical compositions, which can be used in the form in which they are described, or can be modified for the preparation of pharmaceutical compositions containing the compounds of this invention. These compounds can also be administered in the form of pharmaceutically acceptable salts or pharmaceutically acceptable esters, described in the previous section.

The compounds may be administered orally, parenteral, transdermal, rectal, nasal, t is the corresponding conventional non-toxic pharmaceutically acceptable carriers, adjuvants and fillers. The term "parenteral" as applied here involves subcutaneous, intravenous and intramuscular injection. The amount of active compound is, of course, depend on the subject that is being treated, the weight of the subject, the route of administration and assessment of the attending physician. However, the usual dose is in the range of about 0.01 mg/kg/day 10.0 mg/kg/day, more preferably in the range of approximately 1.0 mg/kg/day to 5 mg/kg/day.

Depending on the intended method of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, powders, liquids, suspensions, or similar, preferably in a uniform dosage form suitable for single introduction of an accurate dose. The composition will include, as noted above, an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, and. so on,

For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutically dopestars, magnesium carbonate, etc., Liquid pharmaceutically entered compositions can be, for example, prepared by dissolving, dispersing, etc. an active compound described herein and optional pharmaceutical excipients in the filler, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., with the formation of a solution or suspension. If desired, the pharmaceutical composition, which must be entered, can also contain minor amounts of nontoxic auxiliary substances, such as moisturizing or emulsifying agents, sautereau pH agents, etc., for example, sodium acetate, monolaurate sorbitan, sodium acetate, triethanolamine, triethanolamine oleate, etc., the Actual methods of preparing such dosage forms are known, or will be obvious to a person skilled in the art; see, for example, the link Remington''s Pharmaceutical Sciences, which was given the link above.

For oral administration, the composition will typically be in the form of tablets or capsules, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules for oral administration generally will include one or more generally is also usually added. When using liquid suspensions of the active agent is combined with emulsifying and suspendresume agents. If desirable, can also be added to improve taste and odor, color and/or sweetening agents. Other optional components for inclusion in the oral composition include, but are not limited to, preservatives, suspendresume agents, thickeners, etc.,

Parenteral administration, if it is used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Preferably, sterile injectable suspensions are prepared in accordance with methods known in this field, using suitable dispersing or wetting agents and suspendida agents. Sterile injectable composition may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution Ilmenau non-volatile oil. More recently revised approach for parenteral administration involves use of system slow release or system with prolonged action, so that the constant level of dosage. See, for example, U.S. patent No. 3710795.

The compounds of this invention can also be introduced through the skin or tissue of the mucosa with the use of common systems for percutaneous drug delivery, in which the agent is contained in a lamellar structure, which serves as a device for delivery of drugs attached to the skin. In this structure, the pharmaceutical composition is contained in a layer, or "reservoir," underlying an upper backing layer. This plate design may contain a single reservoir or it can contain multiple reservoirs. In one embodiment, the reservoir contains a polymer matrix pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable adhesive materials for contact with the skin include, but are not limited to, polyethylene, polysiloxane, polesny contact adhesive are present in the form of shared and individual layers, with the adhesive underlying the reservoir, which, in each case, may be either a polymeric matrix as described above, or it can be a reservoir of liquid or hydrogel or may have some other form.

The lining layer in these lamellar (layered) materials, which serves as the upper surface of this device, serves as the first structural element of this lamellar structure and provides a fixture for the most part its flexibility. The material selected for the backing material should be selected so that it is essentially impermeable to the active agent and any other substances that are present; the lining is preferably made of a layer or film of a flexible elastomeric material. Examples of polymers that are suitable for the backing layer include polyethylene, polypropylene, polyesters, etc.,

During storage and prior to use of this plate design includes a wrapper that protects from release. Immediately before use, this layer is removed from the devices for opening its basal surface or tank with drug libranda from release must be made of a material impermeable to the drug/carrier.

Devices for percutaneous delivery of drugs can be manufactured using conventional methods known in this field, for example, by pouring a liquid adhesive, medicines, and media on the backing layer, followed by layering wrapper that protects from release. Similarly, the adhesive mixture can be coated on the wrapper that protects from release, with subsequent layering underlayment. Alternatively, the reservoir (layer) for the medicinal product may be prepared in the absence of a drug or filler and then loaded by soaking in a mixture of drug/carrier.

Plate system for percutaneous delivery of a medicinal product may also contain a power of penetration through the skin. That is, since the characteristic of the skin permeability for certain drugs may be too low to allow therapeutic levels of the drug to pass through an area of intact skin of reasonable size, with such drug srty in this area and include, for example, Dima-tranfixed (DMSO), dimethylformamide (DMF), N,N-dimethyl-ndimethylacetamide (DMA), decelerated (C10MCO)2-C6-alkane-diols and 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylthiophene-2-he (available under the trade name Azone® from Whitby Research Incorporated, Richmond, VA), alcohols, etc., But should pay attention to the fact that the advantage of this invention is the potential for percutaneous delivery of the active agent provided here, without the necessity to use amplifier penetration through the skin; this in particular is true, for example, with compounds of structural formula (I) and (III), where nitrate-(-ONO2-the group is present at position 11.

Alternatively, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. They can be manufactured by mixing the agent with a suitable non-irritating excipient which is solid at room temperature, but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutical pozicii prepared in accordance with the methods, well known in the field of preparation of pharmaceutical preparations can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption accelerators to increase the bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The preferred compositions for vaginal drug delivery are ointments and creams. Ointments are semisolid preparations that are usually made on the basis of vaseline or other oil derivatives. Creams containing the selected active agent are, as is well known in this field, viscous liquid or semisolid emulsions, either oil-in-water type water-in-oil. Basics creams are water washable and contain an oil phase, an emulsifier and the aqueous phase. The oil phase, sometimes called the "internal" phase, usually consists of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, though not necessarily, exceeds the volume of the oil phase usually contains a humidifier. The emulsifier in the composition of the cream is usually nonionic, anionic, cationogenic or amphoteric surface is going to be clear to experts in this field, is the framework that will ensure the optimal delivery of drugs. As in the case of other carriers or fillers, the basis for the cream should be inert, stable, non-irritating and desensibiliziruyuschey. Preferred are also vaginal suppositories. Suppositories can be manufactured using conventional methods, for example, seal, direct pressing or etc., and will contain media that is suitable for vaginal drug delivery, usually of biodiversity-rosemore material that provides the desired release profile of drugs.

Compositions for transbukkalno introduction include tablets, pellets, gels, etc. Alternative, transbukkalno introduction can be performed using the delivery system through the mucous membrane.

The method of obtaining

The compounds of this invention can be obtained with high yield by using a relatively simple, reliable methods given as examples in the following experimental section. The synthesis of typical compounds described in examples 1-39. For additional information relating to the synthesis of compounds having sulfamate the traditional number 08/997 416, entitled "Estrone Sulfamate Inhibitors of Estrone Sulfatase, and Associated Pharmaceutical Compositions and Methods of Use", the authors of the invention Tanabe et al., submitted December 24, 1997.

Experimental part

The practice of this invention will be used, unless otherwise indicated, conventional methods of synthetic organic chemistry, biological testing, etc. that are within the skill in this field. Such techniques are explained fully in the literature. See, for example, Fieser et al., Steroids (New York: Reinhold, 1959), Djerassi, Steroid Reactions: An Outline for Organic Chemists (San Francisco: Holden-Day, 1963) and Fried et al., Organic Reactions in Steroid Chemistry, vols. 1 and 2 (New York: Reinhold, 1972) in relation to information concerning associated with steroids are synthetic procedures. Reference can be made to Littlefield et al., Endocrinology 127:2757-2762 (1990) and Wakeling et al.,

Endocrinology 99:447-453 (1983) concerning procedures for biological testing, applicable for the evaluation of compounds, such as compounds described and claimed here.

It should be clear that, although this invention has been described in connection with its preferred characteristic variations, the above description and examples which follow are intended to illustrate and not to limit the scope of the invention. Other aspects of oblasti, to whom it is addressed.

In the following examples, attempts have been made to ensure accuracy in terms of digital data (e.g., amounts, temperature, etc), but some experimental error and deviation should be taken into account. If not indicated otherwise, temperature is given in °C and a pressure of atmospheric or near atmospheric. All solvents purchased as having VIH-purity and all reactions were performed routinely in an inert atmosphere of argon, unless otherwise indicated. All reagents were obtained commercially, unless otherwise noted. Estrone and estradiol bought from Berlichem U. S.; levonorgestrel purchased from Akzo Nobel. The NMR analyses were performed on Varian Gemini 300 and the standard was chloroform with7,27. FTIR spectra were recorded on a Perkin-Elmer 1610.

Example 1

Obtaining (E)-3-tert-butyldimethylsilyloxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (4)

(a) Synthesis of 3-tert-butyldimethylsilyloxy-1, 3,5(10)-triene-17-she (2):

To a mixture of estrone (1.29 g, 107,3 mmol) and tert-butyldimethylsilyl (18 g, 118 mmol) in THF (350 ml) at room temperature in an atmosphere of argon was added imidazole (18 g, 264 mmol) in DMF (350 ml). After stirring the reaction is of Adak was collected by filtration, was dissolved in CH2CL2and the solution was dried (MgSO4). The desiccant was filtered and the solvent evaporated under reduced pressure to get to 38.8 g of 2 as a white crystalline solid (yield 94%), so pl. 171-172°C.

1H-NMR (300 MHz, CDCl3):to 0.19 (s, 6, Si (CH3)2), of 0.91 (s, 3, CH3), and 0.98 (s, 9, Si(CH3)3), 1,24-to 2.57 (m, 13), 2,85 (m, 2), to 6.57 (d, J=2.4 Hz, 1, ArH), 6,62 (DD, J=2,4, and 8.4 Hz, 1, ArH), 7,12 (d, J=8,4 Hz, 1, ArH).

(b) Synthesis of 3-tert-butyldimethylsilyloxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol (3):

To a solution of 3-tert-butyldimethylsilyloxy-1,3,5 (10) -triene-17-she (2, 4.0 g, 10.4 mmol) in THF (40 ml) at 0°C in an atmosphere of argon was added a solution vinylmania bromide in THF (15 ml, 15 mmol). Then the resulting mixture was heated to room temperature within 2 hours. The reaction mixture was extinguished by pouring into saturated aqueous NH4Cl, then was extracted with a mixture of 40% ethyl acetate/hexane. The combined organic layers were dried (MgSO4). The desiccant was filtered and the solvent evaporated under reduced pressure. Flash chromatography (5% ethyl acetate/hexane) gave of 2.23 g of 3 as a white solid (yield 52%), so pl. 127-128°C.

1H-NMR (300 MHz, CDCl3):

(c) Synthesis of (E)-3-tert-butyldimethylsilyloxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (4)

To a solution of RVG3(0/3 ml, 2.0 mmol) in toluene (5 ml) was added a solution of 3-tert-butyldimethylsilyloxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol (3, 1,46 g, 3.54 mmol) and pyridine (0.1 ml) in toluene (5 ml) at 0°C in an argon atmosphere. The resulting mixture was stirred at 0°C for 1 h, then was heated to room temperature within 1 h, the Reaction mixture was extinguished by pouring into a mixture of ice water, then was extracted with a mixture of 40% ethyl acetate/hexane. The organic layer was washed with saturated aqueous Panso3, then brine and dried (MgSO4). Ossiter was filtered and the solvent was concentrated to obtain resin. Quick filtration through a short plug of silica gel (2% ethyl acetate/hexane) gave 1.2 g of 4 as a pale yellow resin (yield 71%).

1H-NMR (300 MHz, CDCl3):of 0.18 (s, 6, Si(CH3)2), 0,81 (s, 3, CH3), and 0.98 (s, 9, Si(CH3)3), 1,20-1,60 (m, 6), 1,80-to 1.98 (m, 3), 2,16 is 2.55 (m, 4), 2,82 (m, 2), was 4.02 (d, J=8,5 Hz, 2), 5,41 (m, 1), 6,55 (d, J=2.7 Hz, 1, ArH), is 6.61 (DD, J=2,7, 8,2 Hz,1, ArH), 7,12 (d, J=8,2 Hz, 1, ArH).

Following with the, 6), (7) and (8):

Example 2

Obtaining (E)-3-hydroxy-21-(2'-hydroxyethylamino)-19-norpregna-1,3,5(10),17(20)-tetraene (5)

To a solution of ethanolamine (0.5 ml, 8.3 mmol) in THF (0.5 ml) at room temperature in an argon atmosphere was added allylbromide 4 (0.1 g, 0.21 mmol) in THF (1 ml). The reaction mixture was stirred for 20 minutes, then poured into saturated aqueous Panso3and was extracted with 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4). The desiccant was filtered and the solvent was concentrated to obtain oil. The crude product was dissolved in THF (3 ml) and the solution was added tetrabutylammonium in THF (0.5 ml, 0.5 mmol) at 0°C and was stirred for 30 minutes. The reaction mixture was poured into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4), the desiccant was filtered and the solvent was concentrated to obtain resin. Flash chromatography (5% methanol/chloroform) gave 0,044 g of 5 as a white solid (yield 61%), so pl. 203-205C.

1H-NMR (300 MHz, CD3OD):from 0.84 (s, 3, CH3), 2,78 (m, 4), 3,30 (m, 2), of 3.69 (t, J=5.5 Hz, 2), to 5.17 (m, 1), 6,47 (d, J=2,6 Hz, 1, Ar355.

Example 3

Obtaining (E)-3-hydroxy-21-[3'-(N,N-dimethylamino)-propylamino]-19-norpregna-1,3,5(10),17(20)-tetraene (6)

To a solution of 3-dimethylaminopropylamine (0.5 ml, 4.0 mmol) in THF (0.5 ml) at room temperature in an argon atmosphere was added allylbromide (4) (0.1 g, 0.21 mmol) in THF (1 ml). The procedure described in example 2, was used to obtain 0.15 g of 6 as a white powder (yield 19%).

1H-NMR (300 MHz, DMSO-d6):0,81 (s, 3, CH3), of 2.97 (s, 6, N(CH3)2), 3,85 (m, 2), 5,28 (m, 1), 6,46 (d, J=2,6 Hz, 1, ArH), of 6.52 (DD, J=2,6, 8.5 Hz, 1, ArH), 7/08 (d, J=8,5 Hz, 1, ArH).

Example 4

Obtaining (E)-3-hydroxy-21-{2'-[2"-(N,N-dimethylamino)-ethoxy]ethoxy}-19-norpregna-1,3,5(10),17(20)-tetraene (7)

To a solution of 2-[2-dimethylamino)ethoxy]ethanol (0.5 g, 3.75 mmol) in THF (8 ml) at room temperature in an argon atmosphere was added a solution hexamethyldisilazide potassium in toluene (7.0 ml, 3.5 mmol). The resulting solution was stirred for 5 minutes, then the solution was added allylbromide 4 (of 0.13 g, 0.27 mmol) in THF (1.5 ml). After stirring for 5 minutes the reaction mixture was poured into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (gSO4). The desiccant was filtered and the solvent is hydrofloric/pyridine (1 ml) at 0C. the Obtained turbid solution was stirred for 2 h, then poured into water and was extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4). The desiccant was filtered and the solvent was concentrated to obtain oil. Flash chromatography (ethyl acetate; 5% methanol/chloroform) gave to 0.032 g 7 resin (yield 29%).

1H-NMR (300 MHz, CDCl3):of 0.79 (s, 3, CH3), 1,12-of 1.56 (m, 6), 1,79-to 1.98 (m, 3), 2,11-to 2.40 (m, 4), a 2.45 (s, 6, N(CH3)2), is 2.74 (t, J=5.6 Hz, 2), and 2.83 (m, 2), 3,56-to 3.67 (m, 4), of 3.69 (t, J=5.6 Hz, 2), to 4.01 (m, 2), with 5.22 (m, 1), 6,56 (d, J=2.4 Hz, 1, ArH), 6,63 (DD, J=2,4, 8,7 Hz, 1, ArH), to 7.15 (d, J=8.7 Hz, 1, ArH). HRMS of expect. for C26H39NO3, (M+), 413,2930; found, 413,2930.

Example 5

Obtaining (E)-3-hydroxy-21-[3'-(N,N-dimethylamino)-propoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (8)

To a solution of 3-dimethylamino-1-propanol (0.15 ml, of 1.27 mmol) in THF (0.5 ml) at room temperature in an argon atmosphere was added allylbromide (4) (0.1 g, 0.21 mmol) in THF (1 ml). The procedure described in example 2 was used with getting to 0.032 g of 8 as a white powder (yield 40%), so pl. 159-161°C.

1H-NMR (300 MHz, CDCl3):of 0.79 (s, 3, CH3), of 2.38 (s, 6, N(CH3)2), 2,58 (m, 2), of 2.81 (m, 2), of 3.48 (m, 2), 3,95 (m, 2), 5,19 (m, 1), 6,56 (adeno, 383,2825.

The following diagram illustrates the synthetic stage, carried out in examples 6-9 obtaining antiestrogenic compounds(9), (10), (11) and (12);

Example 6

Obtaining (E)-3-hydroxy-21-[2'-(N,N-dimethylamino)-atencio]-19-norpregna-1,3,5(10),17(20)-tetraene (9)

To a suspension of 2-dimethylaminoethanol-Hcl (86 mg, 0.6 mmol) in THF (3 ml) at -78°C in an atmosphere of argon was added a solution of n-utility in hexane (0.7 ml, 1/1 mmol). The resulting mixture was heated to room temperature until a white solid did not dissolve with the formation of the light-yellow solution, and then the solution was cooled to -78°C. To the cooled solution was added allylbromide 4 (0.1 g, 0.21 mmol) in THF (1.5 ml). After heating the reaction mixture to room temperature and stirring for 10 minutes the mixture was poured into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4the desiccant was filtered and the solvent was concentrated to obtain oil. The oil was dissolved in CH3SP (2 ml) and pyridine (1 ml). HF-pyridine (1 ml) was added at 0°C. the solution was stirred for 2 h and then was extracted with a mixture of 80% ethyl acetate/hexane. The joint organization of the Flash-chromatography (ethyl acetate; 5% methanol/chloroform) gave 0,065 g of 9 as a white solid (yield 80%), so pl. 138-140°C.

1H-NMR (300 MHz, CDCl3):to 0.74 (s, 3, CH3), 1,01-of 1.55 (m, 6), 1,75 for 2.01 (m, 4), 2,32 (s, 6, N(CH3)2), 2,61 (m, 4), and 2.79 (m, 2), and 3.31 (m, 2), 5,09 (m, 1), of 6.52 (d, J=2.7 Hz, 1, ArH), 6,56 (DD, J=2,7, 8,3, 1, ArH), to 7.09 (d, J=8,3 Hz, 1, ArH). HRMS of expect. for C24H35NOS (M+), 385,2439; found, 385,2436.

Example 7

Obtaining (E)-3-hydroxy-21-[2'-(pyrrolidinyl)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (10)

To a solution of 1-(2-hydroxyethyl)pyrrolidine (0.15 ml, 1.3 mmol) in THF (2 ml) at 0°C in an atmosphere of argon was added a solution hexamethyldisilazide potassium in toluene (2.0 ml, 1.0 mmol). After stirring for 5 minutes the reaction mixture was cooled to -78°C and the solution was added allylbromide 4 (0.1 g, 0.21 mmol) in THF (2 ml). After heating the reaction mixture to 0°C for 20 minutes the mixture was poured into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4), the desiccant was filtered and the solvent was concentrated to obtain resin. The resin was dissolved in CH3SP (2 ml) and pyridine (1 ml). HF-pyridine (1.0 ml) was added at 0°C. the solution was stirred for 2 h and then poured into water and extravasal and the solvent was concentrated to obtain oil. Flash chromatography (ethyl acetate; 5% methanol/chloroform) gave 0,039 g of 10 as a white solid (yield 47%), so pl. 149-152°C.

1H-NMR (300 MHz, CDCl3):of 0.77 (s, 3, CH3), of 1.12 (m, 1), 1,22-1,58 (m, 5), a 1.75-of 1.94 (m, 7), 2,11 (m, 1), 2,33 (m, 3), 2,72-2,90 (m, 8), the 3.65 (m, 2), 3,99 (m, 2), 5,19 (m, 1), is 6.54 (d, J=2.3 Hz, 1, ArH), 6,60 (DD, J=2,3, 8.0 Hz, 1, ArH), 7,13 (d, J=8.0 Hz, 1, ArH). HRMS of expect. for C26H37NO2(M+), 395,2824; found, 395/2823.

Example 8

Obtaining (E)-3-hydroxy-21-[2'-(morpholinyl)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (11)

To a solution of 4-(2-hydroxyethyl)research (0.15 ml, 1/2 mmol) in THF (0.5 ml) at room temperature in an argon atmosphere was added allylbromide 4 (0.1 g, 0.21 mmol) in THF (1 ml). The procedure described in example 7, was used to obtain 0,062 g of 11 as a white powder (yield 72%), so pl. 140-142°C.

1H-NMR (300 MHz, CDCl3):of 0.79 (s, 3, CH3), of 1.18 (m, 1), 1,28-to 1.60 (m, 5), 1,77-to 1.98 (m, 3), of 2.15 (m, 1), 2,35 (m, 3), of 2.53 (m, 4), 2,62 (t, J=5.8 Hz, 2), 2,82 (m, 2), of 3.57 (m, 2), 3,74 (m, 4), 3,99 (m, 2), a total of 5.21 (m, 1), 6,55 (d, J=2,6 Hz, 1, ArH), is 6.61 (DD, J=2, 6, 8,8 Hz, 1, ArH), to 7.15 (d, J=8,8 Hz, 1, ArH). HRMS of expect. for26H37NO3(M+), 411,2773; found, 411,2774.

Example 9

Obtaining (E)-3-hydroxy-21-[2'-(piperazinil)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (12)

To a solution of 1-allylbromide 4 (0.1 g, 0.21 mmol) in THF (1 ml). The procedure described in example 1 was used to obtain 0,031 g of 12 as a white powder (yield 36%), so pl. 198-200°C.

1H-NMR (300 MHz, CDCl3):of 0.79 (s, 3, CH3) and 1.15 (m, 1), 1,22-to 1.60 (m, 5), a 1.75-to 1.98 (m, 3), of 2.16 (m, 1), 2,32 (m, 3), 2,48-2,70 (m, 10), of 2.81 (m, 2), a 3.01 (m, 2), to 3.64 (m, 2), to 5.17 (m, 1), is 6.54 (d, J=2.3 Hz, 1, ArH), is 6.61 (DD, J=2,3, 8.0 Hz, 1, ArH), 7,13 (d, J=8.0 Hz, 1, ArH). HRMS of expect. for C26H38N2O2(M+), 410,2933; found, 410,2928.

The following diagram illustrates the synthetic stage, carried out in examples 10-14 obtaining antiestrogenic compounds(21), (22), (23), (24), (25) and (27):

Example 10

Obtaining (E)-3-hydroxy-21-[2'-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (21)

(a) Synthesis of 3-acetoxy-19-nor-17-pregna-1,3,5 (10), 20-tetraen-17-ol (15):

A mixture of estrone 1 (10.0 g, 37 mmol) and l3(18.2 g, 74 mmol) in THF (400 ml) at room temperature in an argon atmosphere was stirred for 16 hours To this mixture was added a solution of vinylmania in THF (160 ml, 160 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was extinguished by pouring into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. Obyedinenie 3-hydroxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol in the form of a solid substance.

1H-NMR (300 MHz, CDCl3):of 0.93 (s, 3, CH3), 2,80 (m, 2), 5,20 (m, 2), 6,09 (DD, J=10,7, 17.3 Hz, 1), is 6.54 (d, J=2,6 Hz, 1, ArH), 6,60 (DD, J=2,6, 8.5 Hz, 1, ArH), 7,10 (d, J=8,5 Hz, 1, ArH).

To a solution of 3-hydroxy-19-nor-17-pregna-1,3,5(10), 20-tetraen-17-ol in THF (150 ml) was added pyridine (10 ml) and AU2O (5 ml) at room temperature in argon atmosphere. The resulting mixture was stirred at room temperature for 5 h, then was diluted with a mixture of 80% ethyl acetate/hexane and washed with aqueous Hcl, Panso3and a salt solution. The organic layer was dried (MgSO4), the desiccant was filtered and the solvent was concentrated to obtain a solid substance. Flash chromatography (15% ethyl acetate/hexane) gave an 11.7 g of 15 as a white solid (yield 93%).

1H-NMR (300 MHz, CDCl3):of 0.95 (s, 3, CH3), of 2.28 (s, 3, SLA), of 2.86 (m, 2), 5,18 (m, 2), 6,11 (DD, J=10,7, 17.3 Hz, 1), 6,79 (d, J=2.3 Hz, 1, ArH), 6,83 (DD, J=2,3, 8,3 Hz, 1, ArH), 7,27 (d, J=8,3 Hz, I/ ArH).

(b) Synthesis of (E)-3-acetoxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (18):

To a solution of RVG3in CH2Cl2(0.7 mg, 0.7 mmol) and toluene (5 ml) was added a mixture of 3-acetoxy-19-nor-17-pregna-1,3,5(10 and 0°C for 1.5 h, then extinguished by pouring into cold water and was extracted with a mixture of 40% ethyl acetate/hexane. The organic layer was washed with saturated aqueous Panso3and brine and dried (gS4). The desiccant was filtered and the solvent was concentrated to obtain a white solid. Quick filtration through a plug of silica gel in a mixture of 10% ethyl acetate/hexane gave 0.25 g of 18 as a white solid (yield 85%), so pl. 142-145°C.

1H-NMR (300 MHz, CDCl3):0,81 (s, 3, CH3), to 2.29 (s, 3, PINES3), is 2.88 (m, 2), was 4.02 (d, J=8,5 Hz, 2), 5,43 (m, 1), to 6.80 (d, J=2.3 Hz, 1, ArH), 6,85 (DD, J=2,3, 8,3 Hz, 1, ArH), 7,30 (d, J=8,3 Hz, 1, ArH). HRMS of expect. for C22H27BrO2(M+), 402,1195; found, 402,1203.

(c) Synthesis of (E)-3-hydroxy-21-[2'-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (21):

To a solution of N,N-dimethylethanolamine (0.6 ml, 6.0 mmol) in THF (8 ml) at 0°C in an atmosphere of argon was added hexamethyldisilazide potassium in toluene (11.5 ml, of 5.75 mmol). The solution was stirred for 5 minutes, then was cooled to-78°C. (E)-3-acetoxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraen (18) (0.2 g, 0.5 mmol) in THF (3 ml) was added and the reaction mixture was heated to 0°C for 30 minutes. The yellow cloudy solution was poured into saturated aqueous NaHCOL was filtered and the solvent was concentrated to obtain oil. Flash chromatography (5% methanol/chloroform) gave 0.11 g 21 in the form of a white solid (yield 60%), so pl. 123-124°C.

1H-NMR (300 MHz, CDCl3):of 0.75 (s, 3, CH3), was 1.04 (m, 1), 1,20-of 1.56 (m, 5), 1,72-of 1.92 (m, 3), 2,04 (m, 1), 2,30 (m, 3), of 2.33 (s, 6, N(CH3)2), 2,60 (t, J=5.7 Hz, 2), 2,80 (m, 2), of 3.56 (m, 2), 3,98 (m, 2), 5,19 (m, 1), 6,53 (d, J=2.7 Hz, 1, ArH), to 6.58 (DD, J=2.7, and 8,3 Hz, 1, ArH), 7,11 (d, J=8,3 Hz, 1, ArH). Anal. calculated for C24H35NO2: C, 78,0; N, Of 9.55; N, with 3.79; found: C, Up 77.9; H, 9,50; S, 3,80. HRMS of expect. for C24H35NO2(M+), 369,2667; found, 369,2666.

Example 11

Obtaining (E) -3-hydroxy-7-methyl-21-[2'-(N,N-dimethyl-amino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (22)

(a) Synthesis of (E) -3-acetoxy-7(x-methyl-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (19):

Using the procedure described in stage (a) of example 10, with the replacement of estrone 7-methylestradiol (13) (0,93 g of 3.27 mmol), obtained 3-hydroxy-7-methyl-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol in the form of butter.

1H-NMR (300 MHz, Dl3):of 0.82 (d, J=7,0 Hz, 3, CH3), of 0.95 (s, 3, CH3), 2,50 (d, J=17,0 Hz, 1), totaling 3.04 (DD, J=6, 6, of 17.0 Hz, 1), 5,19 (m, 2), 6,12 (DD, J=10,7, 17.3 Hz, 1), is 6.54 (d, J=2.5 Hz, 1, ArH), is 6.61 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,14 (d, J=8,5 Hz, 1, who was setaccelerator, as described in stage (a) of example 10, to obtain 16 (pale yellow form).

1H-NMR (300 MHz, Dl3):of 0.83 (d, J=7,1 Hz, 3, CH3), of 0.95 (s, 3, CH3), and 2.27 (s, 3, PINES3), to 2.55 (d, J=17,0 Hz, 1), to 3.09 (DD, J=6,7, of 17.0 Hz, 1), 5,18 (m, 2), 6,12 (DD, J=10,7, 17.3 Hz, 1), 6,77 (d, J=2.5 Hz, 1, ArH), 6,83 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,27 (d, J=8,5 Hz, 1, ArH).

Using the procedure described in stage (b) of example 10, and 0.98 g (E)-3-acetoxy-7a-methyl-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (19) were obtained from 16 resin (yield 72%).

1H-NMR (300 MHz, Dl3):0,81 (s, 3, CH3) to 0.85 (d, J=7,1 Hz, 3, CH3), and 2.27 (s, 3, PINES3), to 2.57 (d, J=16,8 Hz, 1), 3,10 (DD, J=6,6, is 16.8 Hz, 1), was 4.02 (d, J=8,5 Hz, 2), 5,42 (m, 1), is 6.78 (d, J=2.3 Hz, 1, ArH), at 6.84 (DD, J=2,3, 8,8 Hz, 1, ArH), 7,29 (d, J=8,8 Hz, 1, ArH).

(b) Synthesis of (E)-3-hydroxy-7-methyl-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (22):

Using the procedure described in stage (C) of example 10, 0.11 g 22 was obtained as a white solid (yield 60%), so pl. 129-132°C.

1H-NMR (300 MHz, Dl3):to 0.78 (s, 3, CH3), 0,81 (d, J=7.2 Hz, 3, CH3), 2,32 (s, 6, N(CH3)2), 2,50 (d, J=16,8 Hz, 2), at 2.59 (t, J=5.7 Hz, 2), 3.04 from (DD, J=6, 6, is 16.8 Hz, 1), of 3.56 (m, 2), 3,99 (m, 2), with 5.22 (m, 1), 6,53 (d, J=2.5 Hz, 1, ArH), is 6.61 (DD, J=2,5, and 8.4 Hz, 1, ArH), to 7.15 (d, J=8.4 and is traena (23)

(a) Synthesis of 3-acetoxy-2-methoxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol (20):

Using the procedure described in stage (a) of example 10, with the replacement of estrone 2-methoxyethanol (14) (0.6 g, 2.0 mmol), 3-hydroxy-2-methoxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol was obtained in the form of butter.

1H-NMR (300 MHz, Dl3):of 0.95 (s, 3, CH3), of 3.84 (s, 3, och3), to 5.17 (m, 2), 6,10 (DD, J=10,8, to 17.4 Hz, 1), 6,63 (s, 1, ArH), 6,77 (s, 1, ArH).

3-hydroxy-2-methoxy-19-nor-17-pregna-1,3,5(10),20-tetraen-17-ol was acetoxysilane, as described in stage (a) of example 10, to obtain 17 in the form of resin.

1H-NMR (300 MHz, Dl3):of 0.96 (s, 3, CH3), is 2.30 (s, 3, SLA), of 3.80 (s, 3, och3), is 5.18 (m, 2), 6,11 (DD, J=10,7, 17.3 Hz, 1), was 6.73 (s, 1, ArH), 6,88 (c, 1, ArH).

Using the procedure described in stage (b) of example 10 and 0.3 g of 20 was obtained from 17 in the form of resin (yield 35%).

1H-NMR (300 MHz, Dl3):to 1.00 (s, 3, CH3), to 2.29 (s, 3, PINES3), of 3.80 (s, 3, och3), and 5.30 (m, 2), 6,14 (m, 1), was 6.73 (s, 1, ArH), 6,86 (s, 1, ArH).

(b) Obtaining (E)-3-hydroxy-2-methoxy-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (23):

Using the procedure described in stage (C) of example 10 was obtained 0.15 g 2>/img>0,81 (s, 3, CH3), to 2.29 (s, 6, N(CH3)2), 2,53 (m, J=5.8 Hz, 2), 2,77 (m, 2), 3,53 (t, J=5.8 Hz, 2), 3,86 (s, 3, och3), of 4.00 (m, 2), of 5.24 (m, 1), 6,64 (c, 1, ArH), 6,80 (c, 1, ArH). HRMS of expect. for C25H37NO3(M+), 399,2773; found, 399,2771.

Example 13

Obtaining (E)-3-hydroxy-21-[2'-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (24)

Amin 24, which is received from allylbromide 18 (0.11 g, 0.26 mmol) and N,N-dimethylethanolamine (0.2 ml, 1.5 mmol) using the same procedure described for amine 21 was obtained as a white solid (0,074 g, 72%).

1H-NMR (300 MHz, Dl3):to 0.78 (s, 3, CH3), 1,24 (t, J=7,1 Hz, 6, N(CH2SN)2), 2,78 (m, 2), 3,00 (m, 6), 3,70 (m, 2), of 3.96 (m, 2), 5,14 (m, 1), is 6.54 (d, J=2, 5 Hz, 1, ArH), 6,60 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,11 (d, J=8,5 Hz, 1, ArH). HRMS of expect. for25H37NO2(M+), 397,2981; found, 397,2985.

Example 14

Obtaining(E)-3-hydroxy-21-[2'-(N,N-dimethylamino)-2-propoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (27)

Using the procedure described in stage (C) of example 10, (E)-3-acetoxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraen (18, 0.15 grams of 0.37 mmol) interacted with 1-dimethylamino-2-propanol (0.3 ml, 2.4 mmol) with the formation of 0.075 g of a mixture of diastereoisomers 1:1 27 in the form of a white powder (yield 53%).

1H-is (s, 6, N(CH3)2), and 2.79 (m, 2), 3,68 (m, 1), to 4.01 (m, 2), 5,20 (m, 1), is 6.54 (d, J=3.0 Hz, 1, ArH), 6,60 (DD, J=3,0, 8,3 Hz, 1, ArH), 7,10 (d, J=8,3 Hz, 1, ArH);

1H-NMR (diastereoisomer B) (300 MHz, Dl3):of 0.75 (s, 3, CH3), of 1.18 (d, J=6.2 Hz, 3, CH3), of 2.33 (s, 6, N(CH3)2), and 2.79 (m, 2), 3,68 (m, 1), 3,90 (DD, J=5,6, and 11.5 Hz, 1), of 4.12 (DD, J=7,7, and 11.5 Hz, 1), 5,20 (m, 1), is 6.54 (d, J=3.0 Hz, 1, ArH), is 6.61 (DD, J=3,0, 8,3 Hz, 1, ArH), 7,12 (d, J=8,3 Hz, 1, ArH).

Example 15

Obtain (Z)-3-hydroxy-21-[2'-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (32)

(a) to Obtain ethyl(E)- and (Z)-3-tert-butultimately-silyloxy-19-norpregna-1,3,5(10),17(20)-tetraen-21-oate (28) and (29):

To a solution of triethylphosphate (2.24 g, 10.1 mmol) in THF (30 ml) in an argon atmosphere at room temperature was added tert-piperonyl potassium in THF (9.1 ml, 9.1 mmol). After stirring for 1.0 h, was added 3-tert-butyldimethylsilyloxy (2, 1, 75, 4,55 mmol) in THF (10 ml) and the solution was heated at the temperature of reflux distilled during the night. The reaction mixture was poured into saturated aqueous Panso3and were extracted with a mixture of 40% ethyl acetate/hexane. The combined organic layers were dried (gSO4), the desiccant was filtered and the solvent was concentrated to obtain a mixture of E - and Z-isomers, 28 and 2 is and 29 (yield 10%).

(28): so pl. 109-110°C; Rf Of 0.56 (10% EtOAc/hexane):1H-NMR (300 MHz, Dl3):to 0.19 (s, 6, Si(CH3)2), 0,86 (s, 3 CH3), and 0.98 (s, 9, Si(CH3)3), 1.29 (t, J=7,1 Hz, 3, CO2CH2CH3), 4,16 (K, J=7, 1 Hz, 2, CO2CH2CH3), 5,59 (t, J=2.4 Hz, 1), 6,56 (d, J=2,6 Hz, 1, ArH), is 6.61 (DD, 2,6, 8,3 Hz, 1, ArH), 7,12 (d, J=8,3 Hz, 1, ArH).

(29): so pl. 154-156°C; Rf Of 0.5 (10% EtOAc/hexane):1H-NMR (300 MHz, Dl3):of 0.18 (s, 6, Si (CH3)2), and 0.98 (s, 9, SiC (CH3)3), was 1.04 (s, 3, CH3), of 1.29 (t, J=7,1 Hz, 3, CO2CH2CH3), 4,14 (K, J=7,1 Hz, 2, CO2CH2CH3), of 5.68 (t, J=2.0 Hz, 1), 6,55 (d, J=2.0 Hz, 1, ArH), is 6.61 (DD, 2,0, 8.6 Hz, 1, ArH), 7,12 (d, J=8.6 Hz, 1, ArH).

(b) Obtain (Z)-3-tert-butyldimethylsilyloxy-21-hydroxy-19-norpregna-1,3,5(10),17(20)-tetraene (30)

To a solution of (Z)-3-tert-butyldimethylsilyloxy-19-norpregna-1,3,5(10),17(20)-tetraen-21-oate (29, 0.1 g, 0.22 mmol) in THF (5 ml) was added sociallyengaged (0.015 g, 0.4 mmol) at 0°C. After stirring for 1 h in argon atmosphere, the reaction mixture was extinguished with water. A white precipitate was removed by filtration and washed several times with a mixture of 80% EtOAc/hexane. The filtrate was dried (MgSO4), the desiccant was filtered and the solvent was concentrated to obtain 30 in the form of solid vases is, ,98 (s, 9, Si(CH3)3), 4,20 (m, 1), 4,34 (m, 1), to 5.35 (m, 1), 6,55 (d, J=2.7 Hz, 1, ArH), is 6.61 (DD, J=2.7, and 8,3 Hz, 1, ArH), 7,11 (d, J=8,3 Hz, 1, ArH).

(c) Obtain (Z)-3-tert-butyldimethylsilyloxy-21-bromide-19-norpregna-1,3,5(10),17(20)-tetraene (31)

To a solution of (Z)-3-tert-butyldimethylsilyloxy-21-hydroxy-19-norpregna-1,3,5(10),17(20)-tetraene (30) in toluene (10 ml) was added pyridine (0.04 ml, 0.49 mmol) and RVG3in CH2CL2(of 0.24 ml, 0.24 mmol) at -78°C in argon atmosphere. After stirring for 2 h the reaction mixture was extinguished by pouring into a mixture of ice water and was extracted with a mixture of 40% ethyl acetate/hexane. The organic layer was washed with saturated aqueous NaHCO3and brine and dried (MgSO4). The desiccant was filtered and the solvent was concentrated to obtain 31 in the form of resin.

1H-NMR (300 MHz, Dl3):of 0.18 (s, 6, Si(CH3)2) to 0.85 (s, 3, CH3), and 0.98 (s, 9, SiC(CH3)3), 4,19 (m, 2), of 5.48 (m, 1), 6,55 (d, J=2.5 Hz, 1, ArH), is 6.61 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,12 (d, J=8,5, 1, ArH).

(d) Receiving (Z)-3-hydroxy-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (32)

To a solution of N,N-dimethylethanolamine (0.15 ml, 1.3 mmol) in THF (2 ml) at 0°C in an atmosphere of argon was added hexamethyldisilazide potassium in toluene (2.0 ml, 1.0 mmol). After premeried-19-norpregna-1,3,5(10),17(20)-tetraen (31, 0.1 g, 0.21 mmol) in THF (2 ml). The solution was heated to 0°C for 20 minutes, then poured into saturated aqueous Panso3and were extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (gSO4), the desiccant was filtered and the solvent was concentrated to obtain resin. To a solution of this resin in CH3SP (2 ml) and pyridine (1 ml) was added HF-pyridine (1.0 ml) at 0°C. After stirring for 2 h cloudy solution was poured into water and was extracted with a mixture of 80% ethyl acetate/hexane. The combined organic layers were dried (MgSO4), the desiccant was filtered and the solvent was concentrated to obtain oil. Flash chromatography (ethyl acetate; 5% methanol/chloroform) gave a white solid. Recrystallization (CH2CL2) gave 0,023 g 32 in the form of a white solid (yield 28% 29).

1H-NMR (300 MHz, Dl3):to 0.88 (s, 3, CH3), of 2.38 (s, 6, N(CH3)2), to 2.66 (t, J=5.8 Hz, 2), and 2.79 (m, 2), to 3.58 (t, J=5, 8 Hz, 2), 4,06 (m, 1), 4,17 (m, 1), with 5.22 (m, 1), 6,53 (d, J=2.4 Hz, 1, ArH), 6,59 (DD, J and 2.4 and 8.2 Hz, 1, ArH), to 7.09 (d, J=8,2 Hz, 1, ArH).

The following diagram illustrates the formation of compounds (33) and (34), as described in examples 16 and 17:

Example 16

Obtaining (E)-3-hydroxy-21-(N-ሺ mol) in dry THF (6 ml) at 0°C in an atmosphere of argon was added a 0.5 M solution of bis(trimethylsilyl)amide potassium in toluene (8,3 ml, to 4.15 mmol) and was stirred for 5 minutes. The solution was cooled to -78°C and the solution was added allyl-bromide, (E)-3-acetoxy-21-bromo-19-norpregna-1,3,5(10)-17 (20)-tetraene (18, 333 g, 823 mmol) in dry THF (5 ml) and the reaction mixture was heated to 0°C for 30 minutes. The turbid yellow solution was poured into saturated aqueous Panso3and were extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated to an oil. Flash chromatography (5-10% methanol/dichloromethane) gave the desired amine 33 in the form of inoob different substances non-standard white (0,025 7,9%).

1H-NMR (300 MHz, Dl3):to 0.73 (s, 3, CH,), 1,10-of 1.54 (m, 7), 1,72-of 2.38 (m, 8), of 2.56 (s, 3, NCH3), to 2.67-2.91 in (m, 4), to 3.02 (m, 1), 3,21 (m, 1), 3,7 (Shir. with a, 1), with 3.89 (m, 2), of 4.12 (m, 1), 5,11 (m, 1), of 6.49 (d, J=2,6 Hz, 1, ArH), to 6.57 (DD, J=2,6, 8,3 Hz, 1, ArH),? 7.04 baby mortality (d, J=8,3 Hz, 1, ArH).

Example 17

Obtaining (E)-3-hydroxy-21-(N-methyl-2(S)-pyrrolidinyl-methoxy)-19-norpregna-1,3,5(10),17(20)-tetraene (34)

Amine 34 was obtained from allylbromide (E)-3-acetoxy-21-bromo-19-norpregna-1,3,5(10),17(20)-tetraene (0.2 g, 496 mmol) and (S)-1-methyl-2-pyrrolidineethanol (314 mg, 2,73 mmol) using the same procedures described in example 16 to obtain the amine 33, to obtain white solids (0,070 g, 36%); so pl. 175-177°C.

1H-NMR (300 MHz, Dl, ), of 2.97 (m, 1), 3,30 (DD, J=6, 8 Hz), 3,43 (DD, J=6, 12 Hz), 3,6 (Shir. with a, 1), 3,91 (m, 2), 5,12 (m, 1), 6,48 (d, J=2,6 Hz, 1, ArH), of 6.52 (DD, J=2, 6, 8,3 Hz, 1, ArH), 7,05 (d, J=8,3 Hz, 1, ArH).

The following diagram illustrates the formation of compounds (35) and (36), as described in examples 18 and 19:

Example 18

Obtaining (E)-3-hydroxy-2-N,N-dimethylaminomethyl-21-[2'-(N',N' -dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (35)

To a stirred solution of 100 mg (0,271 mmol) of (E)-3-hydroxy-21-[2'-(dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene 21 in 3 ml of benzene and 5 ml of ethanol was added 10 mg of paraformaldehyde and 0,054 g (0,528 mmol) N,N,N',N"-tetramethylguanidine and the mixture was heated at 85°C for 15 h in an argon atmosphere. Then the reaction mixture was cooled, the volatiles were removed under high vacuum and the residue was subjected to chromatography (silica gel, 5-10% Me-HE/l3with getting 0,077 g (67%) of product 35.

1H-NMR (300 MHz, Dl3):to 0.80 (s, 3H), 2,32 (2, N), to 2.57 (t, 2H, J=5.8 Hz), 2,82 (Shir.d, 2H), 3,59-3,70 (m, 4H), 4.00 points (t, 2H, J=5.8 Hz), with 5.22 (m, 1H), 6,56 (2, 1H), 6.89 in (s, 1H). MS(DCI) calculated for CHNO, 427; found 427 (M+H; 100%).

Example 19

Obtain 3-hydroxy-2-N,N-dimethylaminomethyl-21-[2'-[N,N'-dimethylamino)ethoxy]-19-norpregna-1,3,5(10)of triens (36)

To mix the solution 0,040 g Nola was added 5 mg of 10% palladium on coal and the mixture was stirred at room temperature in a hydrogen atmosphere for 14 h, filtered through a pillow celite, washed with ethyl acetate and the filtrate was evaporated at room temperature to obtain a residue, which was chromatographically (10% Meon/l3with getting 0,039 g (96%) of product 36.

1H-NMR (300 MHz, Dl3):of 0.62 (s, 3H), 2,32 (C, 6N), 2,42 (C, 6N), to 2.65 (t, 2H, J=5, 8 Hz), 3,40-3,70 (m, 6N), to 6.57 (s, 1H), to 6.88 (s, 1H). MS(DCI) expect. for CHNO, 429; found, 429 (M+H, 100%).

The following diagram illustrates the connection 45, as described in example 20.

Example 20

Obtain 3-hydroxy-11E-[2'-(2"-N,N-dimethylamino-amoxicilian)-1,3,5(10)-17-estrone (45)

(a) Obtaining 3-tert-butyldiphenylsilyl-17-ethylene-dixisti-1,3,5 (10)-triene-11-ol (38):

To a stirred solution of 6.3 g (0.019 mol) of 3-hydroxy-17-atlanticcity-1,3,5(10)-11-ol (37) in 20 ml of anhydrous DMF was added 2.86 g (0,042 mol) of imidazole and 5,46 g (0,021 mol) tert-butyldiphenylsilyl sequentially at room temperature in an argon atmosphere and the mixture was stirred at 60°C for 24 h, cooled to room temperature, diluted with water and was extracted with ether. The combined organic extract was washed with water, brine and dried (Na2SO4). Wyposazenia product 38 in the form of a white solid.

1H-NMR (300 MHz, Dl3):of 0.87 (s, 3H), 1,17 (s, N), 2,69 (Shir.d, 2H), 3,85-3,98 (m, 4H), to 4.15 (m, 1H), 6,60 (m, 2H), 7,34-of 7.48 (m, 6N), of 7.69 (d, 1H, J=8.5 Hz), 7,80 (m, 4H).

(b) Obtaining 3-tert-butyldiphenylsilyl-17-atlanticcity-1,3,5(10)-triene-11-she (39):

To a stirred solution of 1.5 ml (16.5 mmol) of oxalicacid in 15 ml of fresh dichloromethane was added dropwise to 2.35 ml (33.0 mmol) of dimethyl sulfoxide at -65°C (bath with a mixture of chloroform/dry ice) in an argon atmosphere. After 10 minutes, was added dropwise a solution of 6.2 g (10.9 mmol) of 3-tert-butyldiphenylsilyl-17-ethylene-dixisti-1,3,5(10)-triene-11-ol 38 in 15 ml dichloromethane and the reaction mixture was stirred for 40 minutes at the same temperature. Then was added 12 ml (of 87.3 mmol) of triethylamine at -65°C. was slowly allowed to reach room temperature, washed with saturated solution of NH4Cl, water, brine and dried (PA2SO4). Evaporation of the solvent gave a resin, which was chromatographically (15% ethyl acetate/hexane) obtaining 5,18 g (84%) of product 39.

1H-NMR (300 MHz, Dl3):of 0.91 (s, 3H), of 1.16 (s, N), is 2.88 (d, 1H, J=a 12.7 Hz), 3,50 (d, 1H), 3,80-4,00 (m, 4H), 6,59 (Shir.d, 1H), 6,65 (Shir.d, 1H), 7,13 (d, 1H, J=8.5 Hz), 7,40 (m, 6N), of 7.70 (m, 4H). MS(DCI) 584 (M+NH4, 1)-triene-11-ol (40):

3.28 g (1,76 mmol) chloride heptahydrate cerium (III) were placed in a round bottom flask and heated under high vacuum at 120°C for 2 h, cooled to room temperature in argon atmosphere. Then added 10 ml of dry THF and the suspension was stirred for 1 h before formation of a stable milky-white suspension. The flask was cooled to -78°C. and slowly added a 1 M solution 5,28 ml (5,28 mmol) vinylmania in an argon atmosphere and the mixture was stirred for 1 h at the same temperature. Then was added dropwise a solution of 3.28 g (8,8 mmol) 3-tert-butyldiphenylsilyl-17-atlanticcity-1,3,5(10)-triene-11-it 39 in 20 ml of THF at -78°C. the mixture was stirred at -40°C (bath with a mixture of acetonitrile/dry ice) for 3 h, extinguished a saturated solution of NH4Cl was extracted with ether. The combined ether layers were washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave 0,860 mg (82%) of the product 40 in the form of a white solid.

1H-NMR (300 MHz, Dl3):1,10 (s, N), of 1.16 (s, 3H), 3,80-3,95 (m, 4H), 5,10 (d, 1H), 6,62 (d, 1H), 7,40 (m, 6N), to 7.68 (d, 1H), 7,78 (m, 4H). MS(DCI): 612 (M+NH4, 100%), 595 (M+H, 10).

(d) 3-tert-butyldiphenylsilyl-11E-(2'-chloranilide)-17-atlanticcity-1,3,5(10)-triethanol)-17-atlanticcity-1, 3, 5 (10)-triene-11(3--Ola 40 and (0,689 g, 3.35 mmol) dicret-butyl-4-methylpyridine in 15 ml of dry dichloromethane was added dropwise to 0.17 ml (1,61 mmol) of vanadium tetrachloride at -20°C in argon atmosphere. The mixture was stirred for 3 h, allowing to warm to room temperature. The mixture was washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave a residue, which was chromatographically (10% ethyl acetate/hexane with getting to 0.263 g (32%) of the product 41:

1H-NMR (300 MHz, Dl3):to 0.80 (s, 3H), 1,10 (s, N), 3,10 (d, 1H, J=2.7 Hz), 3,92 (m, 4H), 4,00-4,24 (m, 2H), 5,69 (5, 1H, J=8.5 Hz), 6,62 (m, 2H), 6,95 (d, 1H, J=8.5 Hz), 7,40 (m, 6N), 7,72 (m, 4H). MS(DCI): 630 (M+NH4, 20%), 613 (M+H, 40), 577 (M+H-HCl, 100).

(e) Obtaining 3-tert-butyldiphenylsilyl-11E-(2'-acetoacetanilide)-17-atlanticcity-1,3,5(10)-triens (42):

To a mixed solution of 0.3 g (0.49 mmol) of 3-tert-butyldiphenylsilyl-11TH-(2'-chloranilide)-17-atlanticcity-1,3,5(10)-triens 41 in 5 ml of anhydrous DMF was added 0,482 g (4,89 mmol) of potassium acetate and the mixture was stirred at room temperature for 24 h, poured into water and was extracted with ether. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave jsko (300 MHz, Dl3):to 0.80 (s,3H), 1,10 (s, N), from 2.00 (s, 3H), 2,16 (d, 1H, J=and 12.2 Hz), of 3.07 (d, 1H, J=10.4 Hz), 3,95 (m, 4H), of 4.54 (DD, 1H, J=12,4 Hz, J=6,44 Hz), 4,71 (DD, 1H, J=12,4 Hz, J=6,44 Hz), 4,71 (DD, 1H, J=12,4 Hz, J=7,40 Hz), of 5.48 (t, 1H, J=6,7 Hz), is 6.54 (m, 2H), of 6.96 (d, 1H, J=9.5 Hz), 7,40 (m, 6N), 7,74 (m, 4H). MS(DCI): 654 (M+NH4, 100%), 577 (M-SPLA+N, 80).

(f) Obtaining 3-tert-butyldiphenylsilyl-11E-(2'-hydroxyethylidene)-17-atlanticcity-1,3,5(10)-triens (43):

To a stirred solution of 0.06 g (0,094 mmol) 3-tert-butyldiphenylsilyl-11E-(2'-acetoacetanilide)-17-atlanticcity-1,3,5(10)-triens 42 in 3 ml of methanol was added a few drops of 3% solution of sodium methoxide in methanol and the mixture was stirred at room temperature for 3 h, extinguished a saturated solution of NH4Cl, concentrated at room temperature, the residue suspended in water and was extracted with ethyl acetate. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave a residue, which was chromatographically (20% ethyl acetate/hexane) obtaining 0,056 g (96%) of product 43.

1H-NMR (300 MHz, Dl3):0,70 (s, 3H), and 0.98 (s, N), 2,98 (d, 1H, J=a 12.7 Hz), 3,80 (m, 4H), 3.95 to 4,22 (m, 2H), 5,48 (t, J=6.8 Hz), 6,45 (m, 2H), 6.90 to (d, 1H, J=8.5 Hz), 7,30 (m, 6N), 1, 65 (m, 4H).

b) sodium hydride (60% in paraffin) in 3 ml anhydrous DMF was added 40 mg (0,283 mmol) of the hydrochloride of 2-chloroethylamine at 0°C and the mixture was stirred for 10 minutes and Then was added dropwise a solution of 54 mg (0.09 mmol) of 3-tert-butyldiphenylsilyl-11TH-(2'-hydroxyethylidene)-17-Ethylenedioxy-östra-1,3,5 (10)-triens 43 in 3 ml of anhydrous DMF, this mixture was heated at 50°C in argon atmosphere for 2 h, cooled, diluted with water and was extracted with ether. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave 3-tert-butyldiphenylsilyl-11TH-(2'-(2"-dimethylaminoethoxide)-17-atlanticcity-1,3,5(10)-triene 44, to which was added 10 ml of 3% solution of hydrogen chloride in methanol. The mixture was stirred for 3 h at room temperature, extinguished anhydrous solution of NH4Cl, concentrated at room temperature and the residue was distributed between water and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate, washed with water, brine and dried (PA2SO4). Evaporation of the solvent gave a residue, which was chromatographically (10% Meon/l3) to obtain the product 45.

1H-NMR (300 MHz, Dl3):of 0.87 (s, 3H), 2,35 (C, 6N), a 2.75 (t, 2H, J=5.7 Hz), 2,89 (d, 1H, J=a 12.7 Hz), 3,10 (d, 1H, J=9,77 Hz), Android 4.04 (dt, 2H, J=5,70 Hz, J=5.7 Hz), 2,89 (d, 1H, J=a 12.7 Hz), 3,10 (d, 1H, J=9,77 Hz), Android 4.04 (dt, 2H, J=5,70 Hz, J=1,22 Hz), 4,14 (DD, 1H, J=12,6 Hz, J=6.3 Hz), 4,34 (DD, 1H, J=12,6 Hz, J=7,12 Hz), of 5.68 (t, 1H, J=6, 8 Hz), 6,7 (d, 1H, J=2.7 Hz), 6.75 in (DD, 1H, J=2.7 Hz, J=8,79 Hz). MS(DCI): 384 (M+H, 100%).

The following diagram illusion 21

Obtaining (E)-3-tetrahydropyranyloxy-7-methyl-19-norpregna-1,3,5(10),17(20)-tetraene (47A) and (E)-3-Tetra-hydroperoxy-7-methyl-19-norpregna-1,3,5(10)-triene-21-oate (47b)

(a) Receiving 7-mutilation (13): To a solution of 114 g 7-methylandrosta-4-ene-3,17-dione 45A in 1500 ml of glacial acetic acid was added 106 g CuCl2. The mixture was heated with stirring to 60°C for 72 h the Reaction mixture was poured into H2About 500 ml of the reaction mixture to 3500 ml of N2On) and the precipitate was collected by filtration and was dried in air for 18 hours, the Solid was dissolved in methylene chloride (2 l) and washed with saturated Panso3(2 l), N2O (2 l) and saturated NaCl (2 l). Solution in methylene chloride was dried over MgSO4and filtered. Solution in methylene chloride was filtered (suction chromatography) in 1.5 kg of silica gel 60 for flash chromatography (230-400 mesh mesh). Cushion silica gel additional suirable additional l2. l2the solutions were combined and then processed by noricum, filtered through a pad celite and then after evaporation under reduced pressure received of 91.3 g of pure 13 (82%).

(b) Obtaining 3-tetrahydropyranyloxy is electrona 13 (8,18 g, 28.8 mmol) and DHP (4,0 ml and 43.9 mmol) in CH2CL2(100 ml) at 0°C in an atmosphere of argon was added a catalytic amount of p-TsOH and the reaction mixture was stirred for 1 h, the Reaction mixture was poured into saturated aqueous Panso3and was extracted with CH2CL2. The combined organic layers were dried over anhydrous sulfate MgSO4, filtered and concentrated to obtain a pale yellow solid. Flash chromatography (5%; 10% EtOAc/hexane) gave a simple ether 46 in the form of a white solid (10,12 g 95%):

1H-NMR (300 MHz, Dl3):to 0.88 (d, J=7,0 Hz, 3, CH3), of 0.90 (s, 3, CH3), of 5.39 (m, 1), is 6.78 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,19 (d, J=8,5 Hz, 1, ArH).

(C) Obtaining ethyl-(E)-3-tetrahydropyranyloxy-7-methyl-19-norpregna-1,3,5(10),17(20)-tetraen-21-oate (47):

To a solution of 46 (10,12 g, 27,46 mmol) and triethylphosphite (28 ml, 141,1 mmol) in EtOH (130 ml) and THF (30 ml) in an argon atmosphere at 40-45°C was slowly added a 21 wt.% the solution ethoxide sodium in EtOH (52,3 ml, 140 mmol) and the solution was heated at the temperature of reflux distilled during the night. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then the mixture was diluted with water, and ek is Aravali with a yellow resin. Chromatography (5%; 10% EtOAc/hexane) gave ester 47 as a white foam (11 g, 91%):1H-NMR (300 MHz, Dl3):of 0.85 (d, J=7,0 Hz, 3, CH3), of 0.87 (s, 3, CH3), of 1.30 (t, J=7,1 Hz, 3, CO2CH2CH3), 2,89 (m, 2), 3,10 (m, 1), of 3.60 (m, 1), of 3.94 (m, 1), 4,17 (K, J=7,1 Hz, 2, CO2CH2CH3), of 5.40 (m, 1), 5,59 (m, 1), 6,77 (d, J=2.5 Hz, 1, ArH), 6,86 (DD, J=2.5 and 8.7 Hz, 1, ArH), 7,21 (d, J= 8.7 Hz, 1, ArH).

(d) Synthesis of (E)-3-tetrahydropyranyloxy-7-methyl-21-hydroxy-19-norpregna-1,3,5(10),17(20)-tetraene (47A):

To a solution of ester 47 (11 g, 25 mmol) in THF (200 ml) was added a 1.0 M solution of DIBAL diisobutylaluminium hydride in heptane (60 ml, 60 mmol) at -78°C in an argon atmosphere and the reaction mixture was heated to 0°C and stirred for 1.5 hours was Added methanol (5 ml) and water at 0°C and the solution was heated to room temperature and was stirred for 30 minutes. A cloudy solution was extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to obtain allyl alcohol 47A in the form of a white solid (9,63 g, 97%):1H-NMR (300 MHz, Dl3):of 0.82 (s, 3, CH3) to 0.85 (d, J=7,0 Hz, 3, CH3), to 3.09 (m, 1), of 3.60 (m, 1), 3,95 (m, 1), is 4.15 (m, 2), and 5.30 (m, 1), of 5.39 (m, 1), is 6.78 (d, J=2.2 Hz, 1, ArH), 6g>-methyl-19-norpregna-1,3,5(10)-triene-21-oate (47b):

A solution of 33.4 g 47 in 450 ml of ethanol containing 25 ml of triethylamine and 2.0 g of 5% palladium-calcium carbonate in the flask of 1 l was first made on the apparatus for shaking Parra for 18 hours, the Catalyst was removed by filtration through a layer of celite. For washing the layer of celite used an additional amount of ethanol. Ethanol solutions were combined and evaporated to dryness in vacuum with the receipt of 33.5 g (quantitative yield) 47b in the form of a clear oil.

The following diagram illustrates the formation of compounds 48, 50 and 51, as described in examples 23-25.

Example 22

Getting citrate (E)-3-hydroxy-7-methyl-21-[2'-N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (48)

(a) Obtaining (E)-3-hydroxy-7-methyl-21-[2'-N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (25):

To a suspension of NaH (25,0 g, 625 mmol) in DMF (50 ml) at 0°C in an argon atmosphere was added the hydrochloride of 2-N,N-diethylaminoethylamine (8.5 g, 49.4 mmol) in portions and stirred until cessation of hydrogen evolution. The reaction mixture was heated to room temperature and was added allyl alcohol 47A (6.5 ml, 16.5 mmol) in DMF (30 ml) and was stirred for 10 minutes. D is H2About at room temperature and was extracted with ethyl acetate. The combined organic layers were dried over anhydrous gSO4, filtered and concentrated to obtain TNR-ester 25 in the form of crude resin (8.5 g).

To a solution of TNR-ester (8.5 g) in the Meon (80 ml) at room temperature was added p-TsOH (3.4 g, 18 mmol) and was stirred for 10 minutes. The reaction mixture was diluted with water (150 ml) and the methanol evaporated under reduced pressure. The cloudy mixture was poured into saturated aqueous Panso3and were extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to obtain a white solid. Flash chromatography (5% methanol/chloroform) gave amine 25 in the form of a white solid (USD 5.76 g, 85% for two steps):1H-NMR (300 MHz, Dl3):of 0.79 (s, 3, CH3), of 0.82 (d, J=7,0 Hz, 3, CH3), a 1.08 (t, J=7.2 Hz, 6, N(CH2CH3)2), 2,50 (d, J=16.5 Hz, 1), 2,68 (t, J=7.2 Hz, 4, N(CH2CH3)2), was 2.76 (t, J=6, 3 Hz, 2), 3,05 (DD, J=5,5, of 16.5 Hz, 1) and 3.59 (m, 2), 3,99 (m, 2), a total of 5.21 (m, 1), is 6.54 (d, J=2.7 Hz, 1, ArH), 6,62 (DD, J=2.7, and 8,3 Hz, 1, ArH), to 7.15 (d, J=8,3 Hz, 1, ArH).

(b) Obtaining citrate (E)-3-hydroxy-7-methyl-21-[2' -(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-devlali citric acid (0,61 g, 0.32 mmol) and was stirred for 15 minutes. The solvent was removed under reduced pressure and dried with pump during the night with obtaining citrate salt 48 in the form of a white solid with a quantitative output:1H-NMR (300 MHz, CD3OD):of 0.83 (d, J=7,0 Hz, 3, CH3) to 0.85 (S, 3, CH3), is 1.31 (t, J=7,1 Hz, 6, N(CH2CH3)2), of 2.72 (d, J=15,4 Hz, 2), 2,82 (d, J=15,4 Hz, 2), a 3.01 (DD, J=5,7, and 16.5 Hz, 1), of 3.25 (t, J=7.2 Hz, 4, N(CH2CH3)2), to 3.73 (m, 2), 4,07 (m, 2), of 5.24 (m, 1), 6,46 (d, J=2.5 Hz, 1, ArH), is 6.54 (DD, J=2.5 a, 8,8 Hz, 1, ArH), to 7.09 (d, J=8,8 Hz, ArH).

Example 23

Obtaining (E)-3-hydroxy-7-methyl-21-{2'-[2"-(N,N-dimethylamino)ethoxy]ethoxy}-19-norpregna-1,3,5(10),17 (20)-tetraene (50)

(a) Obtaining (E)-3-tetrahydropyranyloxy-7-methyl-21-[2'-(hydroxy)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (49):

A mixture of allyl alcohol 47A (1.0 g, 2,52 mmol), ethylene carbonate resulting (0.33 g, of 3.78 mmol) and triethylamine (0.26 g, 2,52 mmol) in DMF (0.6 ml) was heated to 120°C during the night. The reaction mixture was cooled to room temperature and subjected to flash chromatography (30% EtOAc/hexane). Source material 47A was recovered as a white solid (0.6 g) and the target alcohol 49 watched as a white foam (0.14 g, 32% (based on the extracted Ishan3), to 2.55 (DD, J=5, 5, of 17.0 Hz, 1), to 3.09 (m, 1), a 5.25 (m, 1), of 5.39 (m, 1), 6,77 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2.5 and 8.7 Hz, 1, AGN), 7,21 (d, J=8.7 Hz, 1, ArH).

(b) Obtaining (E) -3-hydroxy-7-methyl-21-{2'-[2"-(N,N-dimethylamino)ethoxy]ethoxy}-19-norpregna-1,3,5(10),17(20)-tetraene (50):

Amin 50, which is received from the alcohol 49 (of 0.13 g, 0.30 mmol) and hydrochloride of 2-diethylaminoethylamine (0.15 g, 1.0 mmol) and freed from the protective groups using the procedure described for amine 25, was recovered as a white solid (0.11 g, 85% for two steps):1H-NMR (300 MHz, Dl3):to 0.80 (s, 3, CH3), or 0.83 (d, J=7,0 Hz, 3, CH3), was 2.34 (s, 6, N(CH3)2), was 3.05 (DD, J=6,2, and 16.4 Hz, 1), 3,62 (m, 6), of 3.96 (m, 2), with 5.22 (m, 1), is 6.54 (d, J=2.5 Hz, 1, ArH), 6,63 (DD, J=2.5 and 8.0 Hz, 1, ArH), 7,16 (d, J=8.0 Hz, 1, ArH).

Example 24

Obtaining (E)- and (Z)-3-hydroxy-7-methyl-21-[2'-(pyrrolidinyl)methoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (51)

To a suspension of NaH (1.0 g, 25 mmol) in DMF (30 ml) at 0°C in an argon atmosphere was added the hydrochloride of 2-pyrrolidinedione (1.29 g, 7.56 mmol) in portions and stirred until cessation of hydrogen evolution. The reaction mixture was heated to room temperature and was added allyl alcohol 46 (1.0 ml, 2,52 mmol) in DMF (10 ml) and was stirred for 10 minutes. Dobavljacima H2O at room temperature and was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to obtain a black resin. The crude mixture was dissolved in Me-and HE was added p-s to the acidic reaction solution. The reaction mixture was diluted with water and the methanol evaporated under reduced pressure. The cloudy mixture was poured into saturated aqueous Panso3and were extracted with ethyl acetate. The combined organic layers were dried over anhydrous gSO4, filtered and concentrated to obtain a white solid. Flash chromatography (5% methanol/chloroform) gave the E - and Z-isomeric mixture (4:1) as pale yellow solid (0.26 g, 25%): E-isomer 51:1H-NMR (300 MHz, Dl3):of 0.79 (S, 3, CH3), 0,81 (d, J=7,0 Hz, 3, CH3), the 2.46 (s, 6, N(CH3)2), is 3.08 (m, 2), 3,40 (m, 1), 3,52 (m, 1), of 4.00 (m, 2), with 5.22 (m, 1), 6,53 (d, J=2.5 Hz, 1, ArH), 6,62 (DD, J=2.5 and 8.6 Hz, 1, ArH), to 7.15 (d, J=8.6 Hz, 1, ArH).

Z-isomer 51:1H-NMR (300 MHz, Dl3):0,76 (s, 3, CH3), 0,86 (d, J=7,0 Hz, 3, CH3), a 2.45 (s, 6, N(CH3)2) and 3.59 (m, 1), are 5.36 (m, 1), 6,53 (d, J=2.5 Hz, 1, ArH), 6,63 (DD, J=2.5 and 9.0 Hz, 1, ArH), 7,14 (d, J=9.0 Hz, 1, ArH).

The following diagram illustrates the connection 59, as if">and 7-ethyl-21-[2'-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17 (20)-tetraene (59)

(a) Obtaining östra-4-ene-3,17-dione (53):

To a solution of 19-nortestosterone 52 (26,85 g, 97,85 mmol) in acetic acid (200 ml) was added SGAs3(7,4 g, 74 mmol) in acetic acid (150 ml) and was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to half of its original volume, poured into 1 M hydrochloric acid (500 ml) and was extracted with EtOAc. The combined organic layers were washed with saturated aqueous Panso3, dried over anhydrous gSO4, filtered and then concentrated to obtain Dion 53 in the form of a white solid (25,3 g, 95%):1H-NMR (300 MHz, Dl3):of 0.94 (s, 3, CH3), to 5.85 (s, 1).

(b) Obtaining östra-4,6-Dien-3,17-dione (54):

A solution of dione 53 (5.0 g, 18,36 mmol) and chloranil (5.4 g, 22 mmol) in dry ethanol (500 ml) was stirred at 60-65°C for 2 h, the Reaction mixture was concentrated under reduced pressure and the residue triturated with dichloromethane. The solid was removed by filtration and the filtrate was concentrated to obtain a brown resin. Chromatography (20% EtOAc/hexane) gave the crude dione 54 in the form of Zheltov is of 6.25 (m, 2).

(c) Obtaining a mixture of 7and 7-ethylester-4-ene-3,17-dione (55):

To the mixture Si(VI3R)4(15.7 g, 40 mmol) in THF (50 ml) was added a 1.0 M solution of EtMgBr in THF (40 ml, 40 mmol) at -30°C and was stirred for 20 minutes. The reaction mixture was cooled to -78°C was added diene 54 (3.5 g, 12,94 mmol). The reaction mixture was heated to -30°C for 0.5 h and poured into saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered and then concentrated to obtain a solid substance. Chromatography (20% EtOAc/hexane) gave Dion 55 in the form of a yellow solid (1.5 g, 39%). Primary 7-ethyl-isomer 55:1H-NMR (300 MHz, Dl3):to 0.89 (t, J=7.0 Hz, 3, CH2CH3), of 0.93 (s, 3, CH3), 2,60 (DD, J=2,4, and 14.3 Hz, 1), to 5.85 (s, 1).

(d) Obtaining a mixture of 3-tetrahydropyranyloxy-7and 7-ethylester-1,3,5(10)-triene-17-she (56):

To a solution of Aenon 55 (0.35 g, 1,17 mmol) in acetonitrile (10 ml) was added Siug2(0.31 g, 1.4 mmol) and was stirred over night at room temperature. Added water to the disappearance of the green color and the acetonitrile was removed under reduced is>
was filtered and the combined organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated to obtain the resin. Chromatography (20% EtOAc/hexane) gave estrone 56 in the form of a yellow solid (0.28 g, 80%). Primary 7-ethyl-isomer 56:1H-NMR (300 MHz, Dl3):of 0.91 (s, 3, CH3), of 0.95 (t, J=7,3 Hz, 3, CH2CH3), 6,59 (d, J=2.5 Hz, 1, ArH), of 6.65 (DD, J-2,5, and 8.4 Hz, 1, ArH), 7,13 (d, J=8,4 Hz, 1, ArH).

(e) Obtaining a mixture of ethyl(E)-3-tetrahydro-pyranyloxy-7and 7-ethyl-19-norpregna-1, 3, 5 (10), 17 (20) -tetraen-21-oate (57):

Appropriate TNR-ether 56, which is received from estrone 56 (0.28 g, were 0.94 mmol) and DHP (0.2 ml, 2.2 mmol) using the same procedures described for this broadcast was received in the form of crude resin (0.4 g).

Ester 57, which was obtained from the crude TNR-ester 56 (0.4 g) and triethylphosphate (1.12 g, 5.0 mmol) using the same procedure described for compound 47A was obtained as a solid (0.34 g, 81% for two steps). Primary 7-ethyl-isomer 57:1H-NMR (300 MHz, Dl3):of 0.87 (s, 3, CH3),, ,17 (K, J=7,1 Hz, 2, CO2CH2CH3), of 5.39 (m, 1), 5,59 (m, 1), 6,79 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2.5 a, 8,8 Hz, 1, ArH), 7,19 (d, J=8,8 Hz, 1, ArH).

(f) Obtaining a mixture of (E) -3-tetrahydropyranyloxy - 7and 7-ethyl-21-hydroxy-19-norpregna-1, 3, 5 (10), 17 (20) -tetraene (58):

Allyl alcohol 58, which is received from the complex ester 57 (0.34 g, from 0.76 mmol) and DIBAL (2.0 g, 2.0 mmol) using the same procedure described for compound 46 was obtained as a white solid (0.28 g, 89%). Primary 7-ethyl-isomer 58:1H-NMR (300 MHz, Dl3):0,81 (s, 3, CH3), of 0.93 (t, J=7,1 Hz, 3, CH2CH3), 2,39 (m, 4), 2,85 (m, 3), of 3.60 (m, 1), 3,95 (m, 1), is 4.15 (m, 2), and 5.30 (m, 1), of 5.39 (m, 1), 6,79 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2.5 and 8.7 Hz, 1, ArH), 7,21 (d, J=8.7 Hz, 1, ArH).

(g) Obtaining a mixture of (E) -3-hydroxy-7and 7-ethyl-21-[2'-(N,N-dimethylamino) ethoxy] -19-norpregna-1,3,5(10), 17 (20) -tetraene (59):

Amin 59, which was obtained from alcohol 58 (0.28 g, of 0.68 mmol) and hydrochloride of 2-diethylaminoethylamine (0.3 g, 2.1 mmol) and freed from the protective groups using the same procedure described for amine 25, received in the form of 7-ethyl - 7-ethyl-isomer 59:1H-NMR (300 MHz, Dl3):of 0.77 (s, 3, CH3), 0,84-of 1.02 (m, 4), 2,42 (s, 6, N(CH3)2), 3,61 (m, 2), 3,99 (m, 2), 5,19 (m, 1), 6,55 (d, J=2,6 Hz, 1, ArH), 6,62 (DD, J=2,6, 8.5 Hz, 1, ArH), 7,12 (d, J=8,5 Hz, 1, ArH).

The following diagram illustrates the formation of compounds 67 and 68, as described in example 26.

Example 26

Obtaining (R)- and (S)-3-hydroxy-20-methyl-21-[2'-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17 (20)-the triens (68)

(a) obtaining a 3-tetrahydropyranyloxy-1,3,5(10)-triene-17-she (60):

TNR-ether 60, which is received from estrone 1 (6.3 g, with 23.3 mmol) and DHP (3.0 g, 33 mmol) using the same procedure described for compound 35 was obtained as a white solid (7.5 g, 91%):1H-NMR (300 MHz, Dl3):of 0.91 (s, 3, CH3), 2,89 (m, 2), of 3.60 (m, 1), 3,92 (m, 1), of 5.40 (m, 1), for 6.81 (d, J=2.5 Hz, 1, ArH), 6,86 (DD, J=2.5 and 8.5 Hz, 1, ArH), 7,20 (d, J=8,5 Hz, 1, ArH).

(b) obtaining the (E,Z)-3-tetrahydropyranyloxy-20-methyl-21-hydroxy-19-norpregna-1,3,5(10),17(20)-tetraene (62):

To a solution of diethyl-(1-cyanoethyl)phosphonate (3.98 g, 20,81 mmol) in THF in an argon atmosphere at room temperature was added a 1.0 M solution of tert-butoxide potassium in THF (20 ml, 20 mmol) and was stirred for 1.0 hours a Solution of estrone 1 (3.0 g, 8,46 mmol) in THF (10 ml) was added and th NaHCO3and were extracted with a mixture of 40% ethyl acetate/hexane. The combined organic layers were dried over anhydrous gSO4, filtered and concentrated to obtain the E - and Z-isomeric mixture in the form of a yellow resin. Flash chromatography (10% EtOAc/hexane) gave a mixture of (Z)- and (E)-20-carbonitril-3-tetrahydropyranyloxy-19-norpregna-1,3,5(10),17(20)-tetraene 61 (0,83 g, 25%).

To a solution of nitrile 61 (0,83 g, 2,12 mmol) in a mixture of toluene/TRF was added 1.0 M solution of DIBAL in heptane (2.5 ml, 2.5 mmol) at -78°C in an argon atmosphere and the reaction mixture was heated to room temperature and was stirred for 3 hours, Methanol (0.5 ml) and water (0.5 ml) was added and the solution was stirred for 40 minutes. A cloudy solution was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to obtain the corresponding aldehyde resin. To a solution of the crude aldehyde (0.85 grams) in THF was added 1.0 M solution of DIBAL in heptane (3.0 ml, 3.0 mmol) at -78°C in an argon atmosphere and the reaction mixture was heated to 0°C and was stirred for 1 h was Added methanol (0.5 ml) and water (0.5 ml) and the solution was stirred for 20 minutes at room temperature. A cloudy solution was extracted with EtOAc. The combined organic layers were dried over anhydrous MgS (0.45 g, 53% for two steps).

(C) Obtain (Z)-3-tetrahydropyranyloxy-20-methyl-21-[2'-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (63) and (E)-3-tetrahydropyranyloxy-20-methyl-21-[2'-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17 (20)-tetraene (64):

Amines 63 and 64, which was obtained from alcohol 62 (0.45 g, 1.13 mmol) and hydrochloride of 2-diethylaminoethylamine (0.5 g, 3.5 mmol) using the same procedure described for amine 25, received in the form of solids. Flash chromatography (5% methanol/chloroform) gave Z-isomer 63 as the main product (0.34 g, 65%) and the target E-isomer 64 as a minor product (0,13 g, 25%). Z-isomer 63:1H-NMR (300 MHz, Dl3):of 0.90 (s, 3, CH3), of 1.65 (s, 3, CH3), is 2.30 (s, 6, N(CH3)2), to 2.55 (t, J=6.0 Hz, 2), 2,85 (m, 2), 3,51 (t, J=6.0 Hz, 2), of 3.60 (m, 1), 3,91 (m, 1), 3,98 (d, J=11.0 cm Hz, 1), 3,98 (d, J=11.0 cm Hz, 1), 4,20 (d, J=11.0 cm Hz, 1), of 5.39 (m, 1), 6,79 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2,5, and 8.4 Hz, 1, ArH), 7,19 (d, J=8,4 Hz, 1, ArH). E-isomer 64:1H-NMR (300 MHz, Dl3):of 0.90 (s, 3, CH3), to 1.79 (s, 3, CH3), 2,32 (s, 6, N(CH3)2), to 2.57 (t, J=6, 0 Hz, 2), of 2.86 (m, 2), 3,49 (m, 2), of 3.60 (m, 1) and 3.59 (m, 1), 3,92 (m, 3), of 5.39 (m, 1), 6,79 (d, J=2.5 Hz, 1, ArH), 6,85 (DD, J=2,5, and 8.4 Hz, 1, ArH), 7,19 (d, J=8,4 Hz, 1, ArH).

(d) Receiving (Z)-3-hydroxy-20-methyl-21-[2'-(N,N-diethylamino)ethoxy]-19-nobi) using the same procedure, described for the amine 25, was obtained as a white solid (0.27 g, 95%):

1H-NMR (300 MHz, Dl3):from 0.84 (s, 3, CH3), of 1.64 (s, 3, CH3), 2,39 (s, 6, N(CH3)2), to 2.67 (t, J=6, 0 Hz, 2), of 2.81 (m, 2), to 3.58 (t, J=6.0 Hz, 2), 3,90 (d, J=11.0 cm Hz, 1), 4,19 (d, J=11.0 cm Hz, 1), is 6.54 (d, J=2.5 Hz, 1, ArH), is 6.61 (DD, J=2,5, and 8.2 Hz, 1, ArH), 7,11 (d, J=8,2 Hz, 1, ArH).

(e) Obtaining (E)-3-hydroxy-20-methyl-21-[2'-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene (66):

Amin 66, which was obtained from a simple ester 64 (of 0.13 g, 0.28 mmol) and p-TsOH (0.06 g, 0.31 mmol) using the same procedure described for amine 25, was obtained as a white solid (0.1 g, 93%):1H-NMR (300 MHz, Dl3):from 0.84 (s, 3, CH3), or 1.77 (s, 3, CH3), 2,39 (s, 6, N(CH3)2), of 2.64 (t, J=5.7 Hz, 2), 2,82 (m, 2), 3,53 (m, 2), 3,86 (d, J=11.2 Hz, 1), 3,95 (d, J=11.2 Hz, 1), is 6.54 (d, J=2.7 Hz, 1, ArH), 6,59 (DD, J=2,7, 8,2 Hz, 1, ArH), 7,12 (d, J=8,2 Hz, 1, ArH).

(f) Receiving (17R,20S)-20-[(4'-N,N-dimethyl)-2'-oxobutyl]-19-norpregna-1,3,5(10)-triene-3-ol (67):

Olefin 65 (35 mg, 0.09 mmol) was first made over 10% palladium on coal (10 mg) in 5 ml of ethanol at room temperature under atmospheric pressure overnight. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum to obtain below the g 86%):1H-NMR (300 MHz, Dl3):of 0.68 (s, 3, CH3), was 1.04 (d, J=6, 6 Hz, 3, CH3), is 2.37 (s,6, N(CH3)2), of 2.64 (m, 2), and 2.79 (m, 2), 3,14 (DD, J=7,6, 8,8 Hz, 1), 3,40 (DD, J=3.3, then to 9.3 Hz, 1), of 3.56 (m, 2), is 6.54 (d, J=2,6 Hz, 1, ArH), is 6.61 (DD, J=2,6, 8.5 Hz, 1, ArH), 7,12 (d, J=8,5 Hz, 1, ArH).

(g) Receiving (17R,20R)-20-[(4'-N,N-dimethyl)-2'-oxobutyl]-19-norpregna-1,3,5(10)-triene-3-ol (68):

Olefin 66 (25 mg, 0,065 mmol) was first made over 10% palladium on coal (10 mg) in 5 ml of ethanol at room temperature under atmospheric pressure overnight. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum to obtain a white solid. Flash chromatography (5% methanol/chloroform) gave amine 68 in the form of a white solid (22 mg, 88%):1H-NMR (300 MHz, Dl3):of 0.68 (s, 3, CH3), were 0.94 (d, J=6, 6 Hz, 3, CH3), a 2.36 (s, 6, N(CH3)2), 2,62 (m, 2), 2,80 (m, 2), 3,21 (DD, J-7,8, 9,0 Hz, 1), 3,55 (m, 3), is 6.54 (d, J=2, 6 Hz, 1, ArH), 6,60 (DD, J=2,6, 8.5 Hz, 1, ArH), 7,12 (d, J=8,5 Hz, 1, ArH).

The following diagram illustrates the formation of compounds 69, 70 and 71, as described in examples 27, 28 and 29:

Example 27

Obtain 3-hydroxy-7-methyl-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10)-triens (69)

Olefin 22 (35 mg, and 0.09 m the Institute during the night. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum to obtain a white solid. Flash chromatography (5% methanol/chloroform) gave amine 69 as a white solid (0,030 g, 86%): so pl. 162 to 165C;1H-NMR (300 MHz, Dl3):of 0.62 (s, 3, CH3), is 0.84 (d, J=7,1 Hz, 3, CH3), 2,32 (s, 6, N(CH3)2), 2,49 (DD, J=1,2, 16.2 Hz, 1), to 2.57 (t, J=5, 8 Hz, 2), 3.04 from (m, 1), 3,44 (m, 2), of 3.56 (t, J=5.8 Hz, 2), is 6.54 (d, J=2.7 Hz, 1, ArH), 6,62 (DD, J=2.7, and 8.0 Hz, 1, ArH), 7,16 (d, J=8.0 Hz, 1, ArH). HRMS for C25H39NO2(M+): expect. 385,2981; found, 385,2976.

Example 28

Obtain 3-hydroxy-2-methoxy-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10))-triens(70)

Olefin 23 (50 mg, 0.125 mmol) was first made over 10% palladium on coal (15 mg) in 5 ml of ethanol at room temperature under atmospheric pressure overnight. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum to obtain a white solid. Flash chromatography (5% methanol/chloroform) gave amine 70 in the form of white solids level (0.041 g, 82%):1H-NMR (300 MHz, Dl3):to 0.63 (s, 3, CH3), 2,31 (s, 6, N(CH3)2), to 2.54 (t, J=5.8 Hz, 2), 2,77 (m, 2), of 3.46 (m, 2), 3,55 (m, 2), 3,85 (s, 3, och

Obtain 3-hydroxy-7-methyl-21-[2'-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10)-triens (71)

Olefin 25 (1,01 mg, 2.68 mmol) was first made over 10% palladium on coal (380 mg) in 50 ml of ethanol at room temperature under atmospheric pressure overnight. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum to obtain a white solid. Flash chromatography (10% ethanol/chloroform) gave amine 71 in the form of a white solid (0,90 g, 81%):1H-NMR (300 MHz, Dl3):of 0.62 (s, 3, CH3), is 0.84 (d, J=7,1 Hz, 3, CH3), of 1.09 (t, J=7,1 Hz, 6, N(CH2CH3), 2,69 (m, 6), to 3.02 (m, 1), 3,47 (m, 2), of 6.52 (d, J=2.7 Hz, 1 ArH), 6,62 (DD, J=2.7, and 8.0 Hz, 1, ArH), 7,16 (d, J=8.0 Hz, 1, ArH).

Example 30

Getting 21-(2'-N,N-dimethylaminoethoxy)-[17(20)E]-19-norpregna-1, 3,5(10),18(20) -tetraen-3-O-sulpham (72)

To a solution of chlorosulfonylisocyanate (of 0.14 ml, 1.5 mmol) in CH2CL2(0.6 ml) was added formic acid (0.3 ml of CH2CL2solution, 5.0 M, 1.5 mmol) at 0°C. the Reaction mixture was heated to room temperature and was stirred for 1 h To a solution of 21-(2'-N,N-dimethylaminoethoxy) -[17(20)E]-19-norpregna-1,3,5(10),17(20)-tetraen-3-ol (21, 0,111 g, 0.3 mmol) in DMF (2.0 ml) is whether in the course of 1 h, added chlorosulfonylisocyanate in formic acid and stirring was continued for 2 hours, the Reaction mixture was extinguished saturated aqueous NaHCO3at 0°C. and was extracted with EtOAc. The combined organic layers were washed N2O, saturated aqueous NaCl and then dried (Na2SO4). The desiccant was filtered and the solvent evaporated under reduced pressure.

The residue was purified column chromatography on silica gel using a mixture l3:Meon (10:1-5:1, V/V) to obtain the 0,121 g 72 (yield 90%), so pl. 147-148°C.

1H-NMR:7,30 (d, 1H, aromatic), 7,13-7,00 (m, 2H, aromatic), and 5.30-by 5.18 (m, 1H, =CH-CH2O-), 4,05-3,90 (m, 2H, =CH-CH2O-), 3,53 (t, 2H, -OCH2CH2N), to 2.55 (t, 2H, -och2CH2N-), 2,30 (s, 6N, -N(CH3)2), to 0.78 (s, 3H, 18-CH3); MS(DCI): m/z 449 (M++H).

Example 31

Connection 75, an antiestrogen agent of the present invention, was obtained with the use of separate reaction stages, illustrated in figure 15, and the same reagents and reaction conditions for the synthesis described in example 32.

Example 32

This example describes the synthesis of compound 80, salt, citric acid 79, as shown in scheme 16:

1H-NMR:of 0.67 (s, 3H), of 0.85 (d, 3H, J=7,1 Hz), of 4.05 (m, 2H), 5,38 (m, 1H), 6.42 per (d, 1H, J=2.3 Hz, ArH), 6,53 (DD, 1H, J=8.7 Hz, 2.3 Hz, AGN), is 6.78 (d, 1H, J=2.4 Hz, ArH), 6,85 (DD, 1H, J=8,8 Hz, 2.4 Hz, ArH), 7,21 (d, 1H, J=8.7 Hz), the 7.43 (d, 1H, J=8,8 Hz), 9,72 (s, 1H).

(b) Synthesis of 2-methoxy-4-[3'-tetrahydropyranyloxy-7'-methyl-19'-norpregna-1', 3', 5'(10')-triene-21'-yloxy]benzaldehyde (77): To a solution of 76 (1.01 g, of 1.95 mmol) in acetone (20 ml) was added anhydrous2CO3(690 mg, 5.0 mmol) and iodine-methane (1,03 g of 7.25 mmol) and the mixture was stirred continuously for 2 days at room temperature. The reaction mixture was extinguished H2Oh, were extracted with ethyl acetate, washed with saline, dried over anhydrous MgSO4was filtered , concentrated and purified by chromatography (14% ethyl acetate/hexane) to produce benzaldehyde (77) as an amorphous solid (780 mg, 75%):1H-NMR:of 0.67 (s, 3H), of 0.85 (d, 3H, J=6.2 Hz), 3,90 (s, 3H), of 4.05 (m, 2H), 5,38 (m, 1H), 6.42 per (d, 1H, J=2.2 Hz, ArH), 6,53 (DD, 1H, J=8,6 Hz, 2.2 Hz, ArH), is 6.78 (d, 1H, J=2.5 Hz, ArH), 6,85 (DD, 1H, J=8,6 Hz, 2.5 Hz, ArH), 7,21 (d, 1H, J=8.6 Hz), the 7.43 (d, 1H, J=8.6 Hz), 10,29 (s, 1H).

(c) Synthesis of 2-methoxy-4-[3'-hydroxy-7' who, 1,45 mmol); recrystallization from a mixture of ethyl acetate/hexane gave 78 in the form of a crystalline solid (555 mg, 85%): so pl. 160-161°C;1H-NMR:of 0.68 (s, 3H), of 0.85 (d, 3H, J=7,1 Hz), 2,50 (d, 1H, J=16.5 Hz), 3,05 (DD, 1H, J=16.5 Hz, 5.5 Hz), 3,90 (s, 3H), 4,00-4,13 (m, 2H), 4.95 points (Shir, 1H, HE), to 6.43 (d, 1H, J=2, 1 Hz, AGN), 6,53 (DD, 1H, J=8,4 Hz, and 2.1 Hz, AGN), 6,55 (d, 1H, J=2.7 Hz, AGN), 6,63 (1H, J=8.7 Hz, 2.7 Hz, AGN), 7,16 (d, 1H, J=8,4 Hz, AGN), of 7.82 (d, 1H, J=8.7 Hz, AGN), 10,28 (s, 1H).

(d) Synthesis of 3-hydroxy-7-methyl-21-[3'-methoxy-4'-(piperidinomethyl)phenoxy]-19-norpregna-1,3,5(10)-triens (79):

Amin 79 was obtained from benzaldehyde 78 (550 mg, of 1.23 mmol) and piperidine (136 mg, 1,60 mmol); recrystallization from Meon gave 79 in the form of a crystalline solid (560 mg, 88%): so pl. 200-202°C;1H-NMR:of 0.67 (s, 3H), of 0.85 (d, 3H, J=7.0 Hz), 2,50 (Shir, 4H), 3.04 from (DD, 1H, J-16,6 Hz, 5.5 Hz), 3,53 (s, 2H), 3,74 (s, 3H), 3,90-was 4.02 (m, 2H), 6,40-6,55 (m, 4H, AGN), 7,12 (d, 1H, J=8,3 Hz, AGN), 7,22 (d, 1H, J=8,8 Hz, AGN).

(e) obtaining the citrate salt of 3-hydroxy-7-methyl-21-[3'-methoxy-4'-(piperidinomethyl)phenoxy]-19-norpregna-1,3,5(10)-triens (80):

To a solution of amine 79 (517 mg, 1.0 mmol) in 15 ml Meon at room temperature in an argon atmosphere was added citric acid (192 mg, 1.0 mmol) and the reaction was stirred for 10 minutes. Enago solids with quantitative output:1H-NMR: 5 of 0.68 (s, 3H), of 0.85 (d, 3H, J=7,1 Hz), a 2.45 (d, 1H, J=16.5 Hz), 2,73 (d, 2H, J=15,4 Hz), and 2.83 (d, 2H, J=15,4 Hz) of 3.00 (DD, 1H, J=16.5 Hz, 5.5 Hz), 3,86 (s, MN), 3,98-4,12 (m, 2H), 4,18 (s, 2H), 6,47 (d, 1H, J=2.5 Hz, ArH), 6,52-6,62 (m, 3H, ArH), 7,07 (d, 1H, J=8,3 Hz, ArH), 7,33 (d, 1H, J=8,2 Hz, ArH).

Examples 33-36

This example describes the synthesis of compounds 81, 82, 83 and 84. This synthesis is illustrated in scheme 17, as follows:

Connections 81, 82, 83 and 84 were obtained similarly to the method described in relation to obtaining a connection 79 from junction 78 in the previous example. Briefly, these compounds were synthesized and characterized as follows:

4-[3'-hydroxy-7'-methyl-19'-norpregna-1', 3', 5' (10')-triene-21'-yloxy]-3-methoxybenzaldehyde (78A): a Simple ether 78A received from the corresponding alcohol (2-hydroxy-ethyl-substituent in position 17(3) and vanillin (382 mg, 2.51 mmol) and was obtained as crystalline solid (785 mg, 66%). Recrystallization gave pure 78A: so pl. 163-164°C;1H-NMR:of 0.67 (s, 3H), from 0.84 (d, 3H, J=7.0 Hz), 2,50 (d, 1H, J=16.5 Hz), 3,05 (DD, 1H, J=16.5 Hz, 5.5 Hz), 3,93 (s, 3H), 4,06-4,20 (m, 2H), 5,12 (Shir, 1H, HE), 6,55 (d, 1H, J=2,5 Hz, AGN), 6,63 (DD, 1H, J=8,4 Hz, 2.5 Hz, AGN), 6,98 (d, 1H, J=8.0 Hz, AGN), to 7.15 (d, 1H, J=8,4 Hz, AGN), 7,42-of 7.48 (m, 2H), 9,85 (s, 1H); MS(DCI) 449 (M+H). HRMS for C29H36-methyl-21-[2'-methoxy-4'-(4"-mailpipe-rainmeter)phenoxy]-19-norpregna-1,3,5(10)-triene (81):

Amin 81 was obtained from benzaldehyde 78A (50 mg, 0,112 mmol) and 1-methylpiperazine (0,018 ml, 0.16 mmol); recrystallization from Meon gave 81 in the form of a crystalline solid (22 mg, 37%): so pl. 214-215°C;1H-NMR:of 0.66 (s, 3H), from 0.84 (d, 3H, J=7,0 Hz) to 2.29 (s, 3H), 2,45-of 2.56 (m, N), was 3.05 (DD, 1H, J=17,0 Hz, 6.0 Hz), of 3.45 (s, 2H), 3,85 (s,3H), 3.95 to 4,08 (m, 2H), of 6.52 (d, 1H, J=2, 6 Hz, AGN),

6,60 (DD, 1H, J=8.6 Hz, 2.6 Hz, AGN), to 6.80 (s, 2H, AGN), 6.89 in (s, 1H, AGN), 7,16 (d, 1H, J 8.6 Hz, AGN).

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(pyrrolidinyl)phenoxy]-19-norpregna-1,3,5(10)-triene (82): Amin 82 was obtained from benzaldehyde 78A (600 mg, of 1.34 mmol) and pyrrolidine (0.15 ml, 1.8 mmol); recrystallization from Meon gave 82 in the form of a crystalline solid (450 mg, 67%): so pl. 192-193°C;1H-NMR:of 0.65 (s, 3H), from 0.84 (d, 3H, J=7,1 Hz), a 2.45 (d, 1H, J=16.5 Hz), 2.57 m (m, 4H), to 3.02 (DD, 1H, J=16.5 Hz, 6.0 Hz), to 3.58 (s, 2H), of 3.77 (s, 3H), 3,92-4,06 (m, 2H), 6,47 (d, 1H, J=2, 6 Hz, AGN), of 6.52 (DD, 1H, J=8,4 Hz, 2.6 Hz, AGN), 6,77-6,83 (m, 2H, AGN), of 6.90 (d, 1H, J=1.6 Hz, AGN), 7,11 (d, 1H, J=8,4 Hz, AGN).

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(N,N-dimethylene-nametil)phenoxy]-19-norpregna-1,3,5(10)-triene (83): Amin 83 was obtained from benzaldehyde 78 (60 mg, 0,134 mmol) of the STW (40 mg, 62%): so pl. 186-187°C;1H-NMR:of 0.65 (s, 3H), from 0.84 (d, 3H, J=7.0 Hz), and 2.26 (s, 6N, N(CH3)2), 2,46 (d, 1H, J=16.5 Hz), to 3.02 (DD, 1H, J=16.5 Hz, 6.0 Hz), 3,40 (s, 2H), 3,80 (s, 3H), 3,93-4,08 (m, 2H), of 6.49 (d, 1H, J=2,6 Hz, AGN), 6,56 (DD, 1H, J=8,4 Hz, 2.6 Hz, AGN), to 6.80 (s, 2H, AGN), 6.89 in (s, 1H, AGN), 7,13 (d, 1H, J= 8,4 Hz, AGN).

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(N,N-diatreme-nametil)phenyloxy]-19-norpregna-1,3,5(10)-triene (84): To a solution of similar methoxybenzaldehyde 78A (0,500 g, 1.12 mmol) and diethylamine (155 μl, 1.5 mmol) in dry 1,2-dichloroethane (10 ml) in an argon atmosphere was added triacetoxyborohydride (0,403 g, 1.9 mmol). A cloudy solution was stirred for 18 h at room temperature. To the turbid mixture was added saturated Panso3followed by extraction with ethyl acetate. The ethyl acetate was washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was led from the Meon to obtain 350 mg 84 (yield 62%): so pl. 123-124°C;1H-NMR:of 0.65 (s, 3H), from 0.84 (d, 3H, J=7.0 Hz), with 1.07 (t, 6N, J=7,1 Hz), 2,46 (d, 1H, J=16 Hz), 2.57 m (K, 4H, J=7,1 Hz), to 3.02 (DD, 1H, J=16.5 Hz), 3,55 (s, 3H), 3,81 (s, 3H), 3,92-4,08 (m, 2H), 6.48 in (d, 1H, J=2,6 Hz, AGN), 6,56 (DD, 1H, J=8,4 Hz), 6,7 for 7.12 (m, 6N).

Example 37

This example describes how to obtain salts of citric acid 85 of analogue rc="https://img.russianpatents.com/chr/945.gif">-methyl-21-[2'-methoxy-4'-(N,N-diethylaminomethyl)phenoxy]-19-norpregna-1,3,5(10)-triens (85):

To a solution of amine (84) (100 mg, 0,198 mmol) in 1 ml of hot EtOH in an atmosphere of argon was added citric acid (38 mg, 0,188 mmol) and the reaction was stirred for 10 minutes. Cooling gave a white crystalline solid, which was filtered and dried to obtain 120 mg (yield 87%) 85: so pl. 166°C (decomposition);1H-NMR (CD3OD)is 0.69 (s, 3H), of 0.82 (d, 3H, J=7.0 Hz), 1,36 (t, 6N, J=7,2 Hz), 2,46 (d, 1H, J=16.5 Hz), 2,77 (, 4H, J=7,2 Hz), 3,86 (s, 3H), 4,24 (s, 2H), 6,40-6,60 (m, 2H, AGN), 6,98-7,16 (m, 4H, AGN).

Example 38

Compound 90 was synthesized as illustrated in scheme 19.

Obtaining (E)-3-tetrahydropyranyloxy-7-methyl-21-hydroxy-19-norpregna-1,3,5(10)-triens (86):

To a solution of 33.5 g 47b in 500 ml THF at -78°C was added 185 ml of 1.0 M diisobutylaluminum hydride in heptane. The reaction mixture was heated to 0°C and stirred at this temperature for 1.5 hours was Added methanol (15 ml) and N2About (15 ml) at 0°C and the solution was heated to room temperature and was stirred for 0.5 h Cloudy suspension was poured in BUT2(1.4 l) and was extracted with EtOAc (3300 ml). United organicism the form of a white solid. The remaining stages of reactions, reagents and reaction conditions similar to those used in the previous examples, examples 31-37.

Example 39

This example describes the synthesis of compound 92 as shown in scheme 20:

(a) Synthesis of 3-hydroxy-7-methyl-21-(2'-N,N-diatreme-noatomic)-19-norpregna-1,3,5(10)-triens (91).

Olefin 25 (18,88 g, 45,94 mmol) was first made over 10% Pd-C (7 g) in 300 ml of ethanol at room temperature under atmospheric pressure overnight. The catalyst was removed by filtration and washed with ethanol. The solvent was removed in vacuum. The residue was recrystallized from isopropyl ether to obtain amine 91 in the form of a crystalline solid (16,13 g, 85%): so pl. 106-107°C;1H-NMR:of 0.62 (s, 3H), from 0.84 (d, 3H, J=7,1 Hz) of 1.09 (t, 6N, N(CH2CH3)2, J=7,2 Hz), 2,48 (d, 1H, J=16.5 Hz), 2,68 (K, 4H, N(CH2CH3)2, J=7,2 Hz), is 2.74 (t, 2H, J=6.3 Hz), 3,03 (DD, 1H, J=16.5 Hz, 6,1 Hz), 3,36-of 3.54 (m, 2H), only 3.57 (t, 2H, J=6, 3 Hz), is 6.54 (d, 1H, J=2,6 Hz, AGN), 6,62 (DD, 1H, J=8.6 Hz, 2.6 Hz, AGN), 7,16 (d, 1H, J=8.6 Hz, AGN); MS(DCI) 414 (M+H).

(b) Citrate 3-hydroxy-7-methyl-21-(2'-N,N-diatreme-noatomic)-19-norpregna-1,3,5(10)-triens (92).

To a solution of amine 91 (0.85 grams, of 2.06 mmol) in 40 ml Meon at room temperature at oritel evaporated under reduced pressure and dried in vacuum to obtain citrate salt 92 in the form of an amorphous solid in quantitative yield. An analytical sample was prepared by crystallization from EtOH: so pl. 106-107°C (decomposition);1H-NMR (CD3OD):of 0.65 (s, 3H), from 0.84 (d, 3H, J=7.0 Hz), 1,31 (t, 6N, N(CH2CH3)2, J=7,3 Hz), 2,43 (d, 1H, J=16.6 Hz), to 2.67 (d, 2H, J=15,4 Hz), 2,82 (d, 2H, J=15,4 Hz), 2,99 (DD, 1H, J=16, 6 Hz, 5.0 Hz), 3,26 (K, 4H, N(CH2CH3)2, J=7,3 Hz), 3,31-to 3.35 (m, 2H), 3,50 (m, 2H), to 3.73 (m, 2H), 6,46 (d, 1H, J=2.2 Hz, AGN), 6,53 (DD, 1H, J=8,7 Hz, 2.2 Hz, AGN), 7,16 (d, 1H, J=8.7 Hz, AGN); MS (DCI) 414 (M+H).

Example 40

Biotest for measuring estrogenic and antiestrogenic activity of test compounds using cells, Ishikawa man

A. Procedure:

The Ishikawa cells are very sensitive to estrogen and compounds with estrogenic activity induce alkaline phosphatase (AlkP) in these cells at such low levels as 10-2M Thus, the estrogenic activity of any target compound can be measured by quantitative determination of the activity of AlkP induced by this compound.

Reagents: Cell Ishikawa person were provided by Dr. Erlio Gurpide (Mount Sinai School of Medicine, N. Y.). Minimum essential medium Needle (MEM), fetal calf serum (FCS) and p-nitrophenylphosphate were purchased from Sigma Chemical Company (St. Louis, MO).

Cell culture: Kitkatla. Cells were sown at a density of 1.5106cells/75 cm2and passively twice a week. Twenty-four hours prior to the experiment environment in almost confluent cell cultures were replaced not containing phenol red MEM containing 5% FCS, purified from endogenous estrogen the dextran-coated charcoal, plus the above additives.

Processing of the medicinal product: the day of the experiment cells were harvested with 0.25% trypsin and were sown in 96-well flat-bottomed microtiter plates in not containing phenol red MEM at a density of 1.5104cells per well. Test compounds were dissolved in DMSO at 10-2M, diluted appropriately not containing phenol red MEM (final concentration of DMSO of 0.1%). Diluted test compounds were added to culture wells, either individually or in combination with 10-9M estradiol. Each experiment included a cultural hole blind control (only medium) and positive control (10-9M). The final volume of medium in each culture well was 200 μl. After all additions, the cells were incubated at 37°C in humidified atmosphere containing 5% CO109,5) see the Tablets were removed from the tank, leaving a residual saline solution in each well, and the washing procedure was repeated once again. Then buffered saline shook from tablets and tablets preventively and gently blotted on a paper towel. Then the tablets were placed on ice and to each well was added 50 μl of ice solution containing p-nitrophenylphosphate (5 mm), MgCl2(0.24 mm) and diethanolamine (1 M, pH 9,8). Then the tablets were heated to room temperature and allowed to develop yellow color, caused by the formation of p-NITROPHENOL. The tablets were observed periodically at 405 nm tablet reader for solid-domasnego enzyme-linked immunosorbent assay (ELISA) to the time when maximally stimulated cells showed uptake of 1.2 at 405 nm. Estrogenic activity of the test compounds is calculated as the percentage of stimulation of the activity of AlkP (i.e., the absorption at 405 nm) test compound, normalized with respect to the driven 10-9M estradiol activity (where absorption of 1.2 at 405 nm = 100% is my 10-9M estradiol AlkP activity of the test compound.

C. Results:

Typical antiestrogenic compounds of this invention were evaluated for anti-estrogenic and estrogenic activity in vitro, as described above. The results obtained with these test compounds shown in table 1 below. Also included the results obtained with tamoxifen, 4-hidroxi-tamoxifenum, DP-TAT-59, TAT-59 and ICI 164384.

Example 41

Uterotrophic and antiuterotrophic test

Test procedure: For this experiment used female rats, Sprague-Dawley (obtained from Simmonsen Laboratories (Gilroy, CA) weighing 40-50 g For the beginning of the experiment, rats were weighed and divided into groups of 5 animals at random. For uterotrophic test different doses of test compounds in sterile saline (0.1 ml for subcutaneous injection, 1.0 ml for oral cressendo the first power) was administered to the animals once a day. The same procedure was used for antiuterotrophic test, but a suspension of 0.5 mg of estradiol benzoate (policereport included two control groups, one of which received only the carrier, and the other only benzoate estradiol.

The introduction was carried out for 3 days. In day 4, animals were weighed and then were killed. Uteri were immediately removed from the animals, freed from fat and then weighed.

Estrogenic activity was determined from the weight of the uterus in the groups receiving only the test compound in comparison with the weight of the uterus in the control groups with the carrier. Antiestrogenic activity was determined from the weight of females in the groups receiving test compound plus estradiol, in comparison with the weight of the uterus in the control groups with estradiol (see tab. 2).

Example 42

Evaluation of translatively

Tissue-specific astrogenetix compounds 85 and 92 were evaluated in comparison with tamoxifen and raloxifene. For this experiment used rats Sprague-Dawley (at the age of seven weeks), purchased from SLC Inc. (Shizuoka), and fed them TD89222. Two weeks after buying the rats were subjected to oophorectomy or falsely operated under light anesthesia with ether. A week after oophorectomy rats were randomly divided into 21 a group of 9 animals (day 0) and was administered to them orally selected drug from day 0 to day 28. On the day after the final dose rats mind and their volumes were determined by the principle of Archimedes. Dry weight was determined after treatment of femoral bone at 110°C for 5 days and the ash was weighed after treatment at 900°C for 5 hours. The mass density was calculated by dividing the weight of the femur on the scope and content of mineral compounds was estimated by dividing the weight of ash on dry weight.

The left femur was subjected to determination of trabecular density and polar strength using peripheral quantitative computed tomography (XART-90 6A, Norland, NY). Analyzed sections, distal (3-5,5 mm) on the growth plate of the femur.

Levels of pyridinium crosslinks in urine samples was determined using Pyrilincs (Metra Bosystems Inc., CA) and corrected using creatinine levels.

Alkaline phosphatase levels were analyzed using ALP-HA (Wako, Osaka). The levels of serum cholesterol was determined using HDL-CIL/PM (Wako pure chemicals, Osaka) and LDL-test for cholesterol (Daiichi pure chemicals, Tokyo).

The results:

All connections to prevent loss of trabecular bone density undergone oophorectomy rats (Fig.1). After 4 weeks of treatment trabecular bone density undergone oophorectomy rats was significantly decreased in comparison with linearizovannogo rat (p<0.01) and twork is IMO more high, than the density undergone oophorectomy rats (p<0,05). Levels of pyridinium crosslinks in urine as Marek resorption of bone tissue in rats treated with antiestrogens were significantly lower than those levels undergo oophorectomy rats after 4 weeks of treatment that involves the inhibition of osteolysis estrogenic activity of compounds (Fig.2). Serum levels of both General and received their bone alkaline phosphatase in rats treated with compound 92, were significantly higher than the levels of the control rats (Fig.3).

Similar results are expected with the structural analogs described and claimed here.

Example 43

Antitumor testing in vivo against xenograft tumors of human breast MCF-7 and its tamoxifen-resistant cell line

Antitumor activity of compounds 85 and 92 against tamoxifen-resistant breast carcinoma person was assessed as follows.

Connection 85, 92, tamoxifen and raloxifene suspended in 0.5% solution of hydroxypropylmethylcellulose; faslodex was dissolved in peanut oil. Used cell carcinoma human breast MCF-7 and tamoxifen-resistant subline, FST-1-cell is ie Nude mice with mutation "nude") (Clea Japan Inc.). The pellet, containing 500 μg/pellet estradiol used for adding estrogen it is thought that. When tumors reached a diameter of 6-7 mm (in two to three weeks after inoculation), mice were given connection 85 (some 10 mg/kg/day, some 30 mg/kg/day), 92 (dose 1 mg/kg/day, 5 mg/kg/day, 25 mg/kg/day, 1 mg/kg/day), tamoxifen (10 mg/kg/day) or raloxifene (50 mg/kg/day) daily for 3-4 weeks, injected oral, or mice were given faslodex subcutaneously (5 mg/mouse/week) once a week for 3 weeks. The size of the tumors was detected after palpation using two perpendicular diameters.

The results:

In relation to tumor MCF-7 all connections found significant inhibitory growth activity. Ten mg/kg/day of compound 85 and 25 mg/kg/day of compound 92 found the strongest growth inhibitory activity, followed by 5 mg/body faslodex, 10 mg/kg/day of tamoxifen and 50 mg/kg/day of raloxifene.

In the case of tumor FST-1 were not observed inhibition of growth with tamoxifen, which indicates that FST-1 retained its resistance against tamoxifen. Ten mg/kg/day of compound 85 and 25 mg/kg/day of compound 92 was found significant inhibitory growth activity against tumor EST. P is ivena not found overwhelming growth activity, and it was found that faslodex was less effective than the connection 85.

Example 44

Evaluation of the compounds of the invention for the treatment of women suffering from dysfunctional uterine bleeding.

At least selected five women for this study. These women are suffering from dysfunctional uterine bleeding. Due to the idiosyncratic and subjective nature of these symptoms, this study has a placebo control group, i.e., these women are divided into two groups, one of which receives the connection of the present invention, such as compound 85 or 92, and the other women's group receives a placebo. These patients are assessed in relation to the nature of their dysfunctional uterine bleeding (blood loss, timing and so on) before the study. Evaluation can also include "points of astrogenetix" biopsy of the uterus, as determined by histological evaluation, and assessment scans using image ultrasound, radioisotope studies, nuclear magnetic diagnostics or computer axial tomography (CAT) endometrial thickness. Women in the test group receive between 30 and 600 mg drug per day by mouth. They continue this Le is bleeding skills in both groups and at the end of this study, these results compare. The results compare between the members of each group, and compare the results for each patient with symptoms reported by each patient before the study. The applicability of the compounds of the present invention is illustrated in therapeutic effect they have on dysfunctional uterine bleeding patient.

Example 45

Evaluation of the compounds of this invention on the inhibition of estrogen-dependent disorders of the Central nervous system in women in postmenopausal period

Select five to fifty women for this study. These women are postmenopausal, i.e. they have stopped menstruating for 6 and 12 months before the study, they have good overall health and are suffering from disorders of the Central, i.e., anxiety, depression, mood swings, tension, irritability, motivational disorders, memory loss or disorder cognitive abilities. Due to the idiosyncratic and subjective nature of these symptoms, this study has a placebo control group, i.e., these women are divided into two groups, one of which receives the connection of the present invention, such as compound 85 or 92, and the other through the mouth. They continue this treatment for 3-12 months. Accurate records are kept regarding the number and severity of CNS disorders in both groups and at the end of this study, these results compare. The applicability of the compounds of the present invention shows therapeutic effect they have on patients suffering from disorders of the Central nervous system, which can be evaluated using this procedure.

Example 46

Evaluation of the compounds of the invention on the inhibition estrogenzawisimy skin and vaginal atrophy in women in postmenopausal period

Inhibition of skin atrophy: Choose from three to twenty women who are postmenopausal and have good health. These women also choose based on the presence of multiple signs of rapid dermal atrophy, such as the rapid increase in the number of facial wrinkles or "crow's feet", the rapid change in skin pigmentation, i.e., "age spots", or other complaints for rapid dermal aging. Because dermal atrophy may be the result of other factors, such as damage by ultraviolet light from the sun or other sudden impact the environment, such patients who suffer from these without the tive and subjective component, i.e. assessment improve the appearance of the patient. Such an assessment requires an initial benchmark for future comparison. Some initial benchmarks can be in the form of a standardized set of questions about how the patient assesses his views, photos of the patient or psychological profile image "I" of the patient. The second component is quantitative; such components include measurement of hydroxyproline excretion with urine, skin moisture content, the amount of glycosaminoglycans in the skin and changes in the elasticity and softness of the skin. Methods for determining these factors can be found in "The Menopause", Ed. R. J. Beard, University Press, Chapter 7 (1977) and "Methods in Skin Research", Ed. Skerrow, D. and Skerrow, C. J. John Wiley & Sons Ltd., Chp., 22, "Analysis of Sebaceous Lipids", p. 587-608 (1985) and additional references cited here. Also get the original benchmark (the benchmark) these quantitative factors.

Women, selected and original assessed, placed in a clinical Protocol for production of 40-400 mg of the active compounds of this invention by oral administration of a single dose or divided doses. Alternatively, these patients are placed in the Protocol for local application to the skin, most of porazeny 5-50% (by weight) active compounds of the present invention, applied to the affected area once or twice a day. Any of these protocols lasts two to twelve months. Subsequent evaluations, both quantitative and qualitative, performed at the appropriate intervals.

A positive result is to improve the overall quantitative index of the views of the patient and/or the improvement of quantitative parameters, such as the increased excretion of hydroxyproline in urine, svidetelstvuya about the increase in turnover and collagen synthesis, increased glycosaminoglycan content in the liquid, the softness or firmness of the skin.

Inhibition of vaginal atrophy: Choose from three to twenty women suffering from vaginal atrophy associated with menopause. These women have overall good health. Since the nature of this violation is vysokoizbiratelnoy and subjective assessment of treatment effectiveness should be necessarily subjective in nature. These patients are asked to keep a daily log, noting details such as vaginal itching and flaking and satisfaction in sexual intercourse. These women are placed in the clinical Protocol similar to the Protocol described above for atrophy of the skin. Pay special attention to the use of vaginal what is the improvement in the comfort of intercourse and/or reduce itching or peeling.

Example 47

Evaluation of the compounds of the invention in the inhibition of estrogen-dependent pulmonary hypertensive diseases

Select from five to fifty women for this study. These women suffer from pulmonary hypertensive disease. Due to the idiosyncratic and subjective nature of these symptoms, this study has a placebo control group, i.e., these women are divided into two groups, one of which receives the connection of the present invention, such as compound 85 or 92, and the other women's group receives a placebo. Women in the test group receive between 30 and 600 mg drug per day by mouth. They continue this treatment for 3-12 months. Accurate records are kept regarding the number and severity of symptoms in both groups and at the end of this study, these results compare. The results compare between the members of each group and the results for each patient are compared with the symptoms reported by each patient before the study. The applicability of the compounds of the present invention is illustrated by the positive impact that is expected they will have on patients being evaluated using this procedure estratriene core molecular fragment, formula(d)

where m denotes an integer from 1 to 6;

p means an integer from 0 to 6;

R29and R30independently represent hydrogen, lower alkyl, or R29and R30associated with education geteroseksualbnogo ring containing 1-3 heteroatoms selected from N or O;

L means a five - or six-membered cyclic aromatic fragment of the molecule, optionally containing 1-2 heteroatoms selected from N and O, or combinations thereof, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, hydroxy, or formula(e)

where m denotes an integer from 1 to 6;

p means an integer from 0 to 6;

R29and R30mean lower alkyl or are linked together with the formation of five - or six-membered geteroseksualbnogo ring containing 1-2 heteroatoms selected from N or O;

Q1, Q2, Q3and Q4independently selected from the group consisting of hydrogen, hydroxyl, alkoxy and alkyl.

2. The method of treatment of an individual with estrogenzawisimy violation, including the introduction to this individual a therapeutically effective amount of the compounds �ata/80/802873.gif">

3. The method according to p. 2, where estrogenzawisimy infringement is breast cancer.

4. The method according to p. 2, where estrogenzawisimy violation is a cancer of the uterus.

5. The method of treatment of an individual with estrogenization cancer, including the introduction to this individual a therapeutically effective amount of the compounds under item 1.

6. The method according to p. 5 where the cancer is resistant to many drugs.

7. Method for enhancing and/or suppressing decrease in bone mass in the body of a mammal, comprising administration to the individual effective to increase bone mass number of connections on p. 1.

8. The method according to p. 7 for the treatment of osteoporosis in the body of a mammal, comprising administration to the individual an effective amount of the compounds under item 1.

9. A method of reducing serum cholesterol in the body of a mammal, comprising administration to the individual effective to reduce serum cholesterol levels number of connections on p. 1.

10. The method of suppressing pulmonary hypertension comprising administration to an individual in need, a therapeutically effective amount of the compounds under item 1.

11. The method of suppressing the skin and/or vaginalicking number of connections on p. 1.

12. The method of suppressing the disturbance of the Central nervous system, including the introduction of individual female in the post-menopausal period effective amount of the compounds under item 1.

13. The method according to p. 12, where the violation of the Central nervous system is estrogenzawisimy violation of the CNS, including prophylactic administration to the individual of the female sex in the postmenopausal period effective amount of the compounds under item 1.

14. The method of synthesis 7-mutilation, useful in the synthesis of compounds 17-deoxy-1,3,5(10)estratriene, comprising contacting the acidic solution 7-methylandrosta-4-ene-3,17-dione with CuCl2.

15. Pharmaceutical composition for the introduction of an antiestrogen agent containing a therapeutically effective amount of the compounds according to paragraphs.1 and 2-4 in combination with a pharmaceutically acceptable carrier.

16. Compounds selected from the group including

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(diethylaminomethyl)-phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[3'-methoxy-4'-(piperidinomethyl)-phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(4"-methyl piperidinomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[2'-methoxy-4'-(N,N-dimethyl aminomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[5'-(N,N-diethylaminomethyl)-2'-pyridyloxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[4'-(2"-(N,N-diethylamino)ethoxy)phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[4'-(2"-piperidineacetic)phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[4'-(2"-(N,N-dimethylamino)ethoxy)phenoxy]-19-norpregna-1,3,5(10)-triene;

3-hydroxy-7-methyl-21-[4'-(2"-piperidinomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene,

and their pharmaceutically acceptable salts.

17.3-Hydroxy-7-methyl-21-[2'-methoxy-4'-(diethylaminomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene.

18. Connection on p. 16, which represents a 3-hydroxy-7-methyl-21-[3'-methoxy-4'-(piperidinomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene.

19. Connection on p. 16, which represents a 3-hydroxy-7-methyl-21-[2'-methoxy-4'-(4"-methylpiperazine)phenoxy]-19-norpregna-1,3,5(10)-triene.

20. Connection on p. 16, which represents a 3-hydroxy-7-methyl-21-[2'-m is droxy-7-methyl-21-[2'-methoxy-4'-(N,N-dimethylaminomethyl)phenoxy]-19-norpregna-1,3,5(10)-triene.

 

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where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; b)where each of R5and R6independently hydrogen or C1-C6alkyl group;)where R7is hydrogen or C1-C6alkyl group, W is a group; (I)where R8- C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group, phenyl group or benzilla group; or (II)where R9- C1-C6alkyl group or a C5-C6cycloalkyl group, or (III)where R5and R6defined above; g)where each of R10and R11- independently hydrogen or C1-C6an alkyl group or both in the static ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group or aryl group; each of R2and R6independently selected from the group consisting of hydrogen, C1-C6of alkyl, C5-C6cycloalkyl, C6-C9cycloalkenyl and aryl, or R2and R3together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; the symboldenotes a single or double bond, provided that when is a double bond, the hydrogen in the 5-position is absent, and its pharmaceutically acceptable salts

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