Derivatives of 19-norsteroids, methods for their preparation, pharmaceutical composition and the intermediate

 

(57) Abstract:

The object of the invention are compounds of the form (I) in which R17and R'17are such that either R17and R'17together form a ketone, hydrazono, oximino or methylene group, or R17and R'17the hydroxy - group, alloctype-C1-C12, R'17is hydrogen, C1-C8-alkyl, ethinyl, R3is hydrogen, C1-C4linear alkyl, cyclic C5-C6-alkyl, acyl-C1-C12, R16is hydrogen, halogen, C1-C4-alkyl, m is 0, 1 or 2, X, Y, and Z are such that X is methylene, phenylene or phenyleneoxy associated with the steroid via a carbon atom, a saturated or unsaturated linear chain C3-C9possibly interrupted by an oxygen atom, Z is a linear alkyl-C1-C5triptorelin-C2-C4pentaverate-C4-C5nonattributed, substituted phenyl, salt accession of these compounds, their receipt, their use as medicaments, compositions containing them, and new intermediates for their preparation.

< / BR>
4 C. and 6 C.p. f-crystals, 4 PL.

The invention relates to a new 19-nor steroids, with the 11-beta position of the CTI containing them.

The object inventions are the compounds of formula (I):

< / BR>
in which R17and R'17are such that R17and R'17form together ketone function, oximino function hidrogenului group or a methylene radical;

or R17is hydroxyl, oximation or aryloxyalkyl having not more than 12 carbon atoms, and R'17is a hydrogen atom, alkyl, alkenyl or quinil having not more than 8 carbon atoms, each of these substituents may be in some cases substituted;

R3is a hydrogen atom, a linear or branched alkyl or cyclic alkyl having not more than 8 carbon atoms, or acyl having not more than 12 carbon atoms;

R16is a hydrogen atom, halogen atom or alkyl having not more than 8 carbon atoms;

m = 0, 1, or 2;

X, Y and Z are such that

X is a methylene radical Allenova or allinoneruby having not more than 10 carbon atoms, linked to the steroid by a carbon atom;

Y is a linear or branched aliphatic chain, saturated or unsaturated, containing 1 to 18 carbon atom, in some cases interrupted by oxygen atom,

and

aryl or arylalkyl radical, each of these radicals optionally substituted and the alkyl radical contains not more than 6 carbon atoms, and the aryl radical is monocyclic radical containing 5 or 6 members, or a radical consisting of condensed cycles containing 8 to 10 members, these radicals optionally containing 1 or more heteroatoms, selected from among oxygen atoms, nitrogen or sulfur,

alkyl radicals, which may be R'17and Z, alkenylamine or alkenylamine radicals, which may be R'17and aryl or arylalkyl radicals, which may be Z, in some cases substituted by one or more radicals, selected from among radicals:

halogen,

amino, alkylamino or dialkylamino in which one or more alkyl radicals have 1 to 4 carbon atom,

hydroxyl, free, esterified carboxy or salt,

of alkyl having 1 to 8 carbon atoms, optionally substituted by one or more halogen atoms,

oxo, cyano, nitro, formyl,

acyl or acyloxy having not more than 2 carbon atoms,

alkoxy or alkylthio having 1 to 4 carbon atoms, carbamoyl,
and their salts connection.

For acyloxyacyl we can talk about, for example, a derivative of aliphatic or cycloaliphatic, saturated or unsaturated acids, namely alanovoy acid, such as, for example, acetic, propionic, butyric or somalina, Valerian or undecisive acid, oxyacanthae acid, such as, for example, oxiana acid, cycloalkylcarbonyl or cycloalkylcarbonyl acids, such as, for example, cyclopropyl, cyclopentyl or cyclohexylcarbonyl cyclopentyl or cyclohexyloxy or propionic acid, benzoic acid, salicylic acid or phenylalkanoic acids, such as phenylacetic acid or phenylpropionate acid, amino acids, such as diethylaminoacetate acid or aspartic acid, formic acid or decollate, in some cases in the form of a salt, such as, for example, Balandina acid or its monosodium salt. Preferably we are talking about a derivative of acetic, propionic or butyric acid.

Under the acyl radical see radical corresponding to the earlier of acyloxyacyl.

For alkyl radicals we are talking about stands, ethyl, propylene, isopropyl, butyle, sobouti is pentile, 3-ethylpentane, n-octyle, 2,2-dimethylhexane, 3.3-dimethylhexane, 3-methyl-3-ethylpentane.

Preferably it is about the stands.

When R3is cyclic alkyl, talking about cyclopropyl cyclobutyl, cyclopentyl or cyclohexyl. The preferred radical is cyclopentyl.

For alkoxyalkyl we are talking about, for example, methoxy, ethoxy, propoxy, butylacetoacetate and alkylthiomethyl we are talking about methylthio, ethylthio, propylthio or butylthiacalix.

Alkilinity radical may be vinyl, propenyl, Isopropenyl, allyl, 2-methylallyl, butenyl or Isobutanol. The preferred radicals are vinyl or propenyl.

Alkinilovymi radical may be atenil, PROPYNYL, propargyl, butynyl or Isobutanol.

When R16is a halogen atom, we are talking about the atom of bromine, chlorine, fluorine or iodine, preferred is bromine atom.

When X is arilena, the preferred radical is phenylene.

When Y is a linear or branched, saturated or unsaturated aliphatic chain, we are talking about a methylene, ethylene, propylene, isopropylene, butylene, isobutilene the Ohm, 2-methylhexanoate, 2,2-dimethylpentane, 3,3-dimethylpentane 3-utilityroom, n-Actilingua, 2,2-dimethylhexylamine, 3,3-dimethylhexylamine, 3-methyl-3-utilityroom, nonrenewal, 2,4-dimethylheptane, n-dellanave, n-undecylenate, n-dodecylamino, n-tridecylamine, n-tetradecanol, n-pentadecanol, n-hexadecanol, n-heptadecanol or n-octadecylamino radicals, preferred are n-pentile, n-hexylen, n-heptylene, n-octile or n-Nonlin.

It can also be vinilovom, isoproterenol, Allilueva, 2-methylanilinium, izovalerianova, butanaminium, interroom, geksanalem, leptanillinae or okanlanwo radicals, preferably about geksanalem radical.

It may also be ethylene, propylene, propylaniline, Butyrina, isobutylene, pentesilea, geksanalem, heptylene or oktilaminom, preferably propylene, geksanalem or oktilaminom.

It can also be a chain interrupted by an oxygen atom, such as exopolymers, preferably oxydiethylene radical.

When Z is a linear or branched alkyl, it can be any of these radical can be one of the defined radicals, for example the stands, ethyl, propylene, isopropyl, bootrom, isobutyl, n-Pentium or n-hexyl, preferably the stands or ethyl.

Aryl group, which may in arylalkyl group is:

monocyclic carbocyclic radical, for example phenyl,

monocyclic heterocyclic radical, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furutani, pyrrolidinyl, imidazolidinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, as well as the isomers of the provisions or heteroatoms to which these radicals may be,

radical, consisting of a condensed carbocyclic cycles, for example, naphthyl or phenanthrene,

radical, consisting of a condensed heterocyclic cycles, such as benzofuranyl, benzothiazol, benzimidazolyl, benzothiazolyl, oil[2, 3] thienyl, thianthrene, isobenzofuran, chloramines, xantener, femoxetine, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazoles, purinol, hemolysins, ethanolic, hinely, phthalazines, cinnoline, pyridinyl, carbazolyl, beta-carbolines, acridines, phenazines, phenothiazines, phenoxazines, indole the present of monocyclic heterocycles, such as defined above, e.g., furo[2,3-b]pyrrole or thieno-[2,3-b]-furan.

When Z is aryl or arylalkyl, and as an example of such aryl radicals, such as phenyl, furyl, such as 2-furyl, imidazolyl, such as 2-furyl, imidazolyl, such as 2-imidazolyl, pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidinyl, such as pyrimid-2-yl, thiazolyl, such as thiazol-2-yl, thiazolyl, such as thiazolin-2-yl, benzimidazolyl, such as benzimidazole-2-yl, benzothiazolyl, such as benzothiazol-2-yl, curini, such as Zurin-7-yl, or chenail, such as 4-chinolin, and as an example arylalkyl radical can result in particular methyl or ethyl radicals, substituted one of the aryl radicals.

The expression is optional, applied to the alkyl radical, which can represent R'17and Z, alkenylphenol or akinrinola radicals that can be represented as R'17and aryl or arylalkyl radicals that can be represented as Z, indicates that they may not necessarily be substituted by one or more radicals, identical or different, chosen among the radicals listed above, namely:
the Ino, such as dimethylamino, diethylamino, methylethylamine,

hydroxyl,

carboxyl, free or esterified, such as alkoxycarbonyl, for example, methoxycarbonyl or etoxycarbonyl, or in the form of a salt, e.g. sodium or potassium,

of alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, optionally substituted by one or more halogen atoms, e.g. fluorine, such as trifluoromethyl,

oxo, cyano, nitro, formyl,

acyl, such as acetyl, propionyl, butyryl, benzoyl,

acyloxy, such as acetoxy, a radical of the formula-O-CO-(CH2)n-COOH, in which n = 1 to 5

alkoxy, such as methoxy, ethoxy, propyloxy, isopropoxy, bucalossi,

alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,

carbamoyl,

alkenyl, such as vinyl, propenyl,

the quinil, such as ethinyl, PROPYNYL,

aryl, such as phenyl, furyl, thienyl.

As examples of such substituted radicals can lead, for example, alkyl radical, substituted by one or more halogen atoms, e.g. fluorine, such as triptorelin, tripcomputer, pentafluoropropyl, pentafet what anilam, which is itself substituted by one or more halogen atoms and/or alkyl radicals, substituted by one or more halogen atoms, such as pentafluorobenzyl, pantothenicacid, pentafluoropropyl, 4-trifluoromethyl-2,3,5,6-tetrafluorobenzyl.

You can mention, for example, aryl radical, substituted by one or more halogen atoms, for example chlorine, such as 2, 3, 4, 5, 6-tetrachloro-4-pyridyl, amino group, such as 4,6-diamino-2-pyrimidinyl, hydroxyl, such as 2, 6-deoxy-4-pyrimidinyl, esterified by carboxyla, such as methoxycarbonyl, such as 2-ethoxycarbonylphenyl, alkyl, such as stands, such as N-methylimidazole, N-methylthiazolyl or N-methyltetrazolyl, optionally substituted by halogen, for example fluorine, such as 7-/trifluoromethyl/-4-chinolin, exography and alkyl radical, such as stands, such as 2,3-dimethyl-2,6-doxorubin-7-yl.

The invention encompasses salts of the compounds of formula (I), for example, when the compounds of formula (I) have an amine function, salts formed with hydrochloric, Hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glio the Tami arenesulfonic acids such as benzene - or para-toluensulfonate acids, and arylcarbamoyl acids, or when the compounds of formula (I) are the acid function, salts of alkaline or alkaline-earth metals or ammonium, in some cases, replaced.

Among the preferred compounds of formula (I) of the invention can result, for example, compounds in which R3and R16are hydrogen atoms.

Among the preferred compounds of formula (I) of the invention can specifically lead compounds in which m = 1, and compounds in which m = 2.

Among the compounds of the invention can be mentioned, for example, the compounds of formula (I) in which R17is hydroxyl, and R17' is a hydrogen atom or stands.

Among the compounds of the invention can in particular be mentioned the compounds of formula (I) in which X is a methylene radical and Y is a linear saturated chain containing 7 to 9 carbon atoms, the compounds in which X is phenylenebis radical and Y is a linear saturated or unsaturated chain containing 3 to 8 carbon atoms, provided that when the chain is unsaturated, it includes vanilinovoi or atinine is Lenox-radical and Y is a linear saturated chain containing 4 to 7 carbon atoms, optionally interrupted by an oxygen atom. When X is phenyleneoxy-radical, Y preferably contains 5 or 6 carbon atoms.

Among the compounds of the invention can specifically lead the compounds of formula (I) in which Z is a linear alkyl containing 1 to 5 carbon atoms, triptorelin containing 2 to 4 carbon atoms, panafcortelone containing 4 or 5 carbon atoms, nonoperation containing 1 to 4 carbon atom,

radical containing substituted phenyl radical, selected from among:

< / BR>
in which the alkyl is an alkyl radical containing 1 to 4 carbon atoms, and q is 1, 2 or 3,

radical containing heterocycle of 5 members selected from among:

< / BR>
radical containing 6-chleny a heterocycle selected among:

< / BR>
radical containing heterocycle with two condensed cycles, selected among:

.

Among the preferred values of Z can lead to more specifically of pencil and pentaverate, namely pentafluoropropyl, PENTACARBONYL or pentafluorophenyl.

Among the preferred compounds of the invention, therefore, can lead connection, the receipt of which is shown below in the experimental the 11-beta-[4-[3-[/methyl-1H-imidazol-2-yl/thio] -1-PROPYNYL] phenyl] -extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[5-[/2-furylmethyl/thio]pentyloxy]phenyl]- extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[5-[/2-pyridinylmethyl/sulfinil] pentyloxy] phenyl] -extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[5-[/3-pyridinylmethyl/sulfinil] pentyloxy] phenyl] -extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[6-[4,4,5,5,5-pentafluorophenyl/sulfinil] hexyloxy] phenyl] extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[5-[4,4,5,5,5-pentafluorophenyl/sulfinil] pentyloxy] phenyl] extra-1,3,5/10/-triene-3,17-beta-diol,

11-beta-[4-[5-/intercultural/pentyloxy] phenyl] -extra-1,3,5/10/ -triene-3,17-beta-diol,

11-beta-[4-[/4,4,5,5,5-pentafluorophenyl/sulphonyl] pentyloxy] phenyl]-17-alpha-methyl-extra-1,3,5/10/-triene-3,17-beta-diol.

The object of the invention is also a method of obtaining compounds of formula (I), characterized in that the compound of formula (II)

,

in which R17aand R'17ahave the meanings indicated for R17and R'17and in which the optional reactive functions are optionally protected,

X and Y have the above values,

R'3is a hydrogen atom or a group protecting the hydroxyl function,

hal is a halogen atom or pseudohalogen group, as tosylate,

podvezennaya for Z, in which the possible reactive functions can be protected, then in some cases, expose the agent, removing protecting groups to obtain the compound of formula (IA), corresponding to the product of formula (I) in which m = 0, and the product of formula (IA) optionally subjected to any of the following reactions in any order:

the restoration of the ketone function, which can be represented by a set of R17and R'17,

join ketone function, which may be represented by R17and R'17metal complex of the formula (IV)

M - R'17a< / BR>
in which M is a metal atom and R'17ahas the specified values, provided that he is not a hydrogen atom,

the transformation of the ketone function, which can be represented by a set of R17and R'17in oximino function, hydrazono group or a methylene function,

selective acylation in position 17 if R17is hydroxyl,

galoidirovaniya or alkylation at position 16,

the alkylation or acylation of the hydroxyl radical in position 3,

partial or full restoration atenololbuy group, if Y is the Nene is sloti or base.

The compounds of formula (IA), corresponding to compounds of formula (I) in which m = 0, get in the interaction of the compounds of formula (II), in which hal is, for example, a chlorine atom, a bromine atom or tosylate, OR3is hydroxyl, optionally protected, for example, acetyl, tert-bootrom or tetrahydropyranyl, and R17a, R'17ahave reaction functions, it is not necessarily protected by known methods, with a compound of formula (III), preferably in the form of a salt obtained by attaching, for example, sodium carbonate, sodium hydroxide or methylate or ethylate sodium, the reaction is carried out in a neutral solvent, such as methanol, dimethylformamide, hexamethylphosphorotriamide (hmpt) or acetonitrile (CH3CN), one or a mixture of working, for example, at approximately the 50oC or by boiling under reflux, if necessary in the presence of a reagent such as sodium iodide, then in some cases, the compound obtained is subjected to the action of the agent, removing the protection of reactive functions.

Depending on the values of the protective group R'3the products of formula (IA) can be products of formula (I).

Protective groups which can b and conventional in organic chemistry groups and more specifically, commonly used in the chemistry of peptides. A non-exhaustive list of groups and methods for their removal can be found in the French patent FK 2499995, the content of which is appended to this application as prior art. One can cite, for example, tetrahydropyranyl or trityl.

In a preferred embodiment of the invention using the compounds of formula (II) containing a chain of 11-beta position, ending with a halogen or pseudohalogen, such as, for example, a group-O-SO2-f-CH3where f denotes phenylene, as shown in the examples below, and the compounds of formula (III) below in the experimental part. Without limiting that can result in a methyl ester of 2-mercaptobenzoic acid, furfurylmercaptan, 2-diasorin-2-thiol, 2-mercaptothiazole, 2-mercapto-1-Mei, 1-methyl-5-mercapto-1,3,4-triazole, 1-methyl-5-mercapto-1,2,3,4-tetrazole, 2-pyridinemethanol, 4,6-diaminopirimidina-3-thiol, 2,3,5,6-tetrachloropyridine-4-thiol, 2-mercaptobenzothiazoles, 7-trifluoromethyl-4-hinokitiol and 4,4,5,5,5-pentecontaetia.

When the compound of formula (IA) has a protected reactive functions, receive appropriate insecure connection under the action of conventional agents such as amylase the diversified ways of removing the protection described in French patent FK 2499995.

When the compound of formula (IA) has the ketone function in position 17, get:

the corresponding 17-beta-gidrauxilirovanne connection, for example under the action of reducing agent such as sodium borohydride in a neutral solvent such as methanol,

the corresponding compound having the radical R'17that represents alkyl, alkenyl or quinil, optionally substituted, get under the action of the compound (IV), such as, for example, lithium complex, according to the method described in European patent EP 57115,

the corresponding connection with oximino function in position 17, under the action of hydroxylamine in the form of a salt, such as hydrochloride, in the presence of a weak base in an environment of alcohol at the boiling point under reflux,

the corresponding connection with hydrazono function in position 17, for example under the action of a derivative of hydrazine, namely hydrazine hydrate is added, in the presence of acid, such as para-toluensulfonate acid,

the corresponding compound having a methylene function in position 17 using in accordance with the Wittig reaction, for example, methyltriphenylphosphonium bromide in alkaline medium.

When the connection poienii 3 or 17-beta connection under the action of selective Alliluyeva agent, for example, acetic anhydride in pyridine.

When the compound of formula (IA) has ethynylene group, receive a corresponding compound having a vinyl bond, or the corresponding saturated compound under the action of a reducing agent for partial or full recovery, or using hydrogen in the presence of palladium on charcoal or barium sulphate and optionally in the presence of a base such as pyridine or quinoline, in the case of a partial recovery, or by using one of palladium hydroxide in the case of a full recovery.

It is possible to obtain compounds having alkyl radical in position 16, for example, under the action of alkyl halide such as methyl iodide or ethyliodide in the presence of a complex of lithium.

You can get a connection having a halogen at position 16, for example, under the action of bromine in acidic environment, namely in the medium of acetic acid, or when such action halogenous agent, as N-bromo - or N-chloroacetamide, or tert-butylhypochlorite.

It is possible to subject the compounds of formula (IA) action agent sulfoximine, such as metaperiodate sodium or metallocarboranes acid to obtain what antinoi acid, to obtain the compounds of formula (I) in which m = 2.

The invention also relates to a method for producing compounds of formula (I), characterized in that the compound of formula (V):

< / BR>
where R17aand R'17ahave the meanings given above for R17and R'17in which the optional reactive functions are optionally protected,

X and Y have the above values,

R'3is a hydrogen atom or a group protecting the hydroxyl,

W is a hydrogen atom or the acyl radical COR in which R is alkyl with 1-5 carbon atoms, is introduced into reaction with the compound of the formula (VI):

Za - hal'

or its salt, in which the radical Za has the values specified for Z, in which the possible reactive functions can be protected, and hal' is a reactive group, such as halogen or pseudohalogen, such as mesilate or tosylate, in the presence of a base, then in some cases are treated with an agent for removing protecting groups to obtain the compound of formula (IA) as defined above, and optionally carry out any of the reactions described for compounds of formula (IA).

In accordance with this variant of the method of the invention the compounds of formula (IA), soooi W is acyl, for example the acetyl, propionyl, Boutillon, OR'3is optional, protected hydroxyl, such as acetyl, tert-bootrom or tetrahydropyranyl; reactive functions that are available in the R17aand R'17amay be protected in the usual way, with the compound of formula (VI) or its salt such as hydrochloride, the reaction is carried out in a solvent such as methanol or dimethylformamide, optionally heated, for example, up to about 50oC or at the boiling point under reflux in the presence of a base, such as sodium methylate or concentrated sodium hydroxide.

In a preferred embodiment of the invention using the compounds of formula (V), containing 11-beta-position of the chain, ending Tilney group or thioacetals, as well as the compounds of formula (VI) given in the experimental part.

Not limited to, one can cite as compounds of the formula (VI) or 3-chloromethylpyridine, 4-chloromethylpyridine, 6-(chloromethyl)-uracil, 2-chloromethylbenzene, 7-(2-chloroethyl)-theophylline and their salts accession, such as the hydrochloride or iodopentane, or mesilate, tosylate or halide derivative pentafluorophenyl or trifloromethyl,5,5-Pentatriacontane, the receipt of which is described in the experimental part, get with ionirovanii corresponding alcohol 4,4,5,5,5-Formentera, intermediate product, which can be obtained, for example, in hydrogenation reactions in the presence of a catalyst, such as Raney Nickel in methanol or platinum oxide in ethanol, partially unsaturated product, corresponding 4,4,5,5,5-pendaftar-2-penten-1-Olu, which is described T. Kitazume et al., J. Am. Chem. Soc., 1985, 107, 5186-5191.

Saturated intermediate alcohol above can also be obtained in accordance with the method described by N. O. Brace, Journal of Fluorine Chemistry, 20 /1982/, 313-327, based on identitarian that condense under pressure with allyl alcohol in the presence of a catalyst, such as, for example, azoisobutyronitrile (AIBN), Raney-Nickel in ethanol, Tetra-KIS-(triphenylphosphine)palladium in hexane or tin and silver acetate in methanol to obtain 2-iodine-4,4,5,5,5-pentafluorophenol, which is introduced into the hydrogenation reaction, for example, with hydrogen in the presence of 10% palladium on magnesium oxide in methanol or Raney Nickel in ethanol, or by reaction with anti-hydride in the presence of azobisisobutyronitrile.

The compounds of formula (IA) obtained in accordance with variable (I).

The compounds of formula (I) possess interesting pharmacological properties. Study products for hormonal receptors has allowed to prove that they in particular have a wonderful antiestrogenic activity and antiproliferative properties, as shown by the test results below. They also have protivoyazennoe activity.

These properties enable the use of the compounds of formula (I) for the control of fertility, for example, in some forms of infertility due to no ovulation, birth control, such as contraceptives, namely as pills after coitus, as well as for the treatment of hormone-dependent carcinomas, such as, for example, carcinomas of breast cancer and their metastases, and for the treatment of benign tumors of the female breast.

Therefore, an object of the invention is the products of formula (I) as medicine.

Among the drugs of the invention can result, in particular, the compounds described in the experimental part, in particular, the products of the examples. Among these products as medicines invention is particularly declares the following compounds of formula (I):

11-beta-/8-//2-pyridinylmethyl/tio/octal/-the-3,17-beta-diol,

11-beta-/4-/5-//2-furylmethyl/tio/pentyloxy/phenyl/- östra 1,3,5/10/-triene-3,17-beta-diol,

11-beta-/4-/5-//2-pyridinylmethyl/sulfinil/pentyloxy/phenyl/- östra 1,3,5/10/-triene-3,17-beta-diol,

11-beta-/4-/5-//3-pyridinylmethyl/sulfinil/pentyloxy/phenyl/-östra 1,3,5/10/-triene-3,17-beta-diol,

11-beta-/4-/6-/4,4,5,5,5-pentafluorophenyl/sulfinil/hexyloxy/ phenyl/östra 1,3,5/10/-triene-3,17-beta-diol,

11-beta-/4-/5-//4,4,5,5,5-pentafluorophenyl/sulfanil/pentyloxy/ phenyl/östra 1,3,5/10/-triene-3,17-beta-diol,

11-beta-/4-/5-/intercultural/pentyloxy/phenyl-östra 1,3,5/10/ -triene-3,17-beta-diol,

11-beta-4-/5-//4,4,5,5,5-pentafluorophenyl/sulphonyl] pentyloxy/ phenyl/-17-alpha-methylestra-1,3,5/10/-triene-3,17-beta-diol.

Useful posologia varies depending on therapeutic effects and routes of administration, it may range, for example, from 1 to 100 mg per day per adult in oral introduction.

The invention encompasses pharmaceutical compositions containing as active principle at least one of these drugs, as defined above.

The compounds of formula (I) use through the stomach, parenteral or locally, for example subcutaneously. They can be written in the simple form of tablets or in the form of pills, capsules, Gramarye prepared in accordance with known techniques.

One or more active principles can be put back together with eccipienti, usually used in these pharmaceutical compositions, as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous media, oils and fats, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

Some of the intermediates of formula (II) or (V) are new products and are, therefore, an object of the invention is also the compounds of formulae (II) and (V) as defined previously.

New intermediate products of the formula (II) as defined previously, get in line with the methodology, an example of which is shown below.

In General the compounds of formula (II) can be obtained according to the following method:

or subjecting the compound of formula (VII)

< / BR>
in which R17aand R'17ahave these values, K is an aliphatic chain containing 2-19 carbon atoms, linked to the steroid nucleus methylene radical or Allenova group

a/ action, activating the alcohol function of the agent, such as tosyl chloride in pyridine, or halogenous agent, nab is retele, when K is an aliphatic chain,

b/ action halide compounds of formula (VIII):

Br - Y - hal

in which Y has the meanings given above and hal is halogen, in the presence of a base, when K is Allenova group, then in both cases the action flavouring agent such as palladium hydroxide on the magnesium oxide in methanol or a mixture of acetyl bromide with acetic anhydride, to obtain respectively the compounds of formula (II) in which X is a methylene radical and compounds of the formula (II) in which X is allinoneruby;

or give the compound of formula (VII), such as defined above, first in the aromatization reaction, then the reaction of a) or b), as described,

or the compound of formula (IX):

< / BR>
in which R'3, R17aand R'17ahave these values, X' are Allenova group and Y' is the same as Y, as defined above, containing 2 carbon atoms on the level of communication with Allenova group, which is represented by X', is subjected to the action of activating the alcohol function of the agent, for example carbon tetrachloride, in the presence of triphenylphosphine in a neutral solvent or taillored in pyridine to obtain soedinenii, if desired, the products can be partially or fully reactions on triple bond.

Some products of the formula (VII) required for implementing the method, are known products. Obtaining them are described in the receipt of the products of example 43 and example 50 in the application for the European patent EP 384842, the contents of which are shown here as prior art. New products of the formula (VII) can be obtained in a similar way, for example, by the method described in this patent application.

The products of formula (IX) necessary for implementing the method, are products that are well-known ways, based on the products of formula (X):

< / BR>
in which R'3, R17a, R'17aand X' have the specified values.

Based on the products of formula (X), receive the products of formula (IX), stirring, for example, or paraformaldehyde in the presence of butyl chloride and lithium chloride in a neutral solvent, when Y' is a methylene radical, or a halide compound of the formula Rp-O-Y'-Hal1in which Hal1is a halogen, and Rp is a protecting group for an alcohol function, in the presence of a strong base, when Y' is an aliphatic chain having at least 2 directly to get some products of the formula (II), in which Hal is halogen, by reaction with a halide compound of the formula Hal2-Y'-Hal1in which Hal1and Hal2respectively, are halogen, in the presence of a strong base.

The products of formula (X) described in the example in the application for the European patent N EP 384842, and other products of the formula (X) can be obtained by analogy, for example, by the method described for in example 31 of the specified application.

New intermediate compounds of formula (V), such as defined previously, get the method that is shown in the example below.

In General, the compounds of formula (V) can be obtained according to the following method.

The compound of formula (II'), corresponding to the compound of formula (II) defined above, in which hal is a chlorine atom or bromine, subject:

or action jodorowski agent, such as sodium iodide, in a neutral solvent such as acetone or methyl ethyl ketone, with optional heated at the boiling point under reflux, then the action of salt thiocarbonic acid of formula (XI):

R - CO - SH

in which R has the above meanings to obtain a compound of formula (V), where W is the acyl radical (XII):

< / BR>
in which R3X, Y, R17aand R'17ahave the specified values, which is treated with a recovery agent disulfide, for example, tri-n-butylphosphine, in a neutral solvent such as water, an organic solvent, to obtain compound of formula (V), where W is a hydrogen atom.

The following examples illustrate the invention without limiting it, the products of formula (I) in which R17is hydroxyl. R'17is a hydrogen atom, m is 0, 1 or 2, and X have the values listed in the table.1, are products that can be obtained in the framework of the invention.

Example 1. 11-beta-[8-[/2-Pyridinylmethyl/thio] octyl] -östra-1,3-5/10/- triene-3,17-beta-diol.

Stage A: 17-beta-atomic charges-11-beta-[/8th atomic charges/octyl]-östra-4,9-Dien-3-one.

To a solution of 1.4 g of 17-beta/atomic charges/-11-beta-/8-axiatel/-östra - 4,9-Dien-3-one in 10 cm3pyridine was added 3.6 cm3acetic anhydride and 95 mg 4-/dimethylamine/pyridine. The solution is stirred for 1 h at room temperature, add 5 cm3and 5 cm3methanol, stirred 10 min at 0 to 5oC, poured into a saturated aqueous solution of ammonium chloride, extracted with these is the pressure after removal of pyridine with toluene. Get to 1.61 g of crude product, which chromatographic on silica, elwira ethylacetoacetate 3 - 7. Thus, the gain of 1.28 g of the target product.

IR spectrum (CHCl3):

C=O 1735 cm-1< / BR>
Dienen 1660-1605 cm-1< / BR>
Stage B. Diacetate 11-beta-[8-/atomic charges/octyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Dissolve 1,273 g of the product obtained in the previous phase, 13 cm3the methylene chloride with 1,3 cm3acetic anhydride and 0.65 cm3acetylamino, stirred 10 min at 0oC, then 1.5 h at room temperature, cool and add 2 drops of water and 3 cm3of methanol. Poured into a saturated solution of sodium bicarbonate, extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. Get 1,387 g of the target product.

IR-spectrum:

C=O 1740-1730 cm-1.

Aromatics 1610-1590-1500 cm-1.

Stage 11-beta-(8-Axiatel)-östra 1,3,5/10/-triene - 3,17-bettiol.

To a solution of 1,337 g of the product obtained in the preceding stage, in 42 cm3methanol is slowly added 20 cm32 N. sodium hydroxide and stirred for 2.5 h at room temperature, was added 21.5 cm32n. Sol is asystem aqueous solution, dried and evaporated to dryness under reduced pressure. Get 1,119 g of the target product, used as such in the next stage.

Stage D. 11-beta-(8-Bromacil)-östra 1,3,5/10/-triene-3,17-bettiol.

To a solution of 1,107 g of the product obtained in the preceding stage, 32.5 cm3acetonitrile from 8.1 cm3of tetrahydrofuran and 2,561 g chetyrehpostovye carbon at 40oC was added dropwise a solution of 2,88 g of triphenylphosphine 8.1 cm3of methylene chloride. Stirred for 1 h at room temperature and evaporated to dryness under reduced pressure. Get 6,05 g of product, which is well chromatographic on silica (eluent ethyl acetate: cyclohexane 3/7). Obtain 283 mg of the target product.

IR-spectrum:

OH 3605 cm-1.

Aromatics 1615-1600-1590-1500 cm-1.

Stage E. 11-beta-[8-[/2-pyridinylmethyl/thio]octyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Stirred for 5 min the mixture of 125 mg of 2-pyridinemethanol and 0.98 cm3solution of 51.3 mg/cm3of sodium methylate in methanol, then added at room temperature a solution of 155 mg of the product obtained at the previous stage, 4 cm3methanol was added 60 mg of sodium iodide and stirred all 1 h at ciplactin solution of sodium chloride and evaporated to dryness under reduced pressure. Collect 224 mg of product, which chromatographic on silica (eluent methylene chloride-methanol to 97.5/2.5 a, then again with ethyl acetate-cyclohexane 40/60).

IR-spectrum:

OH 3604 cm-1.

Aromatics 1616-1598-1584 cm-1.

Heterocycles 1571-1498 cm-1.

Example 2. 11-beta-[4-[3-[/1-methyl-1H-imidazol-2-yl/thio]- 1-PROPYNYL]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Stage A. 3,17-beta-bis-/Tetrahydro-2H-2-pyranyloxy/- 11-beta/4-ethynylphenyl/-östra 1,3,5/10/-triene.

Stirred in an ultrasonic cell mixture from 0.1 cm3chlorobutane, 14 mg of lithium powder, 540 mg of 3-/4-/3,17-beta-bis-/tetrahydro-2H-2-pyranyloxy-östra 1,3,5/10/- trien-11-beta-Il/phenyl/-prop-2-in-1-ol and 2 cm3tetrahydrofuran (THF) for 30 min at 30/35oC and added 29 mg of paraformaldehyde, stirred for several minutes at 30/35oC, diluted with water, acidified with mononatriumfosfaatti, extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. Receive 613 mg of product, which chromatographic on silica (eluent cyclohexane / ethyl acetate 1/1), collected 400 mg of the target product (i.e pl. 214oC).

IR-spectrum:

CCH is missing.

OH 3609 cm-1.

Stirred for 1 h at room temperature and 2 hours at the boil under reflux a solution containing 570 mg of the product obtained in the previous phase, 14 cm3carbon tetrachloride, 2 cm3of tetrahydrofuran and 4 cm3acetonitrile and finally (portions) 530 mg of triphenylphosphine. Add 5 g of silica and evaporated to dryness under reduced pressure. Chromatografic the resulting residue on silica (eluent cyclohexanediacetic 8 - 2). Collect 370 mg of the target product.

IR spectrum (CHCl3on Nicollette):

OH 3598 cm-1.

CC 2268/1/ - 2220 - cm-1.

Aromatics 1606 - 1560 - 1531 - 1506 cm-1.

Stage C. 3,17-beta-bis-/Tetrahydro-2H-2-pyranyloxy/- 11-beta-[4-[3-[/1-methyl-1H-imidazol-2-yl/thio]-1-PROPYNYL]phenyl]- östra 1,3,5/10/-triene.

To the solution cooled tooC, containing 90 mg of 2-mercapto-1-methylimidazole and 2 cm3tetrahydrofuran (THF) was added 38 mg of sodium hydride as a 50% dispersion in oil. Stirred for 1 h at 0oC. Add a solution of 2 g of the product obtained in the preceding stage in 2 cm3tetrahydrofuran (THF). Allowed to warm to room temperature and stirred for another 3 hours Pour the reaction mixture into odniesieniu product chromatographic on silica (eluent ethyl acetate: cyclohexane 2/8). Obtain 180 mg of the target product.

IR spectrum (CHCl3on Nicollette):

OH 3600 cm-1.

CC 2218 cm-1.

Aromatics + heterocycle 1608 - 1582 - 1506 cm-1complex.

Stage D. 11-beta-[4-[3-[/Methyl-1H-imidazol-2-yl/thio]-1-PROPYNYL]phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

Stirred for 2 hours at room temperature the mixture containing 143 mg of the product obtained in the previous phase 2 cm3ethanol and 2 cm32n. of hydrochloric acid. Concentrate to a small volume, extracted with ethyl acetate and evaporated to dryness under reduced pressure. The remainder chromatographic on silica (eluent cyclohexane / ethyl acetate 1/1). Collect 96 mg of the target product.

IR spectrum (CHCl3on Nicollette):

HE 3608 cm-1+ associated.

CC 2210 cm-1< / BR>
Aromatic heterocycle 1583 - 1554 - 1505 cm-1.

Example 3. 11-beta-[4-[5-[/2-furylmethyl/thio]pentyloxy] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Stage A. 11-beta-[4-[/5-chloropentyl/oxy]phenyl]-östra-4,9-diene-3,17-beta-dione.

Heated for 6 h under stirring a solution containing of 28.2 g of 11-beta-(4 oksifenil)-östra-4,9-diene-3,17-dione (obtained in preparation example 43 zavarivat acetone and treated the remainder of the 200 cm3of methylene chloride, washed with water, dried and concentrated to a volume of 100 cm3, add 10 cm3isopropyl ether and concentrate before crystallization, filtered off, dried and collected to 26.3 mg of product, which chromatographic on silica (eluent petrol G-ethyl acetate 1/1). Gain of 4.2 g of the target product (i.e pl. 220oC).

IR spectrum (CHCl3):

17-keto 1735 cm-1,

3-keto 1658 cm-1.

C=C and aromatics 1609-1580-1509 cm-1.

Stage B. 3 atomic charges-11-beta-[4-[15-chloropentyl/oxy] phenyl]- östra-1,3,5(10)-triene-17-one.

To a solution, cooled to +4oC containing 30 g of the product obtained in the preceding stage, 300 cm3of methylene chloride was added 30 cm3acetic anhydride and 15 cm3acetylproline. Allowed to warm to room temperature, stirred for 1 h, was added while cooling to 30 cm3methanol and 500 cm3a saturated solution of sodium bicarbonate. Stirred for 45 min at room temperature, decanted, washed with water, dried, then evaporated to dryness.

Obtain 37 g of the product used as such in the next stage.

Stage C. 3-hydroxy-11-beta-[4-[(5-chloropentyl)oxy]phenyl]-rn is g, obtained in the previous phase, 200 cm3of tetrahydrofuran and 64 cm32n. of sodium hydroxide. Add 64 cm32n. hydrochloric acid and evaporated the solvent under reduced pressure. Extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. Obtain 32 g of the target product, which is used as such in the next stage.

Stage D. 11-beta-[4-[/5-chloropentyl/oxy] phenyl]-östra 1,3,5/10/ -triene-3,17-beta-diol.

To a solution containing 32 g of the product obtained in the previous phase, 150 cm3of tetrahydrofuran, are added 150 cm3methanol and at 0+5oC within 10 min of 2.56 g of sodium borohydride (95%). Stirred at 0+5oC and add 10 cm3acetone, distilled solvents, treat the residue with methylene chloride, washed with water, dried and evaporated to dryness. Obtain 34 g of the product, which chromatographic on silica (eluent toluene-ethyl acetate 8/2). Collect br15.15 g of the target product (i.e pl. 165oC, recrystallized from ethyl acetate).

IR spectrum: (nujol)

Region absorption NH/OH

Aromatics 1618 - 1608 - 1582 - 1512 - 1492 cm-1< / BR>
Stage E. 11-beta-[4-[5-[(2-furylmethyl)thio]pentyloxy] phenyl]-östra 1,3,5/10/-triou 0.15 cm3furfurylmercaptan (90-95%), 81 g of sodium methylate, 90 mg of sodium iodide, 4 cm3methanol and 234 mg of the product obtained in the previous phase. Distilled methanol under reduced pressure, treated with ethyl acetate, washed with water, dried and dispersed to dryness under reduced pressure. Obtain 340 mg of product, which chromatographic on silica (eluent petrol G - ethyl acetate 6-4). Collect 260 mg of product, which chromatographic on Lichrosorb RP18 (eluent methanol-water 9-1). Thus obtain 140 mg of the target product.

IR spectrum (CHCl3):

OH 3602 cm-1.

Aromatics + conjugated system 1610 - 1581 - 1512 - 1504 cm-1< / BR>
Example 4. 11-beta-[4-[5-[/2-pyridinylmethyl/thio]pentyloxy]phenyl]-östra 1,3,5/10/ -triene-3,17-beta-diol.

Refluxed for 3 h, the solution containing 0.17 cm32-pyridinemethanol, 81 mg of sodium methylate, 234 mg of the product obtained in stage D of example 3, and 4 cm3of methanol. Distilled methanol, treated with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. Collect 360 mg of residue, which chromatographic on silica (eluent ethylacetate G8/2) and thus obtain 280 mg of the target product.-1< / BR>
Example 5. 11-beta-[4-[5-[(2-pyridinylmethyl)sulfinil]pentyloxy]- phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

To a solution of 172 mg of the product obtained in example 4 in 12 cm3methanol was added to 3.7 cm3solution of 0.1 M metaperiodate sodium in the water. Stirred for 1.5 h and add 3.4 cm3methanol and 0.6 cm3solution metaperiodate after 30 min stirring the reaction medium is poured into water, extracted with ethyl acetate, washed with salt water and evaporated to dryness under reduced pressure. Obtain 176 mg of residue, which chromatographic on the silicon oxide twice (eluent methylene chloride-methanol 92,5-7,5). Collect 107 mg of the target product

IR spectrum (CHCl3on Nicollette):

OH 3606 cm-1.

Heterocycles and aromatics 1610 - 1596 - 1583 - 1572 - 1512 cm-1< / BR>
Sulfoxide 1031 cm-1.

Example 6. 11-beta-[4-[5-[/3-pyridinylmethyl/thio]pentoxil]phenyl]- östra 1,3,5/10/-triene-3,17-beta-diol.

Stage A. 11-beta, 11'-beta/-11,11'-[Dithiobis-[5,1-pentoxil-(4,1-phenylene)]] di - östra 1,3,5/10/triene-3,17-beta-diol.

Stirred at the boil under reflux for 17 h and 1.9 g of 11-beta-[4-[(5-chloropentyl)oxy] phenyl] -östra 1,3,5- /10/-triene-3,17-beta-diol obtained in stage D Ave is boiling under reflux. Distilled ethanol, treated the residue with ethyl acetate, washed with salt water, dried and evaporated to dryness under reduced pressure. Obtain 2.1 g of residue, which chromatographic on silica (eluent ethyl acetate-petrol G/6/4), collect this 1,72 g of the target product.

IR-spectrum (nujol):

Region absorption NH/OH

Aromatics 1609 - 1580 - 1510 cm-1.

Stage B. 11-beta[4-[5-[(3-Pyridinylmethyl)thio] pentyloxy] phenyl]-östra 1,3,5/10/-Trient-3,17-beta-diol.

and/ Restore disulfide. To a solution of 5 cm3methanol with 10% water and 2 cm3tetrahydrofuran (THF), previously degassed, enter 465 mg of the product obtained in the previous phase, and 0.25 cm3tributylphosphine. Stirred for 2 h at room temperature, extracted with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. Obtain 640 mg of the mercaptan.

b/ Alkylation. Dissolve the resulting mercaptan 5 cm3methanol and added 160 mg of sodium methylate and 342 mg of the hydrochloride (3-chloromethyl)-pyridine 96%.

This suspension is stirred for 55 min at boiling under reflux, allowed to cool to room temperature, acidified with 2 cm32n. calanopia to dryness under reduced pressure. Collect 650 mg of product, which chromatographic on silica (eluent ethylacetate G/8/2). Obtain 370 mg of the target product.

IR spectrum (CHCl3):

HE 3607 cm-1< / BR>
Aromatics 1610 - 1580 - 1512 cm-1.

Example 7. 11-beta-[4-[5-[(3-Pyridinylmethyl)sulfinil]pentyloxy]-phenyl] -östra 1,3, 5/10/triene-3,17-beta-diol.

Work according to the method of example 5 starting from 177 mg of the product obtained in example 6, to obtain 185 mg of the crude product, which was added 24 mg of the preceding product and chromatographic all on the silicon oxide twice (eluent methylene chloride-methanol 9/1). Gather 138 mg of the target product.

IR spectrum (CHCl3on Nicollette):

HE 3606 cm-1+ the total absorption.

Aromatics + heteroaromatic 1610 - 1580 - 1512 cm-1.

Sulfoxide 1030 - 1040 cm-1.

Example 8: 11-beta-[4-[6-[(4,4,5,5,5-Pentafluorophenyl)thio]hexyloxy]phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

Stage A. 11-beta-[4-[(6-chlorhex)oxy] phenyl]-östra-4,9-diene-3,17-dione.

Refluxed for 5 h 362 mg of 11-beta/4 oksifenil/-östra-4,9-diene-3,17-dione, 5 cm3acetone, 1.5 cm36-bromchlormethane and 138 mg of potassium carbonate. Then add 1 surgeryt with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. Collect of 3.48 g of the product, which chromatographic on silica (eluent ethyl acetate-petrol 6/4). The obtained residue is recrystallized from a mixture of methylene chloride-isopropyl ether and receive 290 mg of the target product (i.e pl. 221oC).

Stage B. 3-hydroxy-11-beta-[4-[(6-Chlorhex)oxy]phenyl]-östra 1,3,5/10-triene-17-one.

Work on techniques of stages B and C of example 3, on the basis of 481 mg of the product obtained in stage A above, using 0.5 cm3acetic anhydride and 0.25 cm3acetylproline. Get 483 mg of the target product.

Stage 11-beta-[4-[(6-Chlorhex)oxy] phenyl]-östra 1,3,5/10/ -triene-3,17-beta-diol.

Work on the technique of stage D of example 3, on the basis of 465 mg of the product obtained above, using 60 mg of sodium borohydride. After chromatography on silica (eluent petrol G - ethyl acetate 6/4) and recrystallization from methylene chloride receive 300 mg of the target product (i.e pl. 176oC).

Stage D. 11-beta-[4-[(6-iohexol)oxy]phenyl]-östra 1,3,5/10/ -triene-3,17-beta-diol.

To a solution of 310 mg of the product obtained in stage C, 6 cm3methyl ethyl ketone was added 150 mg of sodium iodide and re is the situation with reflux condenser and 16 h leave at room temperature. Treated with ethyl acetate, washed, dried and evaporated to dryness under reduced pressure. Collect 470 mg of the target product, used as such in the next stage.

Stage E. 11-beta-[4-[(6-Diacetyl)hexyl]oxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

To a solution of 470 mg of the product obtained in stage D, 6 cm3ethanol was added 150 mg of thioacetate potassium and stirred for 1 h 50 min at 50oC. Distilled ethanol, treated with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. Receive 400 mg of residue, which chromatographic on silica (eluent ethyl acetate - petrol 6/4, then 8/2). Collect 265 mg of the target product (the so-coal-seam - 90oC).

IR spectrum (CHCl3on Nicollette):

OH 3602 cm-1.

C=O 1686 cm-1.

Aromatics 1610 - 1581 - 1512 cm-1.

Stage F. 11-beta-[4-[6-[(4,4,5,5,5-Pentafluorophenyl)thio]hexyloxy]phenyl]- -östra 1,3,5/10/-triene-3,17-beta-diol.

To a solution of 200 mg of the product obtained above, and 127 mg of 4,4,5,5,5 pentatriacontane (the receipt of which is below) 5 cm3methanol was added to 0 . .. cm3of sodium hydroxide. Stirred for 1 h at 50oC, then the solvent is evaporated p. the reed, washed with water, dried and evaporated to dryness under reduced pressure. The obtained residue chromatographic on silica (eluent petrol G - ethyl acetate 65/35). Obtain 149 mg of the target product.

IR spectrum (CHCl3):

OH 3600 cm-1< / BR>
Aromatics 1620 - 1580 - 1512 cm-1.

Preparation of starting compounds example 8: 4,4,5,5,5-pentatriacontane.

Stage A. 4,4,5,5,5-Pentafluorophenol.

Dissolve 10 g of 4,4,5,5,5-pendaftar-2-penten-1-ol (obtained according to J. Am. Chem. Soc., 107 (1985), 5186-5191: T. Kitazume et Ishikawa) 100 cm3methanol and hydronaut in the presence of Raney Nickel (0.5 g). The catalyst is filtered off, washed with ethanol and after distillation under reduced pressure to obtain the target alcohol so Kip. 133oC. n2d3: 1,3305.

Stage B 4,4,5,5,5-Pentatriacontane.

To a solution of 2.65 g of triphenylphosphine, and 0.69 g of imidazole in 20 cm3the methylene chloride is added to 2.54 g of iodine and, keeping the temperature below 25oC, the solution obtained in stage A, 3 cm3of methylene chloride. Stirred for 3 h, filtered, distilled methylene chloride and treated the residue several times with pentane. After removal of the pentane gain of 3.45 g of residue containing the target product, which�,4,5,5,5-Pentafluorophenyl)sulfinil] -hexyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

To a solution of 110 mg of the product obtained in example 8, 5.5 cm3methanol was added to 0.61 cm3a 0.5 M solution of metaperiodate sodium in the water. Stirred for 1 h at room temperature and the methanol is evaporated under reduced pressure. The residue is treated with 2n. hydrochloric acid, extracted with methylene chloride. After drying and evaporation to dryness of the solvent the residue chromatographic on silica (eluent-methylene chloride-methanol 95/5). Obtain 96 mg of the target product.

IR spectrum (CHCl3):

OH 3605 cm-1+ associated.

Aromatics 1610 - 1580 - 1512 cm-1.

Sulfoxide 1031 cm-1.

Example 9a. 11-beta-[4-[6-[(/4,4,5,5,5-Pentafluorophenyl/sulfonyl]-hexyloxy]phenyl] -östra 1,3,17-beta-diol.

To a solution of 150 mg of the product obtained in example 8, 2 cm3of methylene chloride was added 150 mg of 70% portaliou acid. Stirred for 1 h 15 min, then add aqueous sodium thiosulfate solution and an aqueous solution of bicarbonate sodium. Extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The obtained residue chromatographic on silica (eluent ethyl acetate-petrol 6/4). Obtain 130 mg of the target product.

IR spectrum (CHClSulfon 1305 - 1132 cm-1.

Examples 10 to 13. Work according to the method of example 1, based on the product obtained in stage D of example 1, to obtain the compound of example 10, operating according to the method of example 1, but from diacetato corresponding compounds of the formula (II), such compounds as defined above, in which Hal is a chlorine atom (example II) or tosylate group (examples 12 and 13), using for each example, the mercaptan of formula (III) where Za is the value specified for Z in the table. 2, or its sodium salt followed by saponification with sodium hydroxide obtained diacetate, get the target diol of the formula (I), the compounds of examples 11 to 13.

The compounds of examples 10 to 13 correspond to the compounds of formula (I) in which R17is hydroxyl, R'17is a hydrogen atom, m is 0, X, Y and Z have the values listed in the table. 2.

The IR spectra of the products of examples 10 to 13 are given in table. 2.

Products corresponding to examples 10 to 13, of the formula I in which m is 1, obtained by the method of example 5.

Examples 14 to 24. Work according to the method of example 2, to obtain compounds of examples 14 to 21 and working according to the method of example 2, but from the corresponding compounds of the formula (II), receive the hydrogen m is 0, X, Y and Z have the meanings given in table. 3, using in each example, the mercaptan of formula (III) in which Z has a value specified for the Z table. 3.

The IR spectra of the products of examples 14 to 24 are given in table. 3.

Products corresponding to examples 14 to 24 of the formula I in which m is 1, receive according to the method of example 5.

Examples 25-29. Working according to the method of example 6, to obtain compounds of examples 25-27, working according to the method of example 8, to obtain the compound of example 28, the compounds of formula (I) in which R17is hydroxyl, R'17is a hydrogen atom, m is 0, X, Y and Z have the values listed in the table. 3, using for each example, the compound of formula (VI), where Za is the value specified for the Z table. 4.

Get the connection corresponding to the examples 25-28 formula (I) in which m is 1, working according to the method of example 5. Example 29 are in this way, proceeding from the compound of example 25.

The IR spectra of the products of examples 25 to 29 shown in table. 4.

Example 30. 11-beta-[4-[5-[(4,4,5,5,5-Pentafluorophenyl)thio] pentyloxy]phenyl]-östra-1,3,5(10)-triene-3,17-beta-diol.

Work according to the method of example 8, but is introduced into the reaction at the stage of A 5-bromchlormethane with 11-beta-/4-oxiodative.

OH 3600 cm-1.

Aromatics: 1625, 1613, 1570, 1511, 1500 cm-1.

Example 31. 11-beta-[4-[5-[(4,4,5,5,5-Pentafluorophenyl)sulfinil] - pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 9 and, on the basis of the product of example 30, get the target connection.

IR spectrum (CHCl3in Nicollette):

OH 3606 cm-1+ associated.

Aromatics: 1622, 1610, 1570, 1511, 1505 cm-1.

Sulfoxide: 1030 cm-1.

Example 32. 11-beta-[4-[5-[(4,4,5,5,5-Pentafluorophenyl)sulfonyl] - pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 9a, from 225 mg of the product of example 30, obtain 206 mg of the target product.

IR spectrum (CHCl3):

OH 3604 cm-1+ associated.

Aromatics: 1622 /shoulder/, 1610, 1570, 1512 cm-1.

SO21306, 1132 cm-1.

Example 33. 11-beta-[4-[5-(Pentity/pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

In solution in 5 cm310% water in methanol and 2 cm3tetrahydrofuran (THF), previously degassed, enter 465 mg of the product obtained at stage A of example 6, and 0.25 cm3triphenylphosphine. Stirred for 1 h at room temperature, probably the keys ethyl acetate, acidified with 1 N. hydrochloric acid, extracted with ethyl acetate, washed with salt water, dried and the solvent is evaporated. After chromatography of the residue on silica (eluent: petrol G - ethyl acetate 70-30) obtain 570 mg of the target product.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1582, 1511 cm-1.

Example 34. 11-beta-[4-[5-(Trifluoromethyl)-4-chinoline] thio] pentyloxy] phenyl-extra-1,3,5/10/-triene-3,17-beta-diol.

Stirred at 95oC for 43 h 400 mg chlorinated obtained in stage D of example 3, 300 mg of 4-mercapto-7-triptoreline and 68 mg of sodium methylate. The solvent is evaporated under reduced pressure, the residue treated with 5% methanol in methylene chloride, washed with a solution of 2n. hydrochloric acid, dried and the solvent is evaporated. After chromatography on silica (eluent: ethyl acetate-petrol G - triethylamine 70-30-1, then ethyl acetate: triethylamine 99-1), collect 391 mg of the target product, which purified the new chromatography on silica (eluent: methylene chloride-methanol 97-3).

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1582, 1512, 1505 cm-1.

A heterocycle: 1571, 1328, 1287, 1135, 1068 cm-1.

P the melt by the method of stage F of example 8, on the basis of 262 mg 4,4,5,5,5-pentatriacontane obtained in example 8, and 410 mg of diacetate made below. Get 335 mg of the target product.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1581, 1512 cm-1.

C2F5: possible.

Preparation of 11-beta-[4-[[4-/acetylethyl/butyl] oxy] phenyl] -östra -1,3,5/10/-triene-3,17-beta-diol used in example 35.

Stage A. 11-beta-[4-[(4-Chlorobutyl)oxy]phenyl]-östra-4,9-diene - 3,17-dione.

Work on the technique of stage A of example 8, on the basis of 11-beta/4 oksifenil/-östra-4,9-diene-3,17-dione and 1.04 cm31-bromo-4-chlorobutane. Obtain 630 mg of the target product. So pl. 194oC.

Stage B. 3-hydroxy-11-beta-[4-[(4-Chlorobutyl)oxy]phenyl]-östra 1,3,5/10-triene-17-one.

Work by the method of stages B and C of example 3, according to 1.35 mg of product obtained in stage A above, using 1.4 cm3acetic anhydride and 0.7 cm3acetylproline. Obtain 1.48 g of the target product.

Stage 11-beta-[4-[(4-Chlorobutyl)oxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage D of example 3, on the basis of 1.48 g of the product obtained above, using 60 mg of Bromhead sodium. Get after chromatographia product. So pl. 194oC.

Stage D. 11-beta-[4-[(4-Iodobutyl)oxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage D of example 8, on the basis of 890 mg of the product obtained above 600 mg of sodium iodide and 10 cm3methyl ethyl ketone. Obtain 1.19 g of the target product

Stage E. 11-beta-[4-[(4-Diacetyl)butyl]oxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage E of example 8, on the basis of 1.18 g of the product obtained in stage D, and 460 mg of thioacetate potassium. Obtain 850 mg of the target product. So pl. = 90oC.

Stage 36. 11-beta-[4-[4-[(4,4,4-Tryptophanyl)thio]butylochki] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage F of example 8, on the basis of 317 mg of 4,4,4-Cryptor-1-iodobutane and 410 mg of thioacetate, obtained as described in preparation 35. Get 335 mg of the target product.

IR spectrum (CHCl3):

OH: 3615 cm-1.

Aromatics: 1610, 1579, 1512, 1501 cm-1.

Stage 37. 11-beta-[4-[5-[(4,4,4-Trifloromethyl)thio]pentyloxy] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage F of example 8, on the basis of 393 mg of 4,4,4-Cryptor-1-iodobutane and 784 mg thioacetate obtained during preparation of example 28. Obtain 640 mg of zelenog the .

Example 38. 11-beta-[4-[6-[(4,4,4-tripcomputer]thio]hexyloxy]- phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage F of example 8, on the basis of 262 mg of 4,4,4-Cryptor-1-iodobutane and 523 mg of thioacetate obtained in stage E of example 8. Obtain 380 mg of the target product.

IR spectrum (CHCl3):

OH: 3602 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

Example 39. 11-beta-[9-[(4,4,5,5,5-pentafluorophenyl] thio]nonyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Dissolve 446 mg of triphenylphosphine in 2 cm3of methylene chloride, cooled to 10oC, was added 116 mg of imidazole, stirred for 15 min, add 431 mg iodine, stirred for 30 min, added to 0.21 cm34,4,5,5,5-pendaftar-2-penten-1-ol, stirred for 4 h at room temperature, washed the organic phase aqueous saturated sodium thiosulfate solution and get methylenchloride a solution of 4,4,5,5,5-pentatriacontane used as such in the subsequent syntheses. Work on the technique of stage F of example 8, on the basis of 618 mg thioacetate obtained below 7 cm3methanol and methylenechloride solution iodirovannoi derivative obtained above. Obtain 1.2 g of the target product.

IR spectrum (CHCl3):

OH: 3601 shotonline 11-beta-[9-/acetylthio/nonyl] -östra 1,3,5/10/- triene-3,17-beta-diol of example 39.

Stage A. [(9-bromanil)oxy]dimethyl-[(1,1-dimethyl)ethyl]silane

Cooled to 0oC 443,5 g Bronnaya at 2090 cm3of methylene chloride, 314 cm3of triethylamine and 4,58 g dimethylaminopyridine. Added over 25 min 318 g of tert-butyldimethylsilyloxy dissolved in 586 cm3of methylene chloride. Stirred for 17 h, filtered, the solvent is evaporated, the residue is treated with hexane, washed with 0.1 G. of aqueous solution of hydrochloric acid, then with salt water. The solvent is evaporated and obtain 620 g of crude product which is distilled and collected 570 g of pure product (so Kip. 110-130oC when to 0.15-0.20 mbar).

Stage B. 11-beta-[9-Oxiranyl]östra-4,9-diene-3,17-dione.

Cooled to 0o/+2oC 5.2 cm3solution of the magnesium compound (0.42 mol/l), obtained from the product of stage A, and 2.3 cm3tetrahydrofuran (THF). Add 30 mg of copper chloride, stirred for 30 min, cooled to -30oC and added 330 mg of 3-Ethylenedioxy-5/10/ -, epoxy-variety-9/11/-EN-17-she dissolved in 2 cm3of tetrahydrofuran, and stirred for 45 minutes Add 6 cm3hydrochloric acid and stirred for 2 h at room temperature. Poured into aqueous saturated sodium bicarbonate solution, extracted with etelaat (eluent: ethyl acetate-cyclohexane 6-4), get 192 mg of the target product.

Stage 11-beta-[9-(4-Methylbenzenesulfonate)nonyl]östra-4,9-diene-3,17-dione.

Stirred for 1.5 h 13,35 g of the product obtained as described in stage B, 65 cm3pyridine, of 12.33 g tosyl-chloride and 0,573 g dimethylaminopyridine. Poured into water, extracted with ethyl acetate, washed with salt water, dried, the solvent is evaporated, chromatografic the residue on silica (eluent: ethyl acetate-cyclohexane 4-6) and get to 11.79 g of the target product.

Stage d 3-hydroxy-11-beta-[9-(4-Methylbenzenesulfonate)nonyl]östra 1,3,5/10/ triene-17-one.

Work by the method of stages B and C of example 3, on the basis of 11,09 g dienone obtained in stage C above. Obtain 9.6 g of crude product which is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane 3-7). Get 9,48 g of the target product.

Stage E. 11-beta-[9-(4-Methylbenzenesulfonate)nonyl]östra 1,3,5/10/- triene-3,17-beta-diol.

Work on the technique of stage D of example 3, based on 889 mg of product obtained in stage D, and obtain 890 mg of the target product.

Stage F. 11-beta-[9-/Acetylthio/nonyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage E of example 8, eluent: ethyl acetate-cyclohexane 3-7) receive 636 mg of the target product.

IR spectrum (CHCl3):

OH: 3602 cm-1< / BR>
Aromatics: 1610, 1584, 1499 cm-1.

Example 40. 11-beta-[4-[2-[2-[(4,4,5,5,5-pentafluorophenyl)thio]-ethoxy]-ethoxy] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage F of example 8, from 194 mg 4,4,5,5,5-pentatriacontane obtained in example 8, and 313 mg of thioacetate obtained above. Obtain 330 mg of the target product.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1584, 1512 cm-1< / BR>
The 11-beta-[4-[2-[2-(acetylthio)ethoxy] ethoxy] phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

Stage A. 2-[2-[[1,1-Dimethylethyl)dimethylsilane]oxy]ethoxy]- ethanol.

Add 20 g of diethylene glycol to 9,07 g of sodium hydride in 320 cm3of tetrahydrofuran, stirred for 45 min, added to 28.3 g of dimethyldichlorosilane, stirred for 3 hours, leaving at room temperature. Extracted with ether, washed with aqueous sodium bicarbonate solution, salt water, dried and the solvent is evaporated. Get 40,25 g of the target product.

Stage B. [2-(2-Bromoethoxy)ethoxy](1,1-dimethylethyl)dimethylsilane.

Added for 15 min at -15o/-20oC 18,2 g chetyrehpostovye carbon to the mixture, steriade the ri -15oC, the solvent is evaporated, treated with pentane, stirred at room temperature, filtered off, washed with pentane and dried at 50oC under reduced pressure.

Get the 10.1 g of the target product (i.e Kip. 58oC/0,04 mbar).

Stage 11-beta-[4-[2-[2-[[(1,1-Dimethylethyl)-dimethylsilane] oxy]-ethoxy]ethoxy]phenyl]-östra-4,9-diene-3,17-dione.

Give 412 mg of the product obtained at stage B, in solution in 2 cm3of dimethylformamide to 362 mg of a mixture of 362 mg of 11-beta/4 oksifenil/-4,9-östra-diene-3,17-dione, 4 cm3of dimethylformamide and 55 mg of sodium hydride. Stirred for 3 h at room temperature, add aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with salt water, dried and the solvent is evaporated. After chromatography on silica (eluent: ethyl acetate-petrol (G-6-4) receive 400 mg of the target product.

Stage D. 11-beta-[4-[2-(2-Acetoxy)ethoxy] phenyl]-östra-4,9 - Dien-317-dione.

Add 1.3 cm32n. hydrochloric acid to 740 mg of the product obtained in stage C, in solution in 8 cm3of methanol. Stirred for 1 h, the solvent is evaporated, treated with ethyl acetate, washed with aqueous sodium bicarbonate solution, the salt in eventality)oxy]ethoxy] ethoxy] phenyl]östra-4,9-diene-3,17-dione.

To 690 mg of the product obtained in stage D, 5 cm3pyridine was added 320 mg of Teilhard and 70 mg of dimethylaminopyridine, then again 2 times 115 mg taillored. Stirred for 2.5 h, acidified with 6N. hydrochloric acid, extracted with ethyl acetate, washed with aqueous sodium bicarbonate solution, salt water, dried and the solvent is evaporated under reduced pressure, chromatografic the residue on silica (eluent: ethyl acetate-petrol G7-3, then ethyl acetate).

Obtain 710 mg of the target product.

Stage F. 3-Hydroxy-11-beta[4-[2-[2-[[(4-methylbenzenesulfonyl)oxy] -ethoxy]ethoxy]phenyl]-östra 1,3,5/10/-triene-17-one.

Work on techniques of stages B and C of example 3, on the basis of 705 mg dienone obtained in stage E earlier. Receive 785 mg of the target product.

Stage G. of 11-beta-[4-[2-[3-[4-Methylbenzenesulfonyl)oxy]ethoxy] -ethoxy] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage D of example 3, on the basis of 785 mg of the product obtained in stage F above, receive 434 mg of the desired product after chromatography on silica (eluent: ethyl acetate-petrol G 6-4).

Stage H. 11-beta-[4-[2-[2-(acetylthio)ethoxy] ethoxy] phenyl] - östra 1,3,5/10/-triene-3,17-beta-diol.

Work on meatpole chromatography on silica (eluent: ethylacetate G 6-4) 325 mg of the target product.

IR spectrum (CHCl3):

OH: 3601 cm-1.

S-C=0: 1689 cm-1.

Aromatics: 1610, 1583, 1512 cm-1.

Example 41. 11-beta[4-[5-[(3,3,4,4,4- Pentafluoroethyl)thio]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Mix 589 mg mercaptan obtained by the method of phase Ba example 6, 790 mg 3,3,4,4,4-pentafluorobutane (obtained as described for pentatriacontane in example 8), 820 mg of cesium carbonate and 6 cm3of dimethylformamide. Heated 1 h at 50oC, cooled to room temperature, acidified with 2n. hydrochloric acid, extracted with ethyl acetate, washed with salt water and the solvent is evaporated. After chromatography on silica (eluent: petrol G-ethyl acetate 6-4) to obtain 360 mg of the target product.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1582, 1512 cm-1.

Example 42. 11-beta[4-[6-[(3,3,4,4,4- Pentafluoroethyl)thio]hexyloxy] phenyl]östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 41, on the basis of 540 mg of the corresponding mercaptan (obtained as described in example 6), 700 mg iodine reagent and 730 mg of cesium carbonate. Get 247 mg of the target product.

IR spectrum (CHCl3):

OH: 3608 cm-1testwuide source diol, containing chain with a sulfur-containing group at position 11, and metaperiodate sodium, receive the products of examples 43 - 53.

Example 43. 3,7-Dihydro-7-[2-[[5-[4-(3,17-beta-deoxy - östra 1,3,5/10/-trien-11-beta-yl)phenoxy] pentyl]sulfinil]ethyl]- 1,3-dimethyl-1H-purine-2,6-dione.

IR spectrum (CHCl3):

OH: 3605 cm-1.

C=O: 1704, 1657 cm-1.

Conjugated system + aromatics: 1608, 1581, 1551, 1512 cm-1.

S _ 0 1031 cm-1.

Example 44. 11-beta[4-[6-[(4,4,4- Trifloromethyl)sulfinil]hexyloxy] phenyl]-östra 1,3,5/10/-triene-3,17 - beta-diol.

IR spectrum (CHCl3):

OH 3604 cm-1.

Aromatics: 1610, 1581, 1512 cm-1.

S _ 0 1031 cm-1.

Example 45. 11-beta[4-[5-[(4,4,4- Trifloromethyl)sulfinil]pentyloxy] phenyl]-östra 1,3,5/10/-triene-3,17 - beta-diol.

IR spectrum (CHCl3):

OH: 3607 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

1030 cm-1.

Example 46. 11-beta[4-[6-[(2,2,2- Triptorelin)sulfinil]hexyloxy]phenyl]-östra 1,3,5/10/-triene-3,17 - beta-diol.

IR spectrum (CHCl3):

OH 3602 cm-1+ associated.

Aromatics: 1610, 1581, 1512 cm-1.

S _ 0 1044 cm-1.

Example 47. 11-beta[4-[4-[(4,4,
OH 3603 cm-1.

Aromatics: 1610, 1581, 1512 cm-1.

S _ 0 1030 cm-1.

Example 48. 11-beta-[4-[4-[(4,4,5,5,5- Pentafluorophenyl)sulfinil]butylochki]phenyl]-östra 1,3,5/10/-triene-3,17 - beta-diol.

IR spectrum (CHCl3):

OH 3598 cm-1.

Aromatics: 1610, 1584, 1512 cm-1.

S _ 0 1031 cm-1.

Example 49. 11-beta-[4-[5-(Pentasulfide)pentyloxy] phenyl] - östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3605 cm-1.

Aromatics: 1610, 1581, 1512 cm-1.

S _ 0 1020 cm-1.

Example 50. 11-beta-[9-[(4,4,5,5,5- (Pentafluorophenyl)sulfinil]nonyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3598 cm-1.

Aromatics: 1614, 1608, 1580, 1499 cm-1.

S _ 0 1020 cm-1< / BR>
Example 51. 11-beta-[4-[5-[(3,3,4,4,4- (Pentafluoroethyl)sulfinil]pentyloxy]phenyl]-östra 1,3,5/10/- triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH: 3596 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

Example 52. 11-beta-[4-[6-[(3,3,4,4,4-pentafluoroethyl)sulfinil]- hexyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3506 cm-1.

Aromatics: 1610, 1580, 151-ethoxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3606 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

S _ 0 1044 cm-1.

Work according to the method of example 9a, from 183 mg of the product obtained as described in example 34, and 172 mg portaliou acid, a product of examples 54 and 55.

Example 54. 11-beta-[4-[5-[7-(Trifluoromethyl)-4-chinoline]- sulfinil]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3602 cm-1+ associated.

Aromatics + heterocycle: 1610, 1583, 1511 cm-1.

S _ 0 1056 cm-1.

Example 55. 11-beta-[4-[5-[7-(Trifluoromethyl)-4-chinoline]- sulphonyl]pentyloxy]phenyl]-extra-1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3604 cm-1+ associated.

Aromatics + heterocycle: 1610, 1583, 1511 cm-1.

SO21336 /square/ and 1160 cm-1.

Example 56. 11-beta-[4-[5-[(4,4,4-Trifloromethyl)sulphonyl] pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Give 255 mg of meta-chloroperbenzoic acid in 250 mg of diol obtained by the method of example 37 6 cm3of methylene chloride, cooled to +4oC. Stirred for 45 min, add sodium thiosulfate, then the solution bikalutamid petrol G 6-4), obtain 210 mg of the target product.

IR spectrum (CHCl3):

OH 3604 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

SO2: 1309 and 1136 cm-1.

Working according to the method of example 56, using the appropriate source diol containing chain with a sulfur-containing group at position 11, and meta-chloroperbenzoic acid, receive the products of examples 57-67.

Example 57. 11-beta-[4-[6-[(4,4,4-Trifloromethyl)sulfonyl] hexyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3602 cm-1.

Aromatics: 1610, 1581, 1512 cm-1.

SO2: 1306 and 1135 cm-1.

Example 58. 11-beta-[4-[4-[(4,4,5,5,5-Pentafluorophenyl)sulfonyl] butylochki]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH 3605 cm-1.

Aromatics: 1610, 1582, 1512 cm-1.

SO2: 1305 and 1132 cm-1.

Example 59. 11-beta-[4-[4-[(4,4,4-Trifloromethyl)sulfonyl) butylochki]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH/NH complex acquisitions.

Aromatics: 1610, 1580, 1511 cm-1.

SO2: 1296 and 1134 cm-1.

Example 60. 11-beta-[4-[4-(Peterculter)pentyloxy] the dryer is ICA: 1610, 1584, 1512 cm-1.

SO2: 1297 and 1130 cm-1.

Example 61. 11-beta-[9-[(4,4,5,5,5-Pentafluorophenyl)sulfonyl) nonyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH: 3601 cm-1.

Aromatics: 1609, 1584, 1500 cm-1.

SO2: 1309 and 1134 cm-1.

Example 62. 11-beta-[4-[5-[(3,3,4,4,4-Pentafluoroethyl)sulfonyl]- pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH: 3596 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

Example 63. 11-beta-[4-[6-[(3,3,4,4,4-Pentafluoroethyl)sulfonyl]- hexyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1580, 1512, 1504 cm-1.

SO2: 1298 and 1134 cm-1.

Example 64. 11-beta-[4-[2-[2-[(4,4,5,5,5-Pentafluorophenyl) sulfonyl]ethoxy]phenyl]-östra 1,3,5/10/-Trient-3,17-beta-diol.

IR spectrum (CHCl3):

OH: 3600 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

SO2: 1317 and 1129 cm-1.

Example 65. 11-beta-[4-[5-[(7-(Trifluoromethyl)-4-chinoline] sulfinil]pentyloxy]phenyl]-östra 1,3,5/10/-Trient-3,17-beta-diol.

This product is identical with the product, aromatica: 1610, 1583, 1511 cm-1.

S _ 0 1056 cm-1.

Example 66. 3-hydroxy-11-beta-[4-[5-[(4,4,5,5,5-Pentafluorophenyl) sulfinil] pentyloxy] phenyl] -östra 1,3,5/10/-Trient-3,17-beta-yl - butenedioate and sodium salt.

a/ Obtaining acid.

Stirred for 4 h at 120oC 380 mg of the product obtained in example 31, 355 mg of succinic anhydride, 40 mg dimethylaminopyridine and 4 cm3pyridine. Allow to cool to room temperature, was added 4 cm3methanol, 4 cm3water and 650 mg of potassium carbonate. Stirred for 6.5 h, cooled to 4oC, acidified with hydrochloric acid, extracted with ethyl acetate, washed with salt water, dried and evaporated solvents. After chromatography on silica (eluent: petrol G - acetone 5-5), receive 400 mg of acid.

IR spectrum (CHCl3):

OH 3600 cm-1+ absorption common type OH acid.

C=O: 1717 cm-1+ complex.

Aromatics: 1610, 1585, 1512 cm-1.

b/ Receiving of salt.

Dissolve 367 mg of the acid obtained above, 4 cm3ethanol was added 36 mg of sodium bicarbonate, dissolved in 4 cm3water, stirred for 30 min, the ethanol is evaporated, add 20 cm3water, filtered, then lyophilizer. Collect the phenyl]-östra 1,2,5/10/-trien-17-beta Il - butenedioate and its sodium salt

Work according to the method of example 66, from 290 mg of the product of example 32, obtain 285 mg of the product in the form of acid.

IR spectrum (CHCl3):

OH: 3598, 3518 cm-1+ the total absorption.

C=O: 1716 cm-1.

Aromatics: 1610, 1582, 1512 cm-1.

SO2: 1304, 1133 cm-1.

Transferred to salt 273 mg of the acid, the result is 235 mg of crude product, given that he is purified by chromatography on silica (eluent: methanol-water 8-2).

Example 68. 3 Cyclopentyloxy-11-beta-[4-[5-[4,4,5,5,5- Pentafluorophenyl)sulfinil]pentyloxy]phenyl]-östra 1,2,5/10/-trien - 17-beta-ol.

Stirred for 30 min to 1 g of the product obtained in example 31, 8.7 cm3of dimethylformamide and 82 mg of sodium hydride. Then add 486 mg cyclopentyl-methylbenzenesulfonate, stirred for 5 h, poured into aqueous ammonium chloride, extracted with ethyl acetate, washed with salt water, dried and the solvent is evaporated. Chromatografic the residue on silica (eluent: methylene chloride-isopropanol 95-5) and get 861 mg of product, which is crystallized from a mixture of methylene chloride/ethyl ether, collected 777 mg of the target product. So pl. 189oC.

IR spectrum (CHCl3):

OH 3608 cm

Stirred for 3 h at room temperature, 1 g of Cyclopentanone, 23 cm3pyridine, 4.42 g of Teilhard and 195,8 mg 4-dimethylaminopyridine, pyridine is evaporated, poured into water, extracted with ethyl acetate, washed with molar aqueous solution of hydrochloric acid, then the salt water and saturated aqueous sodium bicarbonate. Evaporate the solvent, dissolve in methanol, again add sodium bicarbonate, evaporated, chromatografic the residue on silica (eluent: ethyl acetate-petrol G 1-9) and gain of 1.41 g of the target tosilata.

Example 69: 3 Cyclohexyloxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl) sulphonyl]pentyloxy]phenyl]-östra 1,3,5/10/-trien-17-beta-ol.

Work according to the method of example 56, using 698 mg of the product obtained in example 68, and 228 mg of meta-chloroperbenzoic acid, receive 567 mg of the target product. So pl. 166oC.

IR spectrum (CHCl3):

OH 3608 cm-1< / BR>
Aromatics: 1610, 1580, 1512, 1498 cm-1< / BR>
Example 70: 3 Cyclopentyloxy-11-beta-[4-[5-[(4,4,5,5,5 -pentafluorophenyl)sulphonyl] pentyloxy]phenyl]-östra 1,3,5/10/ -trien-17-beta-albumedit and its sodium salt.

Works by the method of example 66, from 384 mg of the product obtained by the method of example 68, Polo">

IR spectrum (CHCl3)

C=O: 1716 cm-1< / BR>
Aromatics: 1610, 1580, 1572, 1512, 1498 cm-1< / BR>
Transferred to salt 285,5 mg of the obtained acid, obtain 295 mg of the target product after lyophilization.

IR spectrum (CHCl3):

OH/NH: the total absorption.

C=O: 1724 cm-1< / BR>
Aromatics: 1609, 1510, 1498 cm-1< / BR>
COO-1578 cv-1.

Example 71: 3-hydroxy-11-beta-[4-[5-[(4,4,5,5,5, -Pentafluorophenyl)thio]-pentyloxy]phenyl]-östra 1,3,5/10/-trien-17-beta-he.

Stage A: 3-Hydroxy-11-beta-[4-[(5-iopentol)oxy] phenyl]-östra-1,3,5,-/10/-triene-17-one.

Work on the technique of stage D of example 8, using 14.9 g of the product obtained by the method of example 3C. Gain of 13.2 g of the target product. Rf= 0,18 (cyclohexane-ethyl acetate 7-3).

Stage B. 3-Hydroxy-11-beta-[4-[[5-(diacetyl)pentyl]oxy]phenyl]-östra 1,3,5/10/triene-17-one.

Work on the technique of stage E of example 8, using of 13.2 g of the product obtained in stage A. Obtain 9 g of the target product. Rf= 0,58 (cyclohexane-ethyl acetate 7-3).

Stage C: 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl)thio]-pentyloxy]phenyl]-östra 1,3,5/10/triene-17-one.

Work on the technique of stage F of example 8, using 9 g of the product obtained in stage B. Get 8,6 afterparty)sulfinil] pentyloxy]phenyl]-östra 1,3,5/10/ -triene-17-one.

Work according to the method of example 9, using 180 mg of the product obtained in example 71. Receive 120 mg of the target product. R=0,37 (methylene chloride-methanol 95-5).

Example 73: 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5 -pentafluorophenyl)-sulphonyl] pentyloxy]phenyl]-östra 1,3,5/10/-triene-17-one.

Work according to the method of example 56, using 180 mg of the product obtained in example 71, and 162 mg of meta-chloroperbenzoic acid. Obtain 160 mg of the target product.

Example 74: 17-Methylene-11-beta-[4-[5-[(4,4,5,5,5 -pentafluorophenyl)-sulphonyl]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3-ol.

Add 500 mg of the product obtained in example 73, a mixture consisting of 815 mg methyltriphenylphosphonium, 5 cm3dioxane and 125 mg of sodium methylate. Stirred for 16 h at room temperature, add 100 cm3an aqueous solution of ammonium chloride, extracted with methylene chloride, dried, remove the solvent under reduced pressure, chromatografic the residue on silica (eluent: cyclohexane-ethyl acetate 7-3). Receive 80 mg of the target product.

IR spectrum (CHCl3):

Little or C=0.

OH: 3596 cm-1.

C=C: 1656 cm-1.

Aromatics: 1610, 1580, 1512 cm-1.

Example 75. 17-beta-(Oxymethyl)-11-br>oC 60 mg of the product obtained in example 74, ... cm3of tetrahydrofuran and add 100 ál of sulfide Dimethylbutane. Stirred for 2 h at room temperature, cooled to 0oC, add 200 ál of sodium hydroxide, then 200 μl of 30% hydrogen peroxide. Allowed to warm to room temperature, then acidified with hydrochloric acid. Extracted with methylene chloride, dried to remove the solvent, chromatografic the residue on silica (eluent: ethyl acetate-cyclohexane 3-7) obtain 35 mg of the target product.

IR spectrum (CHCl3):

OH phenolic: 3590 cm-1.

Aromatics: 1610, 1580, 1511 cm-1.

C=C or C=O conjugated 1660 cm-1.

Example 76. The oxime of 3-hydroxy-11-beta-[4-[5-[(4,4,5,5,5 -pentafluorophenyl)sulphonyl]pentyloxy]phenyl]östra 1,3,5/10/-triene-17-it.

To 1 g of the product obtained in example 73, add a mixture consisting of 30 cm3ethanol and 5 cm3water, then 320 mg hydrochloric acid hydroxylamine and 501 of sodium acetate. 2 hours and refluxed, add 50 cm3water, extracted with methylene chloride, dried, remove the solvent under reduced pressure, the residue is crystallized from isopropyl ether, filtered, chromatographer the IR spectrum (CHCl3):

OH: 3593 cm-1+ associated.

Aromatics: 1610, 1582, 1512 /square/ cm-1.

Example 77. The hydrazone of 3-hydroxy-11-beta[4-[5-[(4,4,5,5,5 -pentafluorophenyl)sulphonyl]pentyloxy]phenyl]-östra 1,3,5/10/-triene-17-it.

Add 100 μl of hydrazine hydrate is added and 3 mg of para-toluensulfonate acid to 300 mg of the product obtained in example 73, to 3 cm3of methanol. Stirred for 16 h at room temperature, add 50 cm3an aqueous solution of sodium bicarbonate, extracted with methylene chloride, the solvent is evaporated, chromatografic the residue on silica (eluent: ethyl acetate), to obtain 190 mg of the target product.

IR spectrum (CHCl3):

OH: 3599 cm-1.

NH2: 3395 cm-1.

C=N and aromatics: 1610, 1588, 1512, 1503 cm-1.

Example 78. 11-beta-[4-[5-[(4,4,5,5,5 -Pentafluorophenyl)sulfonyl]-pentyloxy]phenyl]-17-alpha-methylestra-1,3,5/10/ -triene-3,17-beta-diol.

Dehydration for 2 h at 180oC under reduced pressure heptahydrate cesium chloride, allowed to cool down, enter 1.5 g 15 cm3of tetrahydrofuran, stirred for 1 h, was added at -60oC 4 cm3metallice dissolved in 1.5 M simple ether, stirred for 30 min, cooled to -78othe EOS ammonium chloride, extracted with methylene chloride, the solvent is evaporated, chromatografic the residue on silica (eluent: cyclohexanediacetic 7-3), obtain 198 mg of 17-methyl derivative. Work according to the method of example 56, on the basis of 198 mg of the product obtained above, and 150 cm3meta-chloroperbenzoic acid, to obtain 62 mg of the target product. Rf= 0,37 (cyclohexane-ethyl acetate 1-1).

Example 79. 3-(Cyclopentyloxy)-11-beta-[4-[5-[(4,4,5,5,5- pentafluorophenyl)sulphonyl]pentyloxy]phenyl]-östra 1,3,5/10/- triene-17-one.

Work according to the method of example 68, using 300 mg of the product obtained in example 71, and 170 mg cyclopentyl-4-methylbenzenesulfonate. Extracted with methylene chloride obtained reaction medium, dried, the solvent is evaporated, chromatografic the residue on silica (eluent: ethyl acetate-cyclohexane 3-7) obtain 290 mg of the target product used as such.

Example 80. 3-/Cyclopentyloxy/-11-beta-[4-[5-[(4,4,5,5,5- pentafluorophenyl)sulphonyl] pentyloxy]phenyl]-19-nor-17-alfamega - 1,3-5/10/-triene-20-in-17-beta-ol.

Cooled to -78oC 150 μl of trimethylsilylacetamide 5 cm3of tetrahydrofuran and added dropwise 625 ml n-utility in hexane (1.6 M). Stirred for 30 min, PR is h at room temperature. Add 2 cm31 M solution of tetrabutylammonium in tetrahydrofurane. Stirred for 1 h at room temperature, add 10 cm3water, extracted with methylene chloride, dried and the solvent is evaporated. After chromatography on silica (eluent: cyclohexane-ethyl acetate 7-3), receive 60 mg of the target product.

Example 81. 17-alpha-Ethinyl-11-beta-[4-[5-[(4,4,5,5,5,-Penta - terpentin)thio]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta - diol.

Added 126 mg acetylenic lithium in the form of a complex with Ethylenediamine /Z:-CCH. to 1 g of the product obtained in example 71, 10 cm3of tetrahydrofuran and stirred for 12 h at room temperature. Poured into a saturated solution of ammonium chloride, extracted with methylene chloride, washed with 1N hydrochloric acid, and dried to remove the solvent. After chromatography on silica (eluent: ethyl acetate-cyclohexane 2-8, then methylene chloride-methanol 98-2) obtain 720 mg of the target product, used as such in the following example.

Example 82. 17-alpha-Ethinyl-11-beta-[4-[5-[(4,4,5,5,5-Penta - terpentin)sulphonyl]pentyloxy]phenyl]-östra 1,3,5/10/-triene - 3,17-beta-diol.

Work according to the method of example 56, using 570 mg of the product, the floor is p (CHCl3).

OH: 3598 cm-1.

CCH: 3308 cm-1.

Aromatics: 1610, 1580, 1510, 1502 cm-1.

Example 83. 11-beta-[4-[5-[(Nonattorney)thio]pentyloxy] phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Add in an inert atmosphere, 50 mg of sodium hydride to 466 mg of the product obtained in example 6Ba, dissolved in 10 cm3of dimethylformamide, stirred for 30 min, added to 0.18 cm3performativity, cooled and 15 min irradiated with a mercury lamp. Acidified with 2n hydrochloric acid, extracted with ethyl acetate, washed with water, dried, the solvent is evaporated, chromatografic the residue on silica (eluent:petrol G-ethyl acetate 6-4, then one by ethyl acetate, then methanol-water 9-1). Collect 287 mg of the target product. Rf= 0,24.

IR spectrum (CHCl3):

OH: 3602 cm-1.

Aromatics: 1610, 1583, 1512 cm-1.

Example 84. 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl) sulphonyl] pentyloxy]phenyl]-16-alpha-methylestra-1,3,5/10/- triene-17-one.

Stage A. 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl) thio]pentyloxy]phenyl]-16-alpha-methylestra-1,3,5/10/-triene-17-one.

Cooled to -78oC 500 mg 3 tetrahydropyranyloxy-11-beta- [4-[5-[(4,4,5,5,5-pentafluorophenyl) the min, add 200 mg under the conditions, stirred for 1 h at room temperature, was added a saturated aqueous solution of ammonium chloride, extracted with methylene chloride, dried, the solvent is evaporated, chromatografic the residue on silica (eluent cyclohexane-ethyl acetate 8-2) obtain 280 mg of 16-methyl derivative, to which was added 5 cm3ethanol, then 2 cm3hydrochloric acid, stirred for 3 h at room temperature, was added a saturated solution of ammonium chloride, extracted with methylene chloride, dried and the solvent is evaporated. The remainder chromatographic on silica (eluent: cyclohexane-ethyl acetate 7-3). Receive 150 mg of the target product.

Stage B. 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl) sulphonyl] pentyloxy]phenyl]-16-alpha-methylestra-1,3,5/10/-triene - 17-one.

Cooled to 0oC 100 mg of the product obtained above in 5 cm3of methylene chloride, was added 90 mg of meta-chloroperbenzoic acid, stirred for 1 h at 0oC, was added an aqueous solution of sodium thiosulfate and sodium bicarbonate /1-1/, extracted with methylene chloride, dried, the solvent is evaporated, chromatografic the residue on silica (eluent: cyclohexane-ethyl acetate 7-3), receive 60 mg of product.

Obtaining 3-tetrahydropyranyloxy-11-beta-[4[6[(4,4,5,5,5-pentafluorophenyl)thio] pentyloxy]phenyl]-östra 1,3,5/10/-triene-17-it.

Stirred for 3 h at room temperature, 4 g of 3-hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl)thio] pentyloxy] phenyl]östra 1,3,5/10/-triene-17-she, 40 cm3dioxa and 3 cm3dihydropyran and 100 cm3pair-toluensulfonate acid. Add 100 cm3aqueous saturated solution of sodium bicarbonate, extracted with methylene chloride, dried, the solvent is evaporated, chromatografic the residue on silica (eluent: cyclohexane-ethyl acetate 7-3/ and obtain 4.5 g of the target product.

Work on the technique of stage D of example 3, on the basis of the product obtained in example 84, get the 11-beta[4-[5-[(4,4,5,5,5-pentafluorophenyl)sulphonyl] pentyloxy] phenyl]-16-alpha-methylestra-1,3,5/10/triene-3,17-beta-diol.

Example 85. 11-beta-[4-[5-[(pentafluorophenyl)methylthio]pentyloxy] -phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 6Ba, from 350 mg of the disulfide and 0,19 cm3tributylphosphine. To the solution obtained mercaptan is added to 0.12 cm3alpha-bromo-2,3,4,5,6-pentafluorotoluene and 0.15 cm3of sodium hydroxide. Stirred at 50oC for 40 the spruce, chromatografic the residue on silica (eluent: petrol G-util - acetate 7-3), obtain 227 mg of the target product.

IR spectrum (CHCl3)/

OH: 3598 cm-1.

Aromatics: 1654, 1610, 1580, 1520, 1506 m-1.

Example 86. 11-beta-[4-[5-[[(pentafluorophenyl)methyl]sulfonyl] pentyl]oxy] phenyl]-östra 1,3,5/10/triene-3,17-beta-diol.

Work according to the method of example 56, using 207 mg of the product obtained in example 85, and 169 mg of meta-chloroperbenzoic acid. Obtain 222 mg of the desired product after chromatography on silica (eluent: ethyl acetate-cyclohexane 5-5).

IR spectrum (CHCl3)/

OH: 3603 cm-1.

Aromatics: 1654, 1610, 1580, 1520, 1506 cm-1.

SO2: 1331, 1131 cm-1.

Example 87. 11-beta-[4-[5-[[2-(Pentafluorophenyl)ethyl]thio]pentyloxy]phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol and 11-beta-[4-[5-[(4-ethynyl-2,3,5,6-tetrafluorophenyl)thio]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 6Ba, using 500 mg of the disulfide and 0.27 cm3tri-n-butyldiphenylsilyl. The solution obtained mercaptan treated as described in example 85, using a 0.30 cm31-(2-bromacil)-2,3,4,5,6-pentafluorobenzene. Obtain 420 mg of the desired product in the form of cm is Nol.

Heated to boiling under reflux 2.5 g of 2,3,4,5,6-panafcortelone acid in 25 cm3tetrahydrofuran (THF) in the presence of complex borohydride-dimethyl sulfide. Cool, slowly poured into ice water, add an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with water, dried and the solvent is evaporated. Obtain 2.24 g of the target product.

Stage B. 1-(2-Bromacil)-2,3,4,5,6-pentafluorobenzoyl.

Dissolve 2,225 g of the alcohol obtained in stage A, 21.5 cm3of methylene chloride, cooled to -20oC, added 4.35 g tetrabromomethane and 3,44 g of triphenylphosphine. Stirred at +4oC for 4 h, the solvent is evaporated, the residue is treated with pentane, stirred, filtered, washed insoluble product with pentane, combine the filtrate and the solvent is evaporated under reduced pressure. Get up 3.22 g of the target product.

Example 88. 11-beta-[4-[5-[[2-(Pentafluorophenyl)ethyl]sulphonyl] pentyloxy] phenyl] -östra 1,3,5/10/-triene-3,17-beta-diol and 11-beta-[4-[5-[(4-ethynyl-2,3,5,6-tetrafluorophenyl)sulfinil] pentyloxy] phenyl]-extra-1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 56, using 420 mg of the mixture obtained in example 87, and 346 mg of meta-PI(eluent: ethyl acetate-cyclohexane 5-5, then the acetone-methylene chloride 1-9) obtain 84 mg pentafluorophenol derived and 201 mg tetraterpenes derived.

IR-spectrum (CHCI3):

Pentafluoropropane derived

OH3602 cm-1.

Aromatics: 1656, 1610, 1580, 1522, 1508 cm-1.

SO21323 cm-1< / BR>
Tetraterpene derived

OH3600 cm-1.

C=C: 1648 cm-1.

Aromatics: 1610, 1578, 1512, 1478 cm-1(F).

S _ 0 1055 cm-1< / BR>
Example 89. 11-beta-[4-[5-[3-(Pentafluorophenyl)propyl]thio]pentyloxy]phenyl] - östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 85 using 500 mg of the disulfide obtained by the method of example 6Ba, then 2 cm3methylenechloride solution of 3-improvedperformance. Receive 472 mg of the target product.

IR-spectrum (CHCI3).

OH 3598 cm-1.

Aromatics: 1655, 1610, 1580, 1521, 1504 cm-1.

Obtaining 3-improvedperformance.

Stage A. (2,3,4,5,6-Pentafluorobenzoyl)-propionic acid.

Add 971 mg of rhodium-chloro-Tris-triphenylphosphine to a solution containing 2.5 g of 2,3,4,5-panafcortelone acid, 34 cm3ethanol and 34 cm3toluene, then miss waters is lorida, extracted with aqueous 1N. the sodium hydroxide solution, washed with methylene chloride, acidified with hydrochloric acid, extracted with methylene chloride, dried and the solvent is evaporated under reduced pressure. Crystallized residue from cyclohexane, gain of 2.06 g of the target product.

Stage B. 3-(Pentafluorophenyl)-propanol.

Work as in the preparation of example 87, step A, using 1,99 g of the acid obtained above, and 2.4 cm3complex borohydride-dimethyl sulfide. Get 1,89 g of crude desired product, which chromatographic on silica (eluent: ethyl acetate cyclohexane 4-6).

Stage C. 3-Improvedperformance.

Cooled to +10oC 356 mg of triphenylphosphine in 2 cm3of methylene chloride, was added 95 mg of imidazole, stirred for 15 min, cooled to 0oC, add 357 mg iodine, stirred for 30 min and allowed to warm to room temperature, add 315 mg of the alcohol obtained in stage B, stirred for 4 h and filtered. Washed methylenchloride a solution of 0.2 N. aqueous solution of sodium thiosulfate, then with water, get methylenechloride solution of the target product, used as such in example 89.

Example 90. 11-beta-[4-[5-[3-(Pentafluorophenyl)propels the UYa 451 mg of the product, obtained in example 89, and 365 mg of meta-chloroperbenzoic acid. Obtain 305 mg of the desired product after chromatography on silica (eluent: ethyl acetate-cyclohexane 6-4) and crystallization from ethanol. So pl. 130oC.

IR-spectrum (Nujol):

The area of the complex absorption OH.

Aromatics: 1659, 1610, 1580, 1522, 1510, 1501 cm-1.

SO2: 1358, 1130 cm-1.

Example 91. 11-beta-[4-[5-[[2,3,5,6-Titrator-4-(trifluoromethyl)- phenyl] methylthio]pentyloxy]phenyl]-östra 1,3,5/10/-triene-3,17-beta-diol.

Work according to the method of example 85 using 500 mg of the disulfide obtained by the method of example 6Ba, then 857 mg bromo-alpha, alpha, alpha-2,3,5,6-heptathlon-p-xylene. Obtain 259 mg of the target product.

IR-spectrum (CHCI3):

OH: 3600 cm-1.

Aromatics: 1664, 1610, 1578, 1512, 1500 cm-1.

Getting bromo-alpha, alpha, alpha-2,3,5,6-heptathlon-n-xylene.

Refluxed with 2 g of alpha, alpha, alpha-2,3,5,6-heptathlon-n-xylene 7.4 cm3carbon tetrachloride in the presence of 15 mg of azoisobutyronitrile and added within 30 min of 1.53 g of N-bromosuccinimide, then continue to boil under reflux for 96 hours Cooled, filtered, viparis is as such in example 91.

Example 92. 11-beta-[4-[[5-[[2,3,5,6-Titrator-4-(trifluoromethyl)-phenyl]methyl]sulphonyl] pentyloxy]phenyl]-östra 1,3,5/10/-triene-3-17-beta-diol.

Work according to the method of example 56, using 241 mg of the product obtained in example 91, and 193 mg of meta-chloroperbenzoic acid. Obtain 161 mg of the desired product after chromatography on silica (eluent: ethylacetate-cyclohexane 5-5).

IR-spectrum (CHCI3):

OH: 3610 cm-1.

Aromatics: 1622, 1611, 1578, 1511, 1504 cm-1.

Area CF3+ SO2: 1336 cm-1.

Example 93. 3,17-Diacetate 11-beta-[9-[(4,4,5,5,5-pentafluorophenyl)-sulfonyl]nonyl]-östra 1,3,5/10/- triene-3,17-beta-diol.

Stirred for 45 min at room temperature 3,39 g of the product obtained in example 61, 16.6 cm3pyridine, 3,14 cm3acetic anhydride and 154 mg of dimethylaminopyridine. Add 5.4 cm3methanol, stirred for 10 min, evaporated the solvent, is treated with ethyl acetate, washed with 1M aqueous solution of hydrochloric acid, then sodium chloride, dried and the solvent is evaporated. After chromatography on silica (eluent: ethyl acetate-cyclohexane 5-5, then 3-7) obtain 3.25 g of the target product.

IR-spectrum (CHCI3)

C=O: Max. 1725 with/SUP>.

Example 94. 17-Acetate 11-beta-[9-[(4,4,5,5,5-pentafluorophenyl)sulfonyl] nonyl]-östra 1,3,5/10/- triene-3,17-beta-diol.

Cooled to 0oC of 1.37 g of the diacetate obtained in example 93, 27.5 cm3methanol with 10% water and give 203 mg of potassium bicarbonate, allowed to warm to room temperature and stirred for 19 hours Poured into 220 cm3water, supplemented 55 cm30.1 G. of hydrochloric acid, extracted with ethyl acetate, dried and the solvent is evaporated. Obtain after chromatography on silica (eluent: ethyl acetate-cyclohexane 35-65) and crystallization of the residue from a mixture of methylene chloride/isopropyl ether 973 mg of the target product. So pl. 130oC.

IR-spectrum (CHCI3):

OH3600 cm-1+ associated

OAC: 1724, 1252 cm-1.

Aromatics: 1611, 1585, 1498 cm-1.

SO2: 1308, 1134 cm-1.

Example 95. Acetate-3-methoxy-11-beta-[9-(4,4,5,5,5-pentafluorophenyl)sulfonyl]nonyl]- östra 1,3,5/10/-trien-17-beta-ol.

Add 2.9 cm3water to 1.05 g of the phenol obtained in example 94, dissolved in 3.9 cm3acetone, mix, add 0.3 cm3methyl sulfate and 0,83 cm3aqueous 2n solution of sodium hydroxide and stirred for 1 h at room t is sodium, extracted with ethyl acetate, dried, the solvent is evaporated. After chromatography of the residue on silica (eluent: ethyl acetate-cyclohexane 3-7) receive 959 mg of the target product.

IR-spectrum (CHCI3);

C=O: 1723 cm-1,

Aromatics: 1609, 1575, 1500 cm-1.

Example 96. 3,17-Diacetate 11-beta-[4-[5-[(4,4,5,5,5- pentafluorophenyl]thio] pentyloxy]-östra 1,3,5/10/-triene-3,17-beta-diol.

To 200 mg of the product obtained in example 71, dissolved in 2.5 cm3isopropenylacetate, add 0.1 cm3concentrated sulfuric acid dissolved in 2.5 cm3isopropenylacetate. Heated to 97oC, slowly distilled off the mixture of acetone/isopropenylacetate, add again a solution of sulfuric acid and distilled as before. The residue is treated with an aqueous sodium bicarbonate solution and extracted with ether. Dried, the solvent is evaporated and obtain 510 mg of the target product, used as such in the following example.

Example 97. 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl)thio]- pentyloxy]phenyl]-16-alpha-brahmastra-1,3,5/10/-triene-17-one.

To the product obtained in example 96, dissolved in 3 cm3acetic acid is added dropwise a solution containing 0.025 cm3bromine is, add saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, dried, chromatografic the residue on silica (eluent: ethyl acetate-cyclohexane 3-7) and receive 20 mg of the target product.

Example 98. 3-Hydroxy-11-beta-[4-[5-[(4,4,5,5,5-pentafluorophenyl)sulphonyl] pentyloxy]phenyl]-16-alpha-bromo-östra 1,3,5/10/-triene-17-one.

Work according to the method of example 56, using 120 mg of the product obtained in example 97, and 100 mg of meta-chloroperbenzoic acid. Obtain 38 mg of the target product.

IR spectrum (CHCl3):

C=O: 1750 cm-1.

OH: 3595 cm-1.

Aromatics: 1611, 1580, 1512, 1502 cm-1.

SO2: 1305, 1133 cm-1.

Example 99. 11-beta-[4-[5-[(4,4,5,5,5-Pentafluorophenyl)sulfonyl] - pentyloxy]phenyl]-16-alpha-bromo-östra 1,3,5/10/-triene-3,17-beta-diol.

Work on the technique of stage D of example 3, on the basis of the product obtained in example 98, obtain the target product.

Pharmaceutical compositions

To prepare tablets, corresponding to the following formula:

The product of example 5, 50 mg

Excipient (talc, starch, magnesium stearate) to the final weight of the tablet 120 mg

Pharmacological study of the products of the invention.

1. She is Mature females mice at the age of 18-21 days, removed the uterus, then homogenized at 0oC with the help of the device Potter Teflon-glass in a buffer solution TS /10 mm Tris, 0.25 M sucrose, HCl pH 7,4/1 g tissue in 25 ml TS/. Homogen then ultracentrifuged /209000g30 min at 0oC. Incubate aliquots of the thus obtained supernatant liquid at 25oC for 5 h with a constant concentration /T/ titiraupenga estradiol in the presence of increasing concentrations of cold estradiol (0 - 100010-9M) or chilled tested product (1 - 2500010-9M/. Then measure the concentration associated titiraupenga estradiol (B) each incubate technique of absorption of carbon-dextran.

The calculation of the relative affinity of the link (ARL).

Build 2 these curves. The percentage associated titiraupenga hormone B/BO depending on the logarithm of the concentration of the standard cold hormone or depending on the logarithm of the concentration of cold hormone test.

Define direct the following equation:

I50= 100 /B/BO + Bminutes/BO//2 or I50= 100/1 + Bminutes/BO/A/2 = 50/1 + Bminutes/BO/

where

BO = % bind titiraupenga hormone associated in the absence of any cool product.

B = % threat is this hormone, linked in the presence of a large excess of the standard cold hormone /500 nm/.

The intersection of the line I50and curves allows us to estimate the concentration of the standard cold hormone (CH) and cold tested product (CX) which inhibit by 50% the specific binding titiraupenga hormone to the receptor.

The relative affinity of binding (ARL) of the test product is determined by the equation:

ARL = 100(CH)/(CX)

The product of example - 5H Incubation estrogen receptor at 25oC

5 - 21,2

7 - 26,3

32 - 56

60 - 18,2

78 - 21,8

2-Anti-proliferating activity of the products of the invention on the growth of tumor cells in breast cancer MCF-7.

Description experience

and/ Cultivation of cells.

Line MCF-7 support in the culture environment SVF /1/ at 37oC in a humid atmosphere containing 5% CO2. Fused cells are harvested by trypsinization (trypsin 0,05%, EDTA 0,02%), then washed with a mild centrifugation. Sample suspensions of cells counted in the camera Malassezia.

b/ the Study of growth.

Cells re-suspended in the medium DSE (1) are sown from the calculation of 50,000 cells per cell in tablets with many cells (24 cells on CNA concentration in ethanol: 0,1%) at a concentration of 10-11- 10-6M, control cells give the same concentration of ethanol. Environment update every 48 hours At the end of the experiment (j7-j9) the medium is sucked off and the cells immediately fixed with 150 μl of methanol to dispense ADN.

Anti-proliferative activity of the products assessed on their ability to inhibit the increase of ADN.

in/ Dosing ADN.

ADN dispense a fluorimetric method using DABA (3,5-diaminobenzoic acid) (2): add 150 ál of DABA in each cell; the tablets are then incubated for 45 min at 56oC, then add 2 ml of 1N. HCl. Measure the fluorescence using fluorimetry (wavelength of excitation: 408 nm, the wavelength of emission: 510 nm).

The number of ADN on the cell evaluated in relation to the ethanol spectrum obtained when working in the same conditions with a standard ADN calf thymus.

Results.

The concentration in nm), which inhibits by 50% the growth of cells MCF7(IR50) was determined as described below.

The product of example 1 - IC 50 = 0,024 nm

The product of example 5 - IC 50 = 0,012 nm

The product of example 7 - IC 50 = 0,026 nm

The product of example 32 - IC 50 = 0.1 nm

The product of example 60 - IC 50 = 0,25 nm

The product of example 78 - IC 50 = 0,03 nm

1/ Cos is received:

essential amino acids (FLEXIBLE) 1%,

penalties-strepto (penicillin 100 u/ml, streptomycin 0.1 mg/ml),

Fungizone of 0.1%,

glutamine 2 mm,

sodium bicarbonate 2.25 mg/ml

Wednesday SVF consists of 95% of the primary environment and 5% fetal calf serum.

Environment DSE consists of 95% of the primary medium, 5% fetal calf serum, devoid of steroid on carbon-dextran and 10-10M estradiol.

2/ Puzas et Goodman, Analytical Biochemistry, I. 86, 50 C., 1978.

1. Derivatives of 19-norsteroids General formula I

< / BR>
where R17and R17' together form ketogroup, hydrazone, oxime, or a methylene group, or R17the hydroxy - group, alloctype having up to 12 carbon atoms, and R17'is hydrogen, C1- C8-alkyl, ethinyl;

R3is hydrogen, C1- C4linear alkyl, cyclic5- C6-alkyl, acyl having up to 12 carbon atoms;

R16is hydrogen, halogen or C1- C4-alkyl;

m = 0,1 or 2;

X is methylene, phenylene, phenyleneoxy associated with the steroid via a carbon atom;

Y is a saturated or unsaturated linear chain WITH3- C9possibly interrupted by an oxygen atom;

Z - line is butyl, substituted phenyl selected from the group

< / BR>
< / BR>
where q = 1,2 or 3,

or the five-membered heterocycle selected from the group

< / BR>
< / BR>
or six-membered heterocycle selected from the group

< / BR>
< / BR>
< / BR>
or a heterocycle with two condensed cycles selected from the group

< / BR>
< / BR>
provided that when R3is hydrogen, R17the hydroxy - group, R17'ethinyl or hydrogen, X is 4-phenyleneoxy, Y - (CH2)5-, m = 0, then Z may not be the stands.

2. The compounds of formula I on p. 1, wherein R17the hydroxy - group, R17'is hydrogen or methyl.

3. The compounds of formula I on p. 1, wherein X is methylene, Y is a linear unsaturated chain WITH7- C9.

4. The compounds of formula I under item 1 or 2, wherein X is phenylene, Y is a saturated or unsaturated chain WITH3- C8provided that when the chain is unsaturated, it contains vinyl or etinilnoy group associated directly with phenylenebis radical.

5. The compounds of formula I under item 1 or 2, characterized in that the X - phenyleneoxy, Y is a saturated chain WITH4- C7possibly interrupted by an oxygen atom.

6. -pentyloxy] phenyl]-östra-1,3,5(10) -triene-3,17 - diol; 11- [8-[(2-pyridinylmethyl)thio]octyl] -östra-1,3,5(10)- triene-3,17 - diol; 11- [4-[3-[(1-methyl - 1H-imidazol-2-yl)thio] -1-PROPYNYL]phenyl] -östra-1,3,5(10)-triene-3,17 - diol; 11- [4-[5-[(2-furylmethyl)thio] pentyloxy]phenyl] -östra-1,3,5(10)-triene-3,17 - diol; 11- [4-[5-[(3-pyridinylmethyl)sulfinil] pentyloxy]phenyl] - östra-1,3,5(10) -triene-3,17 - diol; 11- [4-[6-[(4,4,5,5,5-pentafluorophenyl) sulfinil] hexyloxy] -phenyl] -östra-1,3,5(10) -triene-3,17 - diol; 11- [4-[5-[(4,4,5,5,5- pentafluorophenyl) sulfonyl] pentyloxy]phenyl] -östra-1,3,5(10) -triene-3,17 - diol; 11- [4-[5-(peterculter) pentyloxy]phenyl] -östra-1,3,5(10) -triene-3,17 - diol; 11- [4-[5-[(4,4,5,5,5- pentafluorophenyl) sulphonyl] pentyloxy]-phenyl] -17-alpha-methylestra - 1,3,5(10)-triene-3,17 - diol.

7. A method of obtaining a 19-norsteroids General formula I on p. 1, characterized in that the compound of General formula II

< / BR>
where R17aand R17and' matter under item 1 for R17and R17'in which of the available functional groups may be protected;

X and Y have values under item 1;

R3'is hydrogen or a protective group for hydroxyl;

Hal is a halogen atom, pseudohalide, such as mesyl or Casilina group,

expose mercaptan of the General formula III

Za- SH,

where Zsome cases, removing protection,

obtaining the compounds of formula IA, corresponding to the compound of formula I, where m = 0, the compound obtained IA if necessary, enter any of the following reactions in any order: repair existing ketogroup, joining ketogroup metal complex of General formula IY

M - R17A'

where M is a metal atom;

R17a' has a specified value, provided that it is not hydrogen;

turn ketogroup in the oxime, hydrazone or methylene group, selective atsilirovaniya available in 17-position hydroxyl group, haloiding or alkylation in position 16, acylation or alkylation of the hydroxyl group in 3-position, full or partial recovery of the ethylene group, Y is an unsaturated chain, oxidation of sulfur to sulfoxide or sulfon.

8. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of General formula V

< / BR>
where R17Aand R17A' matter under item 1, for R17and R17'in which of the available functional groups may be protected;

X and Y have values under item 1;

R3' - votorola action of compounds of General formula YI

Za- Hal',

where Zamatter under item 1 for Z, in which the available functional groups may be protected;

Hal' matter under item 7 for Hal,

in the presence of a base and then if necessary remove existing protective group to obtain the compounds of formula IA under item 7, which is optionally injected into one of the reactions listed in paragraph 7.

9. Pharmaceutical composition having anti-estrogenic activity, containing the active principle and a pharmaceutically acceptable additive, characterized in that the active agent it contains a derivative of 19 - norsteroids General formula I under item 1, in an effective amount.

10. Intermediate compounds of General formula VII

< / BR>
where M Is Hal or group W - S, where Hal is halogen, and W is hydrogen, acyl COR, where R1- C5-alkyl;

R17Aand R17A' matter under item 1 for R17and R17' and which of the available functional groups may be protected;

R3'is hydrogen or a protective group for hydroxyl;

X and Y have values under item 1, provided that if M - Hal, X and Y cannot be methylene, and R17Amay not be substituted hidroxil

 

Same patents:

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
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

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
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

The invention relates to new esters estramustine and the way they are received, namely esters of the General formula I:

< / BR>
(I) where R1hydrogen atom, a lower alkyl WITH1-C4;

R2a hydrogen atom, a lower alkyl WITH1-C4;

R3a hydrogen atom, a lower alkyl WITH1-C4; or R2and R3together-CH2-CH2-CH2-CH2-,

n is 0,1 or 2

or their pharmaceutically acceptable salts have anti-tumor properties

The invention relates to the field of synthesis of steroid compounds

The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
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

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

FIELD: medicine, gynecology.

SUBSTANCE: the present innovation deals with carrying out hormone-substitution therapy in women during menopause period or in sterilized women. For this purpose the above-mentioned therapy consists of the phase of relative dominant estrogen activity including three daytime dosages of a substance inducing estrogen activity being equivalent to approximately to 1 mg 17beta-estradiol daily, and the phase of relative dominant progestogen activity including combination of a substance inducing estrogen activity being equivalent to approximately 1 mg 17beta-estradiol daily and a substance that demonstrates progestogen activity being equivalent to approximately 90 mcg norgestimate daily. To fulfill such a therapy a pharmaceutical preparation is, also, suggested and a set of mentioned preparations. The innovation provides maximal weakening the symptoms of the disease, in particular, congestions along the safety of application due to decreased risk of known complications of estrogen therapy.

EFFECT: higher efficiency of therapy.

31 cl, 1 dwg, 1 ex, 2 tbl

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: before applying substitute hormonal therapy (SHT) on should evaluate antithrombogenic activity of vascular wall in women. For this purpose one should determine quantitative values of ADP-induced aggregation of thrombocytes, activity of antithrombin III in blood and fibrinolytic blood activity both before and after "cuff"-test. Then one should detect the indices calculated as the ratio of mentioned values both before and after carrying out the mentioned test. If mentioned indices are decreased against the norm by 20-40% women should be prescribed to undergo SHT at additional introduction of aspirin and supradin. The method provides prophylaxis of cardio-vascular diseases in this category of female patients due to correcting affected functional activity of vascular endothelium.

EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: medicine, cosmetology.

SUBSTANCE: one should detect the scope of eruption, the availability of psychoemotional disorders, then, by taking into consideration patient's sex it is necessary to calculate Monakhov's therapeutic acne index (MTAI) by a certain formula to prescribe therapy by taking into account the index obtained. The present innovation provides individual approach to prescribing anti-acne therapy that, in its turn, enables to shorten the terms of disease, decrease the number of jatrogenic complications and prolong remission period.

EFFECT: higher efficiency of anti-acne therapy.

13 ex, 4 tbl

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to steroid compounds of the formula (1)

wherein --- means optional double bonds; R6 means hydrogen atom (H), =CH, -CH3 or -CH2-CH3; R7 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C5)-alkenyl, or (C2-C5)-alkynyl; R11 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C1-C4)-alkylidene; E means 5-7-memberd ring formed with 16 and 17 carbon atoms at α,cis-position relatively to steroid structure and comprising possibly up to two double bonds. Compounds can be used in therapy and in methods for selective modification of activity of estrogen receptors.

EFFECT: improved method for modifying, valuable medicinal properties of compounds.

10 cl, 1 sch, 1 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: pharmaceutical composition possesses an anti-estrogenic effect. The composition comprises fulvestrant in ricinoleate vehicle, a pharmaceutically acceptable anhydrous ester solvent and pharmaceutically acceptable alcohol. The composition is adopted for intramuscular administration and maintains the therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. The composition for intramuscular injection provides satisfied releasing fulvestrant for prolonged time.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

32 cl, 4 tbl, 1 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with applying fulvestrant as a curative preparation of the third line in treating patients with resistant cancer of mammary gland after failed application of tamoxifen and aromatase inhibitor. The innovation shows positive therapeutic result in 41% cases.

EFFECT: higher sensitivity to fulvestrant.

5 cl, 1 ex, 1 tbl

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the substituted 4-benzylaminoquinolines and their heteroanalogs of the general formula (I): P-L-G (I) wherein G means compound of the formula: G(I) wherein K means -OR(7), -NH-CH2-CH2-SO3H, -NH-CH2-CO2H wherein R(7) means hydrogen atom, CH3; R1-R6 mean independently of one another hydrogen atom, -OR(10), -R(10) being one of residues R1-R6 means a bond with L always; R(10) means hydrogen atom, (C1-C4)-alkyl; L means (C1-C15)-alkyl being one or some structural CH2-fragments can be replaced for -C≡C-, -NR(11)-, -CO-, -O- wherein R(11) means hydrogen atom; P means: or wherein A means nitrogen atom (N); B means CH; D means CH; E means CH; R16-R24 mean independently of one another hydrogen atom, F, Cl atoms, (C1-C4)-alkyl being alkyl residues can be mono- or multiple-substituted with fluorine atom, NR(25)R(26), OR(25), COR(25), COOR(25), CONR(25)R(26) being one of residues R16-R(24) means a bond with L always; R25 and R26 mean independently of one another hydrogen atom, (C1-C4)-alkyl or benzyl. Also, invention relates to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and to a drug based on thereof for prophylaxis of supersaturation of bile with cholesterol. Invention provides preparing new compounds and a drug based on thereof that can be used for prophylaxis and treatment of patients suffering with gallstones.

EFFECT: improved preparing method, valuable medicinal properties of compounds and drugs.

10 cl, 32 ex

Up!