11-substituted 19-norsteroid, the retrieval method, compound and pharmaceutical composition

 

(57) Abstract:

Describes the new 11-substituted 19-norsteroid General formula (I) in which n = 5 or 6; R1and R2same or different is a hydrogen atom, a linear or branched alkyl radical WITH1-C8possibly substituted with halogen, or R1-carbamoyl radical, monosubstituted, linear or branched alkyl radical WITH1-C8or phenyl radical, possibly substituted by a halogen atom, and R2is a hydrogen atom, or R1and R2together with the nitrogen atom to which they are attached, form a cyclic urea of formula (II) in which n = 2 or 3, or R1and R2form dialkyl-C1-C4-aminomethylphenol radical. The compounds of formula (I) possess glucocorticoid or antiglucocorticoid, progestational or antiprogestational, androgenic or antiandrogenna, estrogenic or antiestrogenic activity and can be included in pharmaceutical compositions. 4 C. and 6 C.p. f-crystals, 1 PL.

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The present invention relates to a new 19-norsteroids with regulation 11 - phenoxyacetophenone or peroxyacetylnitrate circuit, the method is the fact the present invention are the compounds of formula (I):

< / BR>
in which R17and R'17such that:

or R17and R'17form together ketone;

or R17represents a hydroxyl radical or allegeldy radical containing not more than 12 carbon atoms, and R'17represents a hydrogen atom, alkyl, alkylene or alkynylaryl radical containing not more than 8 carbon atoms, where each of these radicals may be substituted;

R3represents a hydrogen atom, a linear, branched or cyclic alkyl radical containing not more than 8 carbon atoms, or acyl radical containing not more than 12 carbon atoms;

and in which R1and R2the same or different, represents a hydrogen atom, a linear, branched or cyclic alkyl radical comprising from 1 to 8 carbon atoms, with the possibility of substitution acyl radical containing not more than 12 carbon atoms, aryl or Uralkaliy radical, where each of these radicals can be substituted, in which the alkyl radical comprises not more than 6 carbon atoms, and the aryl radical is a mono or polycyclic radical, which may include one or more heteroatoms, chosen the second radical, monosubstituted, linear, branched or cyclic alkyl radical containing not more than 8 carbon atoms, with the possibility of substitution, or aryl or Uralkali radical, where each of these radicals can be substituted, in which the alkyl radical comprises not more than 6 carbon atoms, and the aryl radical is a mono or polycyclic radical, which may include one or more heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, and R2represents a hydrogen atom;

or R1and R2form together with the nitrogen atom to which they are bound, a saturated nitrided 5 or 6 membered heterocycle containing a second heteroatom selected from the group consisting of nitrogen atoms, oxygen, and sulfur, with the possibility of substitution of the alkyl radical comprising from 1 to 4 carbon atoms, or oxo group;

or R1and R2form dialkylaminomethyl radical, each alkyl radical contains from 1 to 4 carbon atoms, and n has an integer value of 18 or more,

as well as their additive salt.

Under acroclinium radical see, in particular, the radical, the corresponding saturated or replaced the example, acetic, propionic, butane or isobutane, Valerian or undecylenoyl acid;

hydroxyalkanoate acid, such as, for example, oxiana acid;

cycloalkylcarbonyl or cycloalkylcarbonyl acid, such as, for example, cyclopropylamine, cyclopentyl or cyclohexylcarbonyl, cyclopentyl or cyclohexyl - acetic or propionic acid; benzoic acid; salicylic or phenylalkanoic acid such as phenylacetic acid or phenylpropionate acid; the amino acid, such as diethylaminoacetate or diethylaminopropylamine; formic acid or dibasic acid with a possibility of turning into a salt, such as, for example, batandjieva acid or its monosodium salt. It is, first and foremost, a derivative of acetic, propionic or butane acid.

Under the acyl radical see radical corresponding to the above-mentioned radical.

Under alkyl radical understand methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, tert-boutigny, n-pentelenyi, n-sexily, 2-methylpentyl, 2,3-dimethylbutyl, n-Gately, 2-methylhexane, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentane, n-octyl is m, ethyl, through botilinum radical.

Under cycloalkenyl radical understand this radical, as cyclopropyl, cyclobutyl, cyclopentyl or tsiklogeksilnogo. First of all we are talking about cyclopentene radical.

When R'17represents alkylene radical, we can talk about such radicals as vinyl, properly, Isopropenyl, allyl, 2-methylallyl, butonly or isobutylene. First of all we are talking about vinyl or propanilol radical.

When R'17represents an alkyl radical, we can talk about this radical, as etinilnoy, prominently, propargyl, routinely or isobutylene. First of all we are talking about etinilnoy or propilyenom radical.

Under monocyclic or polycyclic aryl radical, which may be included in Uralkaliy radical, see:

monocyclic carbocyclic radical, for example phenyl radical,

monocyclic heterocyclic radical, such radicals as thienyl, purely, picaninny, pyrrolidinyl, imidazolidinyl, personilnya, peredelnyj, personilnya, pyrimidinyl, pyridazinyl, theatrically, tetrazolyl, as well as the isomers of the position of the heteroatom (heteroatoms), which may include the above radicals

radical, consisting of a condensed carbocyclic cycles, for example, nattily or phenanthroline radical,

radical, consisting of a condensed heterocyclic cycles, for example, benzofuranyl, benzothiazol, benzimidazolyl, benzothiazolyl, oil [2,3-b] thienyl, thianthrene, isobenzofuran, bromanil, xantener, femoxetine, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazoles, purinol, hemolysins, ethanolic, hinely, phthalazine, naphthyridine, honokalani, hintline, cinnoline, pteridine, carbazole - carbolines, acridines, phenazines, phenothiazines, phenoxazines, indolinyl, isoindolyl, imidazopyridine, imidazopyrimidines or condensed polycyclic system, consisting of heterocyclic monocycles, such for example, as mentioned above, for example, furo [2,3-b] pyrrole or thieno [2,3-b] furan, first and foremost, phenyl radicals, furyl, such as 2-furyl, imidazolyl, such as 2-imidazolyl, pyridyl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, such as pyrimid-2-yl, thiazolyl, such as thiazol-2-yl, thiazolyl, such as thiazolin-2-ol-2-yl, benzothiazolyl, such as benzothiazol-2-yl, purines, such as the purine-7-yl, or chenail, such as 4-chinolin; and as Uralkalij radicals can, in particular, to call methyl or ethyl, substituted by one of the above aryl radicals.

Under saturated nitrogen-containing heterocycle with 5 or 6 atoms, which may include a second heteroatom selected from among nitrogen atoms, oxygen, and sulfur, with the possible substitution of the alkyl moiety or a carbonyl group, you know, first of all, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or imidazolidine.

The various substituents of the radicals listed above, choose, first of all, in the group consisting of:

halogen radical, such as fluorine, chlorine, bromine, iodine;

amine, alkylamino radical, such as methylamine or ethylamine, dialkylamino radical, such as dimethylamine, diethylamine, methylethylamine, each of these dialkylamino radicals may be in oxidized form;

aminoalkylindole radical, such as aminomethyl or aminoaniline;

dialkylaminoalkyl radical, such as dimethylaminomethylene or dimethylaminoethyl;

dialkylanilines radical, free, converted into an ester, such as alkoxycarbonyl, for example, methoxycarbonyl or ethoxycarbonyl, or converted into a salt, for example, by using a sodium atom or potassium;

alkyl radical comprising from 1 to 8 carbon atoms, such as methyl, ethylpropyl, ISO-propyl, boutigny, isobutylene, tert-boutigny, with substitution by one or more halogen atoms, such as, for example, fluorine, such as trifluoromethyl;

exiling, Tianjing, nitrile, formyl radical;

acyl radical such as acetyl, propylaniline, batilly, bentely;

Allexinno radical, such as acetoxyphenyl or a radical of the formula-O-CO-(CH2)nCO2H in which n has a value from 1 to 5;

CNS, such as metaxylene, amoxilina, propylaniline, isopropylaniline, butylaniline;

allylthiourea radical, such as medicinally, aditionally, proportionally, isopropylaniline, butylthioethyl;

karamolegos radical;

alkylene radical, such as vinyl, properly;

akinrinola radical, such as etinilnoy, prominently, and

ar is the R radicals can be called, for example, the alkyl radical, substituted by one or more halogen atoms, such as fluorine radical, such as triptorelin, triptorelin, pentafluoropropionic, PENTACARBONYL, panafcortelone, PENTACARBONYL or nonformally, or, for example, chlorine radical, such as 2-chloraniline.

May also be called, for example, aryl radical, substituted by one or more halogen atoms, such as chlorine radical, such as 4-chloraniline.

The present invention extends, naturally, to salts of compounds of formula (I), for example, salts formed when the compounds of formula (I) include amine functional group with acids such as hydrochloric, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, Glyoxylic, aspartic, hydrogen bromide, alkanesulfonyl, such as methanesulfonate or econsultation, arylsulfonate, such as benzosulfimide or paratoluenesulfonyl and arylcarbamoyl, or when the compounds of formula (I) include amine acid group, using salts or alkaline selecled, in particular, the products of General formula (I) as described above, meets the General formula (I'):

< / BR>
in which R1and R2identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl radical comprising from 1 to 8 carbon atoms, with the possibility of substitution acyl radical containing not more than 12 carbon atoms, or phenyl radical, with the possibility of substitution;

or R1represents carbamoyl radical, monosubstituted, linear, branched or cyclic alkyl radical containing not more than 8 carbon atoms, with the possibility of substitution, or phenyl radical, with the possibility of substitution, and R2represents a hydrogen atom;

or R1and R2form together with the nitrogen atom to which they are bound, a cyclic urea type

< / BR>
in which n has the value 2 or 3,

or R1and R2form dimethylaminomethylene radical, n has a value of not more than 7, as well as their added salt.

The object of the present invention are, in particular, the products of General formula (I) as defined above, in which R17is a hydroxyl radical, and R'17is an atom of water is defined above, in which n has a value of 5 or 6.

The object of the present invention are, in particular, the products of General formula (I) as defined above, in which R1and R2represent a hydrogen atom.

The object of the present invention are, in particular, the products of General formula (I) as defined above, in which R1and R2represent a linear, branched or cyclic alkyl radical containing not more than 8 carbon atoms, with the possibility of substitution by one or more halogen atoms.

The object of the present invention are, in particular, the products of General formula (I) as defined above, in which R1represents a hydrogen atom, and R2is a linear, branched or cyclic alkyl radical containing not more than 8 carbon atoms.

The object of the present invention are, in particular, the products of General formula (I) as defined above, in which R1represents carbamoyl radical, monosubstituted, linear, branched or cyclic alkyl radical comprising from 1 to 8 carbon atoms, or a phenyl radical, where each of these radicals may be segreteria are first of all, the products of formula (I) as defined above, with the following names:

- N-butyl-5-[4-(3, 17- dihydroxy-östra-1,3,5 (10)-trien-11 - yl) phenoxy]-pentanesulfonate,

- N-butyl-5-[4-(3, 17- dihydroxy-östra-1,3,5 (10)-trien-11 - yl) phenoxy]-N-methylpentanoate,

- 5-[4-(3, 17- dihydroxy-östra-1,3,5 (10)-trien-11 - yl) phenoxy]-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylpentanoate.

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

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in which the phenolic functional group may be optionally protected, put:

(a) any impact of the halogenated derivative of formula (III):

X-(CH2)n-SO2-NRAR'A< / BR>
in which X is a halogen atom, n has the above meaning, RAand R'Aidentical or different, represent a hydrogen atom, alkyl radical, with the possibility of substitution of acetyl radical, aryl or Uralkaliy radical, with the ability to replace, and it should be borne in mind that at least one of the substituents RAand R'Ais not a hydrogen atom, or that they form with the nitrogen atom to which they are related is th among nitrogen atoms, oxygen and environment, with the possibility of substitution of the alkyl group, to obtain a product of formula (IV):

< / BR>
in which n, RAand RA'have the same meaning as before, which is exposed to agent flavoring cycle A, and then, if necessary, the effects of agent acylation of the hydroxyl radical in position 3 to obtain a product of formula (IAthe product of formula (I) in which R1=RAand R2= R'A:

< / BR>
in which n, RAand R'Ahave the same meaning as before, and R3represents a hydrogen atom or acyl group, the product of formula (IA), if desired and if necessary, subjected to one or more of the following reactions, in an appropriate manner:

the restoration of the ketone functional group in position 17;

adding to the ketone functional group in position 17 of the metal complex compounds of formula (X):

M - R'17a(X)

in which M represents a metal atom, and R'17ahas the same meaning as R'17with the exception of the hydrogen atom;

selective acylation in position 17 when R17is hydroxyl;

alkilirovanija functional group;

possible salt formation with acids or bases.

b) any effect of the flavoring agent of A cycle, and reactions to protection of hydroxyl radical in position 3, and then selective reactions highlight the protective group of the phenol in position 11 to obtain a product of formula (V):

< / BR>
in which Rprepresents a protective group, which is exposed to the compounds of formula (III'):

X-(CH2n-SO2-N=CH-N(Alk1)(Alk2), (III')

in which X is a halogen atom, Alk1and Alk2are alkyl groups containing from 1 to 4 carbon atoms, and n has a value not exceeding 18, and then hydrolysis of the resulting imine, to obtain the compounds of formula (VI):

< / BR>
in which n and Rphave the same meaning as before, and can, depending on the nature of the group Rpcomply with the product of formula (I), the product of formula (VI), which is optionally and if necessary subjected to one or more of the following reactions, in an appropriate manner:

reactions highlight the protective group Rp;

the restoration of the ketone functional group in position 17;

adding to the ketone funktsionalnoyi;

selective acylation in position 17 when R17is hydroxyl;

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

the influence of the halide of formula (VII):

RB-X

in which RBis an alkyl radical, with the possibility of substitution or acyl radical, and X represents a halogen atom, to obtain the compounds of formula (IB), the corresponding product of formula (I) in which R1= H and R2= RB:

< / BR>
and in which n, R17, R'17and R3have the above meanings;

the impact of the isocyanate of formula (VIII):

Rc- NCO, (VIII)

in which Rcis alkyl, aryl or Uralkali radical, where each of the radicals can be substituted to obtain the compounds of formula (Ic), the corresponding product of formula (I) in which R1represents a monosubstituted carbamoyl radical, and R2represents a hydrogen atom,

< / BR>
in which n, R17, R'17and R3have the above meanings;

the effects of the compounds of formula (IX):

(Alk3O)(Alk4O) CH-N(Alk1)(Alk2), (IX)

in which Alk1, Alk2, Alk3and AlkD), the corresponding product of formula (I) in which R1and R2form dialkylaminomethyl group:

< / BR>
and in which n, R17, R'17and R3have the above meanings;

the alkylation or acylation of the product of formula (IBby exposure to halide (VII) to obtain the corresponding dialkylamino, decelerating or alkylsilanes sulfonamida;

the reaction of cyclization of the product of formula (Ic) when Rcrepresents the radical -(CH2)n-Hal, in which n' is 2 or 3 and Hal represents a halogen atom, to obtain a product of formula (I'c), the corresponding product of formula (I) in which R1and R2form together with the nitrogen to which they are bound, a cyclic urea type

< / BR>
possible salt formation with acids or bases.

The compounds of formula (IA), the corresponding compound (I) in which R1=RAand R2= R'Aget through the serial input connection of the formula (II) in the reaction c:

a) a compound of formula (III) in the presence of a strong base such as sodium hydride, in a bipolar aprotic solvent such as digitiform b) flavouring substance, such as a mixture of acetylproline and acetic anhydride, followed by reaction of the lung saponification in the presence of, for example, sodium hydroxide in methanol or sodium hydroxide in methanol.

The compounds of formula (VI) are obtained by successive entries in the reaction of the compound of formula (II), in which the phenol in position 11 can be protected c:

a) flavouring substance, such as palladium hydroxide to magnesium oxide in methanol, followed by reaction of the protection of the hydroxyl functional group in position 3 by influencing, for example, chlorbenzyl in the presence of potassium carbonate in acetone, acting at the boiling temperature for 7 hours, then the reaction is selective deprotection phenolic functional group in position 11, for example by lightly saponification in the presence of, for example, sodium hydroxide in methanol or sodium hydroxide in methanol to obtain the intermediate compounds of formula (V);

b) a compound of formula (III') in the presence of a strong base such as sodium hydride, in a bipolar aprotic solvent such as dimethylformamide;

C) an agent for the acidic hydrolysis of the imine formed in the previous step, such as, for example, hydrochloric acid in smyly (I), in which R1= H and R2= RBreceive by entering the compounds of formula (VI), in which ORpis hydroxyl, protected, for example, Uralkali radical, in a reaction with the compound of the formula (VII), the reaction is performed, for example, in the presence of sodium hydroxide in acetone at boiling temperature or in the presence of sodium hydride in dimethylformamide at room temperature.

The second alkylation or acylation can be carried out under the same conditions.

The compounds of formula (Ic), corresponding to compounds of formula (I) in which R1=H and R2=CONH-Rcreceive by entering the compounds of formula (VI), in which the protective group of the hydroxyl functional group in position 3 is highlighted and ketone functional group in position 17 is restored, in the reaction with the compound of the formula (VIII), the reaction is performed in the presence of a strong base such as sodium hydride, in a bipolar aprotic solvent such as dimethylformamide, acting, for example, at room temperature.

When Rcrepresents a radical of type -(CH2)n'-Hal, in which n' is 2 or 3, place the cyclization reaction that obaly (ID), the corresponding products of formula (I) in which R1and R2form dialkylaminomethyl group receive by entering the compounds of formula (VI), in which the protective group of the hydroxyl functional group in position 3 is highlighted and ketone functional group in position 17 is restored, in the reaction with the compound of the formula (IX), the reaction is performed, for example, in dimethylformamide at room temperature.

When the compound of formula (I) contains in position 17 ketone functional group, get:

appropriate gidrauxilirovanne connection 17-17-that , for example, by exposure to a reducing agent such as sodium borohydride in a neutral solvent such as methanol;

the corresponding compound containing the radical R'17that represents alkyl, alkylene or alkyl radical, with the possibility of substitution, by adding the compounds of formula (X), such as a compound of lithium, in accordance with the method described in the patent EEC EP 57115.

Of course, if R'17represents alkyl, alkylene or alkynylaryl radical, with the possibility of substitution of the functional group, the latter and 3 gidrauxilirovaniu group, then get the appropriate alkilirovanny steroid using an alkylating reagent, such as an appropriate alkylated or alkylsulfate, for example, methyl sulfate or a corresponding acylated steroid using conventional allerease reagent, such as allalone, for example, acetylchloride.

When the compound of formula (I) contains in position 17 - hydroxy functional group, then get the corresponding 17 - acyloxymethyl steroid using this reagent for the selective acylation, for example, acetic anhydride in pyridine, possibly in the presence of 4-dimethylaminopyridine, or any other method well known to specialists.

Protective groups which can be used to protect functional groups such as hydroxy functional group, choose among the usual groups that are well known in organic chemistry and, in particular, in the chemistry of peptides. A non-exhaustive list of these functional groups, and a description of appropriate methods of selection are described in French patent FR 2499995, the content of which is included for reference in the present patent application and in the article "Protective groups in organic SYN the crystals (II) include such radicals, as acetyl, bentely or tert-butyldimethylsilyl.

As an example, for protection of the hydroxyl in position 3 of the compounds of formulas (V) and (VI) include such radicals, such as acetyl, bentely or benzyl.

For example, the reaction of the protection of the hydroxyl in position 3 benzyl group can be carried out by exposing chlorbenzyl in the presence of a strong base such as sodium hydride, in a bipolar aprotic solvent such as dimethylformamide, operating at room temperature or by exposure benzylbromide in the presence of less strong bases such as potassium carbonate in acetone at boiling point. The interest of such protection is that it is resistant to hydrolysis or saponification.

When intermediate compounds include protected functional group, the corresponding compounds without the protection produced by the impact of conventional agents deprotection. A non-exhaustive list of these functional groups, and a description of appropriate methods of selection are described in French patent FR 2499995, the content of which is included for reference in the present patent application and in the article that when the phenol is protected acetyl functional group, the reaction allocation specified protective group can be carried out with the help of milites, such as sodium hydroxide in alcoholic medium.

When the phenol is protected tert-butyldimethylsilyloxy group, the reaction of the allocation specified protective group can be performed using hydralicious substances, such as hydrochloric acid.

When functional hydroxy group in position 3 is protected benzyl group, the reaction of the allocation specified protective group can be produced by the method of hydrogenolysis by exposure to, for example, hydrogen in the presence of palladium-catalyst on charcoal in a mixture of ethyl acetate, ethanol and acetic acid.

In the preferred method of execution of the present invention:

use of compounds of formula (III) in which X is, first and foremost, a iodine atom;

use of compounds of formula (III') in which X is, first and foremost, a iodine atom;

use of compounds of formula (VII) in which X is in the first place, iodine atom, in the case where RBis an alkyl radical and a chlorine atom, when RBis the acyl radical.

The present invention rasprostranyaetsya to the compound of formula (II), containing in position 17 substitute R17and R'17as specified above.

Needless to say that the introduction of this method, and as described above for radical R'17may be necessary in the interim protective groups of the radicals R17and R'17. These protective groups described above. The above starting materials are known, for example, from published patent EEC N 0384482, or can be prepared by the methods described in this patent application, based on the products of 17-oxo.

The compounds of formula (I) possess interesting pharmacological properties.

Research products on the hormonal receptors revealed that:

the compounds of formula (I) possess glucocorticoid or antiglucocorticoid, progestational or antiprogestational, androgenic or agentagent, antimineralocorticoid, estrogenic or antiestrogenic activity.

The compounds of formula (I) have, in particular, exceptional antiestrogenic activity and antiproliferative properties, as is evident from the following test results.

These features allow use what I violations, caused by increased secretion of glucocorticoids and, in particular, aging in General and, more specifically, hypertension, slow tarabzouni, atherosclerosis, osteoporosis, diabetes, obesity, as well as weakening of the immune system and insomnia.

These products can also be of interest in the treatment of some types of tumors, exprimarea hormone receptors, for which products of formula (I) represent the affinity.

The compounds of formula (I) with antiprogestational properties, can be used in the preparation of the original contraceptives, as a means to terminate the pregnancy or as a means of labour induction.

These products can also be used as a means to call menstruation in women and generally females warm-blooded animals.

In this case, these products are periods during which progesterone plays an important physiological role, that is, in particular, during the luteal phase of the cycle, during nidali (or impregnation of a fertilized egg) and during pregnancy. The contraceptive method according to the present invention Zack is once cycle. In this case, the specified product is introduced preferably into or out of the vagina, but it can also be taken parenterally. Enter the products may also intranasal route.

The products of formula (I) with antiprogestational properties, can also be used in the treatment of hormonal disorders and, in addition, they may be of interest in the treatment of hormone-dependent tumors.

Their effect on pituitary secretion allow the use of these products during menopause.

These products can also be used to synchronize the menstrual cycle and the timing of births in livestock, particularly cattle and small cattle.

These products can also be used to control the fertility of domestic animals such as dogs and cats.

The compounds of formula (I) can be also to have projectmimesis.com properties and therefore can be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiency.

The compounds of formula (I) with antiandrogenna properties, can be used in the treatment of hypertrophy and prostate cancer, hyperandrogen the ka.

The compound of formula (I) with estrogennami properties, can also be used in the treatment of disorders associated with gipoholesterinemia, such as amenorrhea, dysmenorrhea, recurrent abortion, premenstrual disorders, as well as for the treatment of menopause and osteoporosis.

Antiestrogen and antiproliferative properties of the compounds of formula (I) to enable their use in the treatment of hormone-dependent carcinomas, such as, for example, carcinoma breast cancer and its metastases, as well as in the treatment of benign breast tumors.

Thus, the object of the present invention are the compounds of formula (I), and also, as medicaments, add salt, valid from a pharmacological point of view.

Among the drugs that are the subject of the present invention, include, in particular, the compounds described in the experimental part, and, first of all, the products of Examples 2, 7 and 8.

Useful dosages of the medication depends on the disease to be treated, and the manner of their admission; it can vary, for example, from 1 to 100 mg per day for adults by ingestion.

The invention RGM one defined above medicines.

The compounds of formula (I) is administered through the digestive canal, parenterally or locally, for example, by subcutaneous. They may be prescribed in the form of simple or draeven of tablets, capsules, granules, suppositories, balls, injectables, ointments, creams, gels, microspheres, implants, patches, prepared in a traditional manner.

Active principle (active start) may be injected into the base, usually used in the manufacture of pharmaceutical compositions, such as talc, Arabic gum, lactose, amidon, magnesium stearate, cocoa butter, aqueous or anhydrous binder, fats of animal or vegetable origin, derived paraffin, glycols, various moisturizing, dispersion or emulsion agents, preservatives.

Compounds of formula (IV), (V) and (VI) are new intermediate products and, therefore, the object of the present invention, as new industrial products and in particular as intermediates for the implementation of the method of the invention are compounds of formula (IV), (V) and (VI).

Among the new intermediate products which are the subject of the present invention, can be called products, which is nonsulphated,

- 5-[4-(3,17-dioxo-östra-4,9-Dien-11 - yl)phenoxy]-N- (2,2,3,3,4,4,4-heptafluorobutyl)-N-methylmethanesulfonamide,

- 11- (4-hydroxyphenyl)-3-[(phenylmethyl)oxy]-östra-1,3,5(10)- triene-17-one,

- 5-[4-(17-oxo-3-[(phenylmethyl)oxy] -östra-1,3,5(10)-trien-11 - yl]phenoxy]-pentanesulfonate.

The compound of formula (I) necessary to implement the method, described in particular in patent application EEC EP 0 384 842 (Preparation Example 43).

Further, in the experimental part, the examples of preparation of products of formula (III) and (III'). These compounds, as a rule, are already known and their preparation is carried out using methods similar to the methods described in the experimental part.

The following examples illustrate the invention, without limiting it.

Preparation 1: N-[(dimethylamino)methylene]-5 - itintensive

Stage: 5-herpetoculture

In an environment of inert gas into a solution of 2.5 g of 5-herpetocultural (obtaining described in the article: Bull. Soc. Chim. Belg. (1965) 74 21) at 30 tetrahydrofuran at a temperature of 0/+5oC add one drop of 2.5 ml of 28% aqueous ammonia. Then the temperature is allowed to rise from +3oC up to +16oC and shaken at the t in the water, extracted using methylene chloride, washed with water, and then aqueous solution of sodium chloride, dried and evaporated under reduced pressure. So get a 2.01 g of the desired product (tPL62oC).

Infrared spectrum: trichloromethane (CHCl3)

-NH2- 3448 cm-1- 3352 cm-1< / BR>
-SO2- - 1344 cm-1- 1150 cm-1< / BR>
-NH2- 1545 cm-1< / BR>
Stage B: 5-chloro-N-[(dimethylamino)methylene]-pentanesulfonate

In an environment of inert gas into a solution of 1.5 g of the product obtained in the previous step, in 8 ml of dimethylformamide at room temperature, add one drop of 1.29 ml of N,N-dimethylformamidine. Then the solution is shaken at room temperature for 3 h, then poured into 1% aqueous solution of hydrogensulfate sodium, extracted using ethyl acetate, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtained is 1,809 g of the desired product.

IR spectrum (CHCl3)

-N=CH-N< - 1629 cm-1< / BR>
-SO2- - 1349 cm-1- 1119 cm-1< / BR>
Stage B: N-[(dimethylamino)methylene]5-itintensive

IR spectrum (CHCl3)

-N=CH-N< - 1629 cm-1< / BR>
Preparation 2: N-butyl-5-iodine-N-methylmethanesulfonamide

Step A: N-butyl-5-chloro-N-methylmethanesulfonamide

In an environment of inert gas into a solution of 410 mg of 5-herpetocultural in 10 ml of methylene chloride add to 0.47 ml of N-butylmethylamine. Then the temperature is allowed to rise from +13oC up to +26oC and polka cooling to 0/+5oC add with 0.55 ml of triethylamine and shaken for 2 h at room temperature. After that, the solution is poured into aqueous hydrochloric acid solution (molar concentration = 1 mol/l), extracted using methylene chloride, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. So get 486 mg of the target product.

IR spectrum (CHCl3)

-SO2-N< - 1334 cm-1- 114 is radiusim stage, 4.5 ml of methyl ethyl ketone type 526 mg of sodium iodide and shaken for 4 h at boiling temperature. After cooling and evaporation of methyl ethyl ketone under reduced pressure, add water, extracted using ethyl acetate, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus receive 572 mg of the target product.

IR spectrum (CHCl3)

-SO2-N< - 1334 cm-1- 1141 cm-1< / BR>
Preparation of 3: N-(2,2,3,3,4,4,4-heptafluorobutyl)-5-iodine-N - methylmethanesulfonamide

Step A: 5-chloro-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N - methylmethanesulfonamide

In a solution of 200 mg of 5-herpetocultural in 5 ml of methylene chloride is added 500 mg of N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-metilenhloride obtained according to the patent EEC 384842 - Example 75, and then, at a temperature of 0/+5oC of 0.55 ml of triethylamine, and then shaken for 2 h at room temperature. Then add water, extracted using methylene chloride, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtain 378 mg of the desired BR>
Impurity C = O 1730 cm-1< / BR>
Stage B: N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-UN-N - methylmethanesulfonamide

To a solution of 355 mg of the product obtained in the previous step, 3 ml of methyl ethyl ketone added 300 mg of sodium iodide, then cook for 4 hours to boiling point. After evaporation of the solvent the residue is taken in water and extracted using ethyl acetate. Then washed with aqueous sodium thiosulfate solution, and then sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtain 425 mg of the target product as a colorless viscous liquid which slowly crystallized.

IR spectrum (CHCl3)

N-SO2- - 1354 cm-1- 1341 cm-1- 1148 cm-1< / BR>
Preparation example 1: -[4-hydroxyphenyl)-3-[(phenylmethyl) oxy]-östra-1,3,5(10)-triene-17-one

Phase a: 11 -[4-benzoyloxy)phenyl]-östra-4,9-diene-3,17-dione

Inert gas into the solution 8,758 g of 11 -(4-hydroxyphenyl)-östra-4,9-diene-3,17-dione obtained according to the patent EEC 384842 - Example 43, 92 ml of acetone and 27 ml of an aqueous sodium hydroxide solution (molar concentration = 1 mol/l) is added drop by drop at a temperature of 0/+5oC, 3 ml of benzoyl chloride. At the end of the introduction of benzoyl chloride is observed oreature. After that, the mixture was poured into aqueous hydrochloric acid solution (molar concentration = 0.1 mol/l), extracted using ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. So get 12,98 g crude product which is crystallized from a mixture of methylene chloride and easy isopropyl ether. The result is to 9.93 g of the desired product (tPL196oC).

IR spectrum (CHCl3)

> C = O in position 17 + ketone Ar-O-CO-Ph - 1736 cm-1(F)

The conjugated ketone - 1659 cm-1- 1602 cm-1< / BR>
C = C aromatic. - 1505 cm-1- 1490 cm-1< / BR>
Step B: 11- [4-(benzoyloxy)phenyl]-3-hydroxy-östra-1,3,5 (10)-triene-17-one

In the solution 10,07 mg product obtained as described in the previous step, in 104 ml of methanol added to 10.1 g of 20% palladium hydroxide of magnesium. Then heated at boiling temperature for 1 hour and 30 minutes After cooling, the suspension is filtered, washed insoluble catalyst with a mixture of methylene chloride and methanol (50 : 50) and evaporated to dryness of the filtrate under reduced pressure. the remainder (of 10.72 g) is subjected to chromatography on silica (eluant : ethyl acetate-cyclohexane (43)

-OH - 3599 cm-1< / BR>
> C = O - 1733 cm-1(F) - 1611 cm-1- 1602 cm-1< / BR>
C = C aromatic. - 1585 cm-1- 1508 cm-1< / BR>
Stage: 11- [4-(benzoyloxy)phenyl] -3-[(phenylmethyl)oxy] - östra-1,3,5(10)-triene-17-one

In the solution 6,462 mg of the product obtained in the previous step, in 110 ml of acetone add 3,82 g of potassium carbonate and 4.9 ml of brombenzene (Fluka A007832). Then heated for 7 hours to the boiling temperature, and then, after cooling, evaporated to dryness under reduced pressure. The residue is taken in ethyl acetate and poured into aqueous hydrochloric acid solution (molar concentration = 0.5 mol/l), re-extracted using ethyl acetate and washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (12.2 g) is subjected to chromatography on silica (eluant : ethyl acetate-cyclohexane (25 : 75)). The result of 6.68 g of the desired product.

IR spectrum (CHCl3)

> C = O - 1734 cm-1complex. - 1604-1608 cm-1- 1586 cm-1< / BR>
C = C aromatic. - 1576 cm-1- 1508 cm-1- 1501 cm-1< / BR>
Step G: 11- (4-hydroxyphenyl)-3-[(phenylmethyl)oxy]- östra-1,3,5(10)-triene-17-one

In the solution 6,64 mg of the product obtained at p is e concentration = 2 mol/l). Then the solution is shaken for 1 h at room temperature and poured into aqueous hydrochloric acid solution (molar concentration = 0.5 mol/l). Then extracted using ethyl acetate, washed with water, then saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. So get of 6.52 g of the desired crude product, which was subjected to crystallization from methylene chloride. The result is to 4.62 g of the target product (tPL240oC).

IR spectrum (CHCl3)

-OH - 3600 cm-1< / BR>
> C = O - 1733 cm-1- 1613 cm-1- 1594 cm-1< / BR>
C = C aromatic. - 1574 cm-1- 1513 cm-1- 1500 cm-1< / BR>
Example 1: 5-[4-(3, 17- dihydroxy-östra-1,3,5(10)-trien - 11-yl)phenoxy]-pentanesulfonate

Step A: N-(dimethylamino)methylene]-5-[4-[17-oxo-3- [(phenylmethyl)oxy]-östra-1,3,5(10)-triene- -11 - yl]phenoxy]-pentanesulfonate

Inert gas into a suspension of 2.92 g of the product obtained in Step G Preparation of Example 1 in 69 ml of dimethylformamide and 403 mg of sodium hydride at 50% in oil, after stirring for 25 min add a solution of 2.67 g of the product obtained is to obtain a solution, which is kept in agitation at the same temperature for 1 h 15 min Then the solution is cooled to room temperature and poured into 1% aqueous solution of hydrogensulfate sodium, extracted using ethyl acetate, washed with water, then saturated sodium thiosulfate solution, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (6.75 g) is subjected to chromatography on silica (eluant : ethyl acetate). The result is 3.82 g of the desired product.

IR spectrum (CHCl3)

> C = O in position 17 - 1733 cm-1complex.

-N=CH- - 1629 cm-1- 1612 cm-1(Playground) - 1575 cm-1< / BR>
C = C aromatic. - 1512 cm-1- 1500 cm-1< / BR>
-SO2- - 1349 cm-1< / BR>
Stage B: 5-[4-[17-oxo-3-[(phenylmethyl)oxy]-östra - 1,3,5(10)-triene- -11 - yl]phenoxy]-pentanesulfonate

In an environment of inert gas suspended in 3,818 g of the product obtained in the previous step, in 59 ml of methanol and 28 ml of tetrahydrofuran add to 17.7 ml of pure concentrated hydrochloric acid at 22oB. the Mixture is heated at a temperature of +80oC for 1 h 30 min, and then, after cooling, poured into authorized aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (4.15 g) is subjected to chromatography on silica (eluant : ethyl acetate/cyclohexane (60 : 40)). The result 2,89 g of the desired product.

IR spectrum (CHCl3)

-NH2- 3444 cm-1- 3350 cv-1< / BR>
> C = O in position 17 - 1733 cm-1- 1610 cm-1< / BR>
C = C aromatic. - 1580 cm-1< / BR>
+

-NH2- 1545 cm-1< / BR>
Stage B: 5-[4-[ 17 - hydroxy-3-[(phenylmethyl)oxy]-östra - 1,3,5(10)-triene- -11 - yl]phenoxy]-pentanesulfonate

In an environment of inert gas into a solution of 1.36 g of the product obtained in the previous step, in 6 ml methanol and 6 ml of tetrahydrofuran at a temperature of 0o/+5oC add 169 mg of boron hydride and sodium. After stirring for 1 h at a temperature of 0o/+5oC the mixture was poured into aqueous hydrochloric acid solution (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with water and then saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. So get 1,299 g of the desired crude product, which was subjected to crystallization from a mixture of methylene chloride and easy isopropyl ether. The result 3609 cm-1< / BR>
-NH2- - 3444 cm-1- 3353 cm-1- 1609 cm-1< / BR>
C = C aromatic. - 1580 cm-1- 1512 cm-1- 1500 cm-1< / BR>
-NH2- 1544 cm-1< / BR>
Stage G: 5-[4-[3, 17- dihydroxy-östra - 1,3,5(10)-trien - 11 - yl]phenoxy]-pentanesulfonate

In the solution 1,295 g of the product obtained in the previous step, in 50 ml of ethanol and 5 ml of acetic acid add 161 mg of 10% palladium on charcoal (type E 10N, Degussa), and then shaken for 2 h at a pressure of 1640 barov hydrogen. Then filtered, washed with a mixture of methanol and methylene chloride (1 : 1), evaporated to dryness under reduced pressure and distilled acetic acid in toluene. Thus obtain 1.04 g of the crude desired product, which is subjected to crystallization from ethanol. The result is 736 mg of the target product (tPL175oC).

Infrared spectrum (liquid Paraffin)

The integrated absorption in the region of the OH/NH: - 1616 cm-1< / BR>
C = C aromatic. - 1580 cm-1< / BR>
+

-NH2- 1511 cm-1< / BR>
-SO2- 1333 cm-1- 1153 cm-1< / BR>
Example 2: N-butyl-5-[4-[3, 17- dihydroxy-östra - 1,3,5(10)-trien - 11 - yl]phenoxy]-pentanesulfonate

Step A: N-butyl-5-[4-[17-oxo-3-[(phenylmethyl)oxy] - östra-1,3,5(10)-triene - yl]pheno is 6.5 ml of acetone and 0.96 ml of an aqueous sodium hydroxide solution (molar concentration = 1 mol/l) add 0,188 ml of 1-iodobutane. Shaken out at the boiling temperature for 52 hours and cooled before evaporation of the acetone under reduced pressure. Then pick up in ethyl acetate and poured into aqueous hydrochloric acid solution (molar concentration = 0.5 mol/l), extracted using ethyl acetate, washed with water and then saturated sodium thiosulfate solution and saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus receive 612 mg of product, which is subjected to chromatography on silica (eluant : ethyl acetate/cyclohexane (50 : 50)). The result is 68 mg of the desired product (Rf = 0.40 ethyl acetate/cyclohexane (50 : 50)).

IR spectrum (CHCl3)

-NH- - 3400 cm-1< / BR>
> C = O - 1733 cm-1- 1610 cm-1< / BR>
C = C aromatic. - 1579 cm-1- 1511 cm-1- 1510 cm-1< / BR>
-SO2- - 1327 cm-1+ 1141 cm-1< / BR>
Stage B: N-butyl-5-[4-[ 17 - hydroxy-3-[(phenylmethyl)oxy] - östra-1,3,5(10)-triene- -11 - yl]phenoxy]-pentanesulfonate

Inert gas chilled to 0/+5oC solution, including 294 mg of the product obtained in the previous step, 1.3 ml of tetrahydrofuran and 1.3 ml of methanol added 33 mg of Hydra is hydrogen acid (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus receive 300 mg of product, which is subjected to chromatography on silica (eluant : ethyl acetate/cyclohexane (50 : 50)). The result is 194 mg of the desired product (Rf = 0.25 ethyl acetate/cyclohexane (50 : 50)).

Stage B: N-butyl-5-[4-[ 3,17 - dihydroxy-östra-1,3,5(10)-triene- -11 - yl]phenoxy]-pentanesulfonate

To a solution of 194 mg of the product obtained in the previous step, 5 ml of ethyl acetate, 5 ml ethanol and 5 ml of acetic acid added 44 mg of 10% palladium-catalyst on charcoal, and then shaken for 15 min at a pressure of 1700 barov hydrogen. After this suspension was filtered, washed with a mixture of methanol and methylene chloride (1 : 1), the filtrate is evaporated to dryness under reduced pressure, distilled acetic acid with toluene and dried under reduced pressure. Thus obtain 172 mg of product, which is subjected to chromatography on silica (eluant : methylene chloride/isopropanol (96 : 4)). The result is 142 mg of the target product.

IR spectrum (CHCl3)

-OH - 3601 cm-1< / BR>
-NH- - 3400 cm-1< / BR>
Example 3: 5-[4-( 3,17- dihydroxy-östra-1,3,5(10)-trien - 11-yl)phenoxy]-N-[(dimethylamino)methylene)-pentanesulfonate

In a solution of 200 mg of the product obtained in Stage G of Example 1, 1.5 ml of dimethylformamide add 0,062 ml of N, N-dimethylformamidine and shaken for 1 h 30 min at room temperature. Then pour in 1% aqueous solution of hydrogensulfate sodium, extracted using ethyl acetate, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtain 227 mg of product, which is subjected to chromatography on silica (eluant : methylene chloride/isopropanol (95 : 5)). The result is 168 mg of the target product.

IR spectrum (CHCl3)

-OH - 3602 cm-1< / BR>
-N=CH- - 1629 cm-1- 1611 cm-1< / BR>
C = C aromatic. - 1580 cm-1- 1512 cm-1< / BR>
Example 4: N-butyl-N'-5-[4-(3, 17-dihydroxy-östra-1,3,5(10)- trien-11 - yl)phenoxy]peterculter]-urea

In an environment of inert gas into a solution of 200 mg of the product obtained in Stage G of Example 1 in 2 ml of dimethylformamide are added 20 mg of sodium hydride and, after 10 minutes of stirring at room temperature, 0,046 ml butylboronic acid (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtain 317 mg of product, which is subjected to chromatography on silica (eluant : methylene chloride/isopropanol (95 : 5)). The result is 146 mg of the target product.

Infrared spectrum (liquid Paraffin)

OH-NH - 3360 cm-1- + full absorption

> C = O - 1675 cm-1- 1610 cm-1< / BR>
C = C aromatic. - 1577 cm-1< / BR>
+ amide ---> - 1540 cm-1- 1510 cm-1< / BR>
-SO2- 1340 cm-1- 1146 cm-1< / BR>
Example 5: N-(4-chlorophenyl)-N'-5-[4-( 3,17- dihydroxy-östra-1,3,5(10)- trien-11 - yl)phenoxy]peterculter]-urea

In an environment of inert gas into a solution of 183 mg of the product obtained in Stage G of Example 1 in 2 ml of dimethylformamide added 22 mg of 50% sodium hydride and, after 10 minutes of stirring at room temperature, 73 mg of 4-chlorophenylalanine. After sbaltimore for 5 h at room temperature, the mixture was poured into aqueous hydrochloric acid solution (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with saturated aqueous solution of chloride of soda will versaut chromatography on silica (eluant : methylene chloride/isopropanol (92,5 : 7,5)). The result is 86 mg of the target product.

Infrared spectrum (liquid Paraffin)

The integrated absorption in the region of the OH/NH:

> C = O - 1698 cm-1- 1607 cm-1< / BR>
C = C aromatic. - 1540 cm-1< / BR>
+ amide - 1511 cm-1- 1494 cm-1< / BR>
Example 6: 1-[5-[4-( 3,17- dihydroxy-östra-1,3,5(10)- trien-11 - yl)phenoxy]peterculter]-2-imidazolidinone

In an environment of inert gas into a solution of 200 mg of the product obtained in Stage G of Example 1 in 2 ml of dimethylformamide are added 20 mg of 50% sodium hydride and, after 10 minutes of stirring at room temperature, a 0.035 ml of 2-chlorotriazine. After stirring for 1 h 30 min at room temperature, the mixture was poured into aqueous hydrochloric acid solution (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. Thus obtain 278 mg of product, which is subjected to chromatography on silica (eluant : ethyl acetate and then methylene chloride/isopropanol (92,5 : 7,5)). The result is 102 mg of the target product.

Infrared spectrum (liquid Paraffin)

Complex-1- 1505 cm-1(space)

-SO2- - 1155 cm-1< / BR>
Example 7: N-butyl-5-[4-( 3,17 - dihydroxy-östra-1,3,5(10)- trien-11 - yl)phenoxy]N-methylmethanesulfonamide]

Step A: N-butyl-5-[4-(3,17-dioxo-östra-4,9-Dien - 11-yl] phenoxy]-N-methylmethanesulfonamide

In an environment of inert gas suspended in 58 mg of a 50 percent solution of sodium hydride in oil in 6 ml of dimethylformamide add 362,5 mg of 11 -(4-hydroxyphenyl)-östra-4,9-diene-3,17-dione obtained according to the patent EEC 384842 - Example 43, and, after 30 minutes stirring at room temperature, add a solution of 417 mg of the product obtained in Preparation 2 (Step B), in 1.5 ml of dimethylformamide. During the introduction of the temperature allowed to rise to +23oC up to +27oC, and then shaken for 45 minutes the mixture is Then poured into aqueous hydrochloric acid solution (molar concentration = 1 mol/l), extracted using ethyl acetate, washed with water and then saturated sodium thiosulfate solution and saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (883 mg) is subjected to chromatography on silica (eluant : ethyl acetate-cyclohexane (60 : 40)). The result 433 mg of the desired SUP>-1- 1609 cm-1< / BR>
C = C + - 1600 cm-1(space)

C = C aromatic. - 1580 cm-1- 1509 cm-1(strong.) - 1333 cm-1< / BR>
-SO2N< - 1140 cm-1< / BR>
Stage B: N-butyl-5-[4-( 3,17 - hydroxy-östra-1,3,5(10)-trien-11 - yl] phenoxy]-N-methylmethanesulfonamide

1. Aromatization

Inert gas into the solution 404,5 mg of the product obtained in the previous step, 4 ml of methylene chloride at a temperature of 0o/+5oC type of 0.32 ml of acetic anhydride and 0.16 ml of acetylproline. Then shaken for 15 min at the same temperature for 1 h 15 min at room temperature.

2. Saponification of the acetate

In the reaction mixture is cooled to a temperature of 0o/+5oC add 0.3 ml of methanol and, after 10 minutes of stirring, evaporated to dryness under reduced pressure at room temperature. Then take in 2.4 ml of methanol and 2.4 ml of tetrahydrofuran and added to 0.47 ml sodium lye. Then shaken for 45 min at room temperature.

3. The recovery of the ketone in position 17

In the reaction mixture is cooled to a temperature of 0o/+5oC add 131 mg of boron hydride and sodium. After stirring for 45 min at room temperature ispolzovaniem ethyl acetate, washed with water, and then saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (393 mg) is subjected to chromatography on silica (eluant : ethyl acetate: cyclohexane (50 : 50)). The result is 193 mg of the desired product.

IR spectrum (CHCl3)

-OH - 3600 cm-1- 1610 cm-1< / BR>
C = C aromatic. - 1581 cm-1- 1512 cm-1< / BR>
-SO2N< - 1332 cm-1- 1138 cm-1< / BR>
Example 8: 5-[4-( 3,17- dihydroxy-östra-1,3,5(10)-trien-11 - yl)phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylmethanesulfonamide

Step A: 5-[4-(3,17-dioxo-östra-4,9-Dien-yl)phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylmethanesulfonamide

To a solution of 255 mg of 11-(4-hydroxyphenyl)-östra-4,9-diene-3,17-dione obtained according to the patent EEC 384842 - Example 43, 4.5 ml of dimethylformamide, add 40 ml of 50% solution of sodium hydride in oil. After 30 minutes stirring at room temperature add 400 mg of the product obtained in Preparation 3 (Step B) and shaken at room temperature for 45 minutes the mixture is Then poured into aqueous hydrochloric acid solution (molar acid = 1 mol/l), extracted using ethyl acetate, washed with members is evaporated to dryness under reduced pressure. The residue (600 mg) is subjected to chromatography on silica (eluant : ethyl acetate-petrol G (55 : 45)). The result is 335 mg of the desired product.

IR spectrum (CHCl3)

>C = O in position 17 - 1735 cm-1< / BR>
Diene - 1658 cm-1- 1609 cm-1< / BR>
C = C + - 1580 cm-1< / BR>
C = C aromatic. - 1509 cm-1- 1342 cm-1< / BR>
-SO2N< - 1448 cm-1< / BR>
Stage B: 5-[4-( 3,17 - dihydroxy-östra-1,3,5(10)-trien-11 - yl)phenoxy] -N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylmethanesulfonamide

1. Aromatization

To a solution of 430 mg of the product obtained in the previous step, in 3.5 ml of methylene chloride at a temperature of 0o/+5oC add 0.35 ml of acetic anhydride and 0.20 ml of acetylproline and shaken for 40 min at room temperature.

2. Saponification of the acetate

In the reaction mixture is cooled to a temperature of 0o/+5oC add 0.5 ml of methanol and evaporated to dryness under reduced pressure. Then take in 3.5 ml of methanol and add 0.6 ml of sodium lye.

3. The recovery of the ketone in position 17

The reaction mixture was added 228 mg of boron hydride and sodium. After stirring for 20 min at room temperature, acidified to pH = 2 using 2 what happens to dryness under reduced pressure. The residue (429 mg) is subjected to chromatography on silica (eluant : ethyl acetate-petrol G (40 : 60)). The result is 266 mg of the target product (tPL136oC-138oC).

IR spectrum (CHCl3)

-OH - 3615 cm-1- 1610 cm-1< / BR>
C = C aromatic. - 1581 cm-1- 1512 cm-1- 1491 cm-1< / BR>
-SO2N< - 1342 cm-1- 1148 cm-1< / BR>
Pharmaceutical compounds

There were prepared tablets having the following formula:

The product of example 7, 50 mg

The basis for the finished tablet 120 mg

(Detailing the basics: talc, starch, magnesium stearate).

Were prepared suspension for injection having the following formula:

The product of example 7 to 25 mg

Base (water dispersive solution): benzyl alcohol, Polysorbate 80, carboxymethylcellulose (sodium salt), sodium chloride, and water to prepare drugs for injection to the vial with a capacity of 1 ml

Pharmacological study of the products of the invention

1) Study the impact of the products of the invention on hormone receptor

In this study, use either natural hormone receptor rat (AR), or recombinant receptor of the person (PR, GR and ER).

rez 24 h after castration animals wordplays. Then have them cut out the prostate, weighed and homogenized at a temperature of 0oC using tubular shredder Teflon-glass in buffered solution TS (Tris 10 mmol, sucrose 0.25 mol, DTT 2 mmol, MoNa 20 mmol, PMSF (phenylmethanesulfonyl) 0.1 mmol, pH of 7.4) (1 g Dana 8 ml buffer solution). Then the homogenate was centrifuged (209 000 g for 30 min) at a temperature of 0oC. the thus Obtained aliquots nagadoches fluid subjected to incubation at a temperature of 0oC during the incubation period of 24 h at a constant concentration (T) titiraupenga testosterone, and in the presence of increasing concentrations (from 0 to 1000 10-9mol), or testing product (1 to 25000 10-9mol). The concentration associated titiraupenga testosterone (B) is then measured in each incubate by adsorption by charcoal-dextran.

Progesterone receptor human

Recombinant receptor of the person obtained by superexpression in the system of the insect cells Baculovirus in accordance with the General method described by N. R. WEBB co-authors (Journal of Methods in Cell and Molecular Biology, 1990, vol 2, No. 4, pages 173-188), and the use of which is described in the expression of hormonal receptors clover. 209-216).

To enter fragment DNAs with that described by P. CASTERA with co-authors (The EMBO Journal, 1990, vol 9, No. 5, pp. 1603-1614), including the coding region for progesterone receptor of human rights and to prepare the corresponding recombinant virus using the kit "BaculoGolg Transfection Kit (PharMingen, hereafter. 21000K).

Thus obtained recombinant virus is used for the expression of progesterone receptor in insect cells SF9 (ATCC CRL1711) in accordance with the above known method. From 2 to 1072.5 107the SF9 cells cultured in a flask Falcon 175 cm2in the environment of TNM-FH "SIGMA" with the addition of 10% fetal calf serum (SVF) and 50 μg/ml gentamicin. After infection and incubation at a temperature of +27oC for 40-42 h cells subjected to lysis in 1 ml lisanova buffer (1) by performing a cycle of freezing-thawing, which are repeated twice. Nadosadocnuu liquid containing recombinant progesterone receptor human, keep the doses of 1 ml in liquid nitrogen.

Nadosadocnuu fluid diluted at the point of use in accordance with the range of dilutions from 1/10 to 1/100 buffer solution (Tris 10 mmol, sucrose 0.25 mol, HCl at a pH of 7.4 with nigerianisation 17 , 21-dimethyl 19-nor-pregna 4,9-diene-3,20-dione in the presence of increasing concentrations of either cold progesterone (from 0 to 2500 10-9mol) or cold test product (1 to 2500 10-9mol). Then the concentration associated titiraupenga 17,21-dimethyl 19-nor-4,9-pregnan-3,20-dione (V) is measured in each incubate by adsorption by charcoal-dextran.

Glucocorticoid receptor of human

Nadosadocnuu fluid SF9 cells containing recombinant glucocorticoid receptor person will receive according to the method described above for progesterone receptor using fragment DNAs with described With. M HOLLENBERG with co-workers (Nature, 1985, vol 318, N 19/26, page 635), including the coding region for the glucocorticoid receptor of human rights. The obtained cells are subjected to lysis in Lisina buffer (2).

Nadosadocnuu liquid incubated for 24 h at a temperature of 0oC at a constant concentration (E) titiraupenga 11,17-dihydroxy-6,21-dimethyl, pregna 1,4,6-Tien-20-in-3-it, in the presence of increasing concentrations of either cold dexamethasone (from 0 to 1000 10-9mol) or cold test product (1 to 25000 10-9mol). Then the concentration associated titiraupenga 11, what Strana.

Estrogen receptor human

Nadosadocnuu fluid SF9 cells containing recombinant estrogen receptor person will receive according to the method described above for progesterone receptor using fragment DNAs with that described in the expression vector HEGO L. TORAH with co-authors (The EMBO Journal, 1989, vol. 8, No. 7, pp. 1981-1986), including the coding region for the oestrogen receptor, human "wild-type" with glycine at position 400. The obtained cells are subjected to lysis in Lisina buffer (1).

Nadosadocnuu liquid incubated for 24 h at a temperature of 0oC at a constant concentration (T) titiraupenga estradiol in the presence of increasing concentrations of either cold estradiol (from 0 to 100 10-9mol) or cold test product (1 to 25000 10-9mol). Then the concentration associated titiraupenga estradiol (In) measured in each incubate by adsorption by charcoal-dextran.

Expression of results and calculation methods

The calculation of the relative binding effects (ARL)

To start, draw two curves: the percentage associated titiraupenga hormone B/BO depending on the logarithm of the concentration of cold control hormone or zavisimost the equation:

I50= 100 (BO / BO + Bmin/ BO) / 2; I50= 100 (1 + Bmin/ BO) / 2 = 50 (1 + Bmin/ BO),

where:

- BO: Concentration associated titiraupenga hormone in the absence of any cool product.

- B: Concentration associated titiraupenga hormone in the presence of concentrations X cold product;

- Bmin: Concentration associated titiraupenga hormone in the presence of a significant excess of cold control hormone (500 nmol).

The intersection of the line I50and curves allow us to calculate the concentration of cold control hormone (CH) and cold test product (CX) which reduce by 50% the relationship titiraupenga hormone to the receptor.

Relative binding effect (ARL) of the product being tested is determined using equation ARL = 100 (CH) / (CX).

ARL control products: estradiol, progesterone, dexamethasone and testosterone arbitrarily taken equal to 100.

You get the following results ARL (see end of description)

Conclusion

The studied products, in particular products of Examples 2 and 8, have expressed a binding effect on the estrogen receptor.

The products of Examples 2, 7 and 8 have er:

(1) Tris - HCl pH 8 : 20 mmol EDTA : 0.5 mmol, DTT : 2 mm, glycerol : 20%, KCl : 400 mmol, PEAK 1%.

(2) potassium Phosphate pH 7.0 : 50 mmol, DTT : 5 mmol, glycerol : 20%, sodium molybdate : 20 mmol, PEAK 1%.

PEAK: leupeptin, pepstatin A, Aprotinin, antipain, hemostatis. The final concentration of each of them: 2.5 mg/ml

2) Antiproliferative impact products of the invention on the growth of tumor cells of the breast in humans (MCF-7)

Description of the test

a) cell Culture

Line MCF-7 are maintained in culture in a basic environment (see 1) containing 5% fetal calf serum, at a temperature of +37oC in a humid environment containing 5% CO2. Cells with podseleniem collected by tripetala (trypsin : 0.1% EDTA : 0,02%), and then washed with mild centrifugation. The weighted sample of cells is calculated on the cell Malassezia.

b) Investigation of growth

Cells are re-weighted in basic medium without phenol red in the presence of 5% destroydialog SVF and stimulated with either 0.1 nmol estradiol or 10 ng/ml EGF + 1 ng/ml PDGF. The cells are then sow at the rate of 50 thousand cells in each cell of the mesh plates (24 cells at 2.5 cm2). After 24 h after seeding with a concentration of 10-11up to 10-6mol, and controlled cell receive the same concentration of ethanol. Environment containing product, updated every 48 hours At the end of the experiment (days 7 to 9), the medium is aspirated and cells are immediately fixed with 250 μl of methanol for dosing of DNA.

Antiprolifera activity of the products is assessed through their ability to inhibit the increase of DNA relative to the control.

C) the Dosage of DNA

DNA dispense a fluorometric method using GASQUET (3.5 diaminobenzoic acid) (see 2): in each cell add 200 ál GASQUET; then the plates incubated for 45 min at a temperature of +56oC, and then add 2 ml of 1 N. hydrochloric acid. Fluorescence is measured using fluorometry (the length of the exciting wavelength: 408 nm, the length of the radiating wavelength: 510 nm).

The amount of DNA in each cell is measured relative to a reference range obtained by treatment in the same conditions of standard DNA calf thymus.

Results

Concentration in nm, inhibiting by 50% the growth of MCF-7 cells stimulated with EGF + PDGF (CI50), is determined by the above method.

The product of Example 2 : CI50= 0,0 is.

(1) the Basic medium was prepared as follows:

By Wednesday MOS (Minimum basic environment) add:

- non-essential amino acids (GIBCO): 1%,

- penetrate (penicillin 100 units/ml, streptomycin: 0.1 mg/ml),

- Fungizone: 0,1%,

- glutamine: 2 mmol,

- sodium bicarbonate: 2.25 mg/ml

(2) Poses and Goodman, Analytical Biochemistry, volume 86, page 50, 1978

1. 11-Substituted 19-norsteroid General formula I

< / BR>
in which n = 5 or 6;

R1and R2the same or different, is a hydrogen atom, a linear or branched alkyl radical C1- C8possibly substituted with halogen, or R1- carbamoyl radical, monosubstituted, linear or branched alkyl radical C1- C8or phenyl radical, possibly substituted by a halogen atom, and R2is a hydrogen atom, or R1and R2together with the nitrogen atom to which they are attached, form a cyclic urea of the formula

< / BR>
in which n = 2 or 3, or R1and R2form dialkyl-C1- C4-aminomethylphenol radical.

2. The compounds of formula I on p. 1, wherein R1and R2- hydrogen atoms.

3. The compounds of formula I on p. 1, wherein R1
1is a hydrogen atom, and R2- linear or branched alkyl radical alkyl radical C1- C8.

5. The compounds of formula I on p. 1, wherein R1- carbamoyl radical, monosubstituted, linear or branched alkyl radical C1- C8or a phenyl radical substituted by a halogen atom, and R2- the hydrogen atom.

6. The compounds of formula I on p. 1, characterized in that they represent the following compounds:

N-butyl-5-[4-(3,17-dihydroxy-östra-1,3,5(10)-trien-yl)phenoxy]-pentanesulfonate,

N-butyl-5-[4-(3, 17-dihydroxy-östra-1,3,5(10)-trien-yl)phenoxy]-N-methylmethanesulfonamide,

5-[4-(3,17-dihydroxy-östra-1,3,5(10)-trien-11-yl)phenoxy/-N-(2,2,3,3,4,4-heptafluorobutyl)-N-methylmethanesulfonamide.

7. The compounds of formula I on PP.1 - 6, with an antiestrogen and/or antiproliferative activity.

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

< / BR>
in which the phenolic hydroxy-group may be optionally protected,

expose halogen derivatives of the General formula III

X-(CH2)n-SOAthe same or different, is a hydrogen atom, a linear or branched alkyl radical C1- C8possibly substituted with halogen, and at least one of RAand R'Ais not a hydrogen atom,

to obtain compounds of General formula IV

< / BR>
which is then subjected to the action of the agent, flavouring cycle A, obtaining the compounds of formula IA< / BR>
< / BR>
where n and Rphave the above values,

which is then optionally subjected to one or more of the following reactions, in an appropriate order: recovery ketogroup in position 17, the selective acylation at position 3, saponification obtained acyl group, followed by the possible salt formation with the acid, or the compound of formula II

< / BR>
expose flavouring agent a cycle with simultaneous protection of the hydroxy-group in position 3, and then the reaction allocation protective group of the phenol in the position II to obtain compounds of General formula V

< / BR>
in which Rp- protective group,

which is exposed to the compounds of formula III'

X-(CH2)p-SO2-N=CH-N(Alk1)(Alk2)

where X is a halogen atom;

Alk1and the ina to obtain compounds of General formula VI

< / BR>
where n and Rphave the above values,

which if necessary is subjected to the reaction of removing the protective group Rp, restore ketogroup in the 17th position, acylation of the hydroxyl radical in position 3, the effect of the halogen of the formula VII:

RB-X

where RBis an alkyl radical C1- C8possibly substituted with halogen;

X is a halogen atom,

to obtain compounds of General formula IB< / BR>
< / BR>
where n has the above meaning,

or exposure to isocyanate of General formula VIII

Rc-NCO,

in which Rcis an alkyl radical C1- C8possibly substituted with halogen,

to obtain compounds of General formula Iccorresponding to the compound of formula I, where R1- monosubstituted carbamoyl radical, and R2is a hydrogen atom,

< / BR>
where n has the above meaning

the effects of compounds of General formula IX

(Alk3O)(Alk4O)CH-N(Alk1)(Alk2)

in which Alk1- Alk4are alkyl radicals comprising from 1 to 4 carbon atoms,

to obtain compounds of General formula IDthe product of formula I in which R1and R and R3have the meanings specified in paragraph 1 of the formula

the reaction of cyclization of the product of formula Icwhen Rcrepresents the radical -(CH2)n'-Hal, where n' = 2 or 3 and Hal is a halogen atom,

to obtain the compounds of formula Ic, corresponding to the compound of formula I, where R1and R2form together with the nitrogen atom to which they are bound, a cyclic urea of the formula

< / BR>
where n' = 2 or 3,

possible salt formation with acids.

9. Compounds of General formula IV - VI as intermediates in the synthesis PP.8 and 9.

10. Pharmaceutical composition having anti-estrogenic and antiproliferative activity, comprising the active principle and a pharmaceutically acceptable additive, characterized in that the active agent contains a compound of formula I in an effective amount.

 

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