Methods of obtaining derivatives of azasteroid, derived azasteroid-imidazoline, method of its production

 

(57) Abstract:

The invention relates to an improved method of obtaining carboxamido-4-azasteroid General formula I, in which the dashed lines independently represent either simple or double bond, R, R1, R2and R3each represents hydrogen or an organic radical comprising processing the corresponding intermediate compounds of the 17-carbonyl-imidazoles anhydrous acid in the presence of amine and, optionally, hydrogenation of the compounds obtained. The method gives good yields and allows to obtain amides of sterically obstructed and/or having low nucleophilicity and, consequently, the low reactivity of amines. 4 C. and 4 h.p. f-crystals.

The present invention concerns a method of obtaining carboxamido-4-azasteroid and, more specifically, it relates to a method of obtaining 17 carboxamido-4-azasteroid on the basis of the corresponding derivatives of 17-carbonyldiimidazole.

Carboxamido-4-azasteroid, such as, for example, 17-carboxamido-4-azo-5-androstane-3-ones and related derivatives of unsaturated androstadienone are known compounds that have pharmacological activity, and the FDI for the treatment of hyperandrogenic conditions.

To obtain basic information about the pharmacological activity of these compounds, see EP-A-0271220, WO 94/03475 and an article in "Current Pharmaceutical Design, 1996, 2, 59-84. A few ways to get carboxamido-4-azasteroid known in the literature.

For example, as reported in international patent application WO 94/03475, on behalf of the applicant, 17 carboxamido-4-azasteroid obtained by reaction of the appropriately activated 17-carboxy-4-azasteroid with a suitable amine.

Activated accordingly carboxyl groups forming amide linkages include, for example, acylchlorides, complex thioethers, esters of hydroxybenzotriazole, mixed anhydrides and derivatives elimidate.

The majority of these activated groups, although they are suitable for the formation of amide bonds, cannot be used to obtain carboxamido-4-azasteroid due to the fact that they react with the nitrogen atom azasteroid fragment or a double bond in position 5,6 - androst-5-ene or androsta-1,5-diene, if it is present, or, alternatively, due to the fact that they are directionspanel in relation to the selected amine.

Therefore, having a goal to find a synthetic approach to the one obtained by the above activated group was directionspanel in relation to other functional groups, present in the molecule, we have noticed that you can successfully use derivatives imidazoline.

However, steric employed or having low nucleophilicity and therefore insufficient reactivity amines or did not respond 17-carbonyldiimidazole-4-azasteroid, or gave the opportunity to get the expected amides with outputs even lower than 20%.

For example, as reported by A. Bhattacharya et al. log Synthetic Communications, 30, (17), 2683-2690 (1990), attempt to make a direct condensation of 3-oxo-4-azo-androst-1-ene-17-Allendale with tert-butylamine to obtain the corresponding amide, was unsuccessful, even under extremely severe conditions of the reaction.

Similarly, with the aim of obtaining fluorinated amides, condensation between 3-oxo-4-azo-androst-5-ene-17-carbonyldiimidazole and fluorinated amine did not give us the corresponding amide, even when carrying out the reaction in hard conditions, i.e. under pressure in an autoclave.

In European patent application EP-A-0367502 in the name of "Merk and Co. Inc. the described method for the preparation of 3-oxo-4-azasteroid, including derivative 17-carboxamido reaction of the corresponding intermediate compounds - derived 17-carbonyldiimidazole with a suitable amine in which the use of Grignard reagents, especially on an industrial scale, you want to take strong precautions to avoid the risk of dangerous reactions.

Therefore, although the above method will give the desired amide with high outputs, when the industrial application of this method may encounter significant obstacles.

In addition, using the same techniques cannot be obtained fluorinated 17-carboxamide with acceptable yields and purity.

In this regard, we unexpectedly found that these derivatives imidazoline can be converted to the desired amide under mild conditions in the presence of acids.

Therefore, the object of the present invention is a method of obtaining compounds of the formula

< / BR>
in which the dotted line, independently of one another, denote a single or double bond;

R and R1identical or different, represent a hydrogen atom or linear or branched C1-C6-alkyl, phenylalkyl, alkylphenyl or alkylresorcinol group, and these alkyl groups substituted by one or more fluorine atoms;

R2represents a hydrogen atom or a C1-C4is an alkyl group, neobyazatel is Orada; provided that at least one of the groups R and R1contains one or more fluorine atoms, and that when the dotted line in position 5, 6 denotes a double bond,3no;

which involves the reaction of a derivative imidazoline formula

< / BR>
in which the dotted line, R2and R3have the above values; anhydrous acid in the presence of an amine of the formula

HN(R)R1(III)

in which R and R1have the above meanings; and, if desired, the hydrogenation of the compounds of formula (I), in which one or both dotted lines represent a double bond.

The method which is the subject of the present invention, allows to obtain the compounds of formula (I) under mild conditions and, even more importantly, it allows you to obtain the compounds of formula (I) of the amines with low reactivity, such as amines with low nucleophilicity and/or steric employed amines, such as fluorinated or completely fluorinated amines.

In the present description, if it is not specifically mentioned, the term "linear or branched C1-C4or C1-C6is an alkyl group" is covered by a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-C6-fenilalanina, alkylphenyl or alkylphenolethoxylate group" covered phenyl group that is associated with a linear or branched C1-C6is an alkyl group, such as described above.

The term "anhydrous acid" generally refers to the acid with a very low water content, and this acid is a mineral acid, a strong organic acid or a Lewis acid.

Examples of strong mineral or organic acids are hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonate acid, p-toluensulfonate acid, triftormetilfullerenov acid, camphorsulfonic acid, etc.

Examples of Lewis acids are, for example, zinc chloride, zinc bromide, aluminum chloride, aluminum bromide, iron chloride (III) bromide iron (III), etc.

To obtain basic information about the specified acids and, in particular, about the Lewis acids, see, for example, J. March, Advanced Organic Chemistry, sixth ed. , 1992, John Wiley and Sons, Chapter 8, pages 248-272.

In formulas (I-II) above, the dotted line (---- in position 5 indicates a Deputy, in-configuration, i.e. below the plane of the ring, and wedge-shaped lines at positions 10, 13 and 17 indicate the replacement of the mi connections, obtained according to the method of the present invention are the compounds of formula (I) in which one of the radicals R and R1represents a hydrogen atom and the other represents a linear or branched C1-C4-alkyl, phenylalkyl or alkylresorcinol group, substituted in the alkyl fragment, at least one fluorine atom.

Even more preferred compounds in this class are the compounds of formula (I), in which the said alkyl groups are C1-C3-performanceline groups, such as, for example, triptoreline, 1,1,1-triptoreline, 1,1,1,2,2-panafcortelone or 1,1,1,3,3,3-geksaftorpropena group.

The method according to the present invention preferably is carried out to obtain one of the following 17 carboxamido-4-azasteroid:

1)N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androst-1-ene-17-carboxamide;

2)N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide;

3) N-(1,1,1,3,3,3-echapter-2-phenylprop-2-yl)-3-oxo-4-azo-androst-1,5-diene-17-carboxamide;

4) N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-androst-5-ene-17-carboxamide;

5) N-[1,1,1,3,3,3-hexamer-2-(p-were) the-5-androstane-17-carboxamide;

7) N-[1,1,1,3,3,3-hexamer-2-(p-were)prop-2-yl] -3-oxo-4-Asandros-1,5-diene-17-carboxamide;

8) N-[1,1,1,3,3,3-hexamer-2-(p-were)prop-2-yl] -3-oxo-4-Asandros-5-ene-17-carboxamide;

9) N-[1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-azo-5-androst-1-ene-17-carboxamide;

10) N-[1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide;

11) N-[1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-Asandros-1,5-diene-17-carboxamide;

12) N-[1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-Asandros-5-ene-17-carboxamide;

13) N-[1,1,1-Cryptor-2-(p-were)prop-2-yl] -3-oxo-4-azo-5-androst-1-ene-17-carboxamide;

14) N-[1,1,1-Cryptor-2-(p-were)prop-2-yl]-3-oxo-4-azo-5-androstane-17-carboxamide;

15) N-[1,1,1-Cryptor-2-(p-metalpar)prop-2-yl] -3-oxo-4-azo-androst-1,5-diene-17-carboxamide;

16) N-[1,1,1-Cryptor-2-(p-were)prop-2-yl] -3-oxo-4-azo-androst-5-ene-17-carboxamide.

The method according to the present invention is carried out by reaction of a derivative of 17-carbonyldiimidazole formula (II) with anhydrous acid in the presence of an amine of formula (III) in an inert atmosphere.

As indicated above, examples of acids are, for example, gaseous hydrogen chloride or hydrogen bromide and sulfuric acid, methanesulfonate acid, triptorelin oral zinc, the zinc bromide, aluminum chloride, aluminum bromide, ferric chloride and bromide iron (III).

Preferably, these acids are gaseous strong mineral or organic acids.

More preferred acids are methansulfonate acid or hydrogen chloride.

These acids are used in at least stoichiometric quantities, or, preferably, in a molar ratio derived imidazoline: acid = 1:2.

Large excess of acid are equally effective and useless.

The reaction is performed by adding the selected acid to the solution derived imidazoline formula (II) and an amine of formula (III) in a suitable solvent at a temperature ranging from room temperature to the temperature of reflux distilled reaction mixture over a period of time ranging from 1 hour to 12 hours.

Preferably choose the reaction temperature being in the range between 40 and 70oC.

Suitable solvents are chlorinated hydrocarbons, C1-C3such as, for example, methylene chloride, chloroform or 1,2-dichloroethane and acetonitrile, Tetra is,, and so triptorelin p.

It is preferable for implementing the method of the present invention is used as the initial substance derived imidazoline formula (II) containing one double bond in position 5,6 steroid fragment.

Derivatives imidazoline formula (II) described above, in which the dotted line in position 1,2 denotes a simple link, and the dotted line in position 5,6 denotes a double bond, are novel compounds and constitute a further object of the present invention.

In one embodiment, the method of this invention derived imidazoline formula (II) dissolved in the above solvent, is first subjected to a reaction with the specified anhydrous acid.

The proposed additive salt derived imidazoline formula (II) then reacts in situ and therefore without the need for separation and subsequent treatment with a suitable amine of formula (111) to obtain the expected 17 carboxamido-4-azasteroid formula (I).

This reaction is carried out by direct mixing of salt and a suitable amine in the same reaction system, at a temperature in the range between room temperature and topictitle choose the reaction temperature in the range between 40 and 70oC.

The compounds of formula (I) thus obtained with good yields and easily isolated and purified by conventional methods.

Educt of the formula (II) are obtained according to conventional methods by reaction of the corresponding carboxylic acid, possibly in an activated form, with a derivative of imidazole, such as, for example, carbonyldiimidazole, oxalylamino or sulfanilimide.

For basic information about how to obtain the compounds of formula (II), see, for example, the above-mentioned published international application WO 94/03475 and the application for the European patent EP-A-0367502.

Derivatives of 4-Asandros-5-ene-17-carbonyldiimidazole formula (II), which are new compounds, are as defined above, by reaction of 3-oxo-4-Asandros-5-ene-17-carboxylic acids of the formula.

< / BR>
in which

R2represents a hydrogen atom or a C1-C4is an alkyl group, optionally substituted by one or more fluorine atoms;

with carbonyl-diimidazole, sulfonyl-diimidazole or oxalyl-diimidazole, in accordance with those reported in the literature (see, for example, Angew. Chem., 1962, 74, 407).

For information about how to obtain the derivative carb"decision Upjohn and Co.".

Alternatively, amines of formula (III) are known or easily obtained according to known methods as described, for example, in the above-mentioned published international application WO 94/03475.

Thus, using as the starting material the appropriate derivative of the formula (II) having one, two, or not having a single double bond in the steroid part, receive the appropriate carboxamido-4-azasteroid formula (I).

To some extent the experts in this field it is obvious that by hydrogenation of compounds of formula (I) having one or two double bonds, in accordance with the present invention it is possible to obtain the corresponding saturated compounds of formula (I), in which the two dotted lines represent a simple link.

The specified stage hydrogenation is conducted according to conventional methods.

For example, the hydrogenation can be carried out in a suitable solvent, such as methanol, ethanol or acetic acid, in the presence of from about 10 to 30% of conventional hydrogenation catalysts, such as, for example, catalysts based on palladium, platinum or rhodium, at a pressure of hydrogen of from about 3 to 7 atmospheres and at temperatures in the range between room temperature the present invention the compound of formula (I), such as, for example, n-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide used as a medicinal product, obtained by reaction of a derivative of 3-oxo-4-Asandros-5-ene-17-carboxylic acid of formula (IV) in a suitable solvent, such as dimethylformamide, with the required amount of 1,1'-carbonyl-diimidazole.

The reaction mixture was kept under stirring at a temperature of 60oC for 4 hours.

Thus obtained 3-oxo-4-Asandros-5-ene-17-carbonyldiimidazole formula (II) is mixed with the required amount of 1,1,1,3,3,3-hexamer-2-phenylprop-2-yl-amine of formula (III), then slowly treated in nitrogen atmosphere at 60oAnd with good stirring, the desired amount of anhydrous strong acid, such as anhydrous methansulfonate acid. The reaction mixture was kept at 60oWith stirring for 6 hours.

Thus obtained N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-Asandros-5-ene-17-carboxamide formula (I) is isolated and purified by conventional methods, then subjected to catalytic hydrogenation, for example, in the Parr apparatus or in an autoclave in the presence of catalytic amounts of 5% Pt on charcoal, and get N-(1,1,1 is the subject of the present invention, gives a very profitable way of synthesis for the preparation of derivatives of 17-carboxamido-4-azasteroid, with good yields and under mild conditions, using as starting substances are known or easily derived compounds and even without the isolation of intermediate reaction products.

Moreover, it allows to obtain amides of sterically obstructed and/or having low nucleophilicity and, consequently, the low reactivity of amines.

To better illustrate the present invention without limitations the following are the following examples.

Example 1

Obtaining 3-oxo-4-Asandros-5-ene-17-carbonyl-1-imidazole

1,1-Carbonyldiimidazole (70,5 g; 0,435 mol) is added to a vigorously stirred suspension of 3-oxo-4-Asandros-5-ene-17-carboxylic acid (115 g; 0,362 mol) in N,N-dimethylformamide (1,44 l). The mixture is heated to 60oC for 4 hours, and the thus formed precipitate.

The reaction mixture was concentrated in vacuo and diluted with ethyl acetate; the precipitate is filtered off, washed with ethyl acetate and dried in vacuum at 40oWith; get 3-oxo-4-Asandros-5-ene-17-carbonyl-1-imidazole (of 116.7 g) as a pale yellow solid.

Repeating such W is 284-8oWith decomposition; purity >98%, according to analysis by HPLC).

NMR (CDCl3), (ppm): 1,18 (s, 1H, H (2 )), 8,10 (ush. s, 1H, NH (4)), 7,60 (s, 1H, H (5 )), 7,10 (s, 1H, H (4 )), to 4.81 (m, 1H, H (6)), 1,11 (s, 3H, Me (19)), to 0.78 (s, 3H, Me (18)).

Example 2

Obtaining N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-Asandros-5-ene-17-carboxamide

3-Oxo-4-Asandros-5-ene-17-carbonyl-1-imidazole (29,05 g; 79,05 mmol) dissolved in chloroform (174 ml) under nitrogen atmosphere at room temperature.

Added to the resulting solution in one portion of 1,1,1,3,3,3-hexamer-2-phenylprop-2-ylamine (38,45 g; 158,11 mmol).

The temperature of the reaction mixture increased to 60oAnd, with vigorous stirring, added dropwise methanesulfonyl acid (0,26 ml; 58,11 mmol). The mixture was stirred at 60oC for 6 hours in nitrogen atmosphere and then cooled to room temperature, thoroughly washed with 0.5 N. NaOH (300 ml + 250 ml), brine and dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo get a yellowish solid (51,56 g).

The crude product is purified by treatment with stillettos while heating under reflux, concentrated and precipitated by adding tert-butyl methyl ether; after filtration with unplugging the n-17-carboxamide (20,38 g; so pl. 251-3oWith decomposition; purity 99,11%, determined by HPLC).

From the mother solution by similar processing to get the second connection portion (9,20 g; purity 98%, determined by HPLC), which increased the total yield up to 69%.

NMR (CDCl3), (M. D.): 7,60-7,37 (m, 6N, Ph + NH (4)), of 5.83 (s, 1H, NH (21)), to 4.81 (m, 1H, H (6)), 1,11 (s, 3H, Me (19)), 0,76 (s, 311, Me (18)).

Example 3

Obtaining N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide

A solution of N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-Asandros-5-ene-17-carboxamide (23,04 g; of 42.46 mmol) in glacial acetic acid (460 ml) hydronaut in an autoclave in the presence of 5% palladium on coal (23,0 g) under hydrogen pressure of 7 bar at 50oC.

The mixture is cooled to room temperature, the catalyst is filtered off and the filtrate poured into water (3 l). After neutralization with 15% NaOH, the solid is collected by filtration with suction, thoroughly washed with water and dried at 50oWith under vacuum.

Get N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide (21,36 g; output 91,95%) as a white solid (so pl. 254-8oC, with decomposition).

NMR (CDCl3), (M. D.): 7,50-7,30 (m, 5H, Ph), 5,88 (ush. s, 1H, NH (21)), 5,42 (USIA 3-oxo-4-azo-5-androst-1-ene-17-carbonyl-1-imidazole

1,1'-Carbonyldiimidazole (2.00 g; 12,36 mmol) and 3-oxo-4-azo-5-androst-1-ene-17-carboxylic acid (3,14 g; of 9.89 mmol) is suspended in N,N'-dimethylformamide (37 ml) under argon. The mixture is heated to 65oC for 4 hours. Solids are first dissolved and then formed a new precipitate. After cooling, the solvent is evaporated in vacuo and the resulting thick suspension is diluted with methyl tert-butyl ether. After storage at +4oWith in 48 hours the substance is filtered off with suction, washed with methyl tert-butyl ether and dried at 50oWith under vacuum. Get 2,97 g (81,8%) of light brown solid.

NMR (CDCl3), (M. D.): 8,43 (s, 1H, H (2 )), 7,71 (s, 1H, H (5 )), 7,40 (ush. s, 1H, NH (4)), 7,05 (s, 1H, H (4 )), 6,77 (d, 1H, H (1)), 5,57 (LW. d, 1H, H (2)), 3,42 (t, 1H, H (17)), 3,17 (LW. d, 1H, H (5)), of 0.82 (s, 3H, Me (19)), to 0.63 (s, 3H, Me (18)).

Example 5

Obtaining N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androst-1-ene-17-carboxamide

To a suspension of 3-oxo-4-azo-5-androst-1-ene-17-carbonyl-1-imidazole (2,97 g; 8,08 mmol) in chloroform (17,8 ml) is added to argon 1,1,1,3,3,3-hexamer-2-phenylprop-2-ylamine (geksaftortantalatom) (3,93 g; 16,16 mmol). The temperature was raised to 50oWith that added dropwise methanesulfonyl acid (1,05 ml; 16,16 mmol), ZAT the tours, the suspension is filtered through a funnel Guca, the filter plate is washed with methylene chloride (10 ml); the clear filtrate is evaporated to dryness under vacuum, dissolved in tetrahydrofuran (16 ml) and treated with 2 M NaOH with good stirring for 1 hour. The mixture is then diluted with water (50 ml) and extracted with ethyl acetate (325 ml). The collected organic extracts are washed with 0.5 M NaOH (20 ml), dried over sodium sulfate, the solvent is evaporated under vacuum; get 5,63 g crude product.

The crude product is purified by crystallization from ethyl acetate and tert-butyl methyl ether, dried in a drying Cabinet at 50oWith in a few hours; get 2,69 (61,4%) pure white solid connections (so pl. 218-222oC).

NMR (CDCl3), (M. D.): 7,38-rate of 7.54 (m, 5H, PH), 6,79 (d, 1H, H (1)), of 5.89 (s, 1H, NH (21)), of 5.82 (LW. d, 2H, H (2)); 5,39 (s, 1H, NH (4)), 3,33 (LW.d, 1H, H (5)), and 0.98 (s, 3H, Me (19)), from 0.76 (s, 3H, Me (18)).

Mass spectrum (FAB-) (m/z): 541 [M - N]-, 471 [M - CHF3]-.

1. The method of obtaining derivatives of azasteroid formula (I)

< / BR>
in which the dotted line- - - - -independently from each other, represent a simple or a double bond;

R and R1that are the same or different, each represents hydrogen or linear or razvetvitelnye alkyl groups are unsubstituted or substituted by one or more fluorine atoms;

R2represents hydrogen or C1-C4is an alkyl group, optionally substituted by one or more fluorine atoms;

R3when it is present, is a hydrogen atom; provided that at least one of the radicals R and R1contains one or more fluorine atoms, and when the dotted line in position 5,6 denotes a double bond, R3no;

comprising the reaction of derivatives of azasteroid-imidazoline formula (II)

< / BR>
in which the dotted line, R2and R3have the meanings indicated above, with an anhydrous acid in the presence of an amine of formula (III)

HN(R)R1(III)

in which R and R1have the values specified above;

and, if desired, the hydrogenation of the obtained derivative azasteroid formula (I), in which one or both dotted lines represent a double bond.

2. The method according to p. 1, in which the anhydrous acid is methansulfonate acid.

3. The method according to p. 1, in which in the formula (I) one of the radicals R and R2represents hydrogen and the other represents a linear or branched C1-C4-alkyl, phenylalkyl or alkylresorcinol group substituted by stirna line in position 1,2 denotes a simple link, and the dotted line in position 5,6 denotes a double bond.

5. The method according to p. 1, in which the received derived azasteroid formula (I) is a compound selected from

N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androst-1-ene-17-carboxamide;

N-(1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-5-androstane-17-carboxamide;

N-( 1,1,1,3,3,3-hexamer-2-phenylprop-2-yl)-3-oxo-4-azo-androst-5-ene-17-carboxamide;

6. Derived azasteroid-imidazoline formula (II)

< / BR>
in which R2represents hydrogen.

7. The method of deriving azasteroid-imidazoline defined in paragraph 6, including reaction derived Asandros-5-ene of the formula

< / BR>
in which R2is defined as in paragraph 6,

with carbonyl-diimidazole.

8. The method of obtaining the derived azasteroid formula (I)

< / BR>
where one of the radicals R and R1represents hydrogen and the other represents C1-C4-phenylalkyl group, substituted by one or more fluorine atoms;

R2represents hydrogen or C1-C4is an alkyl group, optionally substituted by one or more fluorine atoms;

including

(i) reaction of p is a carbonyl-diimidazole education derived azasteroid-imidazoline formula (II)

< / BR>
in which R2has the values listed above;

(ii) reaction of the obtained derivative azasteroid-imidazoline formula (II) with anhydrous methanesulfonic acid in the presence of an amine of the formula

HN(R)R1(III)

in which one of the radicals R and R1represents a hydrogen atom and the other represents C1-C4-phenylalkyl group, substituted by one or more fluorine atoms;

(iii) hydrogenation of the obtained derivative azasteroid formula (I)

< / BR>
in which R, R1and R2have the values specified above.

 

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The invention relates to a method of obtaining a mixture of sulfated estrogen containing Delta (8,9)-dehydration formula I [Delta(8,9)-DGA] or its derivatives, where R1- H, R2- N and R3- O-acyl or R3- N and R2- O-acyl, or R2and R3together - O and in formula III, R1- silyl (alkyl)3or tetrahydropyranyl, R2and R3together, O or R2and R3together - acetal

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The invention relates to salts of compounds of formula (I) in the case where these compounds contain aminopentyl, in particular with hydrochloric acid, Hydrobromic acid, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, Glyoxylic, aspartic acids, alkanesulfonyl, such as methane - and ethane-sulfonic acids, arylsulfonate, such as benzene and paratroop-sulfonic acids, and arylcarbamoyl acids, and, when the compounds of formula (I) contain an acid function, the salts of alkali, alkaline earth metals and ammonium, optionally substituted

The invention relates to a sulphamate derivatives derivatives of 1,3,5(10)-estratriene General formula (I), where R1- COR3, -COOR4, -CONR5R6, -SO2R4or-SO2NR5R6where R3and R4independently C1- C5alkyl, C3- C6cycloalkyl or phenyl, R5and R6independently C1- C5alkyl; R2is a hydrogen atom or a C1- C5alkyl; R7and R8independently a hydrogen atom or a C1- C5alkoxygroup; R9and R10is a hydrogen atom or together a methylene group; R11- R13independently a hydrogen atom or hydroxyl group, optionally esterified physiologically acceptable inorganic or organic acids, or R12and R13quinil to 5 carbon atoms and R8, R11and R12independently located in theor-position

The invention relates to pharmaceutical industry
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