Derivatives of androstane, replaced by a 16-position quaternary ammonium group, the pharmaceutical composition

 

(57) Abstract:

The invention relates to new androstane derivative of formula I, where R1is a hydrogen atom or alkanoyl: R2- alkanoyl; W1and W2- same or different, or one of the symbols means a chemical bond, and the other , or W1- , and W2- ; one of R3and R4- the hydrogen atom and the other is - OR1or R3and R4together mean oxoprop or C2-5- alkylenedioxy; E, R5- alkyl or alkenyl; provided that derivatives containing a cyclic structure with two atoms of nitrogen, only the Deputy E means the above group, which is connected by a chemical bond with the nitrogen atom not directly related to steroid skeleton of the molecule, while the other alternate E mean free pair of electrons; X-anion, and n and m independently of each other - 2 or 4 provided that the sum of n and m in one cyclic structure is from 4 to 6, regardless of their values in a different cycle. The compounds of formula I possess non-destructive neuromuscular blocking action and can be used to myorelaxation during endotracheal anesthesia, and also in shock therapy and for leczenie relates to new, therapeutically active derivatives of androstane, replaced by the 16-th position of the Quaternary ammonium group and having the formula (I)

< / BR>
in which

R1means a hydrogen atom or a C1-4-alkanoyloxy group;

R2means C1-4-alkanoyloxy group;

W1and W2are the same or different >CR3R4group or one of the symbols means a chemical bond (valence), and the other - >CR3R4or W1means >CR3R4group, and W2- >NER5group;

one of the symbols R3and R4means a hydrogen atom, and the other is-OR1group, or R3and R4together mean oxoprop or C2-5-alkylenedioxy group;

E - means C1-4-alkyl or C3-5-alkenylphenol group with the proviso that the derivative containing a cyclic structure with two atoms of nitrogen, only the Deputy E means the above group, which is connected by a chemical bond with the nitrogen atom, indirectly related to steroid skeleton of the molecule, while the other alternate E mean free pair of electrons;

X-means equivalent to the number of anion and n and m independent is from their values in a different cycle, and also their salts acidic connection and pharmaceutical compositions containing these compounds.

In addition, the invention relates to a method for preparing the above compounds and compositions.

The compounds of formula (I) possess the ability to block neuromuscular transmission.

Hence, the invention also relates to a method of treatment, which is characterized by the introduction into the organism of mammals (including humans) with one or more therapeutically effective doses of the compounds of formula (I) or pharmaceutically acceptable salts of acidic join as individual drug or as a pharmaceutical composition to block the transmission of impulses from nerves in striated muscle.

Numerous literary references, patent applications and scientific publications confirm therapeutic significance of neuromuscular blockers.

The first significant research results in the field of steroidal neuromuscular blockers is described in the patent [1]. This patent describes the synthesis of derivatives of 2, 16-bis(amino)-3, 17-diacetoxy-5 - androstane and their Quaternary salts. These compounds contain piperidinol in the molecules of these compounds can be formed only by nitrogen atoms, associated with the carbon atoms C-2 and C-16 .

The methods of synthesis described in the aforementioned patent, and the results of biological studies summarized in [2].

Described in this publication compounds pancuronium bromide (chemical name 1,1'-[3, 17-bis(acetoxy) -5-androstane-2, 16-diyl] bis[1-methylpiperidine] dibromide) were used in therapy as a neuromuscular blocker, characterized by a prolonged period of influence and nedepoliarizuth mechanism of action.

As vecuronium bromide (chemical name 1-[ 3, 17-bis(acetoxy] -2- (1-piperidinyl)androstane-16-yl]-1-methylpiperidine dibromide hydrochloride) is derived, similar in structure to the pancuronium bromide, except that its molecule contains only one Quaternary group on the nitrogen atom associated with carbon atom C-16, has a shorter period and did not show adverse effects on the cardiovascular system, this connection has more benefits than pancuronium and other bischetvertichnoe derivatives. Preparation of pancuronium described in [3].

The results of later research in the field of neuromuscular blockers is described in [6]. From womanto -2, 16-diyl] bis[1,1-dimethylpiperazine] dibromide) by their efficiency and stabilizing effect on the heart and blood-vascular system exceeds the pancuronium bromide and vecuronium bromide.

In addition, the syntheses of Quaternary derivatives of bis(amino)androstenol described in [4, 5, 6].

The compounds disclosed in these literary sources, still has not found clinical application.

Methods of synthesis of Quaternary derivatives of the so-called Aza-aminosteroids with different chemical structure, described in [8].

Despite the fact that these compounds are characterized by a rapid onset and short duration of action, they show a number of adverse effects on the cardiovascular system and for this reason are not used in the clinic.

Despite the fact that the pancuronium bromide, vecuronium bromide and bromide pipeborne widely used in clinical practice, there is still a demand for drugs that possess the most desirable properties (e.g., faster onset of action).

Convenient for clinical application of neuromuscular blocker must have nedepoliarizuth mechanism of action, should not be vagal roulete stabilizing effect on the cardiovascular system. Another is the rapid onset of drug action, allowing earlier intubation. This property of the drug from the point of view of anesthesia is an important safety factor. Another requirement for a short period, this requirement increases the controllability and safety of use of these compounds for surgical intervention.

The aim of the present invention to provide compounds, which are qualitatively superior to the known level of science, having a stabilizing effect on the cardiovascular system, as well as rapid onset and short duration of action.

Unexpectedly, it was found that derivatives of androstane formula (I), substituted at the 16-th position Quaternary amino group, have a rapid onset and short duration of action and have a stabilizing effect on the cardiovascular system. The main structural difference between these compounds from the compounds described in the previous literature, is that at least one of the substituents at the amine nitrogen atom contains hydroxyl, C1-4- alkanoyloxy or C2-5-alkylbenzenesulfonate) the above properties lead to a more favourable therapeutic application of new derivatives of androstane.

According to the invention the compounds of formula (I) and their salts of acidic accession prepare

a) to obtain androstane derivative of formula (I) containing as W1>CR3R4group, and the number W2the valence bond or >NER5group.

conducting the reaction of a derivative of 17-hydroxy-16-amino -2, 3-epoxidated formula (IV)

< / BR>
in which

Z1mean valence bond or an >NR5group

with the heterocyclic amine of formula (VII)

< / BR>
in which

Z means >CR3R4group;

after that the necessary derivatives 3, 17 - dihydroxy-2, 16-diaminooctane formula (IIIa)

< / BR>
in which

Z2means the same thing, and Z,

A1) is treated with acid for hydrolysis of C2-5-alkylenedioxy group denoted by R3and R4with the formation of the carbonyl group and/or

A2) restore, turning oxoprop, denoted as R3and R4in a hydroxyl group; and acetimidoyl 17-hydroxyl group, or having more than one hydroxyl group with an active derivative of C1-4-alkenylboronic acid in one or more alleluya stud is

ultimately, the obtained acetylated derivative 3, 17-dihydroxy-2, 16-/ diaminonaphthalene formula (IIa)

< / BR>
in which

W1determined as specified in this way, transformed into a Quaternary ammonium salt with C1-4-quinil and C3-5-alkenylamine; or

b) to obtain androstane derivative of formula (I) containing as W1the valence bond or >CR3R4group and as W2>CR3R4the group carried out the reaction of a derivative 17-halogen-2, 3:16, 17-diepoxyoctane formula (VI)

< / BR>
in which

Y is halogen, with the derived heterocyclic amine of the formula (VII) in which Z signifies >CR3R4group; a derivative of 17-oxo-16-amino-2, 3-epoxidated formula (V)

< / BR>
in which

Z2means the same thing, and Z, restore the alkali metal borohydride; conduct reaction derived 17-hydroxy-16-amino-2, 3 - epoxidated formula (IV)

< / BR>
with the derived heterocyclic amine of the formula (VII) in which Z signifies a valency bond or >CR3R4group; of necessity derived 3, 17-dihydroxy -2, 16-diaminooctane formula (IIIB)

< / BR>slotow for hydrolysis of C2-5-alkylenedioxy group denoted by R3and R4and education in the carbonyl group and/or

B2) restore the transformation of the carbonyl group denoted by R3and R4in the hydroxyl group and acetimidoyl on the hydroxyl group in the 17-th position or by having one or more hydroxyl groups with an active derivative of C1-4-alkenylboronic acid in one or more alleluya stages before hydrolysis alkylenedioxy group and/or before and/or after recovery of the carbonyl group;

ultimately, the obtained acetylated derivative 3, 17-dihydroxy-2, 16-/ diaminooctane formula (IIB)

< / BR>
in which

W1and W2determined as provided in this way is converted into a Quaternary ammonium compound with C1-4-alkylhalogenide or C3-5-alkenylamine;

then, if necessary, obtained androstane derivative of formula (I), substituted at the 16-th position of the Quaternary ammonium group into salt sour accession, treating it in a non-toxic inorganic or organic acid.

The compound of formula (IIB) and (IIIB) is symmetric or asymmet the 2-th and 16-th positions.

According to the invention in addition to the derivatives of formula (I) are new compounds are compounds described in formulas (IIA) (IIB), (IIIA) and (IIIB). Also new compounds are intermediate compounds of formulas (V) and (IV) containing the Z2>CR3R4the group in which one of the symbols R3and R4denotes the hydrogen atom and the other is hydroxyl group, or R3and R4together denote C2-4-alkylenedioxy group.

Derivatives of 17-hydroxy-16-amino-2, 3 - epoxidated formula (IV) and derivatives 17-halogen -2, 3:16, 17-diepoxyoctane formula (VI) used according to the invention as starting compounds, are described respectively in [10] and [11].

According to method (a) is preferably carried out the reaction of the compound of formula (IV) with 1,4-dioxa-8 azaspiro[4,5]decane or 4-hydroxypiperidine in the presence of water or in a mixture with an inert organic solvent, for example in a mixture of H-propanol and water, at the boiling temperature of the reaction mixture. Over the course of the reaction is observed by thin layer chromatography (TLC). Upon completion of the reaction (for the occurrence of which requires 70 - 100 hours) the excess of the amine used together with the solvent is distilled off, the wasp is Assiut. In accordance with another variant of cleaning residue is stirred, for example, acetonitrile or acetone, and after deposition of the mother liquor is dried and then, if necessary, recrystallized.

One or more hydroxyl groups of the obtained derivatives 3, 17-hydroxy-2, 16-diaminooctane formula (IIIA) is preferable aeriferous as follows.

After dissolution of the compounds of the formula (IIIA) in a halogenated hydrocarbon, preferably in methylene chloride, and adding the base is a tertiary amine, preferably triethylamine, the solution is cooled to 0-5oC and depending on the number acatalasemia hydroxyl groups of greater or lesser excess in comparison with the equivalent amount of the anhydride alkenylboronic acid or acid chloride alkenylboronic acid, preferably acetylchloride, in portions added to the solution so that the temperature did not exceed 10oC. Then increase the temperature of the reaction mixture to room temperature and maintain it at this level until the end of the reaction. When will acetimidoyl not all the hydroxyl groups of the molecule, with the reaction preferably be monitored using TLC, Thu is by adding water, the solution is washed with water, and then diluted aqueous sodium hydroxide solution until neutral. After distillation of the solvent, the obtained product was then purified using chromatography or recrystallization, or by using both methods.

The compounds of formula (IIa) can also be prepared in another way: the compound of formula (IIIa) containing the Z2>CR3R4the group in which R3and R4mean C2-5-alkylenedioxy group, hydrolyzing boiling in dioxane in the presence of acid to obtain the corresponding derivative of formula (IIIa), containing as Z2>C=O group, and then, upon completion of the reaction, the solution podslushivaet, the dioxane is distilled off, after thorough mixing with water, the residue is filtered, the precipitate washed with water to remove the mother liquor, then dried and recrystallized, after which the compound obtained of the formula (IIIa) acetimidoyl one or more hydroxyl groups in the manner described above.

If necessary, the compound of formula (IIIa), containing as Z2>C= O group, can also be recovered before or after acetylation is preferable Nole or in the solvent of the ether type, preferably tetrahydrofuran or kalogeropoulou, such as methylene chloride, or mixtures of the above solvents, preferably in methanol, at temperatures from -10oC to 10oC.

If necessary, formed when restoring a hydroxyl group can also be proaccelerin the way described above.

Quaternary derivatives of the compounds of formula (IIa) obtained by acylation, prepared as follows: compound of formula (IIa) is dissolved in an inert solvent, for example acetonitrile, methylene chloride or the solvent of the ether type, such as diethyl ether, or ketone solvent, preferably in acetone, and then carry out the reaction with alkylhalogenide in the same solvent, for example, with a solution of bromide or allylbromide in acetone. The reaction mixture was kept until completion of the reaction, then the precipitate is filtered off, washed to remove the mother liquor and then purify.

If the resulting Quaternary salt is crystallized from a solution, it is precipitated by adding diethyl ether.

In accordance with process (b) conducting the reaction of a derivative 17-halogen-2, 3:16, 17 diepoxy-5 - androstane formula (VI) with an amine, predpochtitelnei in acetonitrile at room temperature. Upon completion of the reaction, the reaction mixture was evaporated and the residue diluted with water. The precipitation is filtered off, washed with water to remove the mother liquor, dried and purified by recrystallization. The new product of the formula (V) containing a-aminoketone group in the D ring of the steroid skeleton, to restore connection with 17-oxoprop, using an alkali metal borohydride, better than sodium borohydride, in an inert solvent, for example tetrahydrofuran, methylene chloride, methanol or mixtures of the abovementioned solvents, preferably in methanol. After decomposition of the complex metal hydride and distillate solvent, for example methanol, the product is obtained as a precipitate. After the precipitate was filtered and washed with water to remove the mother liquor, the product is dried and then recrystallized.

Thus obtained compounds of formula (IV) is transformed into the compounds of formula (I) through substances of the formulae (IIIB) and (IIB) through chemical reactions described for compounds of formula (IV).

Salts of Quaternary derivatives with non-toxic mineral or organic is any of the above acids and planting salt by the addition of ether.

Biological efficacy of new androstane derivative of formula (I), substituted at the 16-th position Quaternary amino groups, was studied as follows.

In vitro experiments were performed on preparations phrenic nerve (nervus phrenicus) - dome of the diaphragm rats weighing 300-350 grams or Guinea pigs weighing 400-450 grams. Phrenic nerve is stimulated supramaximal electric pulses of 0.2 MS (at a frequency of 0.1 Hz), while continuously recorded isometric contraction of the muscle. Drugs suspended (kept) in the bath to 50 ml of physiological solution, Krebs (Krebs). The composition of the solution - 113 mmol/l NaCl, 4.7 mmol/l KCl, 1.5 mmol/l of calcium chloride, 1.2 mmol/l of magnesium sulfate, 25 mmol/l of sodium bicarbonate and 11.5 mmol/l glucose. The Krebs solution saturated with a gas mixture of 95%O - 5%CO. Cumulative increasing concentrations of the tested compounds and determine the values of the ED50and ED90(i.e., concentrations that decrease the power /size/ contraction of the muscle - dome of the diaphragm 50% and 90%, respectively). As in the previous experiments it was found that the effect of muscle in Guinea pigs similarly impact observed in the clinic in Ludewig muscle on these species. During in vivo experiments, Guinea pigs were subjected to anesthesia using a mixture of pentobarbital [5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione] and urethane (ethylcarbamate), breath of experimental animals was supported by the ventilator. Separated (analyzed) anterior tibial muscle, stimulate the sciatic nerve using electricity (supramaximal pulses with a duration of 0.2 MS with a frequency of 0.1 Hz), the muscles were recorded. Inhibitory effect of compounds on the vagus nerve was studied in cats subjected to anesthesia using a mixture of chloralose (condensation products of chloral-hydrate and glucose) and urethane. The vagus nerve is stimulated with an electric current (supramaximal pulses with a duration of 0.3 MS with a frequency of 20 Hz), the effect on heart rate and blood pressure were recorded using a recording device Hellige (hellige in Norwegian). All compounds were introduced into the body via the jugular vein. The results of the experiments are summarized and presented in tables (tables 1 - 4).

The data in table 1 show that the neuromuscular blocking effect of bromide 1-[3, 17-bis(acetoxy)-2- (1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-5-androstane-16-yl] -1 the CT other known already used in the clinic muscle. This connection is characterized by a rapid onset and easy reversibility of actions through washing. The effects of the compounds can also be ingibirovalo using antagonists - neostigmine methyl sulfate[3-dimethylcarbamoyl)trimethylammonium methyl sulfate or chloride of hidroponia [ethyl-(3-hydroxyphenyl)-dimethylammonio chloride].

The data in table 2 show that during in vivo studies in Guinea pigs, the onset of action of the compound (example 8) was more rapid, and the duration of action shorter than the corresponding characteristics of other known substances having a similar chemical structure. Thus, for example, after introduction into the organism of experimental double ED90 doses of neuromuscular blockade decreased from 75% to 25% for 10.1 minutes. For comparison, the corresponding characteristic for pancuronium bromide and bromide pipecuronium was 45.6 and 60.6 minutes respectively.

It is known that some nedepoljarizatsii muscle relaxants have unwanted side effects and due to inhibitory effects on the vagus nerve and/or impact on the release of histamine can cause tachycardia and decrease arterializing. The data of table 3 show that during the in vivo tests on cats was not observed irritant compounds (example 8) on the vagus nerve, and electrical stimulation did not cause significant changes in heart rate and blood pressure. At that time, as a 4-fold ED90the dose of pancuronium bromide caused a 50% inhibition of the reduction of heart rate and blood pressure caused by stimulation of the vagus nerve (see above), even 8 times the ED90the dose of a compound (example 8) does not block the vagus nerve and did not inhibit the effects of electrical stimulation of this nerve on heart rate or blood pressure.

The compounds of formula (I) are curariform neuromuscular blockers with nedepoliarizuth mechanism of action, i.e. they inhibit the transmission of nerve impulses to the striated muscles. They do not induce any release of histamine or hypotension, their impact can be adjusted using the antagonist - neostigmine. They have no hormonal side effects. Rapid onset and short duration of their action are additional preimuim.

The compounds of formula (I) can be used, primarily, in surgery for producing muscle relaxation during endotracheal anesthesia. They can be used to prevent injury during electroconvulsive therapy and to reduce muscle tone cramps, etc.

New derivatives of androstane formula (I), substituted at the 16-th position Quaternary amino groups, are used as bases or in the form of their salts, preferably in the form of compositions (compositions) that are widely used in clinical practice. These compositions can be prepared in such a way that it is convenient to use for intravenous injection or infusion, primarily in the form of ampoules with liofilizirovannam dry content. In the preparation of these compositions can be applied widely known fillers, diluents, preservatives, additives and supplements that affect pH or osmotic pressure. The patient is required to produce the desired effect a number of active compounds contained in a given pharmaceutical composition. This dose depends on the desired effect, body weight and sensitivity of the patient to the active drug. Prescribed dose of active drug opredelaetsa For to facilitate the use of the drug, it is proposed to prepare pharmaceutical compositions containing as the unit of single or multiple drug dose, or half or quarter of a single dose.

According to the invention pharmaceutical compositions containing 2-60 mg of active agent per unit dose (vials). Of course, that in some cases the number of active drug may be above or below the specified values.

The invention also relates to a method for blocking the transmission of nerve impulses to the striated muscles. The invention relates to the appointment of therapeutically effective doses of the active compounds of formula (I) or pharmaceutically active salts of the bases (I) mammals (including people).

Testing using thin-layer chromatography was carried out on the adsorbent DC - Alufolitn Kieselgel 60 (Merck, Art. 5553, size 0.2 mm). Developer - iodine. Used eluent:

1) 9:1 (vol.) a mixture of chloroform and methanol,

2) 7:3 (vol.) a mixture of chloroform and methanol,

3) 1:1 (vol.) a mixture of benzene and acetone. Eluent in the examples is indicated as index values of Rf.

The invention is illustrated in detail using the trail is and.

To a suspension containing 60 g of 17-bromo-2, 3:16, 17 diepoxy-5-androstane in 400 ml of acetonitrile at room temperature, with vigorous stirring and in an atmosphere of gaseous nitrogen add 42 ml of pyrrolidine. After stirring for 5 minutes, the suspension becomes transparent at that time, as the temperature of the reaction mixture reaches 50oC. In the reaction starts falling product precipitates. Upon completion of the reaction, the reaction mixture was evaporated, to the residue water is added, the precipitate is filtered off, thoroughly washed with water and dried, obtaining of 55.9 g of the target product, which is recrystallized from methanol, TPL= 167-169oC.

Primer.Prigotovleniya, 3-epoxy-16(1-pyrrolidinyl)-5-androstane-17-ol.

Dissolve 39,2 g 2, 3-epoxy-16-(1-pyrrolidinyl)-5 - androstane-17-she's in a mixture of 392 ml of methanol and 56 ml of methylene chloride. To this solution under stirring and nitrogen atmosphere are added in several portions of 14.7 g of sodium borohydride with such speed that the temperature of the reaction mixture did not exceed room temperature. The solution containing the precipitate, leave for 12 hours, then the methylene chloride is distilled off, the residue diluted with water. The precipitate is filtered off, thoroughly washed with water, dried and the ptx2">

Example 3. Preparation 2-1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-(1-pyrrolidinyl)-5-androstane -3, 17-diol.

After adding 63 g of 1,4-dioxa-8 azaspiro[4.5]decane and 13 ml of water, 17 g of 2, 3-epoxy-16-(1-pyrrolidinyl)-5 - androstane-17-ol, the reaction mixture was incubated for 80 hours in a nitrogen atmosphere at a temperature of 100-105oC. Upon completion of the reaction solution containing the residue, diluted with 200 ml of acetonitrile and after filtration is washed thoroughly with water and acetonitrile, dried and recrystallized from methanol, obtaining the target product with a yield of 18.2 g (76.5%). TPL= 184-187oC.

Example 4. Preparation of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane -3, 17-diol-17-acetate.

After dissolving 10 g of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane-3, 17-diol in 50 ml of methylene chloride to this solution was added 3.5 ml of triethylamine. The solution is cooled to 0oC and drop add 2.5 ml of acetylchloride, maintaining the temperature of the reaction mixture in the range of 0-5oC. then increase the temperature to room and at this temperature, carry out the reaction for 3 hours. Upon completion of the reaction excess acetylchloride decompose water solution in methylene chloride is washed first with a solution hydroxyle which the drying agent is filtered off, and the methylene chloride is distilled off. The residue is purified on a column of silica gel and recrystallized from acetone, getting 7,19 g (65,4%). TPL= 174-177oC.

Example 5. Preparation of bromide 1-[17-acetoxy-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-3-hydroxy-5-androstane-16-yl]-1-(2-propenyl)pyrrolidine.

After dissolving 1.5 g of 2-(1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-16-(1-pyrrolidinyl)-5-/ androstane -3, 17-diol-17-acetate in 30 ml of acetone and to this solution was added 2.5 ml of allylbromide, the reaction mixture was incubated for 24 hours, then the reaction product precipitious with ether, filtered and recrystallized from acetone, obtaining the target product with a yield of 1.4 g (76.5%). TPL= 178-180oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.82 (s, 6H, 18-CH3and 19-CH3), 2.24 (s, 3H, 17-OAc), 2.44-2.8 (m, 5H, 2-H and NCH2), 3.6-4.1 (m, 5H, 3-H and N+CH2), 3.96 (s, 4H, CH2O), 4.18 and 4.42 (m, 2H ), 4.55 (vbr, 1H, 16-H), 5.22 (d, 1H, 17-H), 5.66-5.80 (m, 2H, =CH2), 6.17 (m, 1H, -CH=),

where

ppm - parts per thousand.

Example 6. Preparation of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane -3, 17-diol-diacetate.

To a solution containing 10 g of 2-(1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-16-(1-pyrrolidinyl)-5-androstane -3, 17-diol in 50 ml of methylene chloride, add 7 ml Triada and mixing with such speed, to the temperature of the reaction mixture did not exceed 10oC. after adding acetylchloride cooling stop and heated the reaction mixture to room temperature. For a complete reaction takes about 16 hours. After that, the excess acetylchloride decompose water and solution in methylene chloride is washed with an aqueous solution of sodium hydroxide and then with water until neutral. Organic (methylene chloride) phase is dried, the solvent is distilled off and the residue is purified on a column of silica gel, receiving 9 g (77,1%) of the desired product in the form of foam.

1H-NMR: 300 MHz (CDCl3) ppm: 0.87 (s, 3H, 18-CH3), 0.99 (s, 3H, 19-CH3), 2.06 and 2.11 (s, s, 3H, 3H, 3-OAc and 17-OAc), 2.42 (q, 1H, 2-H), 2.92 (q, 1H, 16-H), 3.93 (s, 4H, CH2O), 4.80 (d, 1H, 17-H), 5.24 (q, 1H, 3-H).

Example 7. Preparation of bromide 1-[ 3, 17 - bis(acetoxy)-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-5 - androstane-16-yl]-1-methyl-pyrrolidine.

After dissolving 1 g of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane-3, 17-diol-diacetate in 20 ml of diethyl ether and add 25 ml of 10% aqueous solution of methyl bromide in acetone, the reaction mixture is left for 48 hours. Then the precipitate is filtered off and recrystallized from a mixture of acetone - diethyl ether, obtaining the target product with vyhoda>), 2.06 (s, 3H, 3-OAc), 2.23 (s, 3H, 17-OAc), 2.61 (br, 4H, NCH2), 3.30 (s, 3H, N+CH3), 3.65 - 4.1 (m, 4H, N+CH2), 3.94 (s, 4H, OCH2CH2O), 4.75 (m, 1H, 16-H), 5.24 (m, 1H, 3 - H), 5.26 (d, 1H, 17-H).

Example 8. Preparation of bromide 1-[ 3, 17 - bis(acetoxy)-2-(1,4-dioxa-8 azaspiro-[4.5]Dec-8-yl)-5-yl]-1-(2-propenyl)pyrrolidine.

After adding 20 ml of allylbromide to a solution containing 13 g of 2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)- -16-(1-pyrrolidinyl)-5-androstane-3, 17-diol-diacetate in 100 ml of acetone, the reaction mixture was kept at room temperature for 24 hours. Upon completion of the reaction, the reaction product precipitious ether, filtered off, washed with a mixture of ether - acetone to remove allylbromide and dried. Thus obtained Quaternary compound (13,4 g) purified by column chromatography on silica gel. After evaporation of the combined fractions containing the target product, the residue is recrystallized from a mixture of acetone - ether, obtaining the target product with a yield of 9 g (55.8 per cent). TPL=186 - 189oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.81 (s, 3H, 18-CH3), 0.99 (s, 3H, 19-CH3), 2.07 (s, 3H, 3-OAc), 2.23 (s, 3H, 17-OAc), 3.75 - 4.1 (m, 4H, N+CH2), 3.94 (s, 4H, OCH2CH2O), 4.18 & 4.38 (m, 2H ), 4.65 (vbr, 1H, 16-H), 5.22 and 5.24 (m, 2H, 3-H and 17-H), 5.66-5.80 (the -3, 17-diol.

After adding 42 ml of 10% aqueous hydrochloric acid solution to 5 g of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl) -16-(1-pyrrolidinyl)-5-androstane-3, 17-diol, dissolved in 100 ml of dioxane, the reaction mixture is refluxed for 3 hours. Upon completion of the reaction, the dioxane is distilled off and the residue is diluted with water. The precipitate is filtered, washed with water until neutral and dried. The crude product is dissolved in acetonitrile, purified with activated charcoal and filtered adsorbent, two-thirds of the acetonitrile is distilled off. The crystalline precipitate is filtered off, obtaining the target product with the release of 4.2 g (92.1 per cent). TPL=136 - 138oC.

Example 10. Preparation of 2-/ (4-oxo-1-piperidinyl)-16- (1-pyrrolidinyl)-5-androstane-3, 17-diol-17-acetate.

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane-3, 17-diol will acetimidoyl according to the method described in example 4, obtaining the target product with a yield of 53.8 per cent. TPL=190 - 192oC.

Example 11. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(1-pyrrolidinyl)-5-androstane-3, 17-diol-17-acetate.

After the solution containing 2 g of 2-(4-oxo-1-piperidinyl)-16-(1-pyrrolidinyl)-5-androstane-3, 17-diol-17-acetate in a mixture of 10 ml of methylene chloride and 10 ml of tagging 3 hours. Upon completion of the reaction, excess reagent is decomposed with water, and after distillation of the methylene chloride, the residue is thoroughly stirred with water, filtered and dried. Yield 1.3 g (64,7%). TPL=206 - 209oC.

Example 12. Preparation of bromide 1-[17-acetoxy-3 - hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1-methylpyrrolidine.

2-(4-hydroxy-1-piperidinyl)-16-(1-pyrrolidinyl)-5 - androstane-3, 17-diol-17-acetate is reacted with methyl bromide according to the procedure described in example 7, with the output 93,6% get target product. TPL=262 - 264oC.

1H-NMR: 300 MHz (DMSO-d6) ppm: 0.77 (s, 3H, 18-CH3), 0.96 (s, 3H, 19-CH3), 2.19 (s, 3H, 17-OAc), 3.09 (s, 3H, N+CH3), 3.96 (m, 1H, 3-H), 4.15 (m, 1H, 16-H), 5.08 (d, 1H, 17-H).

Example 13. Preparation of bromide 1-[17-acetoxy-3 - hydroxy-1-piperidinyl)-5-androstane-16-yl]-1-(2-propenyl)pyrrolidine.

2-(4-hydroxy-1-piperidinyl)-16-(1-pyrrolidinyl)-5 - androstane-3, 17-diol-17-acetate reacts with allylbromide according to the procedure described in example 5, with the release of 74,6% get target product. TPL=227 - 232oC.

Example 14. Preparation of 2-(4-oxo-1-piperidinyl)-16- (1-pyrrolidinyl)-5-androstane-3, 17-diol-diacetate.

2-(4-oxo-1-piperidinyl)-16-(1-pyrrolin duct in the form of foam. R1f= 0,34.

Example 15. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(1-pyrrolidinyl)-5-androstane-3, 17-diol-diacetate.

2-(4-oxo-1-piperidinyl)-16-(1-pyrrolidinyl)-5 - androstane-3, 17-diol-diacetate is restored by the sodium borohydride according to the method described in example 11, receives the output 81% of the target product in the form of foam. R2f= 0,55.

Example 16. Preparation of bromide 1-[3, 17-/ bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1-(2-propenyl)pyrrolidine.

2-(4-hydroxy-1-piperidinyl)-16-(1-pyrrolidinyl)-5 - androstane-3, 17-diol-diacetate is reacted with allylbromide according to the procedure described in example 5, with the output 93,28% get target product.

1H-NMR: 300 MHz (CDCl3) ppm: 0.82 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 2.08 (s, 3H, 3-OAc), 2.23 (s, 3H, 17-OAc), 3.55 - 4.1 (m, 5H, N+CH2and hydroxypiperidine-4-H), 4.18 and 4.37 (m, 2H ), 4.65 (vbr, 1H, 16-H), 5.21 and 5.24 (m, 2H, 3-H and 17-H), 5.65 - 5.80 (m, 2H, =CH2), 6.17 (m, 1H, -CH=).

Example 17. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(1-pyrrolidinyl)-5-androstane-3, 17-diol.

2, 3-epoxy-16-(1-pyrrolidinyl)-5-androstane-17-ol is reacted with 4-hydroxypiperidine according to the procedure described in example 3, with the yield of 76.5% get target product. TPL=188 - 1 is-diacetate.

After you have added 7.9 g of triethylamine to a solution containing 9 g of 2-(4-hydroxy-1-piperidinyl)-16-(1-pyrrolidinyl)-5-androstane-3, 17-diol in 80 ml of methylene chloride, to this solution drop by drop added 9 g of acetylchloride when cooled below 0oC and stirring. Upon completion of addition the reaction mixture was kept at room temperature for 24 hours. Upon completion of the reaction excess acetylchloride decompose water, a solution of methylene chloride is washed with aqueous sodium hydroxide solution to remove the acid, and then washed several times with water until neutral. The organic phase is dried, and the methylene chloride is distilled off, the residue is purified on a column of silica gel, obtaining the target product with a yield of 8.3 g (71.9 percent). R1f= 0,36.

Example 19. Preparation of bromide 1-[3, 17 - bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl]-1-methylpyrrolidine.

2-(4-acetoxy-1-piperidinyl)-16-(1-pyrrolidinyl)-5 - androstane-3, 17-diol-diacetate is reacted with methyl bromide according to the procedure described in example 7, with the output 79,7% get target product. TPL=160 - 180oC.

Example 20. Preparation of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-3, 17-dihydroxy-16-(1-piperidinyl) -5-androstane.

2, the Oh in example 3, with the release of 79,88% get target product. TPL=216 - 218oC.

Example 21. Preparation of 2-(4-oxo-1-piperidinyl)-16- (1-piperidinyl)-5-androstane-3, 17-diol.

2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane-3, 17-diol hydrolyzing in accordance with the procedure described in example 9. Output - 81,66%. TPL=205 - 206oC.

Example 22. Preparation of 2-(4-oxo-1-piperidinyl)-16-/ (1-piperidinyl)-5-androstane-3, 17-diol-17-acetate.

2-(4-oxo-1-piperidinyl)-16-(1-piperidinyl)-5 - androstane-3, 17-diol will acetimidoyl according to the procedure described in example 4, obtaining the target product with a yield of 60.5%. TPL=204 - 207oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.80 (s, 3H, 18-CH3), 0.86 (s, 3H, 19-CH3), 2.09 (s, 3H, 17-OAc), 3.06 (m, 1H, 16-H), 3.89 (m, 1H, 3-H), 4.77 (d, 1H, 17-H).

Example 23. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(1-piperidinyl)-5-androstane-3, 17-diol-17-acetate.

2-(4-oxo-1-piperidinyl)-16-(1-piperidinyl)-5 - androstane-3, 17-diol-17-acetate restore the sodium borohydride according to the procedure described in example 11, getting access to 92.4% of the target product. TPL=202 - 204oC.

Example 24. Preparation of bromide 1-[17-acetoxy-3 - hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1-methylpiperidine.m according to the method described in example 1, with the output 82,97% get target product. TPL= 238-240oC.

1H-NMR: 300 MHz (DMSO-d6) ppm: 0.75 (s, 3H,18-CH3), 0.96(s, 3H, 19-CH3), 2.18 (s, 3H, 17-OAc), 3.13(s, 3H, N+CH3), 3.96 (m, 1H, 3-H), 4.29(m, 1H, 16-H), 5.14 (d, 1H, 17-H).

Example 25. Preparation 2-4-oxo-1-piperidinyl)-16 - 1-piperidinyl)-5-androstane-3, 17-diol-diacetate.

2-(4-oxo-1-piperidinyl)-16-(1-piperidinyl)-5 - androstane-3, 17-diol will acetimidoyl according to the method described in example 6, receives the output 61,05% of the target product. TPL= 179-181oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.82 (s, 3H, 18-CH3), 1.05 (s, 3H, 19-CH3), 2.09 & 2.12 (s, s, 3H, 3H, 3-OAc & 17-OAc), 3.1 (m, 1H, 16-H), 4.83 (d, 1H, 17-H), 5.30 (m, 1H, 3-H).

Example 26. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(1-piperidinyl)-5-androstane-3, 17-diol-diacetate.

2-(4-oxo-1-piperidinyl)-16-(1-piperidinyl)-5 - androstane-3, 17-diol-diacetate restore the sodium borohydride according to the procedure described in example 6, receives the output of 69.5% of the target product. TPL= 108-110oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.81 (s, 3H, 18-CH3), 1.03 (s, 3H, 19-CH3), 2.08 and 2.12 (s, s, 3H, 3H, 3-OAc and 17-OAc), 3.65 (m, 1H, hydroxypiperidine 4-H), 4.81 (d, 1H, 17-H), 5.28 (m, 1H, 3-H).

Example 27. Cooking bromodiphenyl)-16-(1-piperidyl)-5 - androstane-3, 17-diol-diacetate is reacted with methyl bromide according to the procedure described in example 7, with the release of 68.4% of received target product. TPL= 220-230oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.83 (s, 3H, 18-CH3), 1.02 (s, 3H, 19-CH3), 2.09 (s, 3H, 3-OAc), 2.22 (s, 3H, 17-OAc), to 3.41 (s, 3H, N+CH3), 5.15-5.55 (m, 2H, 3-H and 17-H).

Example 28. Preparation of 2-(1,4-dioxy-8 azaspiro[4.5]Dec-yl)-3, 17-dihydroxy-16-(4-methyl-1-piperazine derivatives)-5-androstane.

2, 3-epoxy-17-hydroxy-16-4-methyl-1-piperazine derivatives)-5 - androstane reacts with 1,4-dioxane-8 azaspiro[4.5]decane according to the procedure described in example 3, with the release of 72,34% get target product. TPL=185-187oC.

Example 29. Preparation of 2-(1,4-dioxa-8 azaspiro [4.5] Dec-8-yl)-16-(4-methyl-1-piperazine derivatives)-5-androstane -3, 17-diol-diacetate.

2-1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol will acetimidoyl according to the method described in example 6, obtaining the target product with a yield of 70%. TPL= 162 to 165 of theoC.

Example 30. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-5-androstane-16-yl]-1,1-dimethylpiperazine.

2-(1,4-dioxa-8 azaspiro [4.5] Dec-8-yl)-16-4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate is reacted with metavr the yield of 72%. TPL= 244-250oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.77 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 2.06 (s, 3H, 3-OAc), 2.11 (s, 3H, 17-OAc), 2.44 (m, 1H, 2-H), 2.61 (br, 4H, NCH2), 2.8-3.05 (m, 4H, NCH2), 3.23 (m, 1H, 16-H), 3.56 (s, 6H, N+CH3), 3.60 and 3.70 (m, 4H, N+CH2), 3.93 (s, 4H, OCH2CH2O), 4.78 (d, 1H, 17-H), 5.23 (m, 1H, 3 - H).

Example 31. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(1,4-dioxa-8 azaspiro[4,5] Dec-8-yl)-5 - androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine.

2-(1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate is reacted with allylbromide according to the procedure described in example 5. The reaction is carried out for 5 hours. Get the target product with a yield of 78%. TPL= 205-208oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.77 (s, 3H, 18-CH3)1.00 (s, 3H, 19-CH3), 2.06 (s, 3H, 3-OAc), 2.11 (s, 3H, 17-OAc), 2.44 (m, 1H, 2-H), 2.62 (br, 4H, NCH2), 2.8-3.05 (m, 4H, NCH2), 3.23 (m, 1H, 16-H), 3.43 (s, 3H, N+CH3), 3.4-3.85 (m, 4H, N+CH2), 3.93 (s, 4H, OCH2CH2O), 4.57 (m, 2H ), 4.77 (d, 1H, 17-H), 5.23 (m, 1H, 3-H), 5.76 & 5.90 (2xdd, 2H, =CH2), 6.01 (m, 1H, -CH=).

Example 32. Preparation of 16-(4-methyl-1-piperazine derivatives)-2- (4-oxo-1-piperidinyl)-5-androstane-3, 17-diol.

2-/ (1,4-dioxa-8 azaspiro[4.5] -Dec-8-yl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-di the 9oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.68 (s, 3H, 18-CH3), 0.88 (s, 3H, 19-CH3), 2.29 (s, 3H, NCH3), 3.43 (d, 1H, 17-H), 3.9 (m, 1H, 3-H).

Example 33. Preparation -(4-methyl-1-piperazine derivatives)-2- (4-oxo-1-piperazinyl)-5-androstane-3, 17-diol-17-acetate.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo-1-piperazinyl) -5-androstane-3, 17-diol will acetimidoyl according to the procedure described in example 4, obtaining the target product output 77,34%. TPL=210-215oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0,81 (s, 3H, 18-CH3), 0.87 (s, 3H, 19-CH3), 2.09 (s, 3H, 17-OAc), 2.25 (s, 3H, NCH3), 3.9 (m, 1H, 3-H), 4.75 (d, 1H, 17-H).

Example 34. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-17-acetate.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo-1-piperazinyl)-5 - androstane-3, 17-diol-17-acetate restore using sodium borohydride according to the procedure described in example 11, receiving the target product with a yield of 71%. TPL= 210-214oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.81 (s, 3H, 18-CH3), 0.83 (s, 3H, 19-CH3), 2.09 (s, 3H, 17-OAc), 2.24 (s, 3H, NCH3), 3.08 (m, 1H, 16-H), 3.67 (m, 1H, hydroxypiperidine-4-H), 3.79 (m, 1H, 3-H), 4.76 (d, 1H, 17-H).

Example 35. Preparation of bromide 4-[17-acetoxy-3 - hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1.1-DIMET the range with methyl bromide according to the method described in example 30, with the release of 86,3% get target product. TPL= 295-300oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.76 (s, 3H, 18-CH3), 0.95 (s, 3H, 19-CH3), 2.09 (s, 3H, 17-OAc), 3.14 (s, 3H, N+CH3), 3.19 (m, 1H, 16-H), 3.94 (m, 1H, 3-H), 4.73 (d, 1H, 17-H).

Example 36. Preparation of bromide 4-[17-acetoxy-3 - hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl ]-1-methyl-1-(2-propenyl)piperazine.

(4-hydroxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives) -5-androstane-3, 17-diol-17-acetate reacts with allylbromide according to the procedure described in example 31, with the release of 74,2% get target product. TPL= 274-277oC.

Example 37. Preparation of 16-(4-methyl-1-piperazine derivatives)-2- (4-oxo-1-piperidinyl)-5-androstane-3, 17-diol-diacetate.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo-1-piperidinyl)-5-/ androstane-3, 17-diol will acetimidoyl according to the method described in example 6, obtaining the target product in the form of a foam with a yield of 68.3%.

1H-NMR: 300 MHz (CDCl3) ppm: 0.81 (s, 3H, 18-CH3), 1.06(s, 3H, 19-CH3), 2.08 and 2.12 (s, 3H, 3-OAc and 17-OAc), and 2.26 (s, 3H, NCH3), 4.80 (d, 1H, 17-H), 5.29 (m, 1H, 3-H).

Example 38. Preparation of bromide 4-[3, 17-bis(acetoxy)-2-(4-oxo-1-piperidinyl)-5-androstane-16-yl]-1.1-dimethylpiperazine.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo is 30, with the release of 90.5% to obtain the target product. TPL= 215-220oC (decomposition).

1H-NMR: 300 MHz (CDCl3) ppm:0.79 (s, 3H, 18-CH3), 1.05 (s, 3H, 19-CH3), 2.09 and 2.13 (s, s, 3H, 3H, 3-OAs and 17-OAc), 3.56 (s, 6H, N+CH3), 4.82 (d, 1H, 17-H), 5.28 (m, 1H, 3-H).

Example 39. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(4-oxo-1-piperidinyl)-5-androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo-1-piperidinyl)-5 - androstane-3, 17-diol-diacetate is reacted with allylbromide according to the procedure described in example 31, with access to 89.5% get target product. TPL= 176-180oC.

Example 40. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(4-methyl-1-piperazinil)-5-androstane-3, 17-diol-diacetate.

16-(4-methyl-1-piperazine derivatives)-2-(4-oxo-1-piperidinyl)-5 - androstane-3, 17-diol-diacetate restore borhydride sodium according to the method described in example 11, receives the output 83,05% of the target product in the form of foam. R2f= 0,61.

Example 41. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1,1-dimethylpiperazine.

2-(4-hydroxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate is reacted with methyl bromide according to the methods of the NMR: 300 MHz (CDCl3) ppm: 0.75 (s, 3H, 18-CH3), 0.98 (s, 3H, 19-CH3), 2.00 (s, 3H, 3-OAc), 2.09 (s, 3H, 17-OAc), 3.18 (m, 1H, 16 - H), 3.32 and 3.33 (s, s, 3H, 3H, N+CH3), 3.41 (m, 1H, hydroxypiperidine-4-H), 4.73 (d, 1H, 17-H), 5.15 (m, 1H, 3 - H).

Example 42. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1-methyl-1-(2-propenyl)piperazine.

2-(4-hydroxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives) -5-androstane-3, 17-diol-diacetate is reacted with allylbromide according to the procedure described in example 31, with a yield of 78% receive target product.

1H-NMR: 300 MHz (CDCl3) ppm: 0.77 (s, 3H, 18-CH3), 1.03 (s, 3H, 19-CH3), 2.07 and 2.12 (s, s, 3H, 3H, 3-OAc and 17-OAc), 3.44 (s, 3H, N+CH3), 4.57 (m, 2H ), 4.80 (d, 1H, 17-H), 5.28 (m, 1H, 2-H), 5.65 - 6.2 (m, 3H, -CH=CH2).

Example 43. Preparation of 2-(4-hydroxy-1-piperidinyl) -16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol.

2, 3-epoxy-16-(4-methyl-1-piperazine derivatives)-5-androstane-17-ol is reacted with 4-hydroxypiperidine according to the procedure described in example 3, with the release of 78,57% get target product. TPL=248 - 250oC.

Example 44. Preparation of 2-(4-acetoxy-1-piperidinyl) -16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate.

2-(4-hydroxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives) -5-androstane-3, 17-diol acetimer">

Example 45. Preparation of bromide 4-[3, 17 - bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-[ 16-yl]-1,1-dimethylpiperazine.

2-(4-acetoxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate is reacted with methyl bromide according to the procedure described in example 30, exit 87% receive target product. R2f= 0,14.

Example 46. Preparation of bromide 4-[3, 17-bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16 - yl]-1-methyl-1-(2-propenyl)piperazine.

2-(4-acetoxy-1-piperidinyl)-16-(4-methyl-1-piperazine derivatives)-5-androstane-3, 17-diol-diacetate is reacted with allylbromide according to the procedure described in example 31, with a yield of 81% receive target product. R2f= 0,71.

1H-NMR: 300 MHz (CDCl3) ppm: 0.77 (s, 3H, 18-CH3), 1.01 (s, 3H, 19-CH3), 2.03 (s, 3H, 4'-OAc), 2.06 (s, 3H, 3-OAc), 2.12 (s, 3H, 17-OAc), 2.7 - 3.05 (m, 6H, NCH2), 3.23 (m, 1H, 16-H), 3.41 (s, 3H, N+CH3), 3.4 - 3.87 (m, 4H, N+CH2), 4.54 (m, 2H ), 4.75 (m, 1H, 4'-H), 4.77 (d, 1H, 17-H), 5.23 (m, 1H, 3-H), 5.76 and 5.90 (2xdd, 2H, =CH2), 6.02 (m, 1H, -CH= ).

Example 47. Preparation of 16-(1,4-dioxy-8 azaspiro[4.5] Dec-8-yl)-2, 3-epoxy-5-androstane-17-it.

17-bromo-2, 3:16, 17 diepoxy-5-androstane reacts with 1,4-dioxa-8 azaspiro[4.5] decane according to the procedure described in example 1, with the-8-azaspiro[4.5] Dec-8-yl)-2, 3-epoxy-5-androstane-17-ol.

16-(1,4-dioxa-8 azaspiro[4.5] -Dec-8-yl)-2, 3-epoxy-5-/ androstane-17-he may be restored with sodium borohydride according to the procedure described in example 2, obtaining the target product with access to 91.1%. TPL= 186 - 188oC.

Example 49. Preparation 16(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2-(1-piperidyl)-5-androstane -3, 17-diol.

16-(1,4-dioxa-8 azaspiro[4.5]-Dec-8-yl)-2-epoxy-5-androstan-17-ol is reacted with piperidine according to the procedure described in example 3, to obtain the target product with a yield of 87.5%. TPL= 183 - 185oC.

Example 50. Preparation of 16-(1,4-dioxa-8 azaspiro[4,5] Dec-8-yl)-2-(1-piperidinyl)-5-androstane -3, 17-diol-17-acetate.

16-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2-(1-piperidinyl)-5-androstane-3, 17-diol will acetimidoyl according to the method described in example 6, obtaining the target product with a yield of 63.7%. TPL= 124 - 128oC.

Example 51. Preparation of bromide 8-[3, 17 - bis(acetoxy)-2-(1-piperidinyl)-5-androstane-16-yl]-8-methyl-1,4-dioxa-8 azaspiro[4.5]-decane.

Spend the reaction of 16-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2-(1-piperidinyl)-5-androstane-3, 17-diol-17-acetate with methyl bromide according to the procedure described in example 7, obtaining the target product with access to 64.8%. R2the completed reaction 16-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2, 3-epoxy-17-hydroxy-5-androstane with 1,4-dioxa-8 azaspiro-[4.5] decane in accordance with the method described in example 3, obtaining the target product with a yield of 80.1%. TPL= 180 - 182oC.

Example 53. Preparation of 16-(1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-2-(4-hydroxy-1-piperidinyl)-5 - androstane-3, 17-diol.

Spend the reaction of 16-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2, 3-epoxy-17-hydroxy-5-androstane (4-hydroxypiperidine according to the method described in example 3, obtaining the target product with access to 78.3%. TPL= 199 - 201oC.

Example 54. Preparation of 2-(4-acetoxy-1-piperidinyl) -16-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-5-androstane -3, 17-diol-diacetate.

16-(1,4-dioxa-8 azaspiro[4.5]-Dec-8-yl)-2-androstane-3, 17-diol will acetimidoyl according to the procedure described in example 18, receiving the target product with a yield of 80.8% in the form of foam. R3f= 0,59.

Example 55. Preparation of bromide 8-[3, 17 - bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl] 8-methyl-1,4-dioxa-8 azaspiro-4,5-decane.

Spend the reaction of 2-(4-acetoxy-1-piperidinyl)-16-/ (1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-5-androstane-3, 17 - diol-diacetate with methyl bromide according to the procedure described in example 7, obtaining the target product with a yield of 81%. TPL=157 - 160the lead reaction of 17-bromo-2, 3:16, 17 diepoxy-5 - androstane (4-hydroxypiperidine according to the procedure described in example 1, obtaining the target product with the release of 95,8%. TPL=140-142oC.

Example 57. Preparation of 2, 3-epoxy-16-(4-hydroxy-1-piperidinyl)-5-androstane-17-ol.

2, 3-epoxy-16-(4-hydroxy-1-piperidinyl)-5 - androstane-17-he may be restored with sodium borohydride according to the procedure described in example 2, obtaining the target product output 86,06%. TPL=204-206oC.

Example 58. Preparation of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16 - androstane-3, 17-diol.

Spend the reaction of 2, 3-epoxy-16-(4-hydroxy-1-piperidinyl)-5-androstane-17-ol with 1,4-dioxa-8 azaspiro[4.5]decane according to the procedure described in example 3 was obtained target product output 85,9%. TPL= 253-255oC.

Example 59. Preparation 2, 16-bis(4-hydroxy-1-piperidinyl)-5-androstane-3, 17-diol.

Spend the reaction of 2, 3-epoxy-16-(4-hydroxy-1-piperidinyl)-5-androstane-17-ol with 4-hydroxypiperidine according to the method described in example 3, obtaining the target product with a yield of 85.4%. TPL=248-250oC.

Example 60. Preparation 2, 16-bis(4-acetoxy-1-piperidinyl)-5-androstane-3, 17-diol-diacetate.

After adding 21 ml of triethyl is 5 ml of methylene chloride, the solution is kept for 12 hours, then the excess acetylchloride decompose water. The organic phase (methylene chloride) is washed first with an aqueous solution of sodium hydroxide, cooled to 2-5oC, and then with water until neutral. After drying the methylene chloride is distilled off, got the target product as a foamy residue. The output of 74.9%, R3f= 0,67.

Example 61. Preparation of bromide 4-acetoxy-1-[3, 17 - bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl]-1-methylpiperidine.

Spend the reaction of 2, 16-bis(4-acetoxy-1-piperidinyl) -5-androstane-3, 17-diol-diacetate with methyl bromide according to the procedure described in example 7, obtaining the target product with a yield of 75%. TPL=200-205oC.

Example 62. The composition is in the form of lyophilized powder in vials.

Prepare a solution of mannitol with a concentration of 60 g/liter using distilled water double distillation that is used for injection, the resulting solution filtered for sterility.

At the same time from the active compounds are prepared in a solution with a concentration of 20 g/liter using distilled water double distillation, intended for injection. For the sterility of the solution Attila volume of 1 ml each. The contents of the ampoules lyophilizer, and after keeping in an atmosphere of nitrogen ampoule sealed, receiving a dosage form containing 10 mg of active agent each.

Before use, the contents of the capsules dissolve in physiological solution (containing 0.9% sodium chloride).

Example A. Composition for injection in ampoules containing 10 mg of active agent (compound of example 5).

10 g of the active agent, 1.1 g of sodium hydroxide (additive regulating pH and osmotic pressure) of 8.9 g of acetic acid (additive regulating pH and osmotic pressure) and 17,02 g of sorbitol dissolved in 500 ml of double-distilled water. The solution is filtered to sterilize and bring to 1000 ml double-distilled water. After homogenization the solution was filled ampoules of 1 ml

The same composition was obtained using 17 g of mannitol instead of sorbitol.

Using large capsules, you can make a song with 20 or 50 mg of active agent (ampoule 2 or 5 ml, respectively).

Example B. Composition for injection in ampoules containing 2 mg of active agent.

The above composition can be done by repeating example I, with the proviso that instead of 10 g of outdoor activities is suspiro[4.5]Dec-8-yl-16-(1-pyrrolidinyl)-5-androstane -3, 17-diol-3-acetate.

1.5 g of 2-(1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-16-(1-pyrrolidinyl)-5-androstane-3, 17-diol-diacetate is dissolved in 10 ml of methanol, after which the reaction mixture is heated to boiling and boiled for 30 minutes. Upon completion of the reaction, the reaction mixture is cooled to 10oC, the precipitate is filtered off, dried (1.2 g) and recrystallized from acetonitrile. Output 1,0, TPL=214-217oC.

Example 64. Preparation of bromide 1-[3-atomic charges-2- (1,4-dioxa-8 azaspiro[4.5] Dec-8-yl)-17-hydroxy-5 - androstane-16-/ Il]-1-(2-propenyl)-pyrrolidine.

Spend the reaction of 2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-16-androstane-3, 17-diol-3-acetate with allylbromide according to the procedure described in example 5, obtaining the target product with a yield of 71%. TPL= 220-223oC.

1H-NMR: 300 MHz (CDCl3) ppm: 0.86 (s, 3H, 18-CH3), 1.01 (s, 3H, 19-CH), 2.07 (s, 3H, 3-OAc), 2.43 (br, 1H, 2-H), 2.62 (br, 4H, NCH2), 3.5-4.1 (m, 6H, N+CH2), 3.94 (s, 4H, CH2O), 4.50 (m, 1H, 16-H), 5.23 (m, 1H, 3-H), 5.69 and 5.85 (m, 2H, =CH2), 6.06 (m, 1H, -CH=).

Example 65. Preparation of bromide 1-[3, 17-dihydroxy-2-(1,4-dioxa-8 azaspiro [4.5]Dec-8-yl)-5-androstane-16-yl]-1-(2-propenyl)pyrrolidine.

Spend the reaction of 2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-16-androstane-3, 17-diol with SS="ptx2">

1H-NMR: 300 MHz (CDCl3) ppm: 0.84 and 0.87 (s, s, 3H, 3H, 18-CH3and 19-CH3), 2.45-2.85 (m, 5H, 2-H and: NCH2), 3.5-4.15 (m, 8H, N+CH2, 3-H and 3-OH), 3.96 (s, 4H, CH2O), 4.29 (m, 1H, 17 - H), 4.53 (m, 1H, 16-H), 5.77 (d, 1H, 17-OH), 5.70 and 5.89 (m, 2H, =CH2), 6.06 (m, 1H, -CH=).

Literature

1. The description of the patent in the UK N 1138605.

2. J. Medicinal Chemistry 16, 1116 (1973).

3. The description of the patent specification-analogue Europe N 0008824.

4. The description of the patent in Europe N 0208497.

5. The description of the patent in Europe N 0330253.

6. The description of the patent in Europe N 0288102.

7. The description of the patent Hungary N 172287.

8. W. C. Bowman: Pharmacology of Neuromuscular Function. pp. 99-105. Wright. London. 1980.

1. Derivatives of androstane General formula (1):

< / BR>
replaced by the 16-th position Quaternary ammonium group,

where R1means a hydrogen atom or a C1-4-alkanoyloxy group;

R2means C1-4-alkanoyloxy group

W1and W2mean the same or different group, or one of the symbols means a chemical bond, and the other group; or W1means group, and W2group

one of R3and R4means a hydrogen atom, and the other OR1group, or R3and R4together mean akcoglu the optimum group;

E means C1-4-alkyl or C3-5-alkenylphenol group

provided that derivatives containing a cyclic structure with two atoms of nitrogen, only the Deputy E means the above group, which is connected by a chemical bond with the nitrogen atom not directly related to steroid skeleton of the molecule, while the other alternate E mean free pair of electrons, X-anion;

n and m independently of each other - 2, or 4, provided that the sum of n and m in one cyclic structure is from 4 to 6, regardless of their values in a different cycle.

2. Connection on p. 1, selected from the group of compounds: 1-[17 - acetoxy-2-(1,4-dioxa-8 azaspiro [4,5] Dec-8-yl)-3-hydroxy-5-androstane-16-yl] -1-(2-propenyl) pyrrolidine bromide, 1-[3, 17-bis(acetoxy)-2-(1,4-dioxa-8 azaspiro [4,5]Dec-8-yl)-5-androstane-16-yl]-1-methylpyrrolidine bromide, 1-[3, 17-bis(acetoxy)-2-(1,4-dioxa-8 azaspiro [4,5]Dec-8-yl)5-androstane-16-yl]-1-(2-propenyl)pyrrolidine bromide, 1-[17-acetoxy-3-hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl] -1-methylpyrrolidinium,1-[17-acetoxy-3-hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl] -1-(2-propenyl)pyrrolidine bromide, 1-[3, 17-bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5 - androstane-16-yl] -1-(2-p bromide, 1-[17-acetoxy-3-hydroxy-2-(4-hydroxy-piperidinyl)-5-androstane-16-yl] -1-methylpiperidine bromide, 1-[3, 17-bis(acetoxy)-2-(4-hydroxy-piperidinyl-5-androstane-16-yl] -1-methylpiperidine bromide, 4-[3, 17-bis(acetoxy)-2-(1,4-dioxa-8 azaspiro[4,5]Oct-8-yl)-5-androstane-16-yl] -1,1-dimethylpiperazine bromide, 4-[3, 17-bis(acetoxy)-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-5-androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine bromide, 4-[17-acetoxy-3-hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl]-1,1-dimethylpiperazine bromide, 4-[17-acetoxy-3-hydroxy-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-oxo-1-piperidinyl-5-androstane-16-yl] -1,1-dimethylpiperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-oxo-1-piperidinyl-5-androstane-16-yl]-1-methyl-1-(2-propenyl)piperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl] -1,1-dimethylpiperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-hydroxy-1-piperidinyl)-5-androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl] -1,1-dimethylpiperazine bromide, 4-[3, 17-bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl] -1-methyl-1-(2-propenyl)piperazine bromide, 8-[3, 17 - bis(acetoxy)-2-(1-piperidinyl)-5-androstane-16-is] -8-methyl-1,4-dioxa-8 Sonisphere[4,5] decane bromide, 4-acetoxy-1-[3, 17-bis(acetoxy)-2-(4-acetoxy-1-piperidinyl)-5-androstane-16-yl]-1-methylpiperidine bromide.

3. The pharmaceutical composition capable of inducing neuromuscular blockade, containing the active ingredient mixed with commonly used in the pharmaceutical industry additives for filling and dilution, characterized in that as the active ingredient it contains one or more derivatives of the androstane, replaced by the 16-th position of the Quaternary ammonium group of formula 1 in which R1, R2, W1, W2, R3, R4, R5E, X-n and m are defined as indicated in paragraph 1, or pharmaceutically acceptable salts of acidic joining these derivatives of androstane taken in therapeutically active amounts, and as commonly used ingredients composition further comprises additives for stabilization, regulation of pH and osmotic pressure and/or facilitate the preparation of dosage forms.

 

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

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