Spontaneously dispersible concentrate, pharmaceutical product, therapeutic systemic drug and connections


(57) Abstract:

The invention is intended for the preparation of drugs used in Oncology. Spontaneously dispersible concentrate for the preparation of microemulsions, pharmaceutical drug and therapeutic systemic drug containing as an active start Stereolove esters of the formula I

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where R1- C1- C10-alkyl, C2- C10alkenyl, R2- C4- C32-alkyl, C4- C32alkenyl, C4- C32-alcabalas or retinography. The objective of the invention is the expansion of the range of cancer drugs. 4 C. and 6 C.p. f-crystals, 6 PL.

The invention relates to a spontaneously dispersible concentrates with antitumor activity, containing as active substance one or more compounds stalowych esters, and their new connections.

In the patent description Switzerland N 678276-0 describes sterols derived from extracts of seeds of sunflower (Helianthus annuus L.) and certain varieties of pumpkins (Cucurbita pepo L. and Cucurbita maxima Duch.), their glucosides and esters of fatty acids, as well as the use of drugs to combat tumors.

It was found that these produced semisynthetic Stereolove esters also have a fully marked antitumor activity, provided that they are included according to the invention in a spontaneously dispersible concentrates.

These Stereolove esters have the following basic structures shown in the end of the description scheme 1, where R1- C1-C10-Akilova group or C2-C10-alkenilovyh group, and R2- C4-C32-Akilova group, C4-C32-alkenilovyh group, C4-C32-alkupaiva or retinology group.

Of special importance Stereolove esters, which are produced from the following starting compounds listed in the end of the description in scheme 2, where R2- C4-C32-Akilova-, C4-C32-alkenilovyh-, C4-C32-alkupaiva or retinology group.

The object of the presented invention is spontaneously dispersible concentrates with these compounds stalowych esters. Such concentrates, Sevodnya microemulsions with excellent phase stability and everywhere clearly increased ability of penetration and distribution.

Spontaneously dispersible concentrates according to the invention contain 0.5 to 5 wt.% Stereolove ether according to formula I, 5-20 wt.% employee as hydrotropes (Co-emulsifier) pharmaceutically acceptable agent of the dissolution and for the remainder to 100 wt.% pharmaceutically portable detergent or mixture of detergents.

By choice they can optionally contain 0 to 10 wt.% vitamin or provitamin and/or up to 20 wt.% conventional pharmaceutical excipients and/or diluents.

Surfactants and mixtures of surfactants, which are involved in the invention process can be anionic, cationic or nonionic. It is best if they are nonionic and have the products HLB value (i.e., hydrophiliclipophilic balance) 2 - 18; preferably 2 to 6 on one side and 10 to 15 on the other hand.

The products HLB value indicates the hydrophilic and lipophilic properties of the emulsifier (Paul Becher "Hydrophile - Lypophile Balance: History and recent Developments", Journal of Dispersion Science and Technology. 5(1), 81-96, 1984).

As anionic detergents can be used as so-called water-soluble Soaps and water-soluble synthetic compounds.

As Soaps good use of salts of alkaline, alkaline-earth metal is Evie and potassium salts of oleic and stearic acid, or of natural mixtures of fatty acids, derived from coconut or melted animal fat. In addition, as detergents should mention imokalee salt methyltaurine, and modified and unmodified phospholipids.

However, it is often used so-called synthetic surfactants, especially fatty sulfonates, fatty sulfates, from sulphonated benzimidazole derivatives or sulfonates alkylaryl.

The fatty sulfonates and sulfates are usually in the form of salts of alkali, alkaline-earth metal or substituted ammonium salts and generally have an alkyl residue with 8-22 C atoms, and alkyl includes alkyl part of the alkyl residue. Examples are sodium salt, calcium salt ligninsulfonate acid, ether Modellbau sulfuric acid and sulfonic acids adducts of ethylenoxide fatty alcohol series. From sulphonated benzimidazole derivatives contain mainly two groups of sulfonic acid and the balance of fatty acids with 8-22 C atoms. The sulfonates alkylaryl is, for example, sodium salt, calcium salt or triethanolamine acid dodecylbenzensulfonate, dibutylaminoethanol or condensation products of formaldehyde naphtalenesulfonic acid.

As examples of nonionic detergents include nonylphenolethoxylates, polyglycolic ether of castor oil, adducts of polypropyleneoxide, tributyltinoxide, polyethylene glycol and octylphenoxypolyethoxyethanol. In addition, you can use a fatty acid ester of polyoxyethylenesorbitan, as well as monolaurate or trioleate of polyoxyethylenesorbitan.

Cationic surfactants are primarily Quaternary ammonium salts, which as nitrogen substituents contain at least one alkyl residue with 8-22 C atoms and, as further substituents are low and is it as halides, metilsulfate or ethylsulfate, such as steartrimonium or benzil-di-(2-chloroethyl)-ethylammonium.

B more to obtain spontaneously dispersible presented in the invention concentrates the preferred surfactants ester of phosphoric acid, for example

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Muistiinpanosovellus-18-ester of phosphoric acid, triethanolamine salt

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Nonylphenol-10-polyoxyethylene-mono/dimethyl ether phosphoric acid

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(Tensid 508, CIBA-GEIGY);

TinovetinJU (CIBA-GEIGY), hydroxybiphenyl-10-ethoxy ether phosphoric acid;

Butyl-mono-4-ethoxy ether phosphoric acid (ZerostatRAT CIBA-GEIGY) or

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As hydrotap or as employees as simulator farmaceutiske solvents can be used: ester of aliphatic alcohol (C3-C18) with aliphatic carboxylic acid (C10-C22), for example isopropylene, exellent, isopropylmyristate, isopropyl and laurierated; hydrocarbons with a straight chain of carbon (C12-C32), substituted 6-16 methyl groups and having 1-6 double bonds, examples of which can serve as terpenes, such as polymethylpentene and polymethylene.

Mono is propilenglikolmonostearata and propranololpropranolol.

Ester of aliphatic alcohol (C12-C22with lactic acid, for example myristyl or mainly laurolactam; mono-, di - or trifiro of glycerol with carboxylic acid (C12-C22), such as glyceryl-kaprilat or neutral oil MyglyolR812 (Oleum neutrale).

Ester of poly-(2-7)-etilenpropilendienovogo ether with at least one free gidroksamovoi group with aliphatic carboxylic acid (C6-C22), such as, for example, aliphatic alcohols (C12-C22among them decanol, tetradecanol, alerby alcohol, 2-hexyldecanol and 2-octilinear.

Ester with at least one free gidroksamovoi the group consisting of poly-(2-10)-glycol with aliphatic carboxylic acid (C6-C22), monoufia of polyethylene glycol with aliphatic alcohol (C12-C18), for example polyoxyethylene C10-oktilovom ether.

Heterocyclic compounds such as 1-methyl-2-pyrrolidone.

All technical detergents before inclusion in the spontaneously dispersible concentrates by filtration or chromatography over neutral alumina were purified inert solvent, for example, pontano dispersible concentrates are recommended vitamins and provitamins, for example, vitamin a, retinol, carotene, Tocopherols), as well as free fatty acids, such as Valerian, isovalerianic, sorbic, isocaproate, lauric, myristic, palmitic, Sterol, arahidovaya, Bekenova, hexacosanol, octacosanol, pentadecanol, dezenove, undeceive, oleic, linoleic, arachidonic, erucic, etc.

Used according to the invention ultramicroanalysis type oil-in-water contain 0.01 to 5 wt.% spontaneously dispersible concentrate as described above 85 to 99.99 wt.% distilled water, 5% glucose solution and physiological saline solution (ringer's solution), 0 to 10 wt.% pharmaceutical fillers or additives and/or auxiliary substances.

Required for pharmaceutical applications daily dose of 0.001 - 25 mg/kg of body weight, possibly distributed on 2-3 single dose. For this new containing Stereolove esters, stereopathetic or spontaneously dispersible concentrates, with their compounds are processed in a pharmaceutically usual forms, such as pills, tablets, capsules, powders, granules, pellets, solutions, capsules, emulsions, creams and candles, together with other excipients and/or solvents and is tov or prepared from aqueous microemulsions, can be people orally, by emulsion, injection (intravenous, subcutaneous or intramuscular), or in some other way. If they are present in solid form, such as tablets, granules, beads, powder, or capsules, they are administered orally. These forms may contain additional substances-carriers of drugs, such as sacharine or cellulose base, binders such as starch paste or methyl cellulose, a filler or crumbling tool and so on, and there are additives commonly used in the manufacture of medical and pharmaceutical products. If described in the invention the active substances and their mixtures should be applied in liquid form, but orally, they are made in the form of suspensions, emulsions and syrups, in addition they can be produced as a dry product, which before use is shaped in the form of a solution or emulsion.

If relevant to the invention spontaneously dispersible concentrates prepared in aqueous microemulsions, they can be injected. Solutions for injection can be made into capsules or immediately prior to use, while concentrates suspended in a liquid is

If necessary, in the injected drug, you can add the usual solvents, stabilizers, preservatives and additives to obtain isotonic. Thus obtained inject the drug can be administered intravenously, intramuscularly, subcutaneously or by some other appropriate way.

The invention also concerns pharmaceutical preparations containing active substances and their mixtures and/or described spontaneously dispersible concentrates used to inhibit the growth of tumour cells. The pharmaceutical preparations according to the invention are preparations for internal (oral or rectal), and parenteral or local introduction into the organism of warm-blooded animals containing a spontaneously dispersible concentrates in pure form or pharmaceutically used fillers.

The dosage described in the invention concentrates depends on the species of warm-blooded animals, their age and personal status, and method of application. So, for example, to achieve the effect of dying tumor cells in warm-blooded animals with small body weight, such as mice, rats and hamsters, used in a subcutaneous dose in the settings of 0.1 is real and rectal forms are used in pharmaceutical preparations containing 1 to 95%, mostly 10 - 95%, especially 20 to 95% specified in the invention spontaneously dispersible concentrate. So do you can apply a single dose in the standard form of pills, small balls, tablets, suppositories or ampoules, and above all capsules.

Suitable excipients for oral administration are mostly sugar (e.g. lactose, saccharose, mannitol or sorbitol), preparations of cellulose and/or calcium phosphate (e.g., powder tricalcium phosphate or calcium), binders such as starch glue, derived from corn, wheat, rice or potato starch, gelatin, tragant, methylcellulose, hydroxymethylene cellulose, hydroxypropionic methyl cellulose, natriumchlorid methyl cellulose and/or polyvinylpyrrolidone, and/or (if desirable) explosives, such as the abovementioned starches, and carboxymethylate starch, polyvinylpyrrolidone cross svyazyamie chains, agar, alginic acid or its salt, such as sodium alginate.

As substances that regulate the fluidity of the drug can be used, for example, polyethylene glycols 200 N - 600 and above.

Preferred people is centered diabetes solutions - containing, if necessary, gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanpoker-and lacquer solutions (water or those that can be obtained by the use of organic solvents) or nondestructive gastric juice membranes from solutions of the corresponding preparations of cellulose, such as microcrystalline cellulose (AvicelTM), acetylcellulose (MetoloseTM), getroproperty-cellulosebased-succinate (AQOATTMor of copolymerizate, for example EudragitL30D.

On the basis of the invention is especially useful applied oral pharmaceutical form of the compound capsules manufactured from gelatin and razmagchitsa, such as glycerol or sorbitol. Capsules of soft or hard gelatin, as well as the same of AQOATTM(hydroxypropyl-methylcellulose-acetylsuccinate) may contain, in accordance with the invention spontaneously dispersible concentrates mixed with talc or magnesium stearate and, if necessary, with stabilizers and antioxidants such as, for example, -, - or-tocopherol. It is recommended to use the appropriate liquid, such as liquid polyethylene glycols N 200 - 600 as a diluent, and to them oncentrate, described in the invention are diluted with distilled water. To the thus obtained aqueous injection of the microemulsion is possible to add substances which increase the viscosity, as for example Na-carboxymethylcellulose, sorbitol, mannitol, and/or dextran, and, if necessary, stabilizers and antioxidants.

Pharmaceutical preparations for parenteral administration are primarily 0.1 to 60%, and usually 1 to 40% described spontaneously dispersible concentrate.

Preparations for local use, especially recommended for prophylaxis and therapy of skin cancer, is a cream, ointment, paste, powder, foams, tinctures and solutions containing from 0.01 to 70% described spontaneously dispersible concentrate.

For creams and water-in-oil emulsions containing more than 50% of the water used as an oil basis primarily fatty alcohols, for example lauric, cetyl or stearyl alcohol, liquid and solid wax such as isopropylmyristate, wool and beeswax and/or hydrocarbons, such as petroleum jelly (petrolatum) or paraffin oil. For emulsification of these oily bases are used primarily surface-active, pharmaceutically compatible substances with preimushestvo acid polymeric alcohols or adducts of ethylene oxide (for example, ether polyglycerol fatty acids or polietilensorbit ether fatty acids) with products HLB below 8. Additives to the aqueous phase are, inter alia, substances that prevent the drying creams, for example, polymeric alcohols, such as glycerin, sorbitol, propylene glycol and/or polyethylene glycol 200-600 N, as well as preservatives, flavorings, etc.

Ointments are emulsions of water in oil, which contain up to 70%, preferably 20 to 50% water or aqueous phase.

As the fat phase primarily suitable hydrocarbons, for example vaseline, paraffin oil and/or hard paraffins, which are to improve the water-binding ability contain suitable connections hydroxide, such as fatty alcohol or ester, this is a bit of cetyl alcohol or alcohol wool wax.

Selectively add emulsifiers with HLB-the name under which the value 8 to 16, as for example sorbitan an ester of fatty acid (approximately serbianization). Additives to the aqueous phase, among others, are stabilizer (regulator) humidity as polymeric alcohols (glycerol, propylene glycol, Corbin and/or polyethylene glycol N 200, 400, 600); preservative agent, fragrances, etc.

W is/or liquid paraffins; in addition, natural or partial synthetic fats, such as for example triglycerin acid of coconut oil, as well as incomplete complex fatty acid ester of glycerol, for example, already mentioned in connection with the ointments increase photoadsorption fatty alcohols, emulsifiers and/or additives.

Pasta is creams and ointments with secretaryship parts powder such as metallic oxides (such as titanium oxide or zinc), as well as talc and/or aluminium silicates having a function for binding moisture or secret.

The foam used in cans under pressure, and are water-in-oil emulsion described spontaneously dispersible concentrate in aerosol form, and as foaming substances are used halogenated hydrocarbons (for example, low alkanes chlorofluoro: DICHLORODIFLUOROMETHANE and dichlorotetrafluoroethane). In case you need to add the usual preservatives, etc.

Examples of obtaining patent stalowych esters and stealthstation.

Example 1. Getting ergosta-5,7,22-triene-3-ol-dodecanoate.

2 g dodecanediol acid and 1.8 g of thionyl chloride is boiled for 2 h at reflux in 300 ml tetrahydrofurfurylamine.

After two hours of heating at 70oC by vacuum distillation, the solvent is removed. The remainder precrystallization in acetonitrile/acetone (50/50).

So get clean electrodomestic with melting temperature (i.e. square) of 86.6-to 91.1oC.

In the same way receive connection table.1.

Example 2. Getting stigmasterol-TRANS (separatng) retinite.

To 600 mg transparentnog-retinova acid and 50 mg of dimethylformamide in 70 ml of toluene at 5oC was added dropwise 360 mg oxalicacid in 30 ml of toluene. After 4 h at 20oC half of the solvent is separated by vacuum distillation.

To the remaining solution was added 650 mg of stigmasterol and 50 mg of p-dimethylaminopyridine in 30 ml of toluene. The reaction solution is heated for 2 h at reflux at 100-110oC. After which the solvent is separated by vacuum distillation. The remainder chromatographies on silicagel acid with hexane/acetic acid complex ether (9:1).

Get pure stigmasterol-trans-retinal with a melting point 89oC and UV absorption inmax385,5 nm.

In the same way get a connection having the same properties Cree is>/P>UV(UV) spectra were measured on a spectrophotometer Shimadzu UV-160A.

BI (refractive index) = RI (index of refraction) was measured at DUR-Refractometer Schmidt + Haensch, Berlin.

IR (infrared) spectra were measured on a spectrophotometer Perkin Elmer 983G.

The coefficients Rf patentable compounds obtained in examples 1 or 2, are given in table. 3 and 4 (1% solution in CH2Cl2applied tape form 2 cm/2 l Linomat III CAMAC 10 cm run; UV 366 1:1 H2SO4/MeOH 2 min 120oC).

The Rf coefficients c normal chromatography hexane/acetic ether 90: 10

-Estradiol-di-10-undecenoate - 0,37

-Estradiol-dioleate - 0,48

Ergosterol-trans-retinal - 0,88

Ergosterol-linolenate - 0,82

Ergosterol-linolenate - 0,96

Plate Merck Art. N 5715.

Examples of compounds spontaneously dispersible means according to the invention, containing antitumor substances Sterol according to formulae I - VI:

a) 0.5 to 5 wt.% one or more stalowych esters of formulas I - V, as well as having a certain value of significant components:

5 - 20 wt.% isopropylmyristate, isopropylpalmitate or Miglyol812 (Dynamit - Nobel);

22.5 to 40 wt.% InvadinJFC 800% (CIBA - GEIGY) for aerologic esters according to one of formulas I - VI,

5 - 20 wt.% isopropylmyristate, isopropylpalmitate or Miglyol812 (Dynamit-Nobel),

22.5 to 40 wt.% InvadinJFC 800% (SVA-GEIGY) for the remainder up to 100 wt.% SoprophorFL POULENC).

Miglyol812 - is a neutral oil (Oleum neutrale) company Dynamit-Nobel, corresponding seminarista triglyceride acids fractionated coconut oil C8-C10.

Diphasol3873 is shifted emulsifier consisting of 50% each of both compounds with the formula:

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InvadinJFC 800% (CIBA-GEIGY) is a tertiary octylphenyl-polyoxyethylene ether with 9-10 oxyethylene groups.

TWEEN-20 (ATLAS CHEMICALS, or ICI SPECIALITIES) is sorbitanoleat, I. e. the so-called connection of Polysorbate in the classification of the CTFA.

SoprophorFL-POULENC) is ether tridirectional-polyethylene-18-airfactory or-tea- (triethanolaminato)-salt, surfactant:

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The results of biological testing.

Antitumor activity spontaneously dispersible concentrates of active substances described in the examples of processing (a) and (b) is confirmed by the results of the following tests.

Probe the CSO analysis, working with microtitre plates and rows of diluents. In the culture medium RPMI 1640 allocated 104/ml of tumor cells, inactivated with 10% serum embryo calf (GIBCO); they are planted so sparsely that can grow during in vitro analysis in the so-called mestekawi monolayer. The addition of samples shall be performed through 6-24 h with 100 l in the range to which the first hole mixed with 100 l of the cultural environment. Then from there you select half and inserted into the next hole, again mixed with 100 l of the cultural environment. Thus the geometric dilution range n1/2.

The samples are incubated in reaction resetnavpane for 3-5 days at 37oC with 3.5% CO2. Then you should paint/fix with 0.1% crystal violet (Fluka, Buchs) in a solution consisting of 70% methanol, 1% formaldehyde, 29% water. The evaluation is made under the microscope at 300-fold increase. Is determined by the largest lexicastle dilution. Quantification is carried out by scanning and measuring the absorbance on the spectrophotometer.

Testing the activity of spontaneously emulsifiable concentrate containing 2% ergosterol-linoleate (ergo-serology ether C18:2on chelodina painted, left at the scene of the liver. Introduced a patent-pending spontaneously dispersible concentrates containing 2% ergosterol-10-undecenoate or 2% ergosterol-trans-retinal, diluted with distilled water in the ratio 1:10, 1:100 and 1:1000 and injected with ringer's solution. The work was kindly conducted by the Institute of clinical pharmacology, University of Bern (Prof. Dr R. Preisig). Were taken in 15 fractions over 20 minutes Analytical processing was carried out zone-capillary electrophoresis (12 kW continuous) device company Beckman Instruments (P/ACE System 2000, Version 1.50).

The result: the active substance overcome the barrier of the liver even at the highest tested concentration of 1: 10 (=2000 ppm, the content of active substances), for every 10-12 min hepatic barrier is full.

1. Spontaneously dispersible concentrate with antitumor activity, containing activetestsuite substance and conventional additives, characterized in that as activitiesthese substances it contains 0.5 - 5 wt.% Stereolove ether basic structure I

where R1- C1- C10-alkyl, C2- C10alkenyl;

R2- C4- C32-alkyl, C4- C32alkenyl,4-

2. Concentrate on p. 1, characterized in that as activitiesthese substances it contains serology ether, selected from the following compounds:

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and R2- C4- C32-alkyl, C4- C32alkenyl,4- C32-alcabalas or retinography.

3. Concentrate on p. 1, characterized in that it contains 0.5 - 2 wt.% Stereolove ether of the formula I as activitiesthese substances, 9.5 to 20 wt.% isopropylmyristate, isopropylpalmitate or neutral oil, 39 - 45 wt.% anhydrous Quaternary simple octylphenoxypolyethoxyethanol ether, and 39 to 45 wt.% mixed emulsifier consisting of two compounds of formulas

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when the mass ratio of 1 : 1, or an emulsifier of the formula

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4. Pharmaceutical preparation containing up to 80 wt.% spontaneously dispersible concentrate on p. 1 to 10 wt.% vitamin or provitamin and/or up to 20 wt.% conventional pharmaceutical carrier and/or diluent.

5. Concentrate on PP. 1 and 2, characterized in that as activitiesthese substances it contains Stereolove esters of formula II - VI, and the application as a drug with antitumor activity, characterized in that as activitiesthese substances it contains 0.5 - 2 wt.% at least one compound selected from the group comprising-sitosteryl-cabroilet, -sitosteryl-laurate, -sitosteryl-palmitate, -sitosteryl-stearate, -sitosteryl-arachidate, -sitosteryl-beginat, -sitosteryl-10-undecenoate, -sitosteryl-oleate, -sitosteryl-TRANS-retinal, stigmasteryl-laurate, stigmasteryl-palmitate, stigmasteryl-10-undecenoate, stigmasteryl-linoleate, stigmasteryl-linolenate, stigmasteryl-TRANS-retinal, ergosteryl-palmitate, ergosteryl-beginat, ergosteryl-10-undecenal, ergosteryl-TRANS-retinal.

7. Therapeutic system formulation containing 90 wt.% spontaneously dispersible concentrate on p. 2, 10 wt.% - substances that improve penetration, trap radicals and/or pharmaceutical excipients and are presented in dosage unit form of acceptance in the form of microcapsules, granules, pills, suppositories, ampoules or capsules.

8. The drug under item 7, contains 44 hours of core material to obtain granules or balls (paletto), 25 h concentrate on p. 2 and 31 h are resistant to gastric juice hydroxypropylmethylcellulose-succinate.

9. The drug under item 7 or 8, countrate and fill in a pharmaceutically acceptable capsule from hydroxypropylmethylcellulose-succinate.

10. Connection: stigmasteryl-TRANS-retinal, stigmasteryl-13-CIS-retinal, ergosteryl-TRANS-retinal, ergosteryl-13-CIS-retinal, roosterteeth, ergosteryl-10-undecenoate, ergosteryl-TRANS-2-dodecenal.


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