Beta-substituted 3-carboxylamide, the retrieval method, farmcampsite

 

(57) Abstract:

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

< / BR>
where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; (b) where each of R5and R6independently hydrogen or C1-C6alkyl group; C) , 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-C6alkyl group, or both together 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; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6THE 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 symbol represents 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. Due to their inhibitory activity against 5-reductase, substances of this invention can be used in the treatment of conditions, depending on the level of androgens, 2 S. and 4 C.p. f-crystals.

The invention relates to new derivatives of unsaturated beta-substituted 3-carboxyterminal, method of production thereof, to pharmaceutical compositions containing them, and to the use of the above compounds as inhibitors of androgen activity by suppressing testosterone-5-reductase.

Certain fabrics that respond to androgens, the effect of testosterone is transmitted mainly through its metabolite, ostentation in the DHT is catalyzed by the enzyme 5-reductase and, if the action of 5-reductase is inhibited, the formation of dihydrotestosterone decreases and decreases or prevents its specific androgene action.

Inhibitors of 5-reductase can find medical use in the treatment of conditions associated with the overproduction of male sex hormones, for example, in certain diseases of the prostate, such as benign prostatic hyperplasia and prostate cancer, and certain conditions skin and hair, such as acne, seborrhea, hirsutism in women and is typical for male baldness (Siiteri, P. K. , wilson j. D., J. Chin. Invest. 49, 1737, 1970; Price V. A. Arch. Dermatol. III., 1496, 1975; Sandferg A. A., Urology 17, 34, 1981).

The use of an inhibitor of 5-reductase may also be useful in the treatment of breast cancer, since this type of tumor is progressing, as is well known, in the presence of androgens. Androst-4-EN-3-s-17-carboxylic acid and its methyl ester are one of the first steroid compounds that are described as inhibitors of 5-reductase (Voigt and Hsia, Endocrinology, 92, 1216 (1973); Canadian Patent No. 970, 692).

Two 5,10-secosteroids with a 3-keto-4,5-diene system in the extended ring, as it was discovered, are selective inhibitors epidemically 5-reductase in rats (Robaire et. al.).

New series of enzyme-controlled irreversible inhibitor of 5-reductase were obtained by the introduction of the 6-methylene replacement groups in the substrates of the type of 3-keto-4-progestins and androgens (Petrow at. al., Steroids 38, 352-53, 1981; United States Patent 4.396.615).

Recently it was reported that 4-azasteroid are also inhibitors of steroid 5-reductase (Liang et. al., J. steroid. Biochem. 19, 385-90, 1983; United States Patent 4.377.584 published European Patent Appl. no. 155096).

And finally, it was reported that unsaturated derivatives of 3-carboxyterminal are also uncompetitive inhibitor of 5-reductase testosterone (Biolog. Chem. 17, 372-376, 1989; Eur. Pat. Appl. no 0289327).

The invention is new derivatives of unsaturated 17-substituted 3-carboxyterminal having the following formula:

< / BR>
where Y is oxygen or sulfur;

R - group:

a) OR4where R4is hydrogen or C1-C6alkyl group, or

b) where each of R5and R6independently represent or C1-C6is an alkyl group;

C) , where R7is hydrogen or C1-C6alkyl group; W is a group:

(I) where R8- C1-C6alkyl group, a C5-C6cyclol the I) , where R9- C1-C6is an alkyl group or a C5-C6cycloalkyl group; or

(III) where R5and R6defined above; or

e) , where each of R10and R11is independently hydrogen or C1-C6alkyl group or both radicals together with the nitrogen atom to which they are linked, form a saturated heterophilically ring with 5 or 6 members, possibly containing at least one additional heteroatom selected from oxygen and nitrogen; n is an integer of 2-4; R1is hydrogen, C1-C6alkyl group, a C5-C6- cycloalkyl group, C6-C9cycloalkylation group or aryl group;

each of the C2and C3independently selected from the group consisting of hydrogen, C1-C6-alkyl, C5-C6-cycloalkyl, C6-C9-cycloalkenyl and aryl, or R2and R3taken together with the nitrogen to which they are bound, form a 5 - or 6-membered saturated heterophilically ring may contain at least one additional heteroatom selected from oxygen and nitrogen, the symbol represents a single or double bond, provided that when is a double bond, hydrogen 5 is, hence, adaptation, i.e., below the plane of the ring, and wedge-shaped line indicates a substituent in the-configuration, i.e. above the plane of the ring.

The invention also includes pharmaceutically applicable salts of the compounds and formulas I, as well as all possible isomers of the formula I and mixtures thereof.

In addition, metabolites and metabolicheskie the precursor compounds of formula I are included in the scope of the invention.

In this description, the alkyl groups and alkyl substituent cycloalkyl groups may be straight or branched chain, and C1-C6the alkyl group can be, for example, stands, ethyl, isopropyl, n-bootrom, tert-bootrom or tert-butyllithium (i.e. neopentyl).

C5-C6-cycloalkyl group is cyclopentyl or cyclohexyl, preferably cyclohexyl.

C6-C9-cycloalkylation group can be, for example, cyclohexylmethyl.

The aryl group may be, for example, phenyl or benzyl.

When R is a group-OR4as defined above, preferably R4is hydrogen, methyl or ethyl, most preferably hydrogen;

When R is a group as defined above, preferably each is sustained fashion hydrogen or methyl.

When W is a group , R8- preferably methyl, ethyl, propyl, n-butyl, t-butyl, cyclohexylmethyl, phenyl or benzyl.

When W is a group , R9- preferably methyl, ethyl, n-propyl or cyclohexyl.

When W is a group , preferably each of R5and R6- independently methyl or ethyl.

When R is a group , preferably each of R10and R11is independently hydrogen, methyl, ethyl, propyl, isopropyl or, when R10and R11together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, as defined above, the group preferably represents n is preferably 2, 3.

R1- preferably methyl, ethyl, isopropyl, tert-butyl, cyclohexyl or cyclohexylmethyl.

Preferably each of R2and R3is independently hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, cyclohexylmethyl phenyl, or, when R2and R3together with the nitrogen atom to which they are bound, form a 5 - or 6-membered saturated heterophilically ring, as defined above, the group preferably represents a

Pharmaceutical the technical grounds such as, for example, alkali metal such as sodium or potassium, or alkaline-earth metals, for example calcium or magnesium, or zinc or aluminum hydroxide; and organic bases, such as, for example, aliphatic amines such as methylamine, trimethylamine, ethylamine, and heterocyclic amines such as piperidine.

A preferred class of compounds in accordance with this invention are the compounds of formula I, where Y is oxygen or sulfur;

< / BR>
R1is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl; group represents

< / BR>
< / BR>
the symbol represents a single or double bond, and their pharmaceutically acceptable salts.

Examples of specific compounds, preferred in this invention are:

17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene-3-carboxylic acid;

17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid;

17-[N-tertbutyl-N-(N-tert-butylcarbamoyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid;

17-[N-isopropyl-N-(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid;

17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl the Wai acid;

methyl-17-[N-isopropyl-N-(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

methyl-17-[N-isopropyl-N-(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

methyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

methyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

methyl-17-[N-tert-butyl-N-(N-tert-butylcarbamoyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

methyl-17-[N-methyl-N-(N, N-diethylcarbamoyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

N, N-diethyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene-3-carboxamide;

N, N-diethyl-17-[N-isopropyl-N-(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-Dien-carboxamide;

N, N-diethyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-Dien-carboxamide;

N, N-diethyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-Dien-carboxamide;

N, N-diethyl-17-[N-methyl-N-(N, N-diethylcarbamoyl)carbarnoyl] androsta-3,5-Dien-carboxamide;

acetoacetyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene-3-carboxylate;

Pivaloyloxymethyl-17-[N-isopropyl-N-([N-isopropylcarbamate) carbamoyl] androsta-3,5-diene-3-carboxylate;

(N, N-diethylcarbamoyl)methyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene-3-carboxylate;

2-(N-morpholino)ethyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene-3-carboxylate;

and, where possible, their pharmaceutically acceptable salts.

The compound of the formula I can be obtained by using a method including:

A) reaction of compounds of formula

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where the symbol is a single or double bond; Y, R1, R2, R3defined above, with carbon monoxide (CO) in the presence of C1-C6-Olkiluoto alcohol, thereby obtaining the compound of formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above, R is a group OR4where R4- C1-C6alkyl group; or

B) reaction of compounds of formula II, as defined above, with carbon monoxide in the presence of an amine of the formula

< / BR>
where R5and R6defined above, thereby obtaining the compound of formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above, and R is a group

< / BR>
where R5and R6defined above; or

C) Reaction of compounds of formula I, where si is R4is hydrogen, with a compound of the formula

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where R7and W are defined above, and X is a halogen atom, thereby obtaining the compound of formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above, R is a group , where R7and W are defined above; or

D) Reaction of compounds of formula I, where denotes a single or double bond; Y, R1, R2, R3defined above, the R group OR4where R4is hydrogen, with a compound of the formula

< / BR>
where R10and R11defined above, thereby obtaining the compound of formula I, where is the symbol that represents a single or double bond; Y, R1, R2, R3defined above, the R group

< / BR>
where n, R10and R11defined above; and if desired, converting the compound of formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above, the R group OR4where R4- C1-C6is an alkyl group, by selective hydrolysis into the corresponding compound of formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above, the R group OR4where R4- hydrogen, and/or, if desired, converting the compound of formula is entrusted, separation of a mixture of isomers of compounds of formula I into individual isomers.

The reaction of the compound of formula II with carbon monoxide in the presence of C1-C6-Olkiluoto alcohol in accordance with the method according to option a can be carried out, for example, by interaction of a solution of the compounds of formula II in a suitable organic solvent, preferably dimethylformamide (DMF), with an organic base, such as, for example, triethylamine (tea), and a palladium complex, such as, for example, bis (triphenylphosphine)-palladium (II) acetate or bis(triphenylphosphine)-palladium (II) chloride, and C1-C4is an alkyl alcohol.

Optionally palladium complexes can be prepared in situ by adding, each separately, phosphine, such as triphenylphosphine and palladium salt, such as, for example, palladium, such as palladium (II) acetate or palladium (II) chloride.

Then the reaction mixture is blown with carbon monoxide (CO) in a few minutes and then stirred in an atmosphere of CO for 1-48 hours at a temperature of 0-40oC (a similar process is described, for example, in Jetr. Lett. 26(8), 1109-12, 1985).

The reaction of the compound of formula II with carbon monoxide and an amine of the formula III above, and instead Olkiluoto alcohol is used amine of formula III.

The halogen atom X in the compound of formulae IV and V is preferably a chlorine atom, bromine, iodine, most preferably chlorine or bromine.

The reaction of compounds of formula I with the compound of the formula IV in accordance with the method variant C can be carried out in a solvent such as, for example, dimethylformamide, dimethylacetamide, acetonitrile, in the presence of a base, such as, for example, alkali metal hydride, preferably sodium hydride, or alkali metal alkoxide, preferably sodium methoxide, ethoxide sodium, tert-piperonyl potassium, or amine, preferably pyridine or triethylamine, optionally, when X is iodine, in the presence of alkali metal iodide, preferably sodium iodide, at a temperature in the range from about 0oC to about room temperature for a time varying from about 2 hours to about 24 hours, preferably in a neutral atmosphere of nitrogen.

The reaction of compounds of formula I with the compound of the formula V in accordance with the method option D can be carried out in a solvent such as, for example, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, in the presence of bases is atalla, preferably sodium methoxide, ethoxide sodium, tert-piperonyl potassium, or amine, preferably pyridine or triethylamine, optionally, when X is iodine, in the presence of alkali metal iodide, preferably sodium iodide, at a temperature in the range of from about 0oC to about 80oC for 1-8 hours

The transformation of the substances of the formula I, where the symbol is a single or double bond; Y, R1, R2, R3defined above and R is a group OR4where R4- C1-C4alkyl group, the corresponding compound of formula I, where the symbol is a single or double bond, Y, R1, R2, R3defined above, the R group OR4where R4is hydrogen, can be carried out, for example, in a suitable solvent, such as, for example, methanol, ethanol, tetrahydrofuran, dioxane, in the presence of aqueous concentrated solution of alkali metal hydroxide, such as, for example, potassium hydroxide, sodium hydroxide or, preferably lithium hydroxide, in a period of time ranging from several hours to several days at temperatures varying in the range from about 0oC to the temperature of distillation of the solvent, preferably in an inert atmosphere of nitrogen.

The compound of formula II, where the symbol denotes a single bond, Y, R1, R2, R3defined above, can be obtained from the compounds of formula

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where Y, R1, R2, R3described above, in the following way.

The compound of formula VI is dissolved in a suitable organic solvent, such as, for example, tetrahydrofuran (THF) in the presence of a suitable organic donor of protons, such as, for example, tert-butanol or aniline. Then to the mixture is added regenerating the metal-amine solution, for example a solution of lithium/liquid ammonia, and then the reaction mixture was stirred at a temperature varying in the range from about -100oC to about -30oC, preferably at about -78oC, for about 2-3 hours Then the reaction is stopped by using an organic lithium acceptor, such as, for example, bromobenzoyl, dibromoethane or, preferably, isoprene, and the solvent is removed under vacuum. The solid precipitate is again dissolved in an organic solvent, such as, for example, tetrahydrofuran or diethyl ether, and treated with N-aritificially>C for from about 2 h to about 24 h (about this method is reported, for example, in Jetr. Lett. 1983, 24, 579-982).

The compound of formula II, where the symbol is a double bond, Y, R1, R2, R3defined above, can be obtained from the corresponding compounds of formula VI, where R1, R2and R3defined above and a is a single bond, for example by adding to the solution containing the compound of formula VI, as defined above, and a weak organic base, such as 2,6-di-tertbutyl-4-methylpyridine, in a suitable organic solvent, such as, for example, methylene chloride, triptoreline anhydride, preferably triftormetilfullerenov anhydride, in accordance with the method published in the Synthesis. 438-440, 1979.

The compound of formula VI can be synthesized using known methods, for example in three ways a), (b) and (C) shown in the following diagram:

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According to reaction (a), the compound of formula VI where Y, R1, R2, R3defined above, and R1and R2- non-hydrogen atoms, a R3is hydrogen, can be obtained by reaction of compounds of formula VI where Y described above, with the carbodiimide of the formula VIII, where R1and R2determine Gorod; Y, R1, R2, R3defined above, can be obtained from compounds of formula IX, where R2and R3described above, by alkylation with a compound of formula X, where R1defined above, and is not hydrogen, and X is a halogen atom, such as iodine.

In accordance with the reaction (C) a compound of formula VI, where R3is hydrogen, Y, R1, R2, R3defined above, and R2not hydrogen, can be obtained from compounds of formula XI, where R1described above, by reaction with a compound of formula XII, where R2and Y are defined above, and R2is not hydrogen.

The compounds of formula VII where Y Is S, formula IX, and formula XI can be obtained by reaction of compounds of formula

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where A can be any suitable activating carboxyl function group which is suitable for the formation of amide and peptide bonds, with an appropriate reagent, as shown below.

Suitable activating group may be, for example, one of the following groups:

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Specifically, the compound of formula VII where Y is sulfur, may be, for example, obtained from compounds of formula XIII in accordance with known methods.

One method may include, aphernalia in the solvent, such as, for example, CH2Cl2at room temperature for a time from about 10 minutes to several hours under vigorous stirring by the method described in Synthesis, 671-2, 1985.

Another method may include, for example, the interaction of the compounds of formula XIII, where A - is S-2-pyridylmethyl derivative, with an excess of bisulfite sodium monohydrate. The reaction can be performed in a solvent such as, for example, methylene chloride, tetrahydrofuran, acetonitrile, at a temperature of, for example, from about 0oC to about 50oC over time, for example, from about 1 hour to about 48 hours

Compound of formula VII where Y is sulfur, can also be synthesized in accordance with the basic methods described in the literature on the synthesis thiocarbonic acids, for example by means similar to those described in Houben Weyl, Bd E5, 832 - 842, or Duns F. in Barton and Ollis, Comprehen. sive Organic Chemistry, Vol. 3, Pergamon Press, Oxford, 1979 p. 420-432.

The compound of formula IX, as defined above, can be obtained by the coupling of compounds of formula XIII as defined above, with a urea of the formula

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where R2and R3defined above.

The compound of formula XI can be obtained by the interaction of the compounds formulary XIII can be obtained from compounds of formula VII, where Y is oxygen, well-known methods.

The compounds of formula III, IV, V, VII, where Y is oxygen, the compounds of formulas VIII, X, XII, XIV and XV are commercially available or can be obtained by known methods from known compounds.

Compounds according to the invention specifically inhibit the enzyme testosterone-5-reductase and therefore can be useful for treating conditions, depending on the level of androgens. For example, the inhibitory effect of the compounds of this invention for 5-reductase was determined in virto in accordance with the methodology described below.

Inhibition of 5-reductase was estimated using the fraction of dense particles containing core, microsome assay and mitochondria from homogenates of benign hypertrophic prostate tissue as the source of enzyme.

The fraction of dense particles was obtained by centrifugation of the homogenate prostate when 140000g. The precipitate was washed several times, resuspendable buffer and stored at -80oC in portions containing 10 mg of protein in 1 ml.

Research on 5-reductase was performed in a final volume of 0.5 ml, containing 1 mmol of dithiothreitol, 40 mmol Tris-HCl buffer pH 5.5, 5 mm NADP, 1 µmol 4-14the John incubation at 37oC the reaction was stopped by adding 2.0 ml of diethyl ether and the organic phase was separated, evaporated in an atmosphere of N2and resuspendable in ethyl acetate. The metabolites of testosterone of this extract was separated by TLC on silicagel plates F 254 (Merck) using chloroform, acetone and n-hexane (2:1:2) as developing system of solvents. The radioactivity on the plate was scanned and analyzed using quantitative graphs, printed TLC analyzer (Berthold).

Fractional 5-restore testosterone was calculated by the ratio of 14C-radioactively in the bands 5-recovered metabolites (5-dihydrotestosterone, 3 - and 3-androstendiol) to the total radioactivity in the bands of testosterone and 5 - recovered metabolites.

The concentration of each compound required to reduce the activity of the control and 5-reductase by 50 % (PC50), was determined according to the schedule according to the percentage of suppression from the logarithm of the concentration of the inhibitor.

Thus, for example, in the above study, it was found that the connection representing the invention, namely 17-[N-isopropyl-N-(N-isopropylcarbamate)carbamoyl reductase dose of 3 nm.

In view of the above activity of the compounds of this invention can be therapeutically useful in the cases where it is desirable reduction in androgenic effect by inhibition of 5-reductase, such as benign prostatic hyperplasia, prostate cancer and breast cancer and certain skin conditions and hair, such as, for example, seborrhea, hirsutism in women and male pattern baldness.

They are suitable for pharmaceutical production, and for the treatment of prostate hyperplasia in veterinary medicine.

The toxicity of the compounds of this invention is completely invisible, so that they can be safely used for therapy.

The compounds of this invention can be applied in the form of a number of dosage forms, e.g. orally, in the form of tablets, capsules, pills, coated with sugar or film, solutions and suspensions, rectally in the form of suppositories, parenterally, e.g. intramuscularly or intravenously by injection or infusion, topically, for example in the form of creams.

The dosage depends on age, weight, condition of the patient and the route of administration, for example, the dose for oral administration in adults can from asepticheskie composition, consisting of compounds of this invention in a mixture with farmatsevticheskii acceptable excipient, which may be a carrier or solvent.

The pharmaceutical composition, the content of substances of this invention are usually obtained following conventional methods and are applied in a convenient pharmaceutical form.

For example, the solid oral forms may contain, together with the active substance diluents, for example lactose, dextrose, saccharose, cellulose, corn or potato starch, moving substances such as silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols, binding agents, for example starches, Arabian kemedi, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, loosening agents, for example starch, alginic acid, alginates or starch glycolate, sodium, effervescent mixtures of dyes, sweeteners, moisturizing agents, such as lecithin, Polysorbate, laurilsulfate, and, in General, non-toxic and pharmacologically inactive substances used in the formulations of medicines.

The abovementioned pharmaceutical preparations can be proizvedenim caramel or film coating.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular, the syrup, which will take diabetic patients, may contain as a carrier (base) only substances that are not metabolized to glucose or to metabolisable glucose in very small amounts, for example sorbitol.

Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active substance pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycol, for example propylene glycol and, if desirable, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline rest is low), for example, cocoa butter, polyethylene glycol, surfactant (surfactant), which is a polyoxyethylene ether-sorbitan and fatty acids or lecithin.

Common carriers can be used to produce dosage forms for local use.

The expression "pharmaceutical", etc. used in the description imply the inclusion and values "veterinary and so-called".

The following examples illustrate, but not limit the invention in NMR spectra, the following notation: s - singlet, d-doublet, t-triplet, m-multiplet, b - broad signal, q - Quartet.

Example 1. 1-(3-oxoandrosta-4-EN-17-carbonyl)-1,3-Diisopropylamine [(VI): Y = 0, R1= iPr, R2= iPr, R3= H].

To a stirred solution of androst-4-EN-3-one-17-carboxylic acid (50 g) in ethyl acetate (1.5 l) and triethylamine (33 ml) drops added N,N-diisopropylcarbodiimide (32,4 ml) for 5 min and then the reaction mixture is heated in a flask under reflux for 1 h, the Reaction mixture was cooled and filtered on a Buechner funnel, the filtrate was filtered 1 N. HCl, 0,5 N. NaHCO3, saline solution and dried with sodium sulfate and concentrated to about 150 ml by ohlord provim ether, leaving thus 54 g of white crystalline substance (so pl. 172-175oC) [] D+ 89oC(C = 1, DMF).

Following the same methodology, can be obtained from the below listed substances:

1-(3-oxoandrosta-4-one-17-carbonyl)-1,3-dicyclohexylamine (so pl. 178-180oC []D+77oC (C = 1, DMF);

1-(3-oxoandrosta-4-EN-17-carbonyl)-1,3-distritbution (so pl. 175-177oC) [] D+ 53oC (C = 0,5, DMF).

Example 2. 1-(3-oxoandrosta-4-EN-17-carbonyl)-1,3-diisopropylethylamine [(VI): Y = S, R1= iPr, R2= iPr].

A solution of 2-pyridyl-3-oxoandrosta-4-EN-17-carbothioate [(XIII) ] (3.0 g) in tetrahydrofuran (70 ml) was treated with 70 % of sodium sulfide monohydrate (3,9 g) and the mixture was heated under reflux for 2 hours After acidification of 1 N. hydrochloric acid, the mixture was carefully extracted with methylene chloride.

The combined organic extracts were washed with water until neutral, dried with sodium sulfate and evaporated until dry.

Further purification by thin-layer chromatography on silica gel (eluent - methylene chloride: acetone 95: 5) gives 3.5 g of 3-oxoandrosta-4-EN-17-carbothioic acid [(VII) Y = S].

NMR (CDCI3) : 5,70 (S, 1H, H (4)), 1,2 (s, 3H, the m way in ethyl acetate (59 ml) was treated first with triethylamine (1.6 ml) and then N,N'-diisopropylcarbodiimide (1,54 ml) and the mixture was stirred for 5 h at room temperature.

The reaction mixture was immediately subjected to chromatography on a column of silica gel with elution with methylene chloride/ethyl acetate 90:10, thus obtaining the substance indicated in the name (2,03 g, recrystallized from methylene chloride/ethyl acetate; so pl. 180-183oC) []D+ 146oC (C = 1, DMF).

NMR (CDCl3) : to 6.8 (d, 1H, H), of 5.75 (s, 1H, H(4)), 4,2-4,8 (m, 2H, NH-CH(CH3)2and 1.3 (2d, 12H, 4 isopropyl CH3), 1,2 (s, 3H, CH3(19)) to 0.85 (s, 3H, CH3(18)).

MS (m/z) : 458 M+< / BR>
< / BR>
Following the same methodology, can be obtained the compounds listed below:

1-(3-oxoandrosta-4-EN-17-carbonyl)-1,3-dicyclohexylcarbodimide (so pl. 209-212oC);

1-(3-oxoandrosta-4-EN-17-carbonyl)-1,3-decentralisation.

Example 3. 3-{[(trifluoromethyl)sulfonyl]oxy}-17[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene [(II), Y = 0, R1= iPr, R1= iPr, R3= H, - double bond].

To a stirred solution of 17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl] androst-4-EN-3-one (6.0 g) and 2,6-ditertbutyl alali dropwise triperoxonane anhydride (2,54 ml) for 10 min.

After stirring for 30 min the reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate solution, 1 N. HCl, with water until neutral and dried with sodium sulfate.

The resulting foam was purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 75: 25) to obtain thus to 4.6 g of compound indicated in the title (so pl. 135-140oC).

NMR (CDCl3) : 5:80 (m, 1H, H(4)), the 5.45 (m, 1H, H(6)).

MS (m/h)

Following the same methodology, can be obtained the following compounds:

3-{ [(trifluoromethyl)sulfonyl] oxy} -17-[N-isopropyl-N(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-diene;

3-{ [(trifluoromethyl)sulfonyl] oxy} -17-[N-cyclohexyl-N(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene (so pl. 140-145oC);

3-{ [(trifluoromethyl)sulfonyl] oxy} -17-[N-cyclohexyl-N(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene;

3-{ [(trifluoromethyl)sulfonyl] oxy} -17-[N-tert-butyl-N-tert-butylcarbamoyl) carbarnoyl] androsta-3,5-diene (so pl. 123-124oC);

3-{ [(trifluoromethyl)sulfonyl] oxy} -17-[N-methyl-N - (N,N-diethylcarbamoyl) carbarnoyl] androsta-3,5-diene.

Example 4. Methyl-beta-[N-isopropyl-N-(N-isopropyle= OR4, R4= CH3].

To a solution of 3-{ [(trifluoromethyl) sulfonyl]oxy}-17-[N-isopropyl-N(N-isopropylcarbamate)carbarnoyl] androsta-3,5-diene (4.6 g) in dimethylformamide (17 ml), methanol (17 ml) and triethylamine (2,23 ml) was added bis(triphenylphosphine) palladium (II) acetate (180 mg), the mixture was purged with carbon monoxide for 5 min and then stirred overnight at room temperature in an atmosphere of carbon monoxide, supported in a closed glass flask.

Then added ethyl acetate and the organic solution was washed with water until neutral, dried with sodium sulfate and the solvent was removed under vacuum. The crude product was purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 75:25), thus obtaining 3.5 g specified in the product name (so pl. 15O-155oC)

NMR (CDPCl3) : 7,05 (m, 1H, H (4)), 5,80 (m, 1H, H (6)), 3,75 3H, COOCH3).

MS (m/h)

Following the same methodology, can be obtained from the following ingredients:

Methyl-17-[N-isopropyl-N-(N-isopropylaminocarbonyl) carbarnoyl]androsta-3,5-diene-3-carboxylate;

Methyl-17-[N-isopropyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylate;

Methyl-17-[N-isopropyl-N-(N-cyclohex carbamoyl] androsta-3,5-diene-3-carboxylate (so pl. 110-115oC);

Methyl-17-[N-methyl-N-(N-isopropylaminocarbonyl) carbarnoyl] androsta-3,5-diene-3-carboxylate.

Example 5. Methyl-17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl] androsta-3,5-diene-3-carboxylic acid [(I): Y = 0, R1= iPr, R2= iPr, R3= H, - double bond, R = OR4, R4= H].

A mixture of methyl-beta-[N-isopropyl-N-(N-isopropylaminocarbonyl) carbarnoyl] androsta-3,5-diene-3-carboxylate (3,29 g), methanol (136 ml) and aqueous lithium hydroxide (1,424 g in 36 ml of water) were mixed at room temperature for 5 days. The methanol was evaporated under vacuum and water was added, and the mixture was padillas 1 N. HCl and was extracted with methylene chloride, the organic layers were washed with saturated salt solution and water until neutral, dried with sodium sulfate and the solvent was removed under vacuum.

The yellow solid residue was purified using flash chromatography on silica gel (eluent: methylene chloride/acetone 9:1), thus gained 1.66 g of a white solid, which was crystallized from methylene chloride/ethyl acetate (1,15 g, so pl. 173-175oC Dec.), []D= -132oC (C = 1, CHCl3).

NMR (CDCl3) : 7,13 (m, 1H, H(4)), 6,50 (b m, 1H, CONH), of 5.82 (m, 1H, H(6)), 4,48 (m, 1H, ), 3,98 (m, 1H (18)).

MC (m/h):

Following the same methodology can be obtained from the following ingredients:

17-[N-isopropyl-N-(N-isopropylaminocarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid (so pl. 125-130oC);

17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] (so pl. 253-255oC, AcOEt) []D- 110oC (C = 1, CHCl3);

17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid;

17-[N-tert-butyl-N-(N-tert-butylcarbamoyl)carbarnoyl] androsta-3,5-diene-3-carboxylic acid (so pl. 118-120oC), 134oC (C = 0,5, DMF);

17-[N-methyl-N-(N-diethylcarbamoyl) carbarnoyl] androsta-3,5-diene-3-carboxylic acid.

Example 6. N,N-diethylcarbamoyl-17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl] androsta-3,5-diene-3-carboxamide [(I): Y = 0, R1= iPr, R2= iPr, R3= H, R4= R5= This].

A mixture of 3-{ [(trifluoromethyl) sulfonyl]oxy}-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl]androsta-3,5-diene (574 mg), palladium acetate (6 mg), triphenylphosphine (16 mg) and diethylamine (4,2 ml) in dimethylformamide (4 ml) was purged with carbon monoxide for 10 min and then stirred overnight at room temperature in an atmosphere of carbon monoxide, supported by Zack the shares, dried with sodium sulfate and the solvent was removed under vacuum.

The crude product was purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 60:40), thus obtaining 310 mg of the substance as described in the title.

Following the same methodology, can be obtained from the following ingredients:

N, N-diethyl-17-[N-isopropyl-N-(N-isopropylaminocarbonyl) carbarnoyl] androsta-3,5-diene-3-carboxamide;

N, N-diethyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene-3-carboxamide;

N, N-diethyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl) carbarnoyl] androsta-3,5-diene-3-carboxamide;

N,N-diethyl-17-[N-methyl-N-(N-diethylcarbamoyl)carbarnoyl]androsta-3,5-diene-3-carboxamide.

Example 7. 2-(N-morphine)ethyl-17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl] androsta-3,5-diene-3-carboxylate [(I): Y = 0, R1= iPr, R2= iPr, R3= H

< / BR>
To a solution of 17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl]androsta-3,5-diene-3-carboxylic acid (235 mg) in methylene chloride (2.5 ml) was slowly added 4-(2-hydroxyethyl)-morpholine (7,4 ml) and 4-pyrrolidinedione (3.7 mg), and after them dicyclohexylcarbodiimide (124 mg). After a few minutes, the clear solution became turbid. Lane is every precipitate was filtered methylene-chloride, the filtrate was evaporated to dryness. Thus obtained crude oily substance (394 mg) was purified using flash chromatography on silica gel (eluent: methylene chloride/acetone 8:2) to give 170 mg of the compound indicated in the title.

NMR (CDCl3) : 7,00 (m, 1H, H (4)), 6,50 (b m, 1H, CONH), 5,78 (m, 1H, H(6)), 4,48 (m, 1H, ), 4,27 (m, 2H, OCO-), 3,98 (m, 1H, CONCH (CH3)2), 3,68 (m, 4H, ), to 2.65 (m, 4H ), of 2.50 (m, 2H, ), 1,35-1,15 (4d, N, 4 isopropyl CH3), and 0.50 (s, 3H, CH3(19)), to 0.80 (s, 3H, CH3(18)).

MS (m/z): 583 M+< / BR>
< / BR>
Example 8. Acetoacetyl beta-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl] androsta-3,5-diene-3-carboxylate [(I): Y = 0, R1= iPr, R2= iPr, R3= H, - double bond, R = -O-CH2O-COMe]

To a solution of 17-[N-isopropyl-N-(N-isopropylcarbamate) carbarnoyl]androsta-3,5-diene-3-carboxylic acid (500 mg) in anhydrous dimethylformamide (15 ml), maintained under nitrogen atmosphere and cooled to 0oC in an ice bath, add sodium hydride (of 47.8 mg, 80 % suspension in mineral oil) and the mixture was stirred at 0oC for 1 h Drops add bromomethane (0,31 ml) and the solution was stirred at room temperature for 3 hours the mixture is Then poured into ice water and extracted with toluene (3 x 50 ml), the combined organocatalyst under vacuum, moreover, remains of 500 mg of crude material which is purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 65:35), thus obtaining 270 mg of the substances mentioned in the title, in the form of a white solid precipitate (so pl. 183-185oC).

Elementary analysis for C31H46N2O6:

Calculated, %: C 68,61; H 8,54; N 5,16.

Found, %: C 68,34; H 8,76; N 5,08.

NMR (CDCl3), : 7,05 (m, 1H, H(4)), 6,40 (b m, 1H, CONH), 5,80 (m, 1H, H (6)), of 5.75 (s, 2H, CH3COOCH2OCO-), 4,48 (m, 1H, (CH3)2), 3,98 (m, 1H, -CONHCH(CH3)2), of 2.08 (s, 3H, CH3CO), 1,35 -1,15 (4d, 12H, 4 isopropyl CH3), of 0.90 (s, 3H, CH3(19)), to 0.80 (s, 1H, CH3(18)).

MC (m/C) 542 M+< / BR>
< / BR>
Following the same methodology and using the appropriate starting materials, can be obtained from the following ingredients:

pivaloyloxymethyl 17-[N-isopropyl-N-(N-isopropyl-carbarnoyl) carbarnoyl] androsta-3,5-diene-3-carboxylate;

ethoxycarbonylmethyl 17-[N-isopropyl-N-(N-isopropyl-carbarnoyl) carbarnoyl]androsta-3,5-diene-3-carboxylate.

Example 9. N, N-diethylcarbamoyl 17-[N-isopropyl-N-(N-isopropyl-carbarnoyl) carbarnoyl]androsta-3,5-diene-3-carboxylate [(I): Y = 0, R1= iPr, R2= iPr, R3= H

< / BR>
To a solution of Informatica (13 ml), survive in an atmosphere of nitrogen and cooled to about 0oC in an ice bath, was added sodium hydride (41,1 mg, 80 % suspension in mineral oil) and the mixture was stirred at about 0oC for 1 h

Was added N,N-diethyl-2-chloroacetamide (409,8 mg) and sodium iodide (410,6 mg) at 0oC and then the mixture was stirred at room temperature for 3 hours

Because some amount of source material has not yet reacted, was added an additional amount of N,N-diethyl-2-chloroacetamide (132,9 mg) and sodium iodide (136,8 mg) and the mixture was additionally stirred for 3 h at room temperature.

The reaction mixture was poured into ice water (250 ml) and was extracted with toluene (4 x 50 ml), the combined organic extracts were treated with triethylamine (1 ml) and washed with water (3 x 20 ml), 0.1 G. sodium thiosulfate, saturated salt solution and obezvozhivani sodium sulfate.

After removal of the solvent under vacuum, the resulting crude dark oily product (500 mg) was purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 40: 60), thus obtaining a yellowish solid, which is triturated with ether to powder, giving 320 mg of the compound, analiz for C34H53N2O5:

Calculated, %: C 69,35; H 9,15; N 7,20.

Found, %: C 69,42; H 9,41; N 7,03.

NMR (CDCl3) : 7,17 (m, 1H, H(4)), 6,51 (d, 1H, CONH), to 5.85 (m, 1H, H(6)), 4,80 (s, 1H, COOCH2CO) 4,48 (m, 1H, (CH3)2), 3,98 (m, 1H, CONHCH(CH(CH3)2), to 3.38 (q, 4H, 2 CH2CH3), 1,35-1,15 (4d , 12H, 4 sopraelevata CH3), of 0.90 (s, 3H, CH3(19)), TO 0.80 (S, 3H, CH3(18)).

MS (m/z): 498 M - O=C=N-CH(CH3)2< / BR>
< / BR>
Example 10. 1-(3-oxoandrosta-4-one-17-carbonyl)-3-tertbutylamine [compound (VI): Y = 0, R1= H, R2= tBu, R3= H].

To a mixture of 3-oxo-androst-4-ene-17-carboxylic acid (284 mg) in anhydrous toluene (6.0 ml) was added dropwise oxalicacid (0,72 ml).

The mixture was stirred at room temperature for 1.5 h and then volatile components were removed under vacuum, thereby obtaining a yellowish solid residue 3-oxoandrosta-4-EN-17-carbonylchloride.

To a solution of the obtained acylchlorides in pyridine (4,1 ml) was added powdered tertbutylamine (105 mg). After stirring for 2 h the reaction mixture was poured into ice water (60 ml) and was extracted with methylene chloride, the combined organic extracts washed with 1 N. hydrochloric acid, saturated saline solution, water, substances, which was chromatographically on silica gel (eluent: n-hexane/ethyl acetate 50: 50), thus obtained 230 mg of the compound indicated in the title (so pl. 210-217oC).

NMR (CDCl3) : 8,5 (s, 1H, -CONH -) and 8.1 (s, 1H, -CONH-), 5,7 (m, 1H, H(4)). of 1.35 (s, 3H, TV), 1,1 (s, 3H, CH3(19)), 0,8 (s, 3H, CH3(18)).

Following the same methodology and using the appropriate starting materials, can be obtained the following compounds:

(3-oxoandrosta-4-one-17-carbonyl)urea (so pl. 242-245oC);

1-(3-oxoandrosta-4-EN-17-carbonyl)-3-n-mutilation.

Example 11. 1-(3-oxoandrosta-4-EN-17-carbonyl)-3,3-determation. [compound (VI): Y = 0, R1= H, R2= R3= Et].

To a suspension of potassium hydride (275 mg) in anhydrous tetrahydrofuran (2 ml) under nitrogen atmosphere add powder (solid) N,N-dieselmachine (110 mg), the mixture is stirred at room temperature for 10 min, then heated under reflux for 2 h

After cooling at room temperature acylchlorides obtained from 95,0 mg 3-oxoandrosta-4-ene-17-carboxylic acid by the method described in example 10, dissolved in anhydrous tetrahydrofuran (2 ml), added dropwise.

The mixture was stirred at komnata and water.

After acidification 1 N. HCl the organic layer is separated and the aqueous extracted twice with ethyl acetate. The combined organic extracts washed with water, dehydrated with sodium sulfate and evaporated under vacuum.

Thus obtained crude product (180 mg) is purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 75:25) having an output of 80 mg specified in the connection name (so pl. 187-190oC).

NMR (CDCl3: 7,1 (s, 1H, -CONHCO -) and 5.7 (m, 1H, H (4)), and 3.3 (q, 4H) and 1.15 (t, 6N, 2N-CH2CH3), 1,1 (s, 3H, CH3(19)), 0,8 (s, 3H, CH3(18)).

Following the same methodology and using the appropriate starting materials, to obtain 1-(3-oxoandrosta-4-EN-17-carbonyl)-3,3-dimethyloctane.

Example 12. 1-methyl-1-(3-oxoandrosta-4-one-17-carbonyl)-3,3-determation [compound (VI): Y = 0, R1= CH, R2= R3= Et].

To a suspension of potassium hydride (275 mg) in anhydrous tetrahydrofuran (2 ml) under nitrogen atmosphere was added solid N,N-dieselmachine (33 mg), the mixture was stirred at room temperature for 10 min and then was heated under reflux for 2 h

After cooling at room temperature dropwise over 5 min was added acylchlorides, privates was stirred at room temperature for 1.5 h and was added methyliodide (has 0.168 ml) dropwise.

After stirring at room temperature for 1.5 h, the reaction mixture was cooled to about 0oC and slowly added water.

Extraction with ethyl acetate, dehydrated with sodium sulfate and evaporation of the solvent under vacuum to provide 115 mg of a crude yellow oily product, which was purified using flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 65:35), thus obtaining 52 mg of the substance specified in the title (so pl. 142-145oC).

NMR (CDCl3): 5,7 (m, 1H, H (4)), and 3.3 (q, 4H, ), 2,98 (s, 3H, N-CH3) and 1.15 (t, 6N, 2N-CH2CH3), 1,1 (s, 3H, CH3(13)), 0,8 (S, 3H, CH3(18)).

On the same methodology and using the appropriate starting materials, receive the following substances:

1-ethyl-1-(3-oxoandrosta-4-EN-17-carbonyl)-3,3-determation;

1-methyl-1-(3-oxoandrosta-4-EN-17-carbonyl)-3,3-dimethyloxetane;

1-ethyl-1-(3-oxoandrosta-4-EN-17-carbonyl)-3,3-dimethyloxetane.

Example preparation of dosage forms.

Tablets for oral administration with the risk of with the content in each 250 mg of active substance were obtained as follows.

Ingredients (for 10,000 tablets), g:

17-N-isopropyl-N-(N-isopropylcarbamate)Alicia - 38

The active substance was granulated with a 4 wt. %/about. aqueous solution of methylcellulose.

To the dried granules were added the other ingredients and the final mixture was pressed into tablets of appropriate weight.

1. 17-Substituted 3-carboxylamide General formula I

< / BR>
where Y is oxygen or sulfur;

R group: a) -OR4where R4hydrogen or C1- C6is an alkyl group,

b) -NR5R6where each of R5, R6independently is hydrogen or C1WITH6is an alkyl group;

c) -O-CHR7-W, where R7hydrogen or C1- C6is an alkyl group and the W group

< / BR>
where R8C1C6is an alkyl group or5- C6-cycloalkyl group, or

< / BR>
where R9C1C6is an alkyl group or5- C6-cycloalkyl group;

or

< / BR>
where R5and R6have the specified values;

or d) -O-(CH2)n-NR10R11where each of R11and R11independently hydrogen or C1WITH6is an alkyl group or taken together with the nitrogen atom to which they are attached, form a 5 - or 6-atom saturated heterophilically the PTA, n 2, 3, 4;

R is hydrogen, C1WITH6is an alkyl group or5- C6-cycloalkyl group;

R2and R3each independently selected from the group consisting of hydrogen, C1WITH6is an alkyl group or5- C6-cycloalkyl group, or R2and R3taken together with the nitrogen atom to which they are attached, form a 5 - or 6-atom saturated heterophilically ring, optionally containing at least one additional heteroatom selected from oxygen and nitrogen,

or its pharmaceutically acceptable salt.

2. The compound of formula I under item 1, in which Y is oxygen or sulfur, R is OH, - OCH3, -O-CH2CH3,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R1methyl, ethyl, isuprel, tert-butyl, cyclohexyl;

The group-NR2R3is

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
and its pharmaceutically acceptable salts.

3. Connection on p. 1, selected from the group consisting of compounds 17-[N-isopropyl-N-(N-isopropylcarbamate)- carbarnoyl] androsta-3,5-diene-3-carboxylic acid, 17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl]- androsta-3,5-diene-3-carboxylic acid, 17-[N-tert-butyl-N-(N-tert-butilka the growth-3,5-diene-3-carboxylic acid; methyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl]- androsta-3,5-diene-3-carboxylate; methyl-17-[N-cyclohexyl-N-(N-cyclohexylcarbonyl)carbarnoyl] androsta-3,5-diene 3-carboxylate; methyl-17-[N-tert-butyl-N- (N-tert-butylcarbamoyl)carbarnoyl] -androsta-3,5-diene-3-carboxylate; N,N-diethyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] - androsta-3,5-diene-3-carboxamide; acetoacetyl-17-[N-isopropyl-N-(N-isopropylcarbamate)carbarnoyl] - androsta-3,5-diene-3-carboxylate; (N, N-diethylcarbamoyl)methyl-17-[N-isopropyl-N-(N-isopropylcarbamate)- carbarnoyl] -androsta-3,5-diene-3-carboxylate; 2-(N-morpholino)ethyl-17-[N-isopropyl-N-(N-isopropylcarbamate)- carbarnoyl]-androsta-3,5-diene-3-carboxylate,

and, as appropriate, its pharmaceutically acceptable salt.

4. The method of obtaining the compounds of formula I on p. 1, where Y, R1- R3have the meanings given in paragraph 1, the R group OR4where R4hydrogen or C1WITH6is an alkyl group, or its pharmaceutically acceptable salts, characterized in that the compound of formula II

< / BR>
where Y, R1R3have the meanings given in paragraph 1,

subjected to interaction with carbon monoxide (CO) in the presence of a1WITH6-Olkiluoto alcohol and, if necessary, Sout using selective hydrolysis into the corresponding compound of formula I, where R4hydrogen, and/or, if necessary, turn the compound of formula I into its salt, or turn the salt of the compounds of formula I into the corresponding free compound, and/or, if necessary, separate the mixture of isomers of a compound of formula I into the individual isomers.

5. The pharmaceutical composition inhibiting testosterone-5-reductase, comprising a pharmaceutically acceptable carrier and/or diluent and steroid derivative as an active agent in the weight ratio of active agent carrier and/or diluent 0.01 to 100 1, characterized in that as a steroid derivative it contains unsaturated 17-substituted 3-carboxy-steroid of the formula I under item 1 or its pharmaceutically acceptable salt.

6. The compound of formula I under item 1 or its pharmaceutically acceptable salt having the activity of an inhibitor of testosterone 5-reductase.

 

Same patents:

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

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

R2a hydrogen atom, a lower alkyl WITH1-C4;

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

n is 0,1 or 2

or their pharmaceutically acceptable salts have anti-tumor properties

FIELD: organic chemistry, medicine, pharmacy.

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

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

10 cl, 32 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising drospirenone as the first active agent in the amount corresponding to daily dose from 2 to 4 mg in administration of the composition, and ethynylestradiol as the second active agent in the amount corresponding to daily dose from 0.01 to 0.05 mg in combination with one or some pharmaceutically acceptable vehicles or additives. Drospirenone as a component of the pharmaceutical composition is in the finely divided form. The preparation comprises some separately packages and individually taken medicinal units placed in the unit package and designated for oral administration for at least 21 days at a time and indicated daily medicinal units comprise the combination of drospirenone and ethynylestradiol. The preparation can comprise 7 and less daily doses no containing any active agent or containing ethynylestradiol only. The combination of ethynylestradiol and drospirenone provides the safety contraceptive activity due to using the maximal dose of drospirenone being without adverse effects, in particular, excessive diuresis.

EFFECT: improved and valuable properties of combination.

34 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out laparoscopy and administering Danazol at a dose of 400 mg twice a day for 6 months. Danazol treatment being over and normal prolactinemia being observed in biphasic menstrual cycle, Parlodel is administered at a dose of 2.5 mg twice a day for three menstrual cycles long period.

EFFECT: enhanced effectiveness in normalizing hormone background and pregnancy taking place.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: method relates to composition containing estrogen as the first active ingredient in amount sufficient to treatment of diseases, disorders, and symptoms associated with deficit of endogen estrogen levels in women; and drospyrenon as the second ingredient in amount sufficient to endometrium protection from unfavorable estrogen effects. Methods for treatment also are disclosed. Preparations of present invention are useful in combination therapy for continuous, subsequent or intermittent administration.

EFFECT: method for replacement hormonotherapy in women of improved efficiency.

46 cl, 7 ex

FIELD: organic chemistry, steroids, biology.

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

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 5 dwg, 1 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves applying Sarsasapogenin in combination with one or several compounds taken from group consisting of Smilagen and Anzurogenin-D, for preparing composition for treating Parkinson disease or for treating postural hypotension, autism, chronic fatigue syndrome, heavy myasthenia gravis, Lambert-Eaton disease, Gulf War Syndrome and syndrome caused by professional contact with organophosphorous compounds. Sarsasapogenin selectively increases muscarinic receptors M1 activity, contributing to stimulating synaptic transmission, without М2 receptors activity being influenced (which evoke negative feedback and muscarinic transmission interruption).

EFFECT: enhanced effectiveness of treatment.

3 cl, 8 tbl

FIELD: medicine, chemical-technological industry.

SUBSTANCE: the present innovation deals with applying the antagonist of glucocorticoid receptor (11β,17β)-11-(1,3-benzodioxol-5-il)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-on (Org 34517) for obtaining a medicinal preparation in the form applied for peroral intake for treating patients suffering with considerable depressive disorder and, also, the corresponding method of therapy. The suggested Org 34517 initiated quicker onset of antidepressive action against paroxetin.

EFFECT: higher efficiency of application.

6 cl, 3 dwg, 1 ex

FIELD: organic chemistry, steroids.

SUBSTANCE: invention discloses derivatives of steroid sapogenins of the general formula (I): wherein R means alkylcarbonyl, alkoxycarbonyl substituted possibly with amino-group and others under condition that R is not acetyl and R is not ethoxycarbonyl if C3 is in S and C25 in R-configurations simultaneously; R is nor succinyl if C3 and C25 are in S-configuration simultaneously, or C3 R(α) or S(β), and C25 in R-configuration. Also, invention discloses using these compounds in treatment of cognitive dysfunction, noncognitive neurodegeneration, noncognitive neuromuscular degeneration and loss of receptors in absence of cognitive, nervous and neuromuscular insufficiency. Also, invention discloses methods for synthesis of these compounds, treatment and pharmaceutical composition containing thereof.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical compositions.

30 cl, 2 tbl, 5 dwg, 16 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

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

38 cl, 1 tbl, 18 ex

FIELD: organic chemistry, steroids, chemical technology.

SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.

EFFECT: improved preparing method.

56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex

FIELD: organic chemistry, steroids.

SUBSTANCE: invention describes 17α-alkyl-17β-hydroxyestra-1,3,5(10)-trienes possessing anti-estrogenic properties of the general formula (I): wherein Hal means fluorine (F), chlorine (Cl) atoms; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkanoyl, simple cyclic (C3-C7)-ether comprising O-atom; R17' means H, (C1-C4)-alkyl, (C1-C4)-alkanoyl; R17'' means (C1-C4)-alkyl, (C1-C4)-alkynyl; SK means: U-V-W-X-Y-Z-E wherein U means (C1-C13)-alkylene; V means -CH2; W means -N(R6) wherein R means H, (C1-C4)-alkyl; X means (C1-C12)-alkylene; Y means a direct bond between X and Z; Z means possibly fluorinated (C1-C9)-alkylene; E means -CF3. Also, invention describes 17-oxoestra-1,3,5(10)-trienes and 17β-hydroxyestra-1,3,5(10)-trienes as intermediate substances used in synthesis of estratrienes proposed by the invention. Also, invention describes using 17α-alkyl-17β-hydroxyestratrienes for preparing corresponding medicinal agents and pharmaceutical preparations comprising at least one 17α-alkyl-17β-hydroxyestratriene and at least one pharmaceutically acceptable carrier.

EFFECT: valuable medicinal properties of steroids.

5 tbl, 7 dwg

FIELD: organic chemistry, steroids, biology.

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

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

FIELD: organic chemistry, steroids, medicine.

SUBSTANCE: invention describes compounds or their salts of the general formula (I): wherein values C are disclosed in the invention description. These compounds can be used in preparing medicinal agents used in treatment of acute disorders in portal and hepatic venous circulation.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 tbl, 2 ex

FIELD: steroids, pharmacy.

SUBSTANCE: invention describes a method for preparing crystals showing the mean coarseness index in the required limits from 3 to 25 mcm and maximal size 100 mcm, not above. Method involves the crystallization process of supersaturated solution of compound representing 11β-benzaldoximestra-4,9-diene wherein it is subjected for wetted grinding by using the correspondence device designated for such wetted grinding to obtain suspension of primary grains. Also, invention crystals prepared by the proposed method and a pharmaceutical agent containing these crystals.

EFFECT: improved preparing method.

14 cl, 8 tbl, 4 dwg, 4 ex

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