A method of treating benign prostatic hyperplasia, a pharmaceutical preparation containing an inhibitor of 5 - alpha-reductase

 

(57) Abstract:

The invention is intended for the treatment of benign prostatic hyperplasia. In the treatment of patients injected with approximately 5 mg of inhibitor of 5-reductase in combination with 1 - 10.0 mg per day blocker 1-adrenergic receptor. Pharmaceutical composition for the treatment of this disease includes 2.5 - 5.0 mg of inhibitor of 5-reductase and 0.5-10.0 mg blocker1-adrenergic receptor in a pharmaceutically acceptable carrier. Inhibitors of 5-reductase choose from 17-substituted 4-azasteroid, 17-substituted aazastrida, 17-acyl-3 carboxyester-3,5 dienes derived benzoylaminopyrazolin acid, condensed Benz(thio)amides, cinnamamide, aromatic 1,2-diesters or thioethers, aromatic areallyuniquename acids, rotationalvibrational acids or their pharmaceutically acceptable salts and esters. Combined use of the two active ingredients leads to achieve a greater therapeutic effect. 2 C. and 13 C.p. f-crystals.

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which videoconferencing blocker1- adrenergic receptor.

Benign prostatic hyperplasia (BPH) affects a significant number of men aged over 50 years and usually requires surgical intervention at an advanced stage to attenuate the disease.

It is known that testosterone (T) is secreted by the adrenal glands, but in peripheral areas, including the liver, skin, and prostate gland can undergo conversion into dihydrotestosterone (DHT) via the use of 5 - reductase. DHT preferably binds the nucleus of the cells of the prostate gland, thus indicating that DHT, but not T, is the primary androgen, which is required for prostate growth and activity. These data led to the assumption that by inhibition of 5 - reductase can be reduced formation of DHT and achieved the restoration of the prostate.

Finasteride, 17- (N-tert.-butyl)-carbarnoyl-4-Aza - 5 - androst-1-EN-3-one, was proposed as a compound that has been found to inhibit 5 - reductase and has a positive effect on benign prostatic hyperplasia. Finasteride is a 4-azasteroid and javljaetsja, should not be expected to interfere with the binding and action of T in tissues such as the muscles that respond to T, and, therefore, should not lead to the manifestation of feminine features.

A typical 4-Aza-steroidal inhibitors of 5 - reductase are 4-Aza-steroids, developed by Merck (see U.S. Pat. USA 4377584, Rasmussen and others; U.S. Pat. USA 4220735, Rasmussen and others; U.S. Pat. USA 4845104, Karlin and others; U.S. Pat. USA 4760071, Rasmussen and others, which reveals finasteride, representing 17- (N-tert.-butyl)-carbarnoyl-4-Aza - 5 - androst-1-EN-3-one, known under the brand name PROSCAR: Pat. USA 4732897, Quinella and others; U.S. Pat. USA 4859681, Rasmussen and others; Heb. Pat. 0155076; Heb. Pat. 0004949; and Heb. Pat. 0314189.

In many cases completely stop the process of prostate enlargement is accompanied by symptomatic weakening microtia, indecision and difficulty with urination. However, symptomatic loosening does not occur in all cases. If the inhibitor of 5 - reductase slows down the pace of growth of the prostate gland without an accompanying reduction, the weakening of the symptoms may not be observed.

In this area it is desirable combination therapy for Lesovedenie provides a method of treating suffering from benign prostatic hyperplasia patients, subjected to treatment with 4-Aza-steroidal inhibitor of 5 - reductase and having insufficient attenuation of symptoms requiring such treatment, which involves the step of assigning such patients a therapeutically effective amount of an inhibitor of 5 - reductase, 17 - substituted 4-azasteroid, 17 - substituted neuzustand, 17 - acyl-3-carboxyester-3,5-diene derived benzoylaminopyrazolin acid, condensed benzo(thio)-amide or a derivative cinnamomea, aromatic 1,2-diesters or thioethers, aromatic areallyuniquename acids, ortho-dialkylamino - phenoxyalkanoic acids, their pharmaceutically acceptable salts and esters, in combination with an agent that blocks - adrenergic receptor, referred to in this description, "1- blocker".

Thus, the combined effect of the inhibitor of 5 - reductase, inhibiting the formation of DHT in the prostate gland, and blocker1- adrenergic receptor, for example terazosin leads to achieve a greater impact on growth inhibition and symptomatic loosening process of the weakening of the prostate gland than is achieved at independent use of each agent.

1- blocker in combination with an inhibitor of 5 - reductase inhibitor, or a pharmaceutical product. The active compounds can be used together or in any order described below.

The term "patient in need of such treatment" refers to patients male with a functioning reproductive glands, which are treated with inhibitors of 5 - reductase in therapeutic program, designed to combat benign prostatic hyperplasia (BPH) and that, as found, in need of the weakening of the symptoms.

The use of therapeutically effective amounts of an inhibitor of the reductase and1- blocker in accordance with the present invention effectively treat negative symptoms of BPH, including negrutiu, indecision, reduced urine flow, and similar symptoms.

It is shown that the stimulation of - adrenergic receptors contributes to the blockade of benign prostatic hyperplasia (M. Kaine and others, Br. J. Urol., Vol. 48, pp. 255-263, 1977).

Blockers - adrenergic receptor function normally as antihypertensive agents due to Bleue, which cause the contacting fibrous tissue at the stimulation with norepinephrine, which leads to the reduction of the urinary stream. Therefore, the effect of1the blocker is relaxing fibrous tissue and increases the action under these conditions.

There are very noticeable differences in the relative abilities - adrenergic blocking agents in suppressing influences simpatomimeticeski amines on two subtypes of receptors. It is known that Prazosin has a much greater ability to block1- (polonetsky) receptors than2receptors, which among other effects, modulate neural release of mediator (prepolagaetsya desinations receptors). Phenoxybenzamide is srednegalechny1- blocking agent, whereas phentolamine only 3-5 times more effective at inhibiting receptors than2- adrenergic receptors. On the contrary, yohimbine is a selective2- blocker and, as shown, prevents the antihypertensive action of clonidine,2- agonist.

However, preferred in the present invention are - adrenergic blocking ageruyo activity.

Examples - adrenergic receptor blockers are terazosin (Abbott-Hytrin), the chemical name 1-(4-amino-6,7-dimethoxy - 2-hintline)-4-[(tetrahydro-2-furanyl)carbonyl] piperazine, which is described in U.S. Pat. Germany 264186 and U.S. Pat. USA 4026894; doxazosin (Pfizer-Cardura), the chemical name 1-(4-amino-6,7-dimethoxy-2 - hintline)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)-carbonyl]piperazine, which is described in U.S. Pat. Germany 2847623 and U.S. Pat. USA 4188390; prazosin (Pfizer-Minipres), the chemical name 1-(4-amino-6,7-dimethoxy-2 - hintline)-4-(2-fornicator)piperazine, which is described in Brit. Pat. 1156973. Pat. USA 3511836 and Goal. The application 7206067; bunazosin (Sandoz-Detantol), the chemical name 1-(4-amino-6,7-dimethoxy-2 - hintline)hexahydro-4-(1-oxobutyl)-1H-1,4-diazepin, which is described in the Belgian patent application 806626. Pat. USA 3920636 and YAP. the application 75140474; indoramin (Baratol-Wyeth), chemical name N-[1-[2-(1H-indol-3-yl)-ethyl]-4-piperidinyl] benzamide, which is described in U.S. Pat. South Africa 6803204, Pat. USA 3527761; Alfuzosin (Synthelabs), chemical name N-[3-[(4-amino-6,7-dimethoxy-2-hintline) methylamino]propyl]tetrahydro-2-furancarboxylic, which is described in U.S. Pat. Germany 2904445 and U.S. Pat. USA 4315007.

Preferred is 4-azasteroid formula

< / BR>
where the dotted line represents a double the ode, methyl or ethyl;

R2represents a hydrocarbon radical selected from among linear or branched, saturated or unsaturated alkyl, cycloalkyl, or aralkyl with 1-12 carbon atoms or a monocyclic aryl may contain 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or one or more substituents from halogen atoms;

R' represents halogen or methyl;

R" represents hydrogen or methyl;

R"' represents hydrogen, a - methyl or methyl,

and its pharmaceutically acceptable salts or esters.

In the preferred embodiment of the compound of formula I, which can be used in the method of the present invention, has the formula:

< / BR>
where R1represents hydrogen, methyl or ethyl;

R2represents a branched alkyl, cycloalkyl, aralkyl with 4 to 12 carbon atoms, phenyl, possibly substituted stands, a chlorine atom and fluorine, substituted or unsubstituted 1-, 2-substituted, 1-, 2-adamantylamine, 1-, 2 -, or 7-norberry, 1-, 2 -, or 7-norbornanyl.

Typical compounds of the present invention are the following compounds:

17- (N-tert.-amylcinnamyl)-4L)-4-Aza-5 - androst-1-EN-3-one,

17- (N-ISO-butylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one,

17- (N-tert.-octigabay)-4-Aza-5 - androst-1-EN-3-one,

17- (N-octigabay)-4-Aza-5 - androst-1-EN-3-one,

17- (N-1,1-deliverychannel)-4-Aza-5 - androst-1-EN-3-one,

17- (N-neopentylene)-4-Aza-5 - androst-1-EN-3-one,

17- (N-2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one,

17- (N-1-adamantylamine)-4-Aza-5 - androst-1-EN-3-one,

17- (N-2-norbornanol)-4-Aza-5 - androst-1-EN-3-one,

17- (N-1-norbornanol)-4-Aza-5 - androst-1-EN-3-one,

17- (N-phenylcarbamoyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-benzylcarbamoyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-tert.amylcinnamyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-tert.exaltabitur)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-tert.-butylcarbamoyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-ISO-butylcarbamoyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-tert.-octigabay)-4-Aza-4-methyl-5 - androst-1-EN-3-one,

17- (N-1,1,3,3-tetramethylbutylphenol)-4-Aza-5 - androst-1-EN-3-one,

17- (N-octigabay)-4-Aza-4-methyl-5 - androst-1-EN-3-one

17- (N-1,1-deliverychannel)-4-Aza-4-methyl-5 - androst-1-EN-3-one

17- (N-neopentylene)-4-Aza-4-methyl-5 - androst-1-EN-3-one

17- (N-1-adamantylamine)-4-Aza-5 - EN the Il-4-Aza-5 - androstane-3-one

17- (N-1-adamantanecarbonyl)-4-Aza-5 - androst-1-EN-3-one

17- (N-2-adamantylidene)-4-Aza-5 - androstane-3-one

17- (N-methyl-N-2-adamantylidene)-4-methyl-4-Aza-5 - androstane-3-one

17- (N-2-adamantylidene)-4-methyl-4-Aza-5 - androstane-3-one

17- (N-2-adamantylidene)-4-methyl-4-Aza-5 - androst-1-EN-3-one

17- (N-methyl-N-2-adamantylidene)-4-methyl-4-Aza-androst-1-EN-3-one

17- (N-(3-methyl)-1-adamantylamine)-4-Aza-4-methyl - 5 - androstane-3-one

17- (N-Exo-2-norbornanamine)-4-Aza-4-methyl-5 - androst-1-EN-3-one

17- (N-Exo-2-norbornanamine)-4-Aza-5 - androst-1-EN-3-one

17- (N-2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one,

17- (N-methyl-N-2-adamantylidene)-4-Aza-4-methyl-androstane-3-one,

17- (N-2-adamantylidene)-4-methyl-4-Aza-5 - androstane-3-one,

17- (N-methyl-N-2-adamantylidene)-4-methyl-4-Aza - 5 - androst-1-EN-3-one,

The compounds of the above compounds in which the 4-Aza-Deputy substituted in each of the above-mentioned compounds hydrogen atom, stands or ethyl, forming various N-substituents may contain a double bond, which is shown in dashed lines in position 1.

Alkyl, cycloalkyl, Uralkaliy, monocyclic aryl, 1 - and 2-adamant the existing: C1-C4-linear /branched alkyl, including methyl, ethyl, isopropyl, N.-butyl: the nitro-group; oxoprop; C7-C9-aralkyl, including benzyl; (CH2)nCOOR, where n takes on the values 0 to 2, and the substituent R represents a hydrogen atom or a C1-C4-linear/branched alkyl, including methyl, ethyl; CH2OH: OH: OR, where the substituent R represents a C1-C4-linear/branched alkyl, including methyl, ethyl; a halogen atom, including fluorine, bromine, iodine; COOH; COOR where the substituent R represents a C1-C4-linear/branched alkyl; - CONH2; CH2NH2; CH2NHCOR, where the substituent R represents a C1-C4-linear/branched alkyl, including methyl, ethyl; phenyl; o-, m-, p-substituted phenyl, including p-nitro, p-amino and p-sulfo-phenyl; or cyano, amino group adamantinoma or norbornadiene fragment can also be substituted as a substituent R1the stands and ethyl, and also a hydrogen atom.

Also under the scope of this invention fall pharmaceutically acceptable salts and esters, if substituted alkyl, cycloalkyl, Arakelova, adamantinoma or norbornadiene fragment is present in the main is of ina, sodium, potassium and calcium salt, and similar salts, which are used as the dosing form.

When the connection is basic group such as amino group, the dosing form used acid salt, i.e., hydrochloride, hydrobromide, acetates, pamoate etc.

In addition, in the case when the connection is present COOH group can be obtained pharmaceutically acceptable salts, such as acetate, maleate, pivaloyloxymethyl and the like salts and esters known in this field, for modifying solubility or hydrolysis properties for use in drugs with constant allocation or proletarienne drugs.

Typical examples of the substituent R2are (BP= substituted); 3,5,7-trinitro-1-AD; 4-oxo-1-AD; 1-benzyl-1-AD; 4,4-dimethyl-1-AD 3,7-dimethyl-5-carboxymethyl-1-AD; 3-carboxymethyl-1-AD; 3-chloro-1-AD; 1,3-dihydroxy-6,6-dimethyl-2-AD; 3-chloro-1-AD; 4-carbethoxy-2-AD; 4 carbethoxy-2-AD; 3-isopropyl-1-AD; 3-present-butyl-1-AD; 3-propyl-1-AD; 3-, 5-diethyl-1-AD; 3-hydroxymethyl-1-AD; 2-carboxy-1-AD; 3-methyl-1-AD; 5-hydroxy-2-AD; 2-hydroxy-1-AD 1-aminomethyl-1-hydroxy-2-AD; 2-oxo-1-AD; 2-phenyl-2-AD; 1-aminomethyl-2-AD; 1-carboxy-2-AD; 1-aminocarbonyl-2-AD; 3-gidrol-5-hydroxymethyl-1-AD; 3,5-dimethyl-4-hydroxy-1-AD; 2-hydroxymethyl-2-AD; 3-(p-sulfophenyl)-1-AD; 3-methyl-5-ethyl-1-AD; 2-carboxy-2-AD; 3,5,7-trimethyl-1-AD; 4-iodine-2-AD; 4-bromo-2-AD; 4-chloro-2-AD; 1-acetamidomethyl-2-AD; 1-carboxymethyl-2-AD; 1-methyl-2-AD; 1-aminocarboxylate-2-AD; 1-aminocarbonyl-1-AD; 2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD; 4-hydroxy-1-AD; 1-hydroxy-2-AD; 5-carboxy-3-methyl-1-AD; 3,5-dimethyl-7-carboxy-1-AD; 3-carboxy-1-AD; and the like.

Typical examples of the substituent R2that represents a substituted norbornadienes fragment are (NB = norbornanyl); 2-NR: 1,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB; 3-phenyl-2-carboxy-2-NB; 2-cyano-3-phenyl-2-NB; 3-hydroxy-4,7,7-trimethyl-NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB; 3-allyl-2-NB; 1-NB; 7,7-dimethyl-1-hydroxymethyl-2-NB; 3-methoxy-4,7,7-trimethyl-2-NB; 3-aminocarbonyl-2-NB; 3-etoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7-oxo-1-NB; 3-phenyl-2-NB; 1-carboxymethyl-7,7-dimethyl-2-NB; 1-ethyl-2-NB; 1-methyl-2-NB; 2,2,3,3,5,5,6,6,7,7-deceptor-1-NB; 3-hydroxy-2-NB; 3-chloro-2-NB; 3-(p-methoxyphenyl)-2-NB; 2,2-dimethyl-3-methylene-7-NB; 3-oxo-2-NB; 1-methoxy-2-NB; 7-NB; 3-isopropyl-2-NB; 2-bromo-1-NB; 3-chloro-1-NB; and the like.

Methods of preparing compounds of formula I of the invention, including those mentioned above, are well known in this field.

New connections is facilitated by the known steroid ester (IIIA) formula

< / BR>
( 17- (carbomethoxy)-4-Aza-5 - androstane-3-one), which includes the following stages 1) digidrive the above starting compound to obtain the corresponding compound containing a double bond in the 1,2-position of ring A, 2) conversion of 17-carboxymethylchitin in N-substituted alkyl, cycloalkyl, aralkyl, monocyclic acyl or adamantylidene, and, if desired, alkylation of the nitrogen atom of ring A to the administration of N-methyl or N-ethyl group in position 4 of the ring A. For stage dehydrogenation preferably, to the nitrogen atom of the 4-Aza was unsubstituted. Alternative paths may include one or more separate chemical phases and, if desirable, may be carried out before stage (1) or after stage (1) or stage (3).

In accordance with the method of the present invention (see scheme) products of the present invention are formed as follows; (I) heat 17 - alkoxycarbonyl-4-Aza-5 - androstane-3-ones, compounds III (obtained by the method described in U.S. Pat. USA 4377584) with a dehydrating agent such as benzylideneaniline, in an inert solvent, for example chlorobenzene, leads to a 17 - alkoxycarbonyl-4-Aza-5 - androst-1-EN-3-ONU IV (JACS 1988, Vol. 110, pp. 3318-3319; (2) the interaction obtained in stage 1 of 5 - androst-1-EN-3-about the connection, for example, sodium hydride in an anhydrous environment in an inert solvent, such as dimethylformamide; (3) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide with formation of the corresponding 17 - alkoxy-substituted-carbarnoyl-4-alkyl-4-Aza-5 - androst-1-EN-3-it is V; (4) subsequent hydrolysis of the above 17- -alkoxy-arbonyl-4-alkyl-4-Aza-5 - androst-1-one-3-it is a strong base, such as aqueous-methanol solution of potassium hydroxide by boiling, followed by acidification and isolation of the final steroid acid gives 17 - carboxy-4-alkyl-4-Aza-5 - androst-1-EN-3-one VI; (5) the above steroid acid can then be converted in accordance 2 pyridylthio-ester by boiling with triphenylphosphine and 2,2'-dipyridylium in an inert solvent, such as toluene, and the resulting 17- (2-pyridylthio-carbonyl)-4-alkyl-4-Aza-5 - androst-1-EN-3-one (VII can be separated by chromatography, for example on silica gel; and (6) above pyridylthio-ether may then interact with the 1-substituted-2-adamantylamine or norbornanamine in an inert solvent, for example in tetrahydrofuran, with the formation of desire is chromatography, for example, on silica gel. If the initial reaction is carried out without the initial formation of a double bond in position 1, then obtain the corresponding 17- (N-adamantylamine)-4-alkyl-4-Aza-5 - androstane-3-one (or N-norbornenedicarboxylic connection).

In accordance with another method of the present invention N-unsubstituted 17- (N-adamantylamine)-4-Aza-5 - androst-1-EN-3-one XIV easily get out of 17 (alkoxycarbonyl)-4-Aza-5 - androstan-3-one IV by repeating the above reaction series except under alkylation 2, described above, that is, the processing - androst-1-EN-3-one, such as Amida sodium, and then methyl or ethylbromide through intermediate XII and XIII.

In accordance with another alternative method of the present invention upon receipt of the claimed compounds containing a hydrogen atom as the only substituent at the nitrogen atom of the a-ring, the double bond is introduced into ring And at the last stage of the process. Therefore, 17 (alkoxycarbonyl)-4-Aza - 5 - androstane-3-one III is hydrolyzed to the corresponding steroid acid IX - 17 (carboxy)-4-Aza-5 - androstane-3-one, which in turn is transformed into the corresponding pyridylthio - 17 (2-pyridylthio the spruce R2takes on the values described above as a 1 - or 2-substituted, or 1, 2 -, or 7-norbornanyl, with the formation of 17- (N-adamantylamine)-4-Aza-5 - androstane-3-one XI, which digitalout in accordance with the method described previously, getting the connection XIV - 17- (N-adamantylamine)-4-Aza-5 - androst-1-EN-3-one or the corresponding norbornylene derived.

In accordance with another method of introduction of 17 - N-adamantylamine substituent in the 17- (carboxy)-androstane formula VI compound XII or IX is treated according to the method similar to the method described in the journal Steroids, Vol. 35 # 3, 1980, pp. 1-7, galoretelevision and 1-hydroxybenzotriazole education-5- (1-benzotriazolyl)-4-Aza - 17 - androst-1-EN-3-one, VII, XIII, or join X in which Deputy X represents benzotriazole group.

16-methyl derivative, in which the substituent R"' represents a methyl group, derived from the famous 16-methyl-17-acyl-4-methyl-4-Aza-5 - androstane-3-ones, for example, or 4,16 - dimethyl - 17 - acetyl-4-Aza-5 - androstane-3-one, in accordance with known techniques dehydrogenation of 4-methyl-4-Aza - compounds with formation of the corresponding 4,16 - dimethyl-17 - acetyl-4-Aza-5 - androst-1-EN-3-one.

Description of the IO or 1 benzotriazoles, R2represents 1 - or 2 - substituted or norbornanyl.

Preferred 4-azasteroid are steroids series 17 - acyl-4-Aza-5 - androst-1-one-3-one formula

< / BR>
where the dotted line represents a double bond, if present in the molecule;

R is selected from hydrogen atom, methyl and ethyl;

R2represents: (a) a monovalent radical selected from among linear or branched alkyl or cycloalkyl containing 1-12 carbon atoms which may be substituted by one or more C1-C2-alkilani or halogen atoms; (b) Uralkaliy radical selected from benzyl or panetela: (C) polycyclic aromatic radical, which may be substituted by one or more of: the OH groups, the groups defending the OH-group, group-OC1-C4-alkyl, C1-C4-alkilani, halogen atoms or nitro groups; (d) a monocyclic aromatic radical, which may be substituted by one or more substituents from among: (1) -OH, OC1-C4-alkyl, C1-C4-alkyl, -(CH2)mOH, - (CH2)n COOH, including group protecting the OH-group, where m = 1-4 and n = 1-3, provided that C1-C4) -SH, -SC1-C4-alkyl, -SOC1-C4-alkyl, -SO2C1-C4-alkyl,

-SO2N(C1-C4-alkyl)2C1-C4-alkyl-(CH2)m6H, -S-(CH2)-O-COCH3where m = 1-4 and n = 1-3, provided that C1-C4-alkyl is only present when there is one above serosoderjaschei radicals; (3) N(R3)2group which may be protected, where the substituent R3represents H or C1-C4-alkyl, when monetarily radical can also be substituted C1-C4- alkyl; (4) heterocyclic radicals from among 2 - or 4-pyridyl, 2-pyrrolyl, 2-furil or thiophenyl; and the substituents R', R" and R"' each are selected from hydrogen atom and methyl, and their pharmaceutically acceptable salts.

The preferred embodiment of the compounds of the present invention is an above-mentioned compound of structure IA, where the dotted line represents a double bond, the substituent R represents a hydrogen atom or methyl, and the substituent R2represents a branched alkyl or cycloalkyl containing 4-10 carbon atoms, and R" and R"' represent a hydrogen atom.

The other allows a phenyl or phenyl, substituted by the substituents described above, including, when the substituent R2represents phenyl, 2-, 3 - or 4-tolyl, xylyl, 2-bromophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, AMINOPHENYL, N-acylaminoalkyl, N,N-dialkylaminoalkyl, 4-biphenyl, 3-biphenyl, naphthyl, antracol, tenantry, thiophenyl, methylthiophenyl, methylsulfinylphenyl, methylsulfonylmethyl, aminosulfonyl, diethylphenyl, acetoxymethyl, 17- (4-hydroxyphenyl), 17- (3-hydroxyphenyl), 17- (3,4-dihydroxyphenyl) or 17- (3,5-dimethyl-4-hydroxyphenyl).

Typical compounds of the present invention are:

17- (phenylcarbamoyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (2-trikarbonil)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (3-trikarbonil)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (4-trikarbonil)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (2-brompheniramine)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (2-khlorfenilalanin)-4-Aza-4-methyl-5 - androst-1-EN-3-one;

17- (2,6-dichlorophenylamino)-4-Aza-4-methyl-5 - androst-1-EN-3-one;

17- (2,6-dibromopropionyl)-4-Aza-4-methyl-5 - androst-1-EN-3-one;

17- (killkenny)-4-Aza-4-methyl-5 - androst-1-EN-3-one;

17- (tert.-butylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one;

17- (ISO-butylcarbamoyl)-4-Aza-5 - androst-1-e is 3-he;

17- (neopentylene)-4-Aza-5 - androst-1-EN-3-one;

17- (tert.-amicably)-4-Aza-5 - androst-1-EN-3-one;

17- (tert.-hexylcaine)-4-Aza-5 - androst-1-EN-3-one;

17- (cyclohexylcarbonyl)-4-Aza-5 - androst-1-EN-3-one;

17- (cyclopentanecarbonyl)-4-Aza-5 - androst-1-EN-3-one;

17- (benzylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one;

17- (2-pyridylcarbonyl)-4-Aza-5 - androst-1-EN-3-one;

17- (4-pyridylcarbonyl)-4-Aza-5 - androst-1-EN-3-one;

17- (2-pyrrolidinone)-4-Aza-5 - androst-1-EN-3-one;

17- (2-fullcarbon)-4-Aza-5 - androst-1-EN-3-one;

17- (thienylboronic)-4-Aza-5 - androst-1-EN-3-one;

17- (2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one;

17- (phenylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one;

17- (2-trikarbonil)-4-Aza-5 - androst-1-EN-3-one;

17- (3-trikarbonil)-4-Aza-5 - androst-1-EN-3-one;

17- (4-trikarbonil)-4-Aza-5 - androst-1-he-3-he;

17- (2-brompheniramine)-4-Aza-5 - androst-1-EN-3-one;

17- (2-khlorfenilalanin)-4-Aza-5 - androst-1-EN-3-one;

17- (2,6-dichlorophenylamino)-4-Aza-5 - androst-1-EN-3-one;

17- (2,6-dibromopropionyl)-4-Aza-5 - androst-1-EN-3-one;

17- (killkenny)-4-Aza-5 - androst-1-EN-3-one;

17- (phenylethylamine)-4-Aza 5 - androst-1-EN-3-one;

17- (4-dimethylaminobenzylidene)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-what-he;

17- (3,5-dimethyl-4-diethylaminobenzylidene)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-N-methylaminoethanol)-4-Aza - 5 - androst-1-EN-3-one; or

17- (2-N-ethylamino-4-ethylvinylbenzene)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-phenylbenzyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-phenylbenzyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-biphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-biphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (1-naphthyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (2-naphthyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (1-phenanthrol)-4-Aza - 5 - androst-1-EN-3-one;

17- (2-phenanthrol)-4-Aza - 5 - androst-1-EN-3-one;

17- (1-biphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (9-antracol)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-thienylboronic)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-thienylboronic)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-methylthiofentanyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-methylsulfinylphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-methylsulfonylbenzoyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-methylsulfinylphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-N, N-dimethylaminocarbonylmethyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (2-ethyl-4-methylthiofentanyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-diethylpyrocarbonate)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (4-acetal - 5 - androst-1-EN-3-one;

17- (2-methyl-4-methylsulfinylphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (2-isopropyl-4-methylsulfonylbenzoyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (4-methylthiofentanyl)-4-Aza-4-methyl - 5 - androstane 3-one;

17- (4-methylsulfinylphenyl)-4-Aza-4-methyl - 5 - androstane-3-one;

17- (4-methylsulfonylbenzoyl)-4-Aza-4-methyl - 5 - androstane-3-one;

17- (4-hydroxyphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3-hydroxyphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3,4-dihydroxyphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (3,5-dimethyl-4-hydroxyphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-hydroxymethylene)-4-Aza - 5 - androst-1-EN-3-one;

17- (2-hydroxyethylaminophenol)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-methoxyphenyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-carboxymethyl)-4-Aza - 5 - androst-1-EN-3-one;

17- (4-hydroxyphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (3-hydroxyphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (3,4-dihydroxyphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (3,5-dimethyl-4-hydroxyphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (4-hydroxymethylene)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (2-hydroxyethylaminophenol)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;

17- (4-methoxyphenyl)-4-Aza-4-methyl - 5 - androst-1-EN-3-one;
>/BR>and the corresponding compounds where the hydrogen atom in position 4 in each of the above compounds substituted by methyl or ethyl.

Compounds of the present invention of formula IA get in the way, in which the starting compound is used steroid ester of the formula

< / BR>
with title 17- (4-carbomethoxy)-4-Aza - 5 - androstane-3-one, which involves the following stages: (1) dehydrogenation of the above original product to obtain the corresponding compound containing a double bond in position 1, 2 rings A, (2) the conversion of 17 - carboxymethoxy-substituent in the 17 - acyl Deputy, if necessary, (3) alkylation of the nitrogen atom of ring A to the introduction of 4-methyl or 4-ethyl substituent in ring A. For stage dehydrogenation preferably, to ring A was unsubstituted. Stage dehydrogenation can be performed, for example, by the method described by Dollinger and others, using dichlorodicyanoquinone, JACS (1988), V 110, pp. 3318-3319. Stage (2) may consist of one or more chemical stages and, if necessary, can be carried out up to the stage (1) or after stage (1) or stage (3).

In accordance with the method of the present invention compounds of this is arousin agent, such as resolvenameid in chlorobenzene with the formation of 17- (4-alkoxycarbonyl)-4-Aza - 5 - androst-1-EN-3-one (IV), (2) interaction obtained in stage (1) 5 - androst-1-EN-3-one with sodium hydride in an anhydrous environment in an inert solvent, such as dimethylformamide, (2) contacting the resulting reaction mixture with an alkyl(methyl or ethyl)iodide with formation of the corresponding 17 - alkoxycarbonyl-4-methyl-4-Aza - 5 - androst-1-EN-3-one (V), (3) subsequent hydrolysis of the above 17- (4-alkoxycarbonyl)-4-methyl-4-Aza - 5 - androst-1-EN-3-one boiling in strong base, such as aqueous-methanol solution of potassium hydroxide, followed by acidification and isolation of the resulting steroid acid, 17 - carboxy-4-alkyl-4-Aza-5 - androst-1-EN-3-one (VI), (4) transforming the above steroid acid to the corresponding 2-pyridylthio-ester by boiling with triphenylphosphine and 2,2'-dipyridylium in an inert solvent, such as toluene, emitting get 17- (2-pyridylthio-carbonyl)-4-alkyl-4-Aza - 5 - androst-1-EN-3-one (VII) by means of chromatography, for example, on silica gel; (5) interaction above pyridylthio - ether with R2-Li or R2MgX (X = Cl, Br), for example, Deut.-butylmagnesium in tetrahydrofuran can be separated by chromatography, for example, on silica gel. If the initial reaction is carried out using the R2MgX or R2-Li instead of Deut.-butylacrylamide, then get the corresponding 17- (acyl)-4-alkyl-4-Aza - 5 - androstane-3-one, where the substituent R2represents a carbonyl.

In accordance with the method of the present invention corresponding 17- (acyl)-4-Aza - 5 - androst-1-EN-3-one (XV) are easily obtained from 17- (alkoxycarbonyl)-4-Aza - 5 - androsten-3-one (IV) by repeating the above stages, except stage 2, that is, except for processing 4-Aza - 5 - androstane-3-she amidon sodium followed by treatment of methyl - or ethyliodide.

In accordance with another alternative method of preparing compounds of the present invention, which contain only one atom of hydrogen as the sole substituent in ring A, 1,2-double bond in ring A is injected at the last stage of the process. Therefore, 17 - alkoxycarbonyl-4-Aza - 5 - androstane-3-one (III) is subjected to hydrolysis to the corresponding steroid acids - 17 - carboxy-4-Aza - 5 - androstane-3-one (IX), which, in turn, into corresponding diapirically ether 17- (2-piridindicarbonova)-4-Aza - 5 - androstane-3-one (X), with subsequent processing of e is 17- (acyl)-4-Aza - 5 - androstane-3-one (XI), which digitalout according to the method described above, to the compounds XIV - 17- (acyl)-4-Aza - 5 - androst-1-EN-3-one.

In accordance with another method of preparing compounds of the formula I, if the original product is an ether, in particular methyl ether represented in formulas III to V, the interaction with the Grignard reagent leads to the ketone-17 - R2CO-corresponding to residue R2the Grignard reagent.

16-methyl derivative, in which the substituent R"' represents a methyl group, derived from the famous 16-methyl-17-acyl-4-methyl-4-Aza - 5 - androstane-3-ones, for example from 4,16 - dimethyl - 17 - acetyl-4-Aza - 5 - androstane-3-one, in accordance with known techniques dehydrogenation of 4-methyl-4-Aza-compounds with formation of the corresponding 4,16 - dimethyl - 17 - acetyl-4-Aza - 5 - androst-1-EN-3-one.

The above reactions are schematically represented in scheme II (see end of description),

where X is a 2-pyridylthio, R2takes on the values described above.

The above reaction scheme, where the substituent R2represents the p-hydroxybiphenyl, can be carried out using as starting product bromberger, for example p-bromobiphenyl is em.-butyldimethylsilyloxy, then carrying out the reaction with a Grignard reagent and then removing the protective silyl group, for example, by boiling in water tetrabutylammonium.

The possibility of using other halogen-substituted benzene to obtain a suitable Grignard reagent, which can be used in the present invention should be obvious to anyone skilled in this field specialist.

The term "protected hydroxy-group" used in this description, I understand alcohol or carboxyl OH group which may be protected by conventional protective groups in accordance with the techniques described in the book "Protective groups in organic synthesis", T. W. Greene, Wiley-Intersciene, 1981, New York. Preferred are trigonelline group, for example tert.-butyldimethylsilyl, phenyldimethylsilane, diphenylmethylsilane and stuff like that.

The term "C1-C4-alkyl" used in this description, see linear or branched alkyl, including methyl, ethyl, propyl, ISO.-propyl, N.-butyl, ISO.-butyl, sec.-butyl and tert.-butyl.

If this reaction scheme is carried out with compounds of formula R2MgX or R2-Li, the seer 17- (substituted thiobenzoyl)-4-alkyl-4-Aza - 5 - androst-1-EN-3-one, where phenyl is an R2.

The Grignard reagent R2MgX for the preparation of all the samples of the present invention falling under the scope of the present invention, readily available or can be easily obtained by any qualified in this field specialist. For example, if the substituent R2represents a C1-C4-alkylthiophenes, the Grignard reagent can be obtained from the appropriate C1-C4-alkylthiophene, for example of p-methylthiophenol.

Generated C1-C4-alkylthiophenes can be used to obtain C1-C4-alkylsulfonamides by oxidation, for example, m-chlormadinone acid. The obtained sulfoxide can then be subjected to oxidation using m-chlormadinone acid for longer periods of time corresponding to C1-C4alkylsulfonyl.

Next sulfoxide can be used in the rearrangement of Pummerer with the formation of the corresponding thiol.

Phenyl substituted by a group-SO2N(C1-C4)-alkyl)2(R2) is formed of a suitable bromine benzol, for example of n-N,N-dimethylaminopropanol that neposredno the ilen ring, there is a group of the formula -(CH2)mSH, where m takes on the values 1 through 4 are easily formed in chetyrehletiem the process of alkoxysilylated, Br-C6H4-(CH2)mOCH3. Direct addition of the Grignard reagent derived from the above bromeliifolia derived, to dipyridamole ether leads to Ketoprofen, that is, 17- (4-methoxyacetyl)-4-Aza - 5 - androst-1-EN-3-ONU. It can be easily turned into a thio analogue by processing BBr3at -70oC with the formation of hydroxyalkyl derivative, followed by substitution of the halogen atom, e.g. a bromine atom, and then the transformation of halogenated compounds with NaSH to end-mercapto-compounds. When in the reaction scheme above peridition reacts with aminophenylacetamido compound of formula R2MgX or R2-Li (X = Cl, Br), such as, for example, p-dimethylaminobenzylidene, this process can be carried out in tetrahydrofuran with the formation of the desired product 17- (p-dimethylaminobenzylidene)-4-alkyl-4-Aza - 5 - androst-1-EN-3-one (VIII), which is marked by chromatography on silica gel.

The Grignard reagent R2MgX for making all Oltenia, readily available or can be easily obtained by any qualified in this field specialist.

If the above Grignard reagent contains a substituent R2phenolic type, then the above peridition then reacts with Grignard reagents of formula R2MgX or R2-Li (X = Cl, Br), such as, for example, p-methoxyphenylalanine, in tetrahydrofuran with the formation of the desired product, for example 17- (p-methoxyphenethyl)-4-alkyl-4-Aza - 5 - androst-1-EN-3-one (VIII), which is marked by chromatography on silica gel. If the reaction is carried out with the use of other compounds of formula R2MgX or R2-Li (X = Cl, Br) instead of p-methoxyphenylethylamine, then get the corresponding tetrahydrofuran 17- (substituted benzoyl)-4-alkyl-4-Aza - 5 - androst-1-EN-3-one, where a represents a phenyl substituent R2.

The Grignard reagent R2MgX for the preparation of all the samples of the present invention falling under the scope of the present invention, readily available or can be easily obtained by any qualified in this field specialist.

For example, if the substituent R2is hydroxyphenyl, this process can be made using the group, for example trialkanolamines group, that is, tert.-butyldimethylsilyloxy, then carrying out the reaction with a Grignard reagent and then removing the protective silyl group, for example, by boiling in water tetrabutylammonium.

For the substituent R2representing carboxyphenyl, the same defensive reaction can be carried out using as starting product suitable hydroxyethylamine, for example p-hydroxymethylpropane or p-hydroxyethylbenzene.

If the substituent R2is carboxyphenyl, the Deputy may be obtained by oxidation of chromium acid suitable hydroxymethylbenzene, for example p-bromhidrosis of methylbenzol obtained as described above.

If the substituent R2represents-O-C1-C4-alkyl, for carrying out the Grignard reaction is the corresponding p-methoxypropanol.

The possibility of using other halogen-substituted benzene to obtain a suitable Grignard reagent, which can be used in the invention should be obvious to anyone skilled in this field specialist.

Under the term the which may be protected by conventional protective groups in accordance with the methods described in the book "Protective groups in organic synthesis", T. W. Greene, Wiley-Interscience, 1981, New York. Preferred are trigonelline group, for example tert.-butyldimethylsilyl, phenyldimethylsilane, diphenylmethylsilane and stuff like that.

Also under the scope of the invention falls using product recovery ketones 1A in combination with Minoxidil to treat specific alopecia, which constitute the secondary alcohols of the formula

< / BR>
R2is selected from among hydrogen atom, methyl and ethyl;

R2represents (a) a monovalent radical selected from among linear or branched alkyl or cycloalkyl containing 1-12 carbon atoms which may be substituted by one or more C1-C2-alkilani or halogen atoms; (b) Uralkaliy radical selected from benzyl or Venetia; (C) polycyclic aromatic radical, which may be substituted by one or more of: the OH groups, the groups defending the OH-group, group-OC1-C4-alkyl, C1-C4-alkilani, halogen atoms or nitro groups; (d) a monocyclic aromatic radical, which may be substituted by one or more cover up the> COOH, including group protecting the OH-group, where m = 1-4 and n = 1-3, provided that C1-C4-alkyl is only present when you have one of the above oxygen-containing radicals; (2) -SH, -SC1-C4-alkyl, -SOC1-C4-alkyl, -SO2C1-C4-alkyl, -SO2N(C1-C4-alkyl)2C1-C4-alkyl-(CH2)mSH, -S-(CH2)n-O-COCH3where m = 1-4, n = 1-3, provided that C1-C4-alkyl is only present when there is one above serosoderjaschei radicals; (3) N(R3)2group which may be protected, where the substituent R3represents H or C1-C4-alkyl, when monetarily radical can also be substituted C1-C4-alkyl; (4) heterocyclic radicals from among 2 - or 4-pyridyl, 2-pyrrolyl, 2-furil or thiophenyl;

and the substituents R', R" and R"' each are selected from hydrogen atom and methyl, and where the dotted line represents a double bond, and their pharmaceutically acceptable salts.

Such compounds can be obtained by a simple recovery of the sodium borohydride carbonyl group attached to the substituent R2, - phenyl substituent contains a carbonyl function, it can be protected, and then after the recovery of the borohydride reproduced in the usual way.

The restoration of the borohydride may be performed, for example, in water or in aqueous methanol at a temperature from room temperature up to 50oC, and the resulting product is then isolated and purified by conventional means. These compounds are also active as inhibitors of 5-alpha-reductase in the treatment of typical alopecia.

Compounds of the present invention obtained in accordance with the method described above, are, as already described, potential agents for the treatment of BPH, in combination with an alpha blocker alpha-adrenergic receptor.

17 - substituted steroidal inhibitors of 5 - reductase, which are not 4-Aza-steroids, known in the field and represent the inhibitors developed by Smithkline Beckmann and described in U.S. Pat. USA 4882319. Holt and others ; U.S. Pat. USA 4910226, Holt and others; Europe. Application 0289327, now U.S. Pat. USA 4910226; Europe. Application 0277002, now U.S. Pat. USA 4888336; Europe. Application 0343954; Europe. Application 375344, now U.S. Pat. USA 4970205; Heb. application 0375349, now U.S. Pat. USA 5026882.

In the method of the invention 17 - substituted non-Aza-steroids are compounds of the formula

< / BR>16-C17double bond, when the substituent R3represents two substituent or a divalent Deputy;

Z represents (CH2)n;

n = 0 or 2, provided that substituent Z represents (CH)nif he is in the adjacent position to the double bond;

X represents H, Cl, F, Br, I, CF3or C1-C6-alkyl;

Y represents H, CF3, Cl, F, or CH3provided that substituent Y represents a hydrogen atom, if there is no C5-C6-double bond;

R1represents H or C1-C8-alkyl;

R2if present, represents H or CH3provided that the substituent R2is absent when the carbon atom to which it is attached is unsaturated; and

R3represents a

(1) hydrogen atom, or hydroxyl group, or - acetoxy and/or

(a) a group of the formula

< / BR>
where W represents a bond or C1-C12-alkyliden;

R4represents (I) hydrogen atom, (II) a hydroxy-group, (III) C1-C8-alkylidene R5and R6each independently of one another are selected from among a hydrogen atom, a C1-C8-alkyl, C3-C6-cycloalkyl, phenyl, or the substituents R5and R6together with the nitrogen atom to which they are attached, form a 5-6-membered saturated ring, (VII) OR7group, where the substituent R7represents a hydrogen atom, alkali metal, C1-C8-alkyl, benzyl, or

(b) the group R8O-alkyl, where alkyl represents a C1-C12-alkyliden,

R8represents (I) phenyl C1-C6-alkylsulphonyl, (II) C5-C10-cycloalkylcarbonyl, (III) benzoyl, (IV) C1-C8-alkoxycarbonyl, (V) aminocarbonyl or C1-C8-alkyl substituted aminocarbonyl, (VI) hydrogen atom or (VII) C1-C8-alkyl,

(2) groups of formula-OH-W-COR4or-CH-W-COR8where the Deputy W is a bond or C1-C12-alkyliden, and the substituents R4and R8take the same values as those described above, and the substituent R8can also be a hydrogen or C1-C20-alkylcarboxylic group.

(3) a group of the formula

< / BR>
where broken link replaces the 17 - hydrogen atom,

(4) water is P>5R6group, where the substituents R5and R6take the values described above,

(5) is a hydrogen atom or a cyano,

(6) is a hydrogen atom or tetrazolyl, or

(7) ketogroup,

or their pharmaceutically acceptable salt, with the exception of compounds in which (I) the ring B contains C5-C6-double bond, the substituent R1represents CH3and the substituent R3is catography, methoxycarbonyl, acetyl, or (II) A ring-Nord contains C3-C4-double bond, and the substituent R3represents an acetoxy or acetyl, (III) the substituent R1represents CH3and the substituent R3is acetoxypropionyl or acetyl, or (IV) A ring-Nord contains C3-C4-double bond, and the substituent R1represents methyl, or (V) the ring B contains C3-C4-double bond, the substituent R3is a hydroxy - group.

Typical compounds, synthesis and properties of which are disclosed in the above U.S. patents, as well as their pharmaceutically acceptable salts are the following:

4-methyl-4-Aza-5a-8(14)-pregnen-3-one-(20R)-20-carboxylic acid;

(20R)-hydroxymethyl-4-methyl-4-Aza - 5 - 8(14)-pregnen-3-one;1,3,5(10)-triene-3 - phosphinic acid;

17- (N-tert.-BUTYLCARBAMATE)-variety-1,3,5(10)-triene-3 - phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-variety-1,3,5(10)16-tetraen-3 - phosphinic acid;

17- (N-tert.-BUTYLCARBAMATE)-variety-1,3,5(10),16-tetraen-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-variety-1,3,5(10),6,8-pentaen-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-2-methyl-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-4-methyl-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-variety-1,3,5(10),6 - tetraen-3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-2-chloro-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-4-chloro-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N-butylcarbamoyl)-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N-butylcarbamoyl)-variety-1,3,5(10), 16-tetraen-3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-4-methyl-variety-1,3,5(10)- triene-3-phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-variety-1,3,5(10),6-tetraen - 3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-2-chloro-variety-1,3,5(10) -triene-3-phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-4-chloro-variety-1,3,5(10) -triene-3-phosphinic acid;

17-(N, N-diisopropylcarbodiimide)-e;

17- (N,N-diisopropylcarbodiimide)-variety-1,3,5(10),16-tetraen - 3-acid;

17- (N-tert.-BUTYLCARBAMATE)-variety-1,3,5(10),16-tetraen - 3-acid;

17- (N,N-diisopropylcarbodiimide)-variety-1,3,5(10),6,8-pentaen - 3-acid;

17- (N,N-diisopropylcarbodiimide)-2-methyl-variety-1,3,5(10)- triene-3-acid;

17- (N,N-diisopropylcarbodiimide)-4-methyl-variety-1,3,5(10)- triene-3-acid;

17- (N, N-diisopropylcarbodiimide)-2-chloro-variety-1,3,5(10)- triene-3-acid;

17- (N, N-diisopropylcarbodiimide)-4-chloro-variety-1,3,5(10)- triene-3-acid;

17- (N, N-diisopropylcarbodiimide)-androst-3,5-diene-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-androst-3,5-diene-3 - phosphinic acid;

17- (N-tert.-BUTYLCARBAMATE)-androst-3,5-diene-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)- 5 - androst-3-ene-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)- 5 - androst-2-ene-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-androst-2,4-diene-3 - phosphinic acid;

methyl 17- (N,N-diisopropylcarbodiimide)-androst-3,5-diene-3 - phosphinic acid;

20- (hydroxymethyl)- 5 - proj-3-ene-3 - phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-4-fluoro - 5 - androst-3-ene-3 - phosphinic acid;

20- (hydroxymethyl)-4-ft is N-diisopropylcarbodiimide)- 5 - androst-1,3-diene-3 - phosphinic acid;

17- (N,N-diisopropylcarbodiimide)- 5 - androstane - 3 - phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-variety-3,5(10)-diene-3 - phosphinic acid;

17- (N,N-diisopropylcarbodiimide)-variety-3,5-diene-3 - phosphinic acid;

17- (N, N-diisopropylcarbodiimide)-androst-3,5,11-triene-3 - phosphinic acid;

20- (hydroxymethyl)- 5 - pregn-3-ene-3-carboxylic acid;

N,N-aminobutiramida - 5 - androst-3-ene - 17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida-androst-3,5-Dien - 17 - carboxamide-3 - carboxylic acid;

17- (N,N-diisopropylcarbodiimide)-4-fluoro - 5 - androst-3-ene-3 - carboxylic acid;

20- (hydroxymethyl)-4-fluoro - 5 - pregn-3-ene-3-carboxylic acid;

20- (hydroxymethyl)-A-nor - 5 - pregn-3-ene-3-carboxylic acid;

17- (N, N-diisopropylcarbodiimide)- 5 - androst-1,3-diene-3 - carboxylic acid;

N-tert.butyl-androst-3,5-Dien - 17 - carboxamide-3 - carboxylic acid;

N,N-aminobutiramida - 5 - androst-2-EN - 17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida-androst-2,4-diene - 17 - carboxamide-3 - carboxylic acid;

N,N-aminobutiramida-5 - androst-17 - carboxamide-3-carboxylic acid;

N, N-aminobutiramida variety-3,5(10)-Dien-17 - carboxamide-3-carboxylic acid;

N,N-aminobutiramida variety-3,5-Dien-17 - carboxamide-3-carboxylic acid;

the OIC acid;

N,N-aminobutiramida-androst-3,5-Dien-17 - carboxamide-3-carboxylic acid;

17- (N,N-diisopropylcarbodiimide)-4-fluoro-5 - androst-3-ene-3 - carboxylic acid;

17- (N, N-diisopropylcarbodiimide)-androst-3,5,11-triene-3 - carboxylic acid;

17- (N,N-diisopropylcarbodiimide)-androst-3,5-diene-3 - thiocarbonate acid;

17- (N-tert.-BUTYLCARBAMATE)-androst-3,5,11-triene-3 - carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-androst-3,5-diene-3 - thiocarbonate acid;

N-tert.-butyl-androst-3,5-Dien-17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida-androst-3,5-Dien-17 - carboxamide-3 - carboxylic acid;

20- (hydroxymethyl) -3 - pregn-3-ene-3-carboxylic acid;

20- (hydroxymethyl)-4-fluoro-5 - pregn-3-ene-3-carboxylic acid;

3 carbomethoxy-N,N-aminobutiramida-androst-3,5-Dien-17 - carboxamide;

17- (N, N-diisopropylcarbodiimide) -5 - androst-1,3-diene-3 - carboxylic acid;

N, N-aminobutiramida-5 - androst-2-EN - 17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida-androst-2,4-diene-17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida-5 - androstane-17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida variety-3,5(10)-Dien-17 - carboxamide-3 - carboxylic acid;

N,N-aminobutiramida variety.3,5-Dien-17 - carboxamide-3-garnjost-3,5-Dien-17 - carboxamide-3-carboxylic acid;

20- (hydroxymethyl)-4-fluoro-5 - pregn-3-ene-3-carboxylic acid;

N, N-aminobutiramida-5 - androst-3-ene-17 - carboxamide-3-carboxylic acid;

17- (N,N-diisopropylcarbodiimide)-4-fluoro-5 - androst-3-ene-3-carboxylic acid;

17- (N, N-diisopropylcarbodiimide)-4-fluoro-androst-3,5-diene-3-carboxylic acid;

3 carbomethoxy-N,N-aminobutiramida-androst-3,5-Dien-17 - carboxamide;

17- (N, N-diisopropylcarbodiimide) -5 - androst-1,3-diene-3-carboxylic acid;

N, N-aminobutiramida-5 - androst-2-EN-17 - carboxamide-3-carboxylic acid;

N,N-aminobutiramida-androst-2,4-diene-17 - carboxamide-3-carboxylic acid;

N, N-aminobutiramida-5 - androstane-17 - carboxamide-3 - carboxylic acid;

N, N-aminobutiramida variety-3,5(10)-Dien-17 - carboxamide-3-carboxylic acid;

N,N-aminobutiramida variety-3,5-Dien-17 - carboxamide-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-androst-3,5,11-triene-3-carboxylic acid;

17- (N-tert.BUTYLCARBAMATE)-androst-3,5-diene-3-thiocarbonate acid;

N-tert.-butyl-5 - androst-3-ene-17 - carboxamide-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-6-fluoro- -5 - androst-3-ene-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-6-fluoro-androst-3,5-diene-3-carboxylic acid;

3 carbomethoxy-N-tert.-butyl-androst-util-5 - androst-2-EN-17 - carboxamide-3-carboxylic acid;

N-tert. -butyl-5 - androst-2,4-diene-17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-5 - androstane-17 - carboxamide-3-carboxylic acid and

20- (hydroxymethyl)-A-nor-5 - pregn-1-EN-2-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-androst-3,5,11-triene-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-androst-3,5-diene-3-thiocarbonate acid;

N-tert.-butyl-5 - androst-3-ene-17 - carboxamide-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-6-fluoro-5 - androst-3-ene-3-carboxylic acid;

17- (N-tert. -BUTYLCARBAMATE)-6-fluoro-androst-3,5-diene-3-carboxylic acid;

3 carbomethoxy-N-tert.-butyl-androst-3,5-Dien-17 - carboxamide;

17 - N-butylcarbamoyl-5 - androst-1,3-diene-3-carboxylic acid;

N-tert.-butyl-5-androst-2-EN-17-carboxamide-3-carboxylic acid

N-tert. -butyl-5 - androst-2,4-diene - 17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-5 - androstane-17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-variety-3,5(10)-Dien-17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-variety-4,5-Dien-17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-variety-3,5(10)-Dien-17 - carboxamide-3-carboxylic acid;

N-tert.-butyl-variety-3,5-Dien-17 - carboxamide-3-carboxylic acid;

20- (tert.-b is evermetalhead) -5 - androst-3-ene;

17- (N, N-diisopropylcarbodiimide)-3-(triftormetilfullerenov)-androst-3,5-diene;

17- (N,N-diisopropylcarbodiimide)-3-(triftormetilfullerenov)-4-fluoro-5 - androst-1,3-diene;

20- (tert. -butyldimethylsiloxy)-4-fluoro-3-(triftormetilfullerenov) -5 - pregn-1,3-diene;

17- (N,N-diisopropylcarbodiimide)-3-(triftormetilfullerenov)- 5 - androst-1,3-diene;

17- (N-tert. -BUTYLCARBAMATE)-3-(triftormetilfullerenov)- 5 - androst-3,5-diene;

17- (N, N-diisopropylcarbodiimide)-3-(triftormetilfullerenov)- 5 - androst-2-EN;

17- (N, N-diisopropylcarbodiimide)-3-(triftormetilfullerenov)-androst-2,4-diene;

N-tert.-butyl-androst-3,5-diene-3-bromo - 17 - carboxamide and

N,N-aminobutiramida-androst-3,5-diene-3-bromo-17 - carboxamide.

Also available in 17 - acyl-3-carboxy-androst-3,5-diene formulas;

< / BR>
where substituent R1represents (a) C1-C6- linear or branched alkyl, C3-C12-cycloalkyl, which may be substituted C1-C4alkoxygroup or C1-C4linear/branched alkyl, C6-C12- aryl or C7-C13- aralkyl, which can be substituted by one or more substituents from among: -OH, -OC1-C4-alkyl, C1-C4-alkyl, -(CH23-C12-cycloalkyl, which may be substituted C1-C4- alkoxygroup or C1-C4- linear/branched alkyl, C6-C12-aryl or C7-C13-aralkyl, which can be substituted by one or more substituents from among: -OH, -OC1-C4-alkyl, C1-C4of alkyl, -(CH2)mOH, -(CH2)nCOOH, including protected OH group, where m = 1-4, n = 1-3, Deputy R2is selected from among COOH, SO3H, PO(OH)2PH(O)OH.

Especially offered compounds, in which the Deputy - R1represents a tert. -butyl, cycloalkyl, phenyl, p-hydroxy-phenyl, 1-substituted, 2-substituted, NH-tert.-butyl, NH-ISO-butyl, NH-cyclohexyl, NH-phenyl, NH-p-hydroxyphenyl, NH-1-substituted, NH-2-substituted, and the substituent R2represents a COOH group.

Typical compounds are:

17- (4-hydroxyphenylarsonic)-androsta-3,5-diene-3-carboxylic acid;

17 - benzoyl-androsta-3,5-diene-3-carboxylic acid;

17- (cyclohexylcarbonyl)-androsta-3,5-diene-3-carboxylic acid;

17- (isobutylidene)-androsta-3,5-diene-3-carboxylic acid;

17- (4-hydrooximethylcarbamil)-androsta-3,5-diene-3-carboxylic acid;

17- (2-Gern-3-carboxylic acid;

17- (4-karboksimetiltsellyulozy)-androsta-3,5-diene-3-carboxylic acid;

N-tert.-butyl-androst-3,5-Dien-17 - carboxamide-3-carboxylic acid;

N-phenyl-androst-3,5-Dien-17 - carboxamide-3-carboxylic acid;

N-1-substituted-androst-3,5-Dien-17 - carboxamide-3-carboxylic acid;

N-2-substituted-androst-3,5-Dien-17 - carboxamide-3-carboxylic acid;

Also known in the field and used non-steroidal inhibitors of 5 - reductase, developed ONO Pharmaceutical Ca, LTD, Osaka, Japan, and described in U.S. Pat. USA 4780469; 4847275; 4939141 and Heb. Pat. Application 0173516 and 0291245, as well as in U.S. Pat. USA 4980372; Heb. Application 291247 and U.S. Pat. USA 5037852, revealing some new condensed Benz (thio) amides and derivatives of benzylaminopurine acid.

Derivatives benzylaminopurine acids have the formula

< / BR>
where substituent R1represents a hydrogen atom or alkyl containing from 1 to 4 carbon atoms;

And represents an oxygen atom, a sulfur atom or sulfinyl (SO) group;

both Deputy R1represent methyl or chlorine atom, or both of the substituent R1and the carbon atoms of the benzene ring to which are attached two Deputy R1, WHI is the remains of formulas

< / BR>
< / BR>
or

< / BR>
where Deputy B represents an oxygen atom, a sulfur or a residue of the formula NR11, R11represents a hydrogen atom or alkyl containing from 1 to 4 carbon atoms;

the substituents R3, R4, R5,R6, R7and R8independently from each other represent a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, halogen atom, triptorelin or cyclobutylmethyl group;

m = 0 or 1,

n takes integer values from 1 to 5;

Deputy R9represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms or a group of the formula

< / BR>
or

< / BR>
where the substituents R12, R13, R14and R15independently from each other represent a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, halogen atom, triptorelin or cyclobutylmethyl group;

l takes integer values from 1 to 4;

Deputy R10represents a residue of the formula

< / BR>
< / BR>
or

< / BR>
where the substituents R12, R13, R14and R15independently from each other represent a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, halogen atom, tripiccione salt.

Typical examples of each of these two classes of compounds, the synthesis and properties of which are disclosed in the above U.S. patents are the following connections:

4-[2-(4-benzyloxy-2,3-dimethylbenzylamine)phenoxy]butane acid;

4-[2-(4-(2-methylbenzylamino)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(3-methylbenzylamino)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-methylbenzylamino)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(2-methylbenzylamino)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(2,6-dimethylbenzylamine)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-ethylbenzylamine)-2,3-dimethylbenzylamine)phenoxy]butane acid;

4-[2-(4-(4-propylbenzyl)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-from propylbenzoate)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-from butylbenzoate)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-chlorobenzoyloxy)-2,3-dimethylbenzylamine)phenoxy]butane acid;

4-[2-(4-(4-cyclobutanecarbonyl)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(2-phenylethane)-2,3-dimethylbenzylamine)fenoc-(4-phenylmethoxy)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(5-phenylmethoxy)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(1-(4-ISO-butylphenyl)ethoxy)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-(4-(4-propylbenzyl)-2,3-dimethylbenzylamine)phenylthio] butane acid;

4-[2-(1-(4-ISO-butylphenyl)ethoxy-2,3-dimethylbenzylamine)phenylthio] butane acid;

4-[2-(4-(4-propylbenzyl)-2,3-dimethylbenzylamine)phenylsulfinyl] butane acid;

4-[2-[4-(N-triftormetilfullerenov)amino] -2,3-dimethylbenzylamine] phenoxy] butane acid;

4-[2-[4-(4-from butylbenzoate)-5,6,7,8-tetrahydronaphthalen-1 carbylamine]phenoxy]butane acid;

4-[2-[4-(4-from butylbenzoate)-naphthalene-1-carbylamine]phenoxy] butane acid;

4-[2-[8-(4-from butylbenzoate)-5,6,7,8-tetrahydronaphthalen-1 carbylamine] phenylthio]butane acid;

4-[2-[4-[bis(4-propylphenyl)methoxy] -2,3-dimethylbenzylamine] phenoxy] butane acid;

4-[2-(4-diphenylmethoxy)-2,3-dimethylbenzylamine)phenoxy] butane acid;

4-[2-[4-[bis(4-propylphenyl)methylamino] -2,3-dimethylbenzylamine]phenoxy] butane acid;

4-[2-[4-[bis(4-propylphenyl)methylthio] -2,3-dimethylbenzylamine] phenoxy] butane acid;

4-[2-[4-[N,N-bis(4-propylpentyl)Amin is ethylbenzylamine]phenoxy]butane acid;

4-[2-[4-N-methyl-N-(5,6,7,8-tetrahedronal-1-yl)aminomethyl]-2,3 - dimethylbenzylamine]phenoxy]butane acid;

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6-chloro-1,4-benzodioxan;

8-(m-oxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-heptylbenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-octylbenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-nonylbenzene)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-delventhal)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-undecylenoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-dodecylbenzyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-butyloxycarbonyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-monoxivent)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-propoxyethyl)amino-2-(5-what oxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(o-decyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-ISO-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-ISO-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-[p-(1-methylbutoxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(N-methyl-N-(p-octyloxy)benzoyl)amino-2-(5-tetrazolyl)- 1,4-benzodioxan;

8-(p-octyloxybenzoic)amino-1,4-benzodioxan-2-carboxylic acid and its methyl ether;

8-(p-ISO-heptyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-ISO-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-[p-(3,7-dimethyloctyl)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan;

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan;

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan - 7-carboxylic acid and its methyl ester,

and similar compounds.

Also as an inhibitor of 5 - reductase in the present invention included cinnamic acid amide (cinnamoned) formula

< / BR>
where the substituents R2and R3each independently from each other represent a hydrogen atom or methyl group, slaveboy a hydrogen atom, as the substituent (R1)nis a Deputy chosen from the group comprising 3-pentelow, 4-pentelow, 4-neopentylene group, 4-(2-ethylbutyl)- 4-(2-were), or (II) if the substituent R2represents a hydrogen atom, a substituent R3represents a methyl group, and the substituent (R1)nis a 3-pentelow group

and their non-toxic salts.

Typical compounds are:

4-[2-(4-butylthio -- medicineonline)phenoxy]butane acid;

4-[2-(4-cyclobutylmethyl -- medicineonline)phenoxy]butane acid;

4-[2-(4-cyclohexylmethyl -- medicineonline)phenoxy]butane acid;

4-[2-(4-(4-phenylbutyl) -- medicineonline)phenoxy] butane acid;

4-[2-(4-phenoxy -- medicineonline)phenoxy]butane acid;

4-[2-(3-pentyl -- medicineonline)phenoxy]butane acid;

4-[2-(4-phenethyl-methylcinnamaldehyde)phenoxy]butane acid;

4-[2-(3-pentyl -- medicineonline)phenoxy]butane acid;

4-[2-(4-neopentyl -- medicineonline)phenoxy]butane acid;

4-[2-(4-(2-ethylbutyl) -- medicineonline)phenoxy]butane acid and

4-[2-(2-fluoro-4-pentylene Benz(thio)amides of the formula

< / BR>
where A Deputy is a single bond or a group selected from among methylene, ethylene, trimethylene, tetramethylene, vinylene, propylene, butylene, butadiene or ethynylene, possibly substituted by one, two or three linear or branched alkyl groups containing from 1 to 10 carbon atoms and/or phenyl(s) group(s);

Deputy B is a 4-8-membered heterocyclic ring containing one, two or three heteroatoms selected from the group including atoms of oxygen, nitrogen and sulfur, with the above ring may be substituted by substituents from among oxo, thioxo - and/or hydroxy groups, including rings formulas

< / BR>
or

< / BR>
Deputy T represents an oxygen atom or a sulfur atom;

Deputy R1represents the balance formulas

< / BR>
< / BR>
or

< / BR>
(IV) a linear or branched alkyl, alkenyl or quinil containing from 1 to 20 carbon atoms,

where the substituents R5and R6independently from each other represent a hydrogen atom or a halogen or a branched or linear alkyl, alkenyl or quinil containing from 1 to 20 carbon atoms that can be the market, halogen, nitrogen, benzene rings, thiophene rings, naphthalene rings, carbocyclic rings containing from 4 to 7 carbon atoms, carbonyl groups, carboxyl groups, hydroxyl groups, carboxypropyl, sidegroups and/or nitro groups;

Deputy R2represents a hydrogen atom or a linear or branched alkyl containing from 1 to 6 carbon atoms;

Deputy R3represents a hydrogen atom, a halogen atom, a hydroxy-group, a nitrogroup, a group of General formula-COOR7where substituent R7represents a hydrogen atom or a linear or branched alkyl containing from 1 to 6 carbon atoms, linear or branched alkoxy or ancilliary containing from 1 to 6 carbon atoms;

Deputy R4represents the balance of General formula

-U-(CH2)n-COOR8,

< / BR>
-(CH2)p-COOR8,

or

< / BR>
where Deputy U represents an oxygen atom or sulfur;

Deputy R8represents a hydrogen atom or a linear or branched alkyl containing from 1 to 6 carbon atoms;

n and m take values from 1 to 10 sootvetstvenno is.

Typical compounds are:

7-(n-hexyloxybenzoyl)amino-2-(5-tetrazolyl) benzofuran,

7-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)benzofuran,

7-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)benzofuran,

7-(p-monoxivent)amino-2-(5-tetrazolyl)benzofuran,

7-[n-(4-phenylmethoxy)benzoyl]amino-2-(5-tetrazolyl)benzofuran,

7-[p-(2E,7-octadiene)benzoyl]amino-2-(5-tetrazolyl)benzofuran,

7-[n-(6-chlorhexidine)benzoyl]amino-2-(5-tetrazolyl)benzofuran,

7-(p-petercennamo)amino-2-(5-tetrazolyl)benzofuran,

7-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1 - benzofuran,

7-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-2,3-dihydro-1 - benzofuran,

7-(p-monoxivent)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

7-(p-pentylindol)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

8-[p-(2E,7-octadiene)benzoyl)amino-2-(5-tetrazolyl)quinoline,

8-[p-(4-phenylmethoxy)benzoyl)amino-2-(5-tetrazolyl)quinoline,

8-[p-(6-chlorhexidine)benzoyl]amino-2-(5-tetrazolyl)quinoline,

8-[p-(2E, 7-octadiene)benzoyl]amino-4-hydroxyquinolin-2-carboxylic acid,

8-[p-(4-phenylmethoxy)benzoyl] amino-4-hydroxyquinolin-2-carboxylic acid,

8-[p-(4-(2-thienyl)butoxy)benzoyl] anolin,

8-[p-[4-(2-phenyl)butoxy)benzoyl] amino-4-hydroxy-2-(5-tetrazolyl)quinoline,

8-[p-pentylindol)amino-4-hydroxy-2-(5-tetrazolyl)quinoline,

4-(p-heptyloxybenzoic]amino-2-(5-tetrazolyl)-1,3-benzodioxol,

4-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxol,

4-[n-[4-(phenylmethoxy)benzoyl]amino]-2-(5-tetrazolyl)-1,3-benzodioxol,

4-(p-pentylindol)amino-2-(5-tetrazolyl)-1,3-benzodioxol,

4-[n-[4-(phenylmethoxy)benzoyl] amino]-2-(5-tetrazolyl)-3,4-dihydro - 2H-1,5-benzodioxepin,

9-[p-(2E, 7-octadecanoyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4 - dihydro-2H-1,5-benzodioxepin,

9-[p-(7-octenoate)benzoyl] amino-2-(5-tetrazolyl)-3,4-dihydro - 2H-1,5-benzodioxepin,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4 - benzoxazin,

8-[p-(4-phenyloxy)benzoyl] amino-2-(5-tetrazolyl)-2,3-dihydro-1,4 - benzoxazin,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4 - benzoxazin,

8-[p-(4-phenyloxy)benzoyl] amino-2-(5-tetrazolyl)-4-oxo-4H-1 - benzothiophen,

8-[p-(4-pencilbox)benzoyl] amino-2-(5-tetrazolyl)-3,4 - dihydro-2H-1-benzopyran,

8-[p-(7-octenoate)benzoyl] amino-2-(5-tetrazolyl)-3,4 - dihydro-2H-1-benzopyran,

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-oxo-4H - 1-benzopyran,

8-(p-dryer is-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-heptylbenzoic)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-octylbenzoic)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-nonylbenzene)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-butoxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-monoxivent)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-4-oxo-4H - 1-benzopyran,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-6-fluoro-4 - oxo-4H-1-benzopyran,

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-6-methyl-4 - oxo-4H-1-benzopyran,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-6-methyl-4 - oxo-4H-1-benzopyran,

8-[p-(2E, 7-octadecanoyloxy)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-(p-geranylacetone)amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(2E-nonyloxy)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(2E-octenoate)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(7-octenoate)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-anbesol]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(2E, 7-octadecanoyloxy)benzoyl] amino-2-(5-tetrazolyl)-6-fluoro-4 - oxo-4H-1-benzopyran,

8-[p-(2E-octenoate)benzoyl] amino-2-(5-tetrazolyl)-6-methyl-4 - oxo-4H-1-benzopyran,

8-[p-(2E, 7-octadecanoyloxy)benzoyl] amino-2-(5-tetrazolyl)-6-chloro-4 - oxo-4H-1-benzopyran,

8-[p-(2-octyloxy)benzoyl] amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-[p-(4-chloroethoxy)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(5-chloropentane)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(6-chlorhexidine)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(7-chloroheptane)benzoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(8-chloroacrylate)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(7-chloroheptane)benzoyl] amino-2-(5-tetrazolyl)-6 - methyl-4-oxo-4H-1-benzopyran,

8-[p-(8-chloroacrylate)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(3-phenyl-2E-propenyloxy)benzoyl] amino-2-(5 - tetrazolyl)-4-oxo-4H-1-benzopyran,

8-[p-(4-phenylmethoxy)benzoyl]amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-[p-(4-phenylmethoxy)benzoyl] amino-2-(5-tetrazolyl)-6 - methyl-4-oxo-4H-1-benzopyran,

8-[p-[2-(2-tetrazolyl)-6 - methyl-4-oxo-4H-1-benzopyran,

8-[p-[3-(3,4-dichlorophenyl)propoxy] benzoyl] amino-2- (5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-[p-[3-(3,4-dichlorophenyl)propoxy] benzoyl] amino-2- (5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-[p-[3-(p-chlorophenyl)butoxy] benzoyl] amino-2- (5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-[p-[3-(p-chlorophenyl)butoxy] benzoyl] amino-6-methyl-2- (5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-[p-[4-(2-thienyl)butoxy] benzoyl]amino-2-(5-tetrazolyl)- 4-oxo-4H-1-benzopyran,

8-[p-[4-(2-thienyl)butoxy] benzoyl] amino-6-methyl-2- (5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-pentylindol)amino-4-oxo-4H-1-benzopyran-2 - carboxylic acid and its methyl ester,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-4-oxo-4H - 1-benzopyran,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-6-methyl-4-oxo - 4H-1-benzopyran,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-6-fluoro-4-oxo - 4H-1-benzopyran,

8-(p-pentylindol)amino-6-methyl-4-oxo-4H-1-benzopyran - 2-carboxylic acid and its methyl ester,

8-(p-butylcarbamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1 - benzopyran,

8-(p-existingemail)amino-2-(5-tetrazolyl)-4-oxo-4H-1 - benzopyran,

8-(p-chaptersindigo)amino-2-(5-tetrazolyl)-4-oxo-4H - 1-benzopyran,

8 innamoramento-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-exilica - 4H-1-benzopyran,

8-(p-isohexadecane)amino-2-(5-tetrazolyl)-4-oxo - 4H-1-benzopyran,

8-[p-(2-octyloxy)cynnamoyl]amino-4-oxo-4H-1-benzopyran - 2-carboxylic acid,

8-[p-(5-chloropentane)cynnamoyl] amino-2-(5-tetrazolyl)-4 - oxo-4H-1-benzopyran,

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6-chloro - 1,4-benzodioxan,

8-(m-octylbenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-heptylbenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-octylbenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-nonylbenzene)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-delventhal)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-undecylenoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-dodecylbenzyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-butylacetyl)Amin is roxylenol)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-propoxyethyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(o-decyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-ISO-pentyloxybenzoyl)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-ISO-hexyloxybenzoyl)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[N-methyl-N-(p-octyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-octyloxybenzoic)amino-1,4-benzodioxan-2 - carboxylic acid and its methyl ester,

8-(p-ISO-heptyloxybenzoic)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-ISO-octyloxybenzoic)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3,7-dimethyloctyl)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4 - benzodioxan-7-carboxylic acid

8-[p-(2E-octyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[p-(3-butenyloxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3Z-hexenoate)benzoyl]amino-2-(5-tetrazolyl)-1,4 - Beil]amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[N-methyl-N-[p-(2E-octenoate)benzoyl] amino-2- (5-tetrazolyl)-1,4-benzodioxan,

8-[p-(3E-heptyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-octenoate)benzoyl] amino-1,4-benzodioxan - 2-carboxylic acid and its methyl ester,

8-[p-(2E-heptyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-pentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[p-(2E-desenlace)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-geranyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[p-(2E, 7-octadecanoyloxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-pentyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-butenyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(7-octenoate)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E, 4E,-octadecanoyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-octadecanoyloxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-octyloxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-octyloxy)benzoyl]amino-1,4-benzodioxan-2 - carboxylic acid and its methyl ester,

8-[p-(2-ISO-octyloxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-benzodioxan,

8-(o-pentylthiophene)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(o-reptitiously)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[p-(6-chlorhexidine)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-chloropentane)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-chloroethoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(7-chloroheptane)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(8-chloroacrylate)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(9-chloraniline)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3-bromopentane)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan-2-carboxylic acid and its methyl ester,

8-[p-(hexyloxymethyl)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(cyclohexylmethoxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-cyclohexylmethoxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-cyclohexylmethoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(p-butylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-phenylmethoxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

oil] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-phenylmethoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(o-pentylphenol)methoxybenzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(m-butylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-phenylmethanol)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-phenylethane)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-phenylmethoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-[2-(2-naphthyl)ethoxy] benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-[3-(p-chlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-[4-(p-chlorophenyl)butoxy] benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-ethoxycarbonylmethoxy)benzoyl] amino-2- (5-tetrazolyl)-1,4-benzodioxan,

8-[p-(6-acetylsalicylate)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(6-hydroxyhexyloxy)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-octenoate)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-octanolwater]amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-[p-(3-phenylthiophene)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3-phenoxypropane)benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-Hairdryer who yl)- 1,4-benzodioxan,

8-[p-[2-(3-thienyl)ethoxy] benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-[4-(2-thienyl)butoxy] benzoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-azidoaniline)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-dimethylaminoethoxy)benzoyl] amino-2- (5-tetrazolyl)-1,4-benzodioxan,

8-[p-(4-nitrobutane)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-azidoethoxy)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-asiabooks)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-octanoylthio)benzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(n-pentyloxy-m-methoxybenzoyl)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-octenoate)-m-chlorobenzoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(2-afterburner)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylindol)amino-1,4-benzodioxan-2-carboxylic acid and its methyl ester,

8-(p-chaptersindigo)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-[N-methyl-[N-(pentylindol)] amino] -2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-7-chloro-1,4 - benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazole who yl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-butylcarbamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-6-methyl-1,4 - benzodioxan,

8-(o-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(m-octilinear)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan - 5-carboxylic acid and its methyl ester,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxin - 8-carboxylic acid and its methyl ester,

8-(p-existingemail)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-nonlinear)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan - 6-carboxylic acid and its methyl ester,

8-(p-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan - 7-carboxylic acid and its methyl ester,

8-(p-octilinear)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-decoltissimo)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-ISO-PropertyName)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-ISO-butylcarbamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-ISO-pentylindol)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(n-phenyl-2-methylcinnamic)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-is)-1,4-benzodioxan,

8-(p-Interoceanmetal)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(m-Interoceanmetal)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(o-Interoceanmetal)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(p-propositional)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-butoxycarbonyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-heptyloxybenzoic)amino-2-(5-tetrazolyl)-1,4-benzodioxan,

8-(p-ISO-Interoceanmetal)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(p-ISO-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-[p-(1-methylbutoxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-ISO-heptyloxybenzoic)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(p-ISO-octyloxybenzoic)amino-2-(5-tetrazolyl)-1,4 - benzodioxan,

8-(p-ISO-hexyloxy-2-methylcinnamic)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-ISO-hexyloxy-2-phenylcinnamic)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-octenoate)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-propenyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2Z-pentyloxy)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-nonyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(3E-heptyloxy)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-heptyloxy)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-hexenoate)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-pentyloxy)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-pentyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-butenyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2E-desenlace)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-octyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-pentyloxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-intellicenter)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(m-intellicenter)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(o-intellicenter)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(6-chlorhexidine)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-chloroethoxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(5-chloropentane)cynnamoyl] amino-2-(5-tetranortriterpenoids)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-cyclohexylphenol)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-cyclohexyloxycarbonyl)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-cyclohexylmethoxy)cynnamoyl] amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(4-cyclohexylmethoxy)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-intermittenly)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-(p-phentermetrizine)amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

8-[p-(2-phenylethane)cynnamoyl]amino-2-(5-tetrazolyl)- 1,4-benzodioxan,

5-(p-pentylindol)amino-2-(5-tetrazolyl)-2,3-dihydro - 1,4-detination and its sodium salt.

The invention also includes an aromatic 1,2-di(thio)ethers of the formula

< / BR>
where A represents A residue of a 1,2-disubstituted aromatic ring, preferably a benzene ring;

the substituent R represents O, S, SO, SO2;

the substituent R represents a hydrogen atom, a C1-C4-alkyl, phenyl or substituted phenyl, halogen atom, hydroxy-group, carboxyl group, cyano, C1- C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylsulfanyl group, C1- C4-alkylsulfonyl group, nitrog each other represent a hydrogen atom, halogen atom, a C1-C4-alkyl or C1- C4-alkoxygroup, amino group, or oxoprop when fragments CH-R' or CHR" in the formula become a group-C=O;

y takes on the values 1 to 6;

z takes the values 6 to 20;

(CH)y-R' and (CH)z-R" can independently from each other represent substituted or unsubstituted alkyl radicals or alkeneamine radicals containing at least one alanovoy communication;

and their pharmaceutically acceptable salts.

Compounds of the invention are inhibitors of testosterone-5-reductase enzyme of man.

Compounds falling under the scope of the invention represented by the above formulas.

Description of formulas used the following concepts:

Deputy X in the above General formula represents O or S, preferably, if one of the substituents X is an oxygen atom, and more preferably, when both substituent X are oxygen atoms, that is, the target compound has a structure of catechol.

"C1-C4-alkyl" means a linear or branched alkyl, for example methyl, ethyl, n-propyl, ISO-propyl, cyclopropyl, n-bottlenose alkoxygroup, for example methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy.

By "halogen" refers to fluorine atom, chlorine, bromine or iodine.

"Substituted phenyl" means phenyl, substituted by one or more C1-C4-alkilani, C1- C4-alkoxygroup, halogen atoms, etc. as defined above, examples of such substituents are o, m and p-methoxyphenyl, 2,4-acid, 2-chloro-4-ethoxyphenyl, 5,5-acid, 2,4-dichlorophenyl, 2-bromo-4-were, on forfinal etc.

The concept of "halogenated includes C1-C4is an alkyl group described above substituted by one or more atoms of halogen as defined above, for example - triptorelin group, 2,2-dichloroethylene etc.

Deputy "C1-C4-alkylthio" means C1-C4-alkyl described above, substituted by at least one divalent diography (S), including methylthio, ethylthio, out-propylthio, n-butylthio, and stuff like that.

Deputy "C1-C4- alkylsulfonyl" means C1-C4is an alkyl group described above substituted by at least one-SO-group, for example, methylsulfinyl, ethylal the SUB>4is an alkyl group described above substituted by at least one sulfopropyl-SO2is, for example methylsulphonyl, ethylsulfonyl, isopropylphenyl, n-butylsulfonyl etc.

Deputy "C1-C4-mono or dialkylamino" means an amino group substituted by one or more C1- C4-alkyl groups described above, such as methylamino, ethylamino, n-butylamino, tert.-butylamino, N,N-dimethylamino, N,N-diethylamino, methyl-tert.-butylamino etc.

The substituent R or the substituents at the benzene ring may be present from the first stage of the process, for example, as substitutes for the original product I in the reaction scheme A, such as phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy, or can be entered later using conventional reactions, for example, such substituents as chlorine by chlorine, nitro-group by nitration, or by transformation of the original or input groups, such as the transformation of the nitro group to the amino group in the catalytic reduction, followed by alkylation of the amino group to the mono - or dialkylamino. The amino group may be subjected to diazotization with obtaining a hydroxy-group, which can then be promyelocytes method described in J. Org. Chem. 31, pp 3980 - 3984 (1966) Newman and Carnes, and J. Org. Chem. 31, pp 410 (1966) Quota and Evans. The resulting thiols can be preaccelerated to alkylthiophene, which can be, in turn, oxidized to the corresponding sulfoxidov and sulfones. Preferred substituents are a hydrogen atom, a C1-C4-alkyl, C1-C4-alkoxy and phenyl. Such reactions and their sequences are common in this area and for anyone qualified in the field specialist will be obvious how to carry out change of the benzene ring to make it the substituents described above.

Under the name of "their pharmaceutically acceptable salts and esters" understand salts and esters obtained according to the acid group of the final product, which can be used as a medicinal system for a person and which include: salts of sodium, potassium, calcium, ammonium, salts, substituted ammonium, Quaternary ammonium salts, and esters - ethyl ester, aceturate, besylate, acetate, phenpropionate, acetates, pamoate and esters, which act as proletarienne drugs, which are hydrolyzed in the body under the action of the physiological environment OBR is one connection.

The residue (CH)yR', where y = 1 to 6, preferably 3, may contain at least one substituent R' defined above, and may represent, for example, -CH2-; -CH2-CH2-; -CH2-CH2-CH2-;

< / BR>
< / BR>
and similar substituents.

The Deputy (CH)yR' may also be present Allenova communication, for example, in the case of such substituents as-CH2-CH=CH-; -CH2-CH=CH-CH2-; -CH2-CH=CH-(CH2)2and similar substituents.

The residue (CH)zR", where z = 6 to 20, preferably 10 to 16, may contain at least one substituent R" defined above, and may represent, for example, -(CH2)6-; -(CH2)20-;

< / BR>
< / BR>
and similar substituents.

The Deputy (CH)zR" may also be present Allenova communication, for example, in the case of such substituents as-CH2-CH=CH-(CH2)8-; -(CH2)8-CH= CH-(CH2)2-; -(CH2)9-CH= CH-(CH2)9-; -(CH2)4-CH= CH-(CH2)4and similar substituents.

The substituents R' and R" may also represent a group-NHCOCH3that can be easily hydrolyzed to amino groups by means of which oxoprop, obtained, for example, adding HBr to an alkene, followed by conversion of the alcohol oxidation to the ketone.

Preferably, if one of the substituents R' or R" is H, and especially preferably, when both Deputy (CH)yR' and (CH)zR" are alkilani.

Preferred compounds of the invention represented by the following formula

< / BR>
where one of the substituents X is an oxygen atom;

the substituents R, R' and R", y, or z take the values defined above. Particularly preferably the compound of the formula

< / BR>
where the Deputy X represents an oxygen atom or sulfur, a takes values from 10 to 16.

Compounds of the invention can be obtained according to the method described in scheme A-1 (see the end of the description).

As is evident from figure A-1, compound I is the initial product of the method of the invention and represents a 1,2-substituted benzene. Deputy X can represent O or S, and "PG" represents a hydroxy - or thosewithout group, which erectiondosan in process stage (A), but in the future may be removed, for example using palladium on coal with ethanol in an atmosphere of hydrogen.

"PG"protection is ESE", N. W. Green, 1981-Jonn Wiley. - Chapter 2, "Protection of hydroxyl groups, 1,2-and 1,3-diols", page 16 of 87, and Chapter 6, "Protecting Tilney group", pages 193 - 218).

Typical examples of "PG"-groups are benzyl, p-methoxybenzyl, p-halogenmethyl, including p-Chlorobenzyl, p-tormentil, etc. with the Possibility of using other protective groups for stage (A) should also be obvious to anyone skilled in this field specialist.

Examples of compounds which can be used in the present invention include, but are not limited to, the following compounds: 2-(benzyloxy)phenol, 2-benzyloxy-thiophenol, 2-(benzylthio)phenol, 3-methoxy-2-benzyloxyphenol, 2-benzyloxy-4-methoxyphenol, 3-methyl-2-benzyloxyphenol, 2-benzyloxy-5-methoxyphenol, 2-benzyloxy-4-methoxyphenol, 2-benzyloxy-5-methoxyphenol, 2-benzyloxy-3,5-diisopropylphenol, 2-benzyloxy-3,5-di-tert. -butylphenol, 2-benzyloxy-4-tert.-the butylphenol, 2-benzyloxy-3-ethylphenol, 2-benzyloxy-5-phenylphenol, 2-benzyloxy-4-methyl-1-thiophenol, 2-benzyloxy-5-trifluoromethyl-1-thiophenol, 2-benzyloxy-6-methoxy-1-thiophenol, 2-benzylthio-4-methyl-1-thiophenol, 2-benzylthio-5-methylsulphonyl-phenol, and the like compounds

Examples of compounds II, which can be COI who is halogen, including bromine, chlorine, or sulfonate and similar groups, Rais a linear or branched C1-C4is an alkyl part of the ether, for example methyl, ethyl, isopropyl, tert.-butyl, sec-butyl, etc. and the substituents R1and Y take the values defined above, include, but are not limited to, the following connections: Br-CH2-COOMe, Cl-CH2CH2CH2COOCH2CH3, Br-CH2CH2CH2CH2COOMe, Br-CH2CH2CH2CH2CH2COOEt, Br-CH2CH2CH2CH2CH2CH2COOCH2CH2CH2OH3,

Br-(CH2)2CH2(CH3)COOMe, Br-CH2CH(CH3)CH2COOEt, Br-CH2CH2CH2COOMe,

Br-CH2CH(OCH3)CH3COOCH(CH3)2Cl-CH2CH(OCH2CH3)CH2COOMe, Br-CH2CH(F)CH2COOMe, Cl-CH2CH2COOEt and similar compounds.

At the stage of (A) condensation of the compounds I and II with the formation of compound III is carried out in a non-hydroxyl polar organic solvent, such as acetone, ethyl acetate, methylethylketone, dioxane, THF, diethylketone and similar solvents, in the presence of a proton acceptor, for example carboplatin or stand for a long time at room temperature. Treat the reaction mass in the usual way.

At the stage (B) the protective group "PG" off-catalytically at room temperature at high pressure in an atmosphere of hydrogen in an organic solvent, to obtain compound IV, which represents phenyl or thiophenol. As catalyst using 5% palladium on coal and other similar catalysts. The organic solvent should be inert under the reaction conditions and examples of such solvents are ethyl acetate, ethanol, methanol, dioxane, etc.

At the stage (C) the interaction of compound IV to compound V with obtaining diapir VI. Reaction conditions similar to the conditions described for stage (A), using an inert organic solvent and proton acceptor.

Examples of compounds V, used in the invention are the following compounds: Br(CH2)6COOMe, Br(CH2)7COOMe, Br(CH2)8COOMe, Br(CH2)9COOMe,

Br(CH2)10COOMe, Br(CH2)11COOMe, Cl(CH2)12COOEt, Cl(CH2)13COOCH(CH3)2,

Cl(CH2)14COOCHCH2CH3, Br(CH2)15COOMe, Br(CH2)16COOMe, Br(CH2)16COOCH2CH20COOMe,

Br(CH2)2CH(CH3)-(CH2)10COOMe, BrCH2CH(CH3)-(CH2)10COOMe, BrCH2CH3CH(CH3)CH2COOEt, BrCH2CH(OCH3)(CH2)7COOCH(CH3)2, ClCH2CH(OCH2CH3)CH2CH2COOMe, BrCH2(NHCOCH3)-(CH2)10-CH2COOMe,

ClCH2C(=O)(CH2)11COOEt, Br-CH2-CH=CH-(CH2)8COOEt, BrCH2-C(= CH2)(CH2)10CH2COOMe, Br-CH2-(CH2)9-CH=CH-COOEt.

At stage (D) fluids can be deesterification by basic hydrolysis in aqueous medium, for example, using NaOH in MeOH/H2O selection after acidification of decollate.

Scheme B1 is given at the end of the description.

As is evident from figure B1, 2-benzyloxyphenol 1, ethyl-bromobutyrate 2 and anhydrous K2CO3for example, in dry acetone, boiled, or stand at room temperature for a long period of time in a nitrogen atmosphere, thus obtaining the ethyl-4-(2-benzyloxyphenyl)butyrate 3, stage (A).

A solution of compound 3, for example, ethyl acetate is subjected to catalytic hydrogenation at room temperature in hydrogen atmosphere under a pressure of 40 pounds per square inch in the presence of cutest interaction of compounds 4 and methyl-12-bromododecane 5 with potassium carbonate in acetone, similarly, stage (A), with nanometrology ether 6.

At stage (a) W 6 undergoes deesterification, for example, using NaOH in water-methanol solution, with formation after acidification of the final product - decollate 7.

Stage C-1 presents a synthesis of Sultanova compound 7, compound 7A. The method involves basically the same stages, which are described in stage B.

Diagram C-1 is given at the end of the description.

Certain replacement compounds II and 2 other substituted and unsubstituted halogenoalkane esters, which are known and which are described in this paper, and some replacement compounds V and 5 other available and described above bromopyrene will be accompanied by a receipt of all compounds that fall under the scope of the claims.

Examples of compounds obtained in accordance with this method are:

4-(2-(20-carboxymethoxy)phenoxy)butane acid,

4-(2-(19-carboxyaniline)phenoxy)butane acid,

4-(2-(18-carboxymethoxy)phenoxy)butane acid,

4-(2-(17-carboxypeptidase)phenoxy)butane acid,

4-(2-(16-carboxylesterase)phenoxy)butane acid is Ulanova acid,

4-(2-(13-carboxymethoxy)phenoxy)butane acid,

4-(2-(12-carboxymethoxy)phenoxy)butane acid,

4-(2-(11-carboxyphenoxy)phenoxy)butane acid,

4-(2-(10-carboxymethoxy)phenoxy)butane acid,

4-(2-(9-carboxyphenoxy)phenoxy)butane acid,

4-(2-(8-carboxymethoxy)phenoxy)butane acid,

4-(2-(7-carboxypeptidase)phenoxy)butane acid,

4-(2-(6-carboxymethoxy)phenoxy)butane acid,

4-(2-(20-carboxymethoxy)phenylthio)butane acid,

4-(2-(19-carboxyaniline)phenylthio)butane acid,

4-(2-(18-carboxymethoxy)phenylthio)butane acid,

4-(2-(17-carboxypeptidase)phenylthio)butane acid,

4-(2-(16-carboxylesterase)phenylthio)butane acid,

4-(2-(15-carboxypenicillins)phenylthio)butane acid,

4-(2-(14-carboxytetramethyl)phenylthio)butane acid,

4-(2-(13-carboxymethoxy)phenylthio)butane acid,

4-(2-(12-carboxymethoxy)phenylthio)butane acid,

4-(2-(11-carboxyphenoxy)phenylthio)butane acid,

4-(2-(10-carboxymethoxy)phenylthio)butane acid,

4-(2-(9-carboxyphenoxy)phenylthio)butane sour the I acid,

4-(2-(6-carboxymethoxy)phenylthio)butane acid,

4-(2-(20-carboxymethy)phenoxy)butane acid,

4-(2-(19-carboxymethylthio)phenoxy)butane acid,

4-(2-(18-carboxymethylthio)phenoxy)butane acid,

4-(2-(17-carboxymethylthio)phenoxy)butane acid,

4-(2-(16-carboxymethylthio)phenoxy)butane acid,

4-(2-(15-carboxymethylthio)phenoxy)butane acid,

4-(2-(14-carboxytetramethyl)phenoxy)butane acid,

4-(2-(13-carboxaldehyde)phenoxy)butane acid,

4-(2-(12-carboxymethylthio)phenoxy)butane acid,

4-(2-(11-carboxymethylthio)phenoxy)butane acid,

4-(2-(10-carboxymethylthio)phenoxy)butane acid,

4-(2-(9-carboxyaniline)phenoxy)butane acid,

4-(2-(8-carboxymethylthio)phenoxy)butane acid,

4-(2-(7-carboxymethylthio)phenoxy)butane acid,

4-(2-(6-carboxymethylthio)phenoxy)butane acid,

4-(2-(20-carboxymethy)phenylthio)butane acid,

4-(2-(19-carboxymethylthio)phenylthio)butane acid,

4-(2-(18-carboxymethylthio)phenylthio)butane acid,

4-(2-(17-carboxymethylthio)phenylthio)butane acid,

4-(2-(16-Carbo is R>
4-(2-(14-carboxytetramethyl)phenylthio)butane acid,

4-(2-(13-carboxaldehyde)phenylthio)butane acid,

4-(2-(12-carboxymethylthio)phenylthio)butane acid,

4-(2-(11-carboxymethylthio)phenylthio)butane acid,

4-(2-(10-carboxymethylthio)phenylthio)butane acid,

4-(2-(9-carboxyaniline)phenylthio)butane acid,

4-(2-(8-carboxymethylthio)phenylthio)butane acid,

4-(2-(7-carboxymethylthio)phenylthio)butane acid,

4-(2-(6-carboxymethylthio)phenylthio)butane acid,

3-(2-(16-carboxylesterase)phenoxy)propionic acid,

3-(2-(15-carboxymethylcellulose)phenoxy)butane acid,

3-(2-(14-carboxytetramethyl)phenoxy)butane acid,

5-(2-(13-carboxymethoxy)phenoxy)valeric acid,

5-(2-(12-carboxymethoxy)phenoxy)valeric acid,

5-(2-(11-carboxyesterase)phenoxy)valeric acid,

4-(2-(11-carboxyphenoxy)phenoxy)valeric acid,

4-(2-(10-carboxymethoxy)phenoxy)valeric acid,

4-(2-(9-carboxyphenoxy)phenoxy)valeric acid,

6-(2-(9-carboxyphenoxy)phenoxy)hexanoic acid,

6-(2-(8-carboxymethoxy)phenoxy)Kapranov and)enanthic acid,

7-(2-(6-carboxymethoxy)phenoxy)enanthic acid,

7-(2-(5-carboxyethylidene)phenoxy)enanthic acid,

2-(2-(12-carboxymethylthio)phenoxy)acetic acid,

2-(2-(11-carboxymethylthio)phenoxy)acetic acid,

2-(2-(10-carboxymethylthio)phenoxy)acetic acid,

3-(2-(9-carboxyphenoxy)phenylthio)propionic acid,

3-(2-(12-carboxymethoxy)phenylthio)propionic acid,

3-(2-(11-carboxyphenoxy)phenylthio)propionic acid,

3-(2-(11-carboxyphenoxy)phenylthio)butane acid,

3-(2-(11-carboxymethylthio)-4-methyl-phenylthio)butane acid,

3-(2-(12-carboxymethylthio)phenylthio)butane acid,

5-(2-(11-carboxymethylthio)phenylthio)valeric acid,

5-(2-(10-carboxymethoxy)phenylthio)valeric acid,

5-(2-(9-carboxyphenoxy)phenylthio)valeric acid,

3-(2-(9-carboxyphenoxy)phenylthio)valeric acid,

3-(2-(11-carboxymethoxy)phenylthio)valeric acid,

3-(2-(10-carboxymethoxy)phenylthio)valeric acid,

6-(2-(9-carboxyphenoxy)phenylthio)hexanoic acid,

6-(2-(12-carboxymethoxy)phenylthio)hexanoic acid,

6-(2-(11-carboxyphenoxy)phenylthio)nylon-methylphenylthio)enanthic acid,

7-(2-(12-carboxymethylthio)phenoxy)enanthic acid,

4-(2-(11-carboxyphenoxy)-4-methylphenoxy)butane acid,

4-(2-(10-carboxymethoxy)-3-methylphenoxy)butane acid,

4-(2-(9-carboxyphenoxy)-5-methylphenoxy)butane acid,

4-(2-(12-carboxymethoxy)-6-methylphenoxy)butane acid,

4-(2-(11-carboxymethylthio)-3-(methylthio)phenoxy)butane acid,

4-(2-(11-carboxymethylthio)-3-(methylsulphonyl)phenoxy)butane acid,

4-(2-(11-carboxymethylthio)-4-(methylsulphonyl)phenoxy)butane acid,

4-(2-(12-carboxymethoxy)-5-ethylenoxy)butane acid,

4-(2-(11-carboxyphenoxy)-4-phenyleneoxy)butane acid,

4-(2-(10-carboxymethoxy)-3,5-dimethylphenoxy)butane acid,

4-(2-(9-carboxyphenoxy)-4-pertenece)butane acid,

4-(2-(12-carboxymethoxy)-5-triptoreline)butane acid,

4-(2-(12-carboxymethylthio)-3-nitrophenoxy)butane acid,

4-(2-(11-carboxymethylthio)-4-methylphenoxy)valeric acid,

4-(2-(11-carboxymethylthio)-3,5-dimethylphenoxy)butane acid,

4-(2-(12-carboxymethoxy)-4-(dimethylamino)phenoxy)butane acid,

4-(2-(11-carboxyphenoxy)-5-(ethylamino)siloxy)phenoxy)-3-methylpropionate acid,

4-(2-(10-carboxymethoxy)phenylthio)-3-methoxybutanol acid,

4-(2-(9-carboxyaniline)phenylthio)-3-etxebarria acid,

4-(2-(11-carboxyphenoxy)phenoxy)-2-butenova acid,

4-(2-(9-carboxyphenoxy)phenoxy)-2-butenova acid,

4-(2-(11-carboxy-2-methylundecane)phenoxy)butane acid,

4-(2-(11-carboxyphenyl-7-enocsi)phenoxy)butane acid,

4-(2-(13-carboxy-2-methylene-tridecylamine)phenoxy)butane acid,

4-(2-(11-carboxyphenoxy)phenylsulfonyl)butane acid,

4-(2-(11-carboxyphenoxy)phenylsulfonyl)butane acid,

4-(2-(11-carboxypenicillins)phenoxy)butane acid,

4-(2-(11-carboxyphenylsulfate)phenoxy)butane acid,

4-(2-(11-carboxypenicillins)phenylsulfonyl)butane acid,

4-(2-(11-carboxyphenylsulfate)phenylsulfonyl)butane acid,

and similar compounds.

Also in the invention as an inhibitor of 5-reductase feature is enabled for the treatment of symptomatic alopecia in combination with Minoxidil the following formula:

< / BR>
where A is a 1,2-substituted aromatic ring selected from among: (a) benzene, 1,2-substituted naphthalene; (b) a 5-6-clandestinely D and E independently of one another are-COOH, CONH2, CONHRb, COORb, SO2OH, SO3(OH), SO2NH2SSO2ONa, PH(O)(OH), P(O)(OH)2; Deputy X represents O, S, SO or SO2;

the substituent R represents H;

the substituent R represents a hydrogen atom, a C1-C4-alkyl, phenyl or substituted phenyl, halogen atom, hydroxy-group, carboxyl group, cyano, C1- C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylsulfanyl group, C1- C4-alkylsulfonyl group, a nitrogroup, an amino group, a C1-C4-mono - or di-alkylamino;

the substituents R' and R" independently from each other represent a hydrogen atom, a halogen atom, a C1-C4-alkyl or C1- C4-alkoxygroup, amino group, or oxoprop when fragments CH-R' or CHR" in the formula become a group-C=O;

Ra= H, C1-C4-alkyl;

Rb= C1-C12-alkyl, phenyl, phenyl C1-C4-alkyl;

y = 1 - 6;

z = 6 to 20, and

where fragments (CH)y-R' and (CH)z-R"can independently from each other represent substituted or unsubstituted alkyl radicals or alkeneamine radicals containing at least oldstable a inhibitors testosterone-5 - reductase enzyme of man.

Compounds falling under the scope of the invention represented by the above formulas.

Description of formulas used the following concepts:

Deputy X in the above General formula represents O or S, preferably an oxygen atom.

"C1-C4-alkyl" means a linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert. -butyl, and "C1-C12-alkyl" means alkyl group containing up to 12 carbon atoms, for example n-octyl, tert.-decyl, n-dodecyl.

"Phenyl C1-C4-alkyl" means benzyl, 2-phenethyl and the like substituents.

"C1-C4-alkoxygroup" means a linear or branched alkoxygroup, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy.

By "halogen" refers to fluorine atom, chlorine, bromine or iodine.

The term "heteroaromatic ring" means a 5 - to 6-membered ring containing 1 to 2 nitrogen atom, 1 sulfur atom or oxygen, or a combination thereof, for example pyridine, thiophene, furan, imidazole, 1,3-thiazole, 1,3-oxazole, 1,2,3-thiadiazole, and other Limitation is that aciklama are pyridine, furan and thiophene.

"Substituted phenyl" means phenyl, substituted by one or more C1-C4-alkilani, C1- C4-alkoxygroup, halogen atoms, etc. as defined above; examples of such substituents are o, m and p-methoxyphenyl, 2,4-acid, 2-chloro-4-ethoxyphenyl, 3,5-acid, 2,4-dichlorophenyl, 2-bromo-4-were, on forfinal etc.

The concept of "halogenated" alkyl includes C1- C4is an alkyl group described above substituted by one or more atoms of halogen as defined above, for example - triptorelin group, 2,2-dichloroethylene etc.

Deputy "C1-C4-alkylthio" means C1-C4-alkyl described above, substituted by at least one divalent diography (S), including methylthio, ethylthio, isopropylthio, n-butylthio, and stuff like that.

Deputy "C1-C4- -alkylsulfonyl" means C1-C4is an alkyl group described above substituted by at least one group, such as methylsulfinyl, ethylsulfinyl, isopropylphenyl etc.

Deputy "C1-C4-alkylsulfonyl" means C1-C4is an alkyl group described above, C is sulfonyl, n-butylsulfonyl etc.

Deputy "C1-C4-mono or dialkylamino" means an amino group substituted by one or more C1- C4-alkyl groups described above, such as methylamino, ethylamino, n-butylamino, tert.-butylamino, N,N-dimethylamino, N,N-diethylamino, methyl-tert.-butylamino etc.

The substituent R or the substituents at the benzene ring may be present from the first stage of the process, such as, phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy (for example, as in the case of o-NITROPHENOL, 1-source product in scheme A), or can be entered later using the normal reactions, such as chlorine substituents by chlorination, the nitro-group by nitration, or by transformation of the original or input group, for example, the transformation of the nitro group to the amino group in the catalytic reduction, followed by alkylation of the amino group to the mono - or dialkylamino. The amino group may be subjected to diazotization with obtaining a hydroxy-group, which can then be prometherion to metoxygroup. Similarly, the hydroxy-group can be converted into Tilney group according to the method similar to the method described in J. Org. Chem is Yerevani to alkylthiophene, which can be, in turn, oxidized to the corresponding sulfoxidov and sulfones. Preferred substituents are a hydrogen atom, a C1-C4-alkyl, C1-C4-alkoxy and phenyl. Such reactions and their sequences are common in this area and for anyone qualified in the field specialist will be obvious how to carry out change of the benzene ring to make it the substituents described above.

Under the name of "their pharmaceutically acceptable salts and esters" understand salts and esters obtained according to the acid group of the final product, which can be used as a medicinal system for a person and which include: salts of sodium, potassium, calcium, ammonium, salts, substituted ammonium, Quaternary ammonium salts, and esters - ethyl ester, aceturate, besylate, edetate, phenpropionate, acetates, pamoate and esters, which act as proletarienne drugs, which are hydrolyzed in the body under the action of the physiological medium with the formation of the original acid, such as pivaloate, that is, pivoxil and pivoxil, as well as esters of Kanebo and similar compounds.

The residue (CH)yR', devise, and may constitute, for example-CH2-; -CH2-CH2-; -CH2-CH2-CH2-;

< / BR>
< / BR>
< / BR>
< / BR>
and similar substituents.

The Deputy (CH)yR' may also be present Allenova communication, for example, in the case of such substituents as-CH2-CH=CH-; -CH2-CH=CH-CH2-; -CH2-CH2-CH=CH; -(CH2)3-CH=CH - and the like substituents.

The residue (CH)zR", where z takes the values 6 to 20, preferably 10 to 16, may contain at least one substituent R" defined above, and may represent, for example, -(CH2)6-; -(CH2)20-;

< / BR>
< / BR>
< / BR>
and similar substituents.

The Deputy (CH)zR" may also be present Allenova communication, for example, in the case of such substituents as-CH2-CH=CH-(CH2)8-; -(CH2)8-CH= CH-(CH2)2-; -(CH2)9-CH= CH-(CH2)9-; -(CH2)4-CH= CH-(CH2)4and similar substituents.

Preferably, if one of the substituents R' or R" is H, and especially preferably, when both Deputy (CH)yR' and (CH)zR" are alkilani.

Preferred BR>
< / BR>
Especially preferred are the following compounds

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where the Deputy X represents an oxygen atom or sulfur;

the substituents R, R', R", and y and z take values defined above.

The preferred compounds of this class are

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where X represents O or S;

n = 8 - 14.

Also preferred compounds of this class are

< / BR>
where n = 8 to 14.

< / BR>
where n = 8 to 14.

Compounds of the invention can be obtained in accordance with schemes of reactions A-2, B-2, C-2, D-2, E-2, F-2, G-2, H-2 presented at the end of the description.

As is evident from figure A-2, o-NITROPHENOL, 1,4-bromobutyrate 2 and anhydrous K2CO3for example, in dry acetone, boiled, or stand at room temperature for a long period of time in a nitrogen atmosphere, while receiving 4-(2-nitrophenoxy)butyrate 3 (stage A).

A solution of compound 3, for example, ethyl acetate is subjected to catalytic hydrogenation at room temperature in hydrogen atmosphere under a pressure of 40 pounds per square inch in the presence as catalyst of a 5% Pd/C, receive a 4-(2-aminophenoxy) butyrate 4.

At stage (D) onomatology ether acid 6 boiled with thionyl chloride for 5 hours and get monochloride nanometrology ether 7.

At stage (E) monochloride 7 reacts with amine 4, for example, at 0 to 10oC, for example, in dry ether in the presence of an acceptor of hydrogen chloride, for example in the presence of triethylamine, with the formation of amide 8.

At stage (F) apyramid 8 deesterification, for example, using a 2.5 N. water-methanolic solution of NaOH with the release after acidification of the final product - decollate 9.

Scheme B-2 illustrates the synthesis of the corresponding tizaidine.

Stage (G) represents the reaction of o-aminobenzoyl with ethyl-4-bromobutyrate, which can be carried out, for example, in a dry dimethoxyethane, in nitrogen atmosphere, in the presence of a proton acceptor, for example, powder K2CO3will get a connection 11.

Stage (H) is the acylation of the amino group of compound (11) with 11-bradikinin in a dry solvent, for example, in dry ether at 0oC in the presence of acceptor oxygen, for example in the presence of pyridine.

Stage (I) is the hydrolysis of diapir to the final acid 13, which can b is s, similar to the conditions of stage (A).

At stage (K) is represented by the restoration of the nitro group with, for example, Raney-Nickel in a mixture of ethanol/NH3in an atmosphere of hydrogen under a pressure of 40 pounds per square inch.

Stage (L) represents triptoreline connection 24 using, for example, triperoxonane anhydride in dry ether in the presence of dry powder of sodium carbonate.

At stage (M) shows the N-methylation, which can be carried out using, for example, under the conditions in dry acetone in the presence of powdered KOH and subsequent removal of the N-trifluoracetyl group using MeOH/H2O.

At stage (N) shows the N-acylation of compound 27 using acylchlorides, for example, compound 7 in dry methylene chloride and pyridine at 0oC.

Phase (O) is dibenzylamine connection 28, which may be conducted, for example, using 10% Pd/C in methanol in an atmosphere of hydrogen.

Phase (P) represents the O-alkylation of compound 29 using, for example, ethyl 4-bromobutyrate and K2CO3in anhydrous acetone.

Phase (Q) represents the hydrolysis of diapir 30's, acids and esters.

Stage (R) is a condensation of compound 4 with 11-bromoundecanoic acid in anhydrous methylene chloride using N,N-dicyclohexylcarbodiimide and 4-dimethylaminopyridine with obtaining important bromo-intermediate 32.

At the stage (S) shows the reaction of the compound 32 with triethylphosphite, for example, if 180oC in nitrogen atmosphere to obtain phosphonate ester 33.

Stage (T) represents the transformation of the connection 33 through bromotrimethylsilane in monocellate 34.

Stage (U) represents the hydrolysis similar to the hydrolysis stage (F), resulting in a gain of phosphoric-carboxylic decollato 35,

Scheme E-2 illustrates the synthesis of sulfonic acids of the present invention.

At the stage (Y) is shown the reaction of intermediate 32 with thiourea in EtOH/H2O in nitrogen atmosphere at 90oC with the formation of isothiuronium salt 36.

On stage (W) shows the reaction of the compound 32 with sodium thiosulfate in conditions similar to the conditions of stage (Y), with the formation of thiosulfate ester 37.

Further oxidation of ethers 36 and 37 according to the method Sovella or Ziegler described in stage (W) in the examples, leads to the corresponding sulfonic acid 38.

Matched with the om, JACS 59, 2440 (1937).

The corresponding sulfonamides can be obtained from the sulfonic acid 38 by protecting, for example, carboxylic acid ester group, conversion of sulfonic acid to sulphonylchloride, processing sulphonylchloride ammonia followed by hydrolysis of the ether carboxylic acid to the corresponding acid.

Diagram F-2 represents the synthesis of the corresponding pyridine analogues 8 and 9.

At the stage of (X) nitrogenoxides O-alkylate in conditions similar to the conditions of stage (A) to the junction 40.

At the stage (Y) shows the restoration of the nitro group in the same way described for Stage (B).

On stage (Z) shows the acylation of the amino group by the same method described for compound 8 in stage (E) obtaining diapir 42. When the hydrolysis get decollato 43.

In the diagram G-2 shows the receipt of some amides 46 of the present invention.

On stage (AA) o-aminophenol reacts directly with compound 7 in the conditions described in stage (E) to give the N-acylated phenol 44.

On stage (BB) carry out the alkylation of compound 44 using 4-bromobutyronitrile in similar terms of the stud is using MnO2.

Scheme H-2 illustrates an alternative method of obtaining the compound (9) using as starting compound o-aminophenol, which alkylate to connection 44 with the subsequent interaction of compound 44 in the conditions of Stage (A) to give compounds 8 and hydrolysis to compound (9) in conditions similar to the conditions of Stage (F).

Thus, according to the methods described above in schemes using the above reagents and starting materials, the following compounds included in the formula of the invention can be synthesized by any qualified specialist.

It is obvious that in scheme A-2 and C-2 can be used other NITROPHENOL, in order to get all of the compounds of the present invention, and among these compounds include: 2-NITROPHENOL, 2-nitro-6-METHYLPHENOL, 2-nitro-5-METHYLPHENOL, 2-nitro-4-METHYLPHENOL, 2-nitro-3-METHYLPHENOL, 2-nitro-4-phenylphenol, 2-nitro-5-phenylphenol, 2-nitro-4-terfenol, 2-nitro-4-triptoreline, 2-nitro-4-hydroxyphenol, 2-nitro-4-methoxyphenol, 2-nitro-6-ethoxyphenol, 2-nitro-4-methylthiophenol, 2-nitro-4-methylsulfinylphenyl, 2-nitro-4-methylsulfinylphenyl, 4-nitro-3-hydroxypyridine, 3-nitro-4-hydroxy-5-methylpyridine, 3-nitro-4-hydroxy-6 is in 2-hydroxy-3-nitro-5-chloropyridine, 2-nitro-3-hydroxy-5-triptorelin, 2-methoxy-4-nitro-5-hydroxypyridine, 3-nitro-4-hydroxy-5-ethoxypyridine, 2-methylthio-4-nitro-5-hydroxypyridine, 2-nitro-3-hydroxy-thiophene, 3-nitro-4-hydroxy-thiophene, 3-hydroxy-2-nitro-5-methylthiophene, 3-hydroxy-2-nitro-4-methylthiophene, 2-hydroxy-3-nitro-5-phenylthiophene, 2-nitro-3-hydroxy-4-phenylthiophene, 2-hydroxy-3-nitro-4-chlorothiophene, 2-hydroxy-3-nitro-4-fortifed and similar compounds.

It is obvious that, with appropriate connection replacement 2 other known halogenoalkane esters and the corresponding connection replacement 6 other available diesters, you will receive all ester-amide derivatives falling under the scope of the claims.

Examples of compounds 2, which can be used in the method of the present invention, include, but are not limited to, the following compounds: Br-CH2-COOMe, Cl-CH2CH2CH2COOCH(CH3)3, Br-CH2CH2CH2CH2COOMe, Br-CH2CH2CH2CH2CH2COOEt, Br-CH2CH2CH2CH2CH2CH2COOCH2CH2CH2CH3,

Br-CH2CH(CH3)-COOMe, Br-CH2CH(CH3)CH2COOEt, Br-CHSUB>2COOMe, Br-CH2CH(F)CH2COOMe. Examples of other compounds which can be used in the method of the present invention as compounds are the following compounds: HOOC(CH2)6COOMe, HOOC(CH2)7COOMe, HOOC(CH2)8COOMe, HOOC(CH2)9COOMe, HOOC(CH2)10COOMe, HOOC(CH2)11COOMe, HOOC(CH2)12COOEt, HOOC(CH2)13COOCH(CH3)2,

HOOC(CH2)14COOCH2CH2CH3, HOOC(CH2)15COO(CH2)3CH3, HOOC(CH2)16COOCH3,

HOOC(CH2)17COOCH3, HOOC(CH2)18COOMe, HOOC(CH2)19COOEt, HOOC(CH2)20COOPh,

HOOC(CH2)10COOPh, HOOCCH2CH3CH(CH3)(CH2)10COOMe, HOOCCH2CH3CH(CH)CH2COOEt,

HOOCCH2CH2CH(Cl)CH2COOEt, HOOCCH2CH(OCH3)(CH2)7COOCH(CH3)2where Ph = phenyl, and similar compounds.

Examples of compounds of the present invention, which is obtained in accordance with this method, described in the following list.

For acid radicals use the following nomenclature:

P(O)(OH)2- phosphono;

-COOH - carboxy;

-CONH2- aminocarbonyl;
4-(2-(20-carboxymethylamino)phenoxy)butane acid;

4-(2-(19-carboxymethylamino)phenoxy)butane acid;

4-(2-(18-carboxymethylamino)phenoxy)butane acid;

4-(2-(17-carboxymethylamino)phenoxy)butane acid;

4-(2-(16-carboxylesterase-N-methylamino)phenoxy)butane acid;

4-(2-(15-carboxymethylamino)phenoxy)butane acid;

4-(2-(14-carboxymethylamino)phenoxy)butane acid;

4-(2-(13-carboxyrhodamine)phenoxy)butane acid;

4-(2-(12-carboxymethylamino)phenoxy)butane acid;

4-(2-(11-carboxymethylamino)phenoxy)butane acid;

4-(2-(10-carboxymethylamino)phenoxy)butane acid;

4-(2-(9-carboxyaniline)phenoxy)butane acid;

4-(2-(8-carboxymethylamino)phenoxy)butane acid;

4-(2-(7-carboxymethylamino)phenoxy)butane acid;

4-(2-(6-carboxymethylamino)phenoxy)butane acid;

4-(2-(20-carboxymethylamino)phenylthio)butane acid;

4-(2-(19-carboxymethylamino)phenylthio)butane acid;

4-(2-(18-carboxymethylamino)phenylthio)butane acid;

4-(2-(17-carboxypropanoyl->/BR>4-(2-(15-carboxymethylamino)phenylthio)butane acid;

4-(2-(14-carboxymethylamino)phenylthio)butane acid;

4-(2-(13-carboxyrhodamine)phenylthio)butane acid;

4-(2-(12-carboxymethylamino)phenylthio)butane acid;

4-(2-(11-carboxymethylamino)phenylthio)butane acid;

4-(2-(10-carboxymethylamino)phenylthio)butane acid;

4-(2-(9-carboxyaniline)phenylthio)butane acid;

4-(2-(8-carboxymethylamino)phenylthio)butane acid;

4-(2-(7-carboxymethylamino)phenylthio)butane acid;

4-(2-(6-carboxymethylamino)phenylthio)butane acid;

3-(2-(16-carboxymethylamino)phenoxy)propionic acid;

4-(2-(15-carboxymethylamino)phenoxy)butane acid;

4-(2-(14-carboxymethylamino)phenoxy)butane acid;

5-(2-(13-carboxyrhodamine)phenoxy)valeric acid;

5-(2-(12-carboxymethylamino)phenoxy)valeric acid;

5-(2-(11-carboxymethylamino)phenoxy)valeric acid;

5-(2-(11-carboxymethylamino)phenoxy)valeric acid;

5-(2-(10-carboxymethylamino)phenoxy)valeric acid;

5-(2-(9-ka the PTA;

6-(2-(8-carboxymethylamino)phenoxy)hexanoic acid;

6-(2-(7-carboxymethylamino)phenoxy)hexanoic acid;

7-(2-(7-carboxymethylamino)phenoxy)enanthic acid;

7-(2-(6-carboxymethylamino)phenoxy)enanthic acid;

7-(2-(5-carboxymethylamino)phenoxy)enanthic acid;

2-(2-(12-carboxymethylamino)phenoxy)acetic acid;

2-(2-(11-carboxymethylamino)phenoxy)acetic acid;

2-(2-(10-carboxymethylamino)phenoxy)acetic acid;

3-(2-(9-carboxyaniline)phenoxy)propionic acid;

3-(2-(12-carboxymethylamino)phenylthio)propionic acid;

3-(2-(11-carboxymethylamino)phenylthio)propionic acid;

3-(2-(11-carboxymethylamino)phenylthio)isobutane acid;

5-(2-(11-carboxymethylamino)phenylthio)valeric acid;

5-(2-(10-carboxymethylamino)phenylthio)valeric acid;

5-(2-(9-carboxyaniline)phenylthio)valeric acid;

4-(2-(12-carboxymethylamino)phenylthio)isovalerianic acid;

4-(2-(11-carboxymethylamino)phenylthio)isovalerianic acid;

4-(2-(10-carboxyaniline)phenylthio)hexanoic acid;

4-(2-(12-carboxyrhodamine the BR>
7-(2-(11-carboxymethylamino)-4-methylphenylthio)enanthic acid;

7-(2-(12-carboxymethylamino)phenoxy)enanthic acid;

4-(2-(11-carboxymethylamino)-4-methylphenoxy)butane acid;

4-(2-(10-carboxymethylamino)phenoxy)-3-methylbutanoate acid;

4-(2-(9-carboxymethylamino)-5-methylphenoxy)butane acid;

4-(2-(12-carboxymethylamino)-6-methylphenoxy)butane acid;

4-(2-(11-carboxymethylamino)-3-chlorophenoxy)butane acid;

4-(2-(10-carboxymethylamino)-4-methylphenoxy)butane acid;

4-(2-(9-carboxymethylamino)-5-forfinally)butane acid;

4-(2-(12-carboxymethylamino)-6-methylphenoxy)butane acid;

5-(2-(11-carboxymethylamino)-3-methylthiophene)valeric acid;

4-(2-(11-carboxymethylamino)-3-methylsulfinylphenyl) butane acid;

4-(2-(11-carboxymethylamino)-4-methylsulfinylphenyl) butane acid;

4-(2-(12-carboxymethylamino)-5-ethylenoxy)butane acid;

4-(2-(11-carboxymethylamino)-4-phenyleneoxy)butane acid;

4-(2-(10-carboxymethylamino)-3,5-dimethylphenoxy)butane acid;

4-(2-(9-carboxymethylamino)-4-pertenece)butane, decanoylamino)-5-hydroxyphenyl)butane acid;

4-(2-(10-carboxymethylamino)-4-hydroxyphenyl)butane acid;

4-(2-(9-carboxymethylamino)-3,5-dimethoxyphenylthio)butane acid;

4-(2-(12-carboxymethylamino)-5-nitrophenoxy)butane acid;

5-(2-(11-carboxymethylamino)-4-nitrophenoxy)valeric acid;

4-(2-(11-carboxymethylamino)-5-aminophenoxy)butane acid;

4-(2-(11-carboxymethylamino)-5-amino-4-methylphenylthio) butane acid;

4-(2-(12-carboxymethylamino)-5-triptoreline)butane acid;

4-(2-(11-carboxymethylamino)-5-hydroxyphenyl)butane acid;

4-(2-(12-carboxymethylamino)-4-dimethylaminoethoxy)butane acid;

4-(2-(11-carboxymethylamino)-5-ethyleneoxy)butane acid;

3-(2-(12-carboxymethylamino)phenoxy)-3-methylpropionate acid;

3-(2-(11-carboxymethylamino)phenylthio)-2-chloropropionic acid;

4-(2-(10-carboxymethylamino)phenylthio)-3-methoxybutanol acid;

4-(2-(9-carboxyaniline)phenylthio)-3-etxebarria acid;

4-(2-(12-carboxymethylamino)-4-methyl-3-pyridyloxy)butane acid;

4-(2-(11-carboxymethylamino)-4-methyl-3-pyridyloxy)butane acid;

4-(2-and 3-pyridyloxy)butane acid;

4-(2-(12-carboxymethylamino)-6-dimethylamino-3 - pyridyloxy)butane acid;

4-(2-(11-carboxymethylamino)-3-pyridylthio)butane acid;

4-(2-(10-carboxymethylamino)-6-methylsulphonyl-3 - pyridyloxy)butane acid;

4-(2-(9-carboxymethylamino)-5-chloro-3-pyridylthio)butane acid;

4-(2-(12-carboxymethylamino)-5-methylpyridinium)butane acid;

4-(2-(11-carboxymethylamino)-5-methylsulphonyl-3 - pyridylthio)butane acid;

4-(2-(11-carboxymethylamino)-6-methyl-3-pyridylthio)butane acid;

4-(2-(11-carboxymethylamino)-4,6-dimethyl-3 - pyridyloxy)butane acid;

4-(2-(12-carboxymethylamino)-5-methylthio-3 - pyridyl)butane acid;

4-(2-(11-carboxymethylamino)pyridyloxy)butane acid;

4-(2-(10-carboxymethylamino)-5-methoxy-3-pyridyloxy)butane acid;

4-(2-(9-carboxymethylamino)-4-fluoro-6-methyl-3 - pyridyloxy)butane acid;

4-(2-(12-carboxymethylamino)-5-methylamino-3 - pyridyloxy)butane acid;

4-(2-(11-carboxymethylamino)-4-phenyl-3-pyridylthio)butane acid;

4-(2-(10-carboxymethylamino)-5-methyl-3-pyridylthio)butane acid;

4-(2-(9-carboxymethylamino)-6-methoxy-3 the slot;

5-(2-(11-carboxymethylamino)-4-methyl-3-titilate)valeric acid;

4-(2-(11-carboxymethylamino)-4-methyl-3-tianity)butane acid;

4-(2-(12-carboxymethylamino)-5-methyl-3-tianity)butane acid;

4-(2-(11-carboxyamide)-4-methyl-3-tianity)butane acid;

4-(2-(10-carboxymethylamino)-5-methyl-3-tianity)butane acid;

4-(2-(9-carboxymethylamino)-4-hydroxy-3-titilate)butane acid;

4-(2-(12-carboxymethylamino)-4-methylthio-3-titilate)butane acid;

4-(2-(11-carboxymethylamino)-4-methylthio-3-titilate)butane acid;

4-(2-(10-carboxymethylamino)-4-methylsulphonyl-3-titilate)butane acid;

4-(2-(9-carboxymethylamino)-4-methylsulphonyl-3-titilate)butane acid;

4-(2-(12-carboxymethylamino)-5-trifluoromethyl-3-titilate)butane acid;

5-(2-(11-carboxymethylamino)-5-chloro-3-titilate)valeric acid;

4-(2-(11-carboxymethylamino)-4-methyl-5-phenyl - 3-titilate)butane acid;

4-(2-(11-carboxymethylamino)-5-dimethylamino - 3-titilate)butane acid;

4-(2-(11-carboxymethylamino)-3-titilate)butane acid;

4-(2-(20-phosphonothiolate)Fenox is decanoylamino)phenoxy)butane acid;

4-(2-(16-alvinocarididae-N-methylamino)phenoxy)butane acid;

4-(2-(15-disulfidediethylamine)phenoxy)butyramide sodium salt;

4-(2-(14-phosphotyrosine-N-methylamino)phenoxy)butane acid;

4-(2-(12-selfdetermining)phenoxy)butane acid;

4-(2-(11-sulfonanilide)phenoxy)butane acid;

4-(2-(10-sulfidecontaining)phenoxy)butane acid;

4-(2-(9-coalitionbuilding)phenoxy)butane acid sodium salt;

4-(2-(8-coalitionbuilding)phenoxy)butane acid sodium salt;

4-(2-(7-alvinocarididae)phenoxy)butane acid;

4-(2-(6-phosphonopentanoate)phenoxy)butane acid;

4-(2-(19-sulphonanilide)phenylthio)butane acid;

4-(2-(18-sulfonanilide)phenylthio)butane acid;

4-(2-(17-disulphophenyl-N-ethylamino)phenylthio)butane acid;

4-(2-(16-phosphomonoesterase)phenylthio)butane acid;

4-(2-(14-selfinteraction)phenylthio)butane acid;

4-(2-(12-disulfidediethylamine)phenylthio)butane acid sodium salt;

4-(2-(10-sulfidecontaining)phenylthio)butane acid;

4-(2-(9-R>
4-(2-(7-carboxymethylamino)phenylthio)butanedisulfonate;

4-(2-(20-carboxymethylamino)phenoxy)budantseva acid;

4-(2-(19-carboxymethylamino)phenoxy)butanesulfonate;

4-(2-(18-carboxyrhodamine-N-butylamino)phenoxy) butanesulfonate;

4-(2-(17-carboxymethylamino)phenoxy)budantseva acid;

4-(2-(15-carboxymethylamino)phenoxy)budantseva acid;

4-(2-(14-carboxymethylamino)phenoxy)butanesulfonate;

4-(2-(13-carboxyrhodamine)phenoxy)butanesulfonate;

4-(2-(12-carboxymethylamino)phenoxy)butanedisulfonate sodium salt;

4-(2-(10-carboxymethylamino)phenoxy)budantseva acid;

4-(2-(9-carboxyaniline)phenoxy)butanesulfonate;

4-(2-(8-carboxymethylamino)phenoxy)butanesulfonic acid;

4-(2-(7-carboxymethylamino)phenoxy)butanedisulfonate sodium salt;

4-(2-(20-carboxymethylamino)phenylthio)budantseva acid;

4-(2-(19-carboxyrhodamine-N-methylamino)phenylthio)butanesulfonate;

4-(2-(18-carboxymethylamino)phenylthio)butanesulfonate;

4-(2-(17-carboxymethylamino)phenylthio)butanal the-carboxytetramethyl-N-propylamino)phenylthio)budantseva acid;

4-(2-(13-carboxyrhodamine)phenylthio)butanesulfonate;

4-(2-(12-carboxymethylamino)phenylthio)butanesulfonate;

4-(2-(11-carboxymethylamino)phenylthio)butanedisulfonate sodium salt;

4-(2-(9-carboxyaniline)phenylthio)butanesulfonate;

4-(2-(8-carboxymethylamino)phenylthio)butanesulfonate;

4-(2-(7-carboxymethylamino)phenylthio)butanesulfonate;

4-(2-(6-carboxymethylamino)phenylthio)butanedisulfonate sodium salt;

3-(2-(15-carboxymethylamino)phenoxy) isobutyrophenone acid;

3-(2-(14-carboxymethylamino)phenoxy)isobutane acid;

5-(2-(13-carboxyrhodamine)phenoxy)pentanesulfonate;

5-(2-(12-phosphonothiolate)phenoxy)valeramide;

5-(2-(11-sulfonylamino)valeric acid;

5-(2-(10-Alfentanil-N-methylamino)phenoxy)valeric acid;

5-(2-(9-coalitionbuilding)phenoxy)valerianic acid sodium salt;

6-(2-(9-postnominally)phenoxy)hexanoic acid;

6-(2-(7-sulfametoxazol-N-methylamino)phenoxy)hexanoic acid;

7-(2-(7-sulfidogenic-N-ethylamino)phenoxy)enanthic acid;

7-(2-(6-thiosulfates
2-(2-(11-sulfonylamino)phenoxy)acetic acid;

2-(2-(10-solpadeine-N-propylamino)phenoxy)acetic acid;

3-(2-(9-sulfonanilide)phenoxy)propionic acid;

3-(2-(12-disulfidediethylamine)phenylthio)propionamide sodium salt;

3-(2-(11-phosphorodichloridate)phenylthio)propionic acid;

3-(2-(11-sulfonylamino)-4-methylphenylthio)isobutane acid;

3-(2-(12-solventogenesis)phenylthio)isobutyramide;

5-(2-(11-disulphophenyl-N-butylamino)phenylthio)valerianic acid sodium salt;

5-(2-(10-phosphonopentanoate)phenylthio)valeric acid;

5-(2-(12-phosphonothiolate)phenylthio)pentanesulfonate;

5-(2-(11-carboxymethylamino)phenylthio)pentanesulfonic acid;

5-(2-(10-phosphonopentanoate)phenylthio)potentialhabitat;

6-(2-(12-phosphonothiolate)phenylthio)exapostilaria acid;

4-(2-(11-sulfanilamide)-4-methylphenoxy)butanedisulfonate sodium salt;

4-(2-(12-selfdetermining)-6-methylphenoxy)butanesulfonate;

4-(2-(11-sulfidecontaining)-3-chlorophenylthio)butanesulfonic acid;

4-(2-(10-sulfidecontaining)-4-methylphenoxy)butanesulfonate NAT is decanoylamino)-3-methylphenylthio)pentanesulfonate;

4-(2-(11-sulfanilamide)-3-methylsulfinylphenyl)butanesulfonic acid;

4-(2-(11-sulfanilamide)-4-methylsulfinylphenyl)butanesulfonate;

4-(2-(12-solventogenesis)-5-ethylenoxy)budantseva acid;

4-(2-(10-sulfidecontaining)-3,5-dimethylphenoxy)butanesulfonate;

4-(2-(9-coalitionbuilding)-4-pertenece)butane acid sodium salt;

4-(2-(10-coalitionally)-4-hydroxyphenyl)butunfortunately acid sodium salt;

4-(2-(9-phosphonocarboxylate)-3,5-dimethylphenyl)butane acid;

5-(2-(11-sulfonylamino)-4-nitrophenoxy)valeric acid;

4-(2-(11-sulfanilamide)-5-amino-3-methylphenoxy)butane acid;

4-(2-(11-coalitionbuilding)-5-amino-4 - methylphenylthio)butane acid sodium salt;

4-(2-(12-phosphinothricin)-4-dimethylaminoethoxy)butane acid;

4-(2-(10-sulfidecontaining)phenoxy)butane acid;

3-(2-(9-sulfonanilide)phenoxy)propionic acid;

3-(2-(12-disulfidediethylamine)phenylthio)-3-methylpropionic acid sodium salt;

3-(2-(11-phosphorodichloridate)titilate)-2-chloropropionic acid;

4-(2-(9-Sul is tanova acid;

7-(2-(11-coalitionbuilding)phenoxy)-6-aminoalkanoic acid sodium salt;

5-(2-(11-phosphorodichloridate)-3-methylphenoxy)-4-oxo - valeric acid;

4-(2-(12-selfdetermining)phenoxy)but-2-ANOVA acid;

4-(2-(11-sulfidecontaining)phenoxy)but-2-ANOVA acid;

4-(2-(10-coalitionally)phenoxy)-4-methylene - valerianic acid sodium salt;

4-(2-(9-postnominally)phenoxy)-4-fluoro-2-butane acid;

4-(2-(11-sulfo-3-methylbutylamine)titilate)butane acid;

4-(2-(11-Alpino-3-chlorotoluene)titilate)butane acid;

4-(2-(9-thiosulfate-3-methoxyaniline)titilate)butane acid sodium salt;

4-(2-(4-phosphino-2-ethoxymethylene)phenoxy)butane acid;

4-(2-(14-sulfo-14-fluoro-2-acetamidoacrylate)-3 - methylphenoxy)butane acid;

4-(2-(13-Alpino-2-extralegally)-4-methylthiophene)butane acid;

4-(2-(12-cosultation-3-enamine)phenoxy)butane acid;

4-(2-(11-phosphonobutane-7-enamino)phenoxy)butane acid;

4-(2-(4-sulfo-2-fluoro-2-butenylamine)phenoxy)butane acid;

4-(2-(12-solventogenesis)-4-methyl-3-pyridyloxy)butane Ki is noitamina)-5-methyl-3-pyridyloxy)butane acid;

4-(2-(11-sulfidecontaining)-4-nitro-3-pyridylthio)butane acid;

4-(2-(10-coalitionally)-6-methylsulphonyl-3 - pyridyloxy)butane acid sodium salt;

4-(2-(9-gosfinansirovanie)-5-chloro-3-pyridylthio)butane acid;

4-(2-(11-sulfonylamino)-5-methyl-3-pyridylthio)butane acid;

4-(2-(11-sulfonylamino)-6-methyl-3-pyridylthio)butane acid;

4-(2-(11-coalitionbuilding)-4,6-dimethyl-3 - pyridyloxy)butane acid sodium salt;

4-(2-(12-phosphonothiolate)-5-methylthio-3 - pyridyloxy)butane acid;

4-(2-(10-sulfidecontaining)-5-methoxy-3-pyridyloxy)butane acid;

4-(2-(9-sulfonanilide)-4-fluoro-6-methyl-3 - pyridyloxy)butane acid;

4-(2-(12-disulfidediethylamine)-5-methylamino-3 - pyridyloxy)butane acid sodium salt;

4-(2-(11-phosphorodichloridate)-4-phenyl-3-pyridylthio)butane acid;

4-(2-(9-sulfonanilide)-6-methoxy-3-pyridylthio) butane acid;

4-(2-(12-solventogenesis)-6-trifluoromethyl-3 - pyridyloxy)butane acid;

4-(2-(11-coalitionbuilding)-4-methyl-3 - thiophenoxy)valerianic acid sodium salt;

4-(2-(11-phosphinotricine)-4-IU is the same;

4-(2-(11-sulfanilamide)-4-methyl-3-tofanelli)butane acid;

4-(2-(10-coalitionally)-5-methyl-3-tianity)butane acid sodium salt;

4-(2-(11-sulfidecontaining)-4-methylthio-3-titilate)butane acid;

4-(2-(10-sulfidecontaining)-4-methylsulphonyl-3-titilate)butane acid;

4-(2-(9-coalitionbuilding)-4-methylsulphonyl-3 - titilate)butane acid sodium salt;

4-(2-(12-phosphonothiolate)-5-trifluoromethyl-3 - titilate)butane acid;

4-(2-(11-sulfonylamino)-4-methyl-5-phenyl-3 - titilate)butane acid;

4-(2-(12-dislipoproteinemia)-5-dimethylamino-3 - titilate)butane acid sodium salt;

4-(2-(11-phosphorodichloridate)-4-amino-3-titilate)butane acid;

Preferred compounds of the invention are:

4-(2-(11-carboxymethylamino)phenoxy)butane acid;

4-(2-(11-carboxymethylamino)phenylthio)butane acid;

4-(2-(9-carboxyaniline)phenoxy)butane acid;

4-(2-(10-carboxymethylamino)phenoxy)butane acid;

4-(2-(12-carboxymethylamino)phenoxy)butane acid;

4-(2-(13-carboxyrhodamine)phenoxy)butane sour is ethylenoxy)butane acid;

4-(2-(11-carboxymethylamino)-5-methylphenoxy)butane acid.

The invention also includes as an inhibitor of 5 - reductase inhibitor compounds of the following formula

< / BR>
where A is a 1,2-disubstituted aromatic ring, preferably a benzene ring;

Deputy D represents OH, NH2, NHRc, ORc;

Deputy X represents O, S, SO, SO2;

the substituent R represents a hydrogen atom, a C1-C4-alkyl, phenyl or substituted phenyl, halogen atom, hydroxy-group, carboxyl group, cyano, C1- C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylsulfanyl group, C1- C4-alkylsulfonyl group, nitro group, amino group, C1-C4-mono - or di-alkylamino;

the substituents R' and R" independently from each other represent a hydrogen atom, a halogen atom, a C1-C4-alkyl or C1- C4-alkoxygroup, amino group, or oxoprop when fragments CH-R' or CHR" in the formula become a group-C=O;

Deputy Rarepresents H or C1-C4-alkyl;

the substituents Rband Rcindependently from each other is>z = 6 to 20, and

fragments (CH)y-R' and (CH)z-R" can independently from each other represent substituted or unsubstituted alkyl radicals or alkeneamine radicals containing at least one alanovoy communication,

and their pharmaceutically acceptable salts.

Compounds of the invention are inhibitors of testosterone-5 - reductase enzyme of man.

Compounds falling under the scope of the invention represented by the above formulas.

Description of formulas used the following concepts.

Deputy X in the above General formula represents O or S, preferably when both substituent X are oxygen atoms, that is, the target compound has a structure of catechol.

"C1-C4-alkyl" means a linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert. -butyl, and "C1-C12-alkyl" means alkyl group containing up to 12 carbon atoms, for example N-octyl, tert.-decyl, n-dodecyl.

"Phenyl C1-C4-alkyl" means benzil, 2-phenethyl and the like substituents.

"C1-C4-amoxi, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy.

By "halogen" refers to fluorine atom, chlorine, bromine or iodine.

"Substituted phenyl" means phenyl, substituted by one or more C1-C4-alkilani, C1- C4-alkoxygroup, halogen atoms, etc. as defined above, examples of such substituents are o, m and p-methoxyphenyl, 2,4-acid, 2-chloro-4-ethoxyphenyl, 3,5-acid, 2,4-dichlorophenyl, 2-bromo-4-were, on forfinal etc.

The concept of "halogenated" alkyl includes C1- C4is an alkyl group described above substituted by one or more atoms of halogen as defined above, for example triptorelin group, 2,2-dichloroethylene etc.

Deputy "C1-C4-alkylthio" means C1-C4-alkyl described above, substituted by at least one divalent diography (S), including, methylthio, ethylthio, isopropylthio, n-butylthio, and stuff like that.

Deputy "C1-C4- alkylsulfonyl" means C1-C4is an alkyl group described above substituted by at least one-SO-group, such as methylsulfinyl, ethylsulfinyl, isopropylphenyl etc.

Zam is built at least one sulfopropyl-SO2is, for example methylsulphonyl, ethylsulfonyl, isopropylphenyl, n-butylsulfonyl etc.

Deputy "C1-C4-mono or dialkylamino" means an amino group substituted by one or more C1- C4-alkyl groups described above, such as methylamino, ethylamino, n-butylamino, tert.-butylamino, N,N-dimethylamino, N,N-diethylamino, methyl-tert.-butylamino etc.

The substituent R or the substituents at the benzene ring may be present from the first stage of the process, such as phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy (for example, as in the case of o-NITROPHENOL, 1-source product in scheme A), or can be entered later using conventional reactions, for example, such substituents as chlorine by chlorine, nitro-group by nitration, or by transformation of the original or input group, for example, the transformation of the nitro group to the amino group in the catalytic reduction, followed by alkylation of the amino group to the mono - or dialkylamino. The amino group may be subjected to diazotization with obtaining a hydroxy-group, which can then be prometherion to metoxygroup. Similarly, the hydroxy-group can be converted into a t is. rg. Chem., 31, pp. 410, (1966) Quota and Evans. The resulting thiols can be preaccelerated to alkylthiophene, which can be, in turn, oxidized to the corresponding sulfoxidov and sulfones. Preferred substituents are a hydrogen atom, a C1-C4-alkyl, C1-C4-alkoxy and phenyl. Such reactions and their sequences are common in this area and for anyone qualified in the field specialist will be obvious how to carry out change of the benzene ring to make it the substituents described above.

Under the name of "their pharmaceutically acceptable salts and esters" understand salts and esters obtained according to the acid group of the final product, which can be used as a medicinal system for a person and which include: salts of sodium, potassium, calcium, ammonium, salts, substituted ammonium, Quaternary ammonium salts, and esters - ethyl ester, aceturate, besylate, edetate, phenpropionate, acetates, pamoate and esters, which act as proletarienne drugs, which are hydrolyzed in the body under the action of the physiological medium with the formation of the original acid, for example, pivaloate, that is what takes the value of 1 - 6, preferably 3, may contain at least one substituent R' defined above, and may represent, for example, -CH2-; -CH2-CH2-; -CH2-CH2-CH2-;

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and similar substituents.

The Deputy (CH)yR' may also be present Allenova communication, for example, in the case of such substituents as-CH2-CH=CH-; -CH2-CH=CH-CH2-; -CH2-CH=CH-; -(CH2)3-CH=CH - and the like substituents.

The residue (CH)zR", where z takes the values 6 to 20, preferably 8 to 14, may contain at least one substituent R" defined above, and may represent alkyl; for example, (CH2)n-COOH, where n is preferably 8 to 14, and other similar substituents.

The Deputy (CH)zR" may also be present Allenova communication, for example, in the case of such substituents as -(CH2)4-CH=CH-(CH2)4and similar substituents.

Preferably, if one of the substituents R' or R" is H, and especially preferably, when both Deputy (CH)yR' and (CH)zR" are alkilani.

Preferred compounds of the present izobretenii R, R', R", y, z, and Rbtake the values defined above.

Especially preferred compounds

< / BR>
< / BR>
where n = 8 to 14;

Deputy Rbrepresents methyl, ethyl, cyclopropyl, isopropyl, n-propyl, tert.-butyl, phenyl or benzyl.

These compounds of the invention can be obtained in accordance with reaction schemes A-3, B-3, C-3, presented at the end of the description.

As is evident from figure A-3, o-NITROPHENOL 1, ethyl-4-bromobutyrate 2 and anhydrous K2CO3for example, in dry acetone, boiled, for example for 12 - 100 h or incubated at room temperature for a long period of time in a nitrogen atmosphere, while receiving 4-(2-nitrophenoxy)butyrate 3 (stage A).

A solution of compound 3, for example, ethyl acetate is subjected to catalytic hydrogenation at room temperature in hydrogen atmosphere under a pressure of 40 pounds per square inch in the presence as catalyst of a 5% Pd/C, obtain ethyl 4-(2-aminophenoxy) butyrate 4, stage (B).

Stage (C) includes the interaction of the 12-bromododecane acid 5 isopropylmalate in a suitable solvent, for example in dimethoxyethane, at 80 - 86oC with the formation of acid 6.

To study the room temperature in dry methylene chloride, it is possible in the presence of 4-dimethylaminopyridine, with the formation of amide 7.

At stage (E) ester-amide 7 deesterification, for example, using a 2.5 N. NaOH in water-methanol solution until monocellate 8.

Monocellate 8 can be processed using NaJO4in a mixture of acetone/water at room temperature for 4 to 24 h to obtain the corresponding sulfoxide 8A. In addition, compound 8 can be processed using a meta-chlorbenzoyl acid (CHCl2) at a temperature of approximately 0 - 25oC for 1 to 24 h to obtain the corresponding sulfone 8b.

At stage (F) ether 7 is treated with ammonia in methanol at room temperature for, for example, 1 to 7 days from receipt of amide 9.

In scheme B-3 shows the synthesis of sulfoanalogues the claimed compounds.

At stage (G) ortho-aminophenol reacts with bromoform 2 in conditions analogous to stage A, with the formation of tiefer 11.

At stage (H) thioethers 11 react with allylthiourea acid under conditions analogous to the conditions used in stage D in the case of DCC, with the formation of the acylated ester 12.

At stage (I) ether 12 undergoes hydrolysis to free timeslot 13, Kotor is ü further oxidized to the sulfoxide Stage Ja, since tizaidine 14, to obtain the sulfoxide 15, which can be hydrolyzed under conditions similar to the conditions at the first stage, to the active acid 16.

In a similar way connection 14 can be turned into sulfon-ether 17, which can then be hydrolyzed under conditions similar to the conditions of Stage I, to the corresponding acid 18.

Similarly, the sulfur in on-nitrobenzamide, which is used as the source of the product, similar to compound 1, may be associated with the formation of alkylthiophene corresponding to the connection 3, which can be oxidized to the corresponding sulfoxide or sulfone, followed by reduction of nitro group to amino group and then connected with a suitable reagent, for example, compound 6, with the formation of linear amide containing unoxidized sulfur atom, similar to the connection 7. An additional modification is that sulfurylase agent is first oxidized to the corresponding sulfoxide and sulfone, and then bind with the amino group, for example, compound (11), obtaining, for example, compounds 13, containing only the oxidized sulfur atom in the amide chain.

It is obvious that in scheme A-3 other NITROPHENOL may the words of such NITROPHENOL includes: 2-NITROPHENOL, 2-nitro-6-METHYLPHENOL, 2-nitro-5-METHYLPHENOL, 2-nitro-4-METHYLPHENOL, 2-nitro-3-METHYLPHENOL, 2-nitro-4-phenylphenol, 2-nitro-5-phenylphenol, 2-nitro-4-chlorophenol, 2-nitro-4-triptoreline, 2-nitro-4-methoxyphenol, 2-nitro-6-ethoxyphenol and similar compounds.

The raw materials added to the connection 10 for carrying out the reaction schemes B-3 and C-3 are commercially available and can easily be obtained by methods known from the prior, and this includes all of the above compounds, where the SH-group replaces the OH-group in ortho-position to the nitro-group.

Other source compounds used as compounds 2 in scheme A-3, and scheme B-3, are: Br-CH2-COOMe, Cl-CH2CH2CH2COOCH(CH3)3, Br-CH2CH2CH2CH2COOMe, Br-CH2CH2CH2CH2CH2COOEt,

Br-CH2CH2CH2CH2CH2CH2COOCH2CH2CH2CH3, Br-CH2CH(CH3)-COOMe, Br-CH2CH(CH3)CH2COOEt, Br-CH2CH2CH2COOMe, Br-CH2CH(CH3)CH2COOCH(CH3)2,

Cl-CH2CH(OCH2CH3)CH2COOMe, Br-CH2CH(F)CH2COOMe and similar compounds. Other source connection of Auda the following connections: MeS-(CH2)6COOH, MeS-(CH2)7COOH, (CH3)2CHS-(CH2)8COOH,

EtS-(CH2)9COOH, CH3CH2CH2S(CH2)10COOH, MeS-(CH2)12COOH, EtS(CH2)13COOH,

CH3CH2CH2S(CH2)14COOH, (CH3)2CHS(CH2)15COOH, CH3(CH2)3S(CH2)16COOH,

(CH3)2CHCH2S(CH2)17COOH, CH3CH2CH2S(CH2)18COOH, (CH3)2CHS(CH2)19COOH,

EtS-(CH2)20COOH, MeS-CHCH3-(CH2)10COOH, (CH3)2CHSCH2CH2CH(CH3)CH2COOH,

MeSCH2CH2CH(Cl)CH2COOH, EtS-CH2CH(OCH3)(CH2)7COOH, CH3CH2CH2SCH2CH(OCH2CH3) CH2CH2COOH, CH3(CH2)7SCH2COOH, (CH3)2(CH2)5SCH2COOH, CH3(CH2)9SCH2COOH,

CH3(CH2)11SCH2COOH and the like compounds.

Typical compounds of the invention include, but are not limited to, the following connections:

4-(2-(20-isopropylacetanilide)phenoxy)butane acid;

4-(2-(19-methylthioadenosine)phenoxy)butadienestyrene)phenoxy)butane acid;

4-(2-(16-methyldiethanolamine)phenoxy)butane acid;

4-(2-(15-methylsulfinylphenyl)phenoxy)butane acid;

4-(2-(14-methylsulfonylmethane)phenoxy)butane acid;

4-(2-(13-BC-propylthiophenethylamine)phenoxy)butane acid;

4-(2-(12-N.-butylcyclopentadienyl)phenoxy)butane acid;

4-(2-(11-Deut.-butyldiethanolamine)phenoxy)butane acid;

4-(2-(10-phenyldiethanolamine)phenoxy)butane acid;

4-(2-(10-benzylideneamino)phenoxy)butane acid;

4-(2-(10-best-butylanthraquinone)phenoxy)butane acid;

4-(2-(9-tert.-butyldiethanolamine)phenoxy)butane acid;

4-(2-(8-ethylsulfonylimidazo)phenoxy)butane acid;

4-(2-(7-ISO-propositionally)phenoxy)butane acid;

4-(2-(6-methyldiethanolamine)phenoxy)butane acid;

4-(2-(20-ethylsulfonylimidazo)phenylthio)butane acid;

4-(2-(19-isopropylacrylamide)phenylthio)butane acid;

4-(2-(18-methyldiethanolamine)phenylthio)butane acid;

4-(2-(17-ethylthiophenethylamine)phenylthio)butane acid;

4-(2-(16-every-propertyexception(14 methylsulfonylmethane)phenylthio)butane acid;

4-(2-(13-BC-methylsulfonylamino)phenylthio)butane acid;

4-(2-(12-N.-propertydeclaration)phenylthio)butane acid;

4-(2-(11-Deut.-butylcyclopentadienyl)phenylthio)butane acid;

4-(2-(10-sec.-butyldiethanolamine)phenylthio)butane acid;

4-(2-(10-phenyldiethanolamine)phenylthio)butane acid;

4-(2-(10-benzylideneamino)phenylthio)butane acid;

4-(2-(9-out.-butylsulfonyl)phenylthio)butane acid;

4-(2-(8-tert.-butyldiethanolamine)phenylthio)butane acid;

4-(2-(7-arilsulfonilglitsiny)phenylthio)butane acid;

4-(2-(6-isopropylacrylamide)phenylthio)butane acid;

4-(2-(16-methylsulfonylamino)phenoxy)butane acid;

4-(2-(15-methylsulfonylamino)phenoxy)butane acid;

4-(2-(14-N.-propertiestraditional)phenoxy)isobutane acid;

4-(2-(13-BC-butylcyclopentadienyl)phenoxy)valeric acid;

4-(2-(12-Deut.-butyldiethanolamine)phenoxy)valeric acid;

4-(2-(11-isobutyltrimethoxysilane)phenoxy)valeric acid;

4-(2-(11-tert.-butyldiethanolamine)valeric kinoki)valeric acid;

4-(2-(9-tert.-butyldiethanolamine)phenoxy)butane acid;

6-(2-(9-methylthiophenethylamine)phenoxy)hexanoic acid;

6-(2-(8-ethylthiophenethylamine)phenoxy)hexanoic acid;

6-(2-(7-isopropylacetanilide)phenoxy)hexanoic acid;

7-(2-(7-methylheptacosane)phenoxy)enanthic acid;

7-(2-(6-methylsulfonylamino)phenoxy)enanthic acid;

7-(2-(5-methylsulfonylamino)phenoxy)enanthic acid;

2-(2-(12-N.-propertydeclaration)phenoxy)acetic acid;

2-(2-(11-BC-butylcyclopentadienyl)phenoxy)acetic acid;

2-(2-(10-sec.-butyldiethanolamine)phenoxy)acetic acid;

3-(2-(9-out-butylsulfonyl)phenoxy)propionic acid;

3-(2-(2-tert.-butyldiethanolamine)phenylthio)propionic acid;

3-(2-(11-ethylsulfinylmethyl)phenylthio)propionic acid;

4-(2-(11-isopropylacrylamide)phenylthio)butane acid;

4-(2-(11-methylthiophenethylamine)-4-methylthiophene)butane acid;

5-(2-(11-isopropylacrylamide)phenylthio)valeric acid;

5-(2-(10-methyldiethanolamine)phenylthio)valeric acid;

5-(2-(9-methylsulfinylphenyl the
5-(2-(11-BC-propylthiophenethylamine)phenylthio)valeric acid;

5-(2-(10-ad-butylanthraquinone)phenylthio)valeric acid;

6-(2-(9-sec.-butyldiethanolamine)phenoxy)hexanoic acid;

6-(2-(12-out.-butylcyclopentadienyl)phenylthio)hexanoic acid;

6-(2-(11-tert.-butyldiethanolamine)phenylthio)hexanoic acid;

7-(2-(11-ethylsulfinylmethyl)-3-methylphenylthio)enanthic acid;

7-(2-(11-isopropylacrylamide)-4-methylphenylthio)enanthic acid;

7-(2-(12-methylthioadenosine)phenoxy)enanthic acid;

4-(2-(11-phenyldiethanolamine)-4-methylphenoxy)butane acid;

4-(2-(10-benzyldimethylamine)-3-methylphenoxy)butane acid;

4-(2-(9-methylthiophenethylamine)-5-methylphenoxy)butane acid;

4-(2-(12-methylsulfonylamino)-3-phenylthio)butane acid;

4-(2-(10-ad-propylthiophenethylamine)-4-methylphenoxy)butane acid;

4-(2-(9-ad-butylsulfonyl)-5-formatierte) butane acid;

4-(2-(12-Deut. -butyldiethanolamine)-6-methylphenoxy)butane acid;

5-(2-(11-isobutylacetophenone)-3-methylphenylthio)valeric acid;

4-(2-(11-tert. -built tilsley - phenylthio)butane acid;

4-(2-(12-isopropylacrylamide)-5-ethylenoxy)butane acid;

4-(2-(11-methylthiophenethylamine)-4-phenyleneoxy)butane acid;

4-(2-(10-ethylthiophenethylamine)-3,5-dimethylphenoxy)butane acid;

4-(2-(9-isopropylideneuridine)-4-fluoro-phenoxy)butane acid;

4-(2-(12-methylthioadenosine)-5-triptoreline)butane acid;

4-(2-(11-isopropylacrylamide)phenoxy)butane acid;

4-(2-(11-ethylthiophenethylamine)phenylthio)butane acid;

4-(2-(9-isopropylideneuridine)phenoxy)butane acid;

4-(2-(10-from.-propertydeclaration)phenoxy)butane acid;

4-(2-(12-out.-propertydeclaration)phenoxy)butane acid;

4-(2-(13-butyldiethanolamine)phenoxy)butane acid;

4-(2-(15-tert.-butyldiethanolamine)phenoxy)butane acid;

5-(2-(11-isopropylacrylamide)phenoxy)valeric acid;

4-(2-(11-ethylsulfinylmethyl)phenoxy)butane acid;

4-(2-(11-isopropylaminocarbonyl)-4-methylphenoxy) butane acid;

4-(2-(11-ethylsulfinylmethyl)-5-methylphenoxy)butane acid.

All of the compounds described above in the invention and p is to be placed BPH in combination with alpha-adrenergic blocker by receiving oral, parenteral or by local application.

In this invention blockerI- adrenergic receptor and inhibitor of 5 - reductase can be assigned in combination or by separate application, or as one combined pharmaceutical formulations for oral or parenteral administration. Preferably blockerI- adrenergic receptor and inhibitor of 5 - reductase are used orally in the form of individual drugs.

The amount of each component used is determined in accordance with the clinical analysis of the etiology and severity of the disease, the patient's condition and his age, the efficiency of each component, etc.

DrugIblocker is usually administered in accordance with the latest reference Physician''s Desk Reference (PDR), which is published by medical Economics Co., Inc. of Oradell^ NJ 07649. The spacing of the doses mentioned in this description, taken from PDR44 (publ. 1990). For example, terazosin is administered in a dose of from about 1 to 10 mg q.d.) once a day, while prazosin administered twice a day (b.i.d.).

The drug is an inhibitor of 5 - reductase inhibitor is administered in doses of about 5 mg / day when taken once a day (q.d.).

In the preferred imputation men in a single daily dose of about 5-10 mg, as an inhibitor of 5 - reductase represents finasteride, which is prescribed for oral administration in a single daily dose of about 5 mg

BlockerI- adrenergic receptor and inhibitor of 5 - reductase can be combined in one dose in a format suitable for oral or parenteral use. For convenient oral administration forms are tablets, capsules or caplets. These drugs, used in the invention are usually obtained with the addition of a conventional pharmaceutical excipient, such as lactose, subjected to spray drying, and magnesium stearate, in the form of tablets or capsules intended for oral administration. One or more active substances, with or without the addition of auxiliary active compounds can be obtained in the form of tablets or pills by mixing solid, powdered carrier such as sodium citrate, calcium carbonate or dicalcium phosphate, and binders, such as polyvinylpyrrolidone, gelatin or cellulose derivatives, adding, if necessary, lubricants such as magnesium stearate, sodium lauryl sulfate, carbonex or polyethylene glycol. Of course, in preparations intended for on the Sabbath./P> As other forms application, you can use the closed capsules, for example, hard gelatin, and closed soft gelatin capsules containing razmestiteli or plasticizer, such as glycerol. The sealed capsules contain the active ingredient in the form of a granulate, for example a mixture of filler. Such as lactose, sucrose, mannitol, starch, such as potato or amylopectin, cellulose derivatives or highly dispersed silicic acid. In soft capsules the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oil or liquid polyethylene glycol.

Active ingredients used in accordance with the invention can also be retseptoriani in preparation for a single use per day or in a preparation with a constant selection using conventional techniques known in this field.

Instead of oral administration, the active compounds can be used parenterally. In such cases, a solution of the active substance, such as sesame (sesame) oil or olive oil.

When carrying out the above-described treatment by the described mode, the symptoms Docsavage thread reduced.

To determine the treatment of the prostate measured concentrations of testosterone (T), dihydrotestosterone (DHT) and acid phosphatase prostate cancer (EC) in blood plasma, as well as the volume of the prostate gland. The decrease in the concentration of DHT and AF and restore the volume of the prostate indicate successful treatment. The concentration of the above components in the blood plasma can be measured by standard methods known to a skilled in this area specialists (see , e.g., R. Neri and M. Monaghan, Invest & Urology, 1972, 10, 123-130 for AF and the work that is Namlea and D. L. Lorica, Z Klin. Biochem. 1972, 4, 164 for the radioimmunological determination of T).

The volume of the prostate is measured by rectal assessment and/or by transrectal ultrasound. Objective assessment of response to treatment is physical methods, which are well known qualified in this field specialists, for example, using the invention, obtained using nuclear magnetic resonance, and by physical examination.

When using conditions similar to conditions effective impact on alleviating the symptoms of BPH in a patient, which will be higher than the impact of any separate connections.

The method of obtaining compounds of the invention that was described above for the General case, additionally illustrated by the following examples which, however, should not be construed as limiting the scope of invention.

Part 1

Example 1. Methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate

Suspension 83,7 g of methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate (Rasmusson Johnston and Arth, Pat. USA 4377584, March 22, 1983) and 126,5 g benzamidenafil anhydride 2.09 l of chlorobenzene was heated 2 hours Condensing refrigerator was replaced with a distillation column and the mixture was slowly remove the water formed during the reaction (2 h). The solution was evaporated and received 198 g of wet sediment. The remainder in the form of a solution in dichloromethane washed with saturated aqueous NaHCO3and saturated NaCl solution, then dried and evaporated. Received 172,4, the product was chromatographically 2.56 kg of silica gel (eluent initially dichloromethane (5 l), and then a mixture of dichloromethane/acetone, 4:1). The desired product was washed 8 l and received at 53.4 g of product, which was washed with diethyl ether and dried, received a 49.5 g of the specified connection, so pl. 278-280oC. Similarly, following >252-254oC;

1b R = CONHO(CH3)2CH2C(CH3)3224-226oC.

Example 2. Methyl 4-methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate

A suspension of 25 g of the product of example 1 and 2.25 g of sodium hydride in 500 ml of dry dimethylformamide was stirred under nitrogen atmosphere for 15 minutes was added dropwise methyliodide (1 ml) and the resulting mixture was stirred for 30 min at room temperature. Then add another 5 ml under the conditions and the mixture was stirred at 50oC for 2 hours After cooling, the mixture was diluted with water to 2 liters of Separated solid residue, obtained 25.4 g of product, so pl. 159-161oC.

In a similar way the following compounds were converted into the corresponding 4-methylpropane:

< / BR>
< / BR>
2a R = CONHC(CH3)2CH2C(CH3)3, androsten 148-150oC;

2b R = CONHC(CH3)3, -1-androsten 153 to 155oC;

2c R = CONHC(CH3)2CH3O(CH3)3, -1-androsten 168-170oC.

Example 3. S-(2-pyridyl)-4-methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate

A suspension of 25 g of the product of example 2 in 125 ml of methanol was treated with a solution of KOH (*12.5 g) in 12.5 ml of water. After boiling for 4 h, the reaction mass was acidified with 6NH

Untreated dry acid (23 g), triphenylphosphine (of 36.4 g) and 2,2,-veridicality (30,4 g) suspended in 138 ml of toluene under stirring for 3 h at room temperature. The reaction mass was chromatographically on a column with 4.5 kg of silica gel (eluent ethyl acetate/acetone, 9:1), was obtained 2.4 g of product, so pl. 218-220oC.

Further elution with acetone resulted in the selection of 5.2 g a by-product of the merger of methanol S-(2-Pyridyl)- 1 - methoxy-4-methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate, T. pl. 221-223oC.

3A. By a similar method the product of example 1 was converted into S-(2-pyridyl)-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate, T. pl. 230-232oC.

3B. A similar technique methyl 3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate was converted into S-(2-pyridyl)- 3-oxo-4-Aza - 5 - androst-1-ene-17 - dicarboxylate, so pl. 232 - 234oC.

Example 4. N-tert. -butyl 4-methyl-3-oxo-4-Aza-5 - androst-1-ene-17 - carboxamide

Anhydrous tert. -butylamine was added to a suspension of 2.5 g of pyridostigmine example 3 in 70 ml of tetrahydrofuran. After 60 min the resulting solution was evaporated, the residue was chromatographically on 125 g of silica gel (eluent ethyl acetate/dichloromethane, 20:1), was obtained 1.5 g of product, so pl. 152 - 154oC.

<>/BR>4b N-tert. -butyl 3-oxo-4-Aza-5 - androst-1-ene-17 - carboxamide, so pl. 275 - 276oC.

4c N-(2,4,4-noticed-2-pentyl 3-oxo-4-Aza-5 - androst-1 - ene-17 - carboxamide, so pl. 168-170oC

Example 5. 5-oxo-3,5-Selatan-3,20-diva acid

To a solution of 200 g of 3-oxo-4-Etien-17 - OIC acid in 375 l of tert.-butanol at 80oC was added a solution of 198.4 g of sodium carbonate in 474 ml of water. Then add warm (65oC) solution 948,5 g metaperiodate sodium and of 6.96 g of permanganate in 5.5 g of water with such speed that the temperature of the reaction mixture was kept at 80oC. the mixture is Then boiled for 1 h and

kept at room temperature during the night. The inorganic salt was filtered and the filter cake washed with 225 ml of water. To reduce the amount of presence of iodine was added 5% aqueous solution of sodium bisulfite. Tert.-the butanol was removed in vacuo and the aqueous residue was acidified with concentrated hydrochloric acid. The separated resin was extracted with dichloromethane and washed with 5% aqueous solution of sodium bisulfite, and then was dried and evaporated to a colorless residue (214 g). When suspendirovanie of the residue in ether was obtained crystalline product, which was washed with hexane, exit 152, so pl. 169-19250 ml of ethylene glycol was treated with 80 ml of liquid ammonia. The resulting solution was heated with a speed of 3o/min to 180oC and kept at this temperature for 15 minutes, After cooling, was added 1 l of water and the mixture was acidified using 10% hydrochloric acid to pH of 1.5. The product was isolated and washed with water, and then dried in the air. Received of 57.5 g of the product, so pl. 310oC.

Example 5C. 3-oxo-4-Aza-5 - Etien-2O-OIC acid

A solution of 136 g of 5-acid of example: B in 16,32 ml of acetic acid was first made at 60oC in the presence of platinum catalyst (16,32 g PtO2at a pressure of 40 psi for 3 h the Catalyst was removed, the solution was concentrated and received 128,2 g crude product. The product is washed with 3 l of water, then dried in the air. Received 125 g of white solid product, so pl. 310oC.

This product was also obtained by saponification of methyl-3-oxo-4-Aza-5-androstane-17 - carboxylate (methyl-3-oxo-4-Aza-5 - Etien-17 - oate) 7% solution of potassium hydroxide in methanol followed by acidification.

Example 5D. N-(2,4,4-trimethyl-2-pentyl)-3-oxo-4-Aza-5 - androstane - 17 - carboxamide

A solution of 5 g of the product of example 50, at 3.35 g dicyclohexylcarbodiimide and 3,18 g of 1-hydroxybenzotriazole in 500 ml of dichloromethane was stirred at room temperature overnight. Solid is the solution kept at room temperature for 64 hours

A small amount of solid product was separated, and the solution was washed successively 10% aqueous solution of sodium hydroxide, 10% hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried, concentrated and passed through 240 g of silica gel (eluent acetone/dichloromethane, 3:7), was obtained 5.5 g of the product, so pl. 250-251oC.

Example 5E. Repeating the example 5D using tert.-of butylamine instead of 2,4,4-trimethyl-2-pentylamine and received N-(tert. -butyl)-3-oxo-4-Aza - 5 - androstane - 17 - carboxamide, so pl. 274-276oC.

Example 6. Synthesis of 17- (N-1-adamantylamine)-4-Aza - 5 - androst-1-EN--3-one

Suspended 100 g of 17-methyl ether (0,305 mmol) of example 1 in 3.0 ml of THF (dried over molecular sieves 3A) and then added USD 183.0 mg 1-adamantanamina (1.2 mmol). The suspension was cooled to 5-10oC and then added 590 KML 2.0 M solution of Mg Et Br in THF. The resulting mixture was stirred for 10 min, and then boiled for 1-2 h in nitrogen atmosphere. The mixture was cooled to 0oC and then was added a saturated solution of NH4Cl (approximately 10 ml). The organic layer was extracted with three volumes of methylene chloride.

The organic layers were combined, washed twice with water, three times a feast upon the OK was led in ethyl acetate and received 75,0 mg of product. Recrystallized from methanol and dried at 110oC for 2 h/0.1 mm, received the product, so pl. 305-306oC.

Molecular weight (FAB) M+= 451;

Computed = 451

Elemental analysis: for C29H42N2O2< / BR>
Calculated, %: C 77,28; H 9,40; N 6,21;

Found, %: C 76,84; H 9,73, N 5,93.

Example 7. Synthesis of 17- (N-2-adamantylidene)-4-Aza - 5 - androst-1-EN-3-one

According to the method described in example 6, but using 2-adamantanamina (obtained by neutralization of the hydrochloride in water, followed by extraction and selection) instead of 2-adamantanamina, and boiling for 7 hours instead of 1-2 hours received a named connection, so pl. 284 - 285oC.

Example 8. Synthesis of 17- (N-1-adamantylamine)-4-Aza - 5 - androstane-3-one

100 mg Adamantine derivative obtained in example 6, was dissolved in 5.0 ml of dry THF. Added 300 ml of a 5% Pd/C and the mixture was first made for 6 h at room temperature and a pressure of 40 pounds per square inch. The mixture was filtered through celite, the filter cake washed with THF (3 times) and the solvent was evaporated in vacuo, got 97,0 mg crude product. The NMR spectrum was no signal of olefinic protons. The crude product was applied on the column with 15.0 g of silica gel and erwirooment, received 77,98 mg. is an NMR Spectrum consistent with proposed structure. Recrystallization from ethyl acetate gave 65,59 mg this product, so pl. 323-324oC.

Elemental analysis for C29H44N2O21/4H2O

Calculated,%: C 76,18; H 9,81; N 6,13;

Found, %: C 75,91; H To 9.93; N 6,06.

Example 9. Synthesis of 17- (N-1-adamantylamine)-4-methyl-4-Aza-5 - androst-1-EN-3-one

120 mg dipyridamole ether of example 3 are suspended in 20 ml of dry THF and the suspension was added 175 mg of 1-adamantanamina (nitrogen atmosphere). The reaction was carried out at room temperature for 16 h under nitrogen atmosphere. Monitoring the progress of reactions was performed using thin-layer chromatography on silica, eluent acetone/hexane, 1:1. The product was isolated by TLC on plates 20 cm x 20 cm x 1000 micron silica, eluent acetone/hexane, 1:1. The product was led by ethyl acetate, received 50.0 mg net connection, so pl. 202-205 areoC.

Molecular weight (FAB) M+= 465;

Computed = 465.

Recrystallization gave 19.14 per mg of pure product, so pl. 202-202,5oC.

Elemental analysis for C30H44N2O2H2O

Calculated,%: C 74,44; H 9,60; N 5,80;

Found,%: C 74,32; H for 9.47 the measure 1 17 - understandability hydrolyzed using a 7% solution of KOH in isopropanol or methanol, followed by treatment with an acid. Received the corresponding acid, which was used in example 11.

Example 11. N-(1-substituted)-3-oxo-4-Aza-5 - androstane-17 - carboxamide

A solution of 5.0 g of the product of example 10, at 3.35 g dicyclohexylcarbodiimide and 3,18 g 1-hydroxybenzotriazole in 500 ml of dichloromethane was stirred at room temperature overnight. The solid product was filtered and the filtrate was treated with 1-adamantanol. The resulting solution was kept at room temperature for 64 h, filtered and the filter was washed successively 10% aqueous solution of sodium hydroxide, 10% hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried MgSO4concentrated and passed through 240 g of silica gel (eluent acetone/dichloromethane, 3:7), was obtained 5.5 g of the product, so pl. 323-324oC.

Example 12. Synthesis benzotriazol-1-yl-3-oxo-4-methyl-4-Aza-5 - androst-1-ene-17 - carboxylate

Suspension 83,7 g of methyl-3-oxo-4-methyl-4-Aza-5 - androstane - 17 - carboxylate (see Rasmusson, etc., J. Med.Chem., 1986, 29, pp. 2298-2315) hydrolyzed in 7% methanol solution of KOH, acidified and obtained the corresponding 17 - carboxylic acid.

Acid was easily turned into benzotriazol-1-yl-3-oxo - 4-the aspects derived) was purified by TLC (4 plates 20 x 20 cm x 1000 microns of silicon dioxide), eluent MeOH/CHCl3, 4: 96. The isolated product was washed with ether and received activated ester, so pl. 198-200oC (decomp.).

Example 13. Synthesis of 17- (N-1-adamantylamine)-4-methyl-4-Aza-5 - androstane-3-one

Dissolved 100.0 mg of 4-methyl-4-Aza-benzotriazole derived, the receipt of which is described in example 12, 20,0 ml of methylene chloride. To the clear solution was added 127 mg of 1-adamantane. The reaction mass was stirred over night at room temperature in a nitrogen atmosphere.

Crystallization from ethyl acetate after filtering through a Teflon Acrodisk CR gave 26,32 mg of product, so pl. 210-217oC. the Product was further purified on a column with 1 g of silica gel (EM silica gel), eluent acetone/hexane, 1:1 was recrystallized from ethyl acetate, received a 21.75 mg of the named product as white needles, so pl. 203-205oC.

Elemental analysis for C30H46N2O21,5 H2O:

Calculated,%: C 73,58; H 9,68; N 5,62;

Found,%: C 73,15; H Of 9.30; N 5,67.

Example 14. Diastereomeric synthesis of 17- (N-Exo-2-norbornanamine)-4-Aza-5 - androst-1-EN-3-one

In 3.0 ml of dry THF under nitrogen atmosphere was dissolved 100.0 mg of the appropriate 4-H-dipyridamole ether of example Chem. , 1986, 29, pp. 2298-2315). To the clear solution was added 477 μl () -racemate Exo-2-aminomorpholine. The reaction mass was kept for 16 h at room temperature in a nitrogen atmosphere and was evaporated in vacuum. The residue was dissolved in chloroform and washed with 2.5 G. hydrochloric acid (three times), water (three times) and saturated sodium chloride solution (three times), dried MgSO4, was filtered and was evaporated in vacuum to dryness. Received 56,3 mg racemic diastereomeric mixture.

The crude product was chromatographically using TLC (2 plates, 20 cm x 20 cm x 50 μm silica gel), eluent chloroform/acetone 70:30, got to 43.4 mg of the named product. After recrystallization from acetic acid ethyl ester was obtained 30 mg of the product, so pl. 245-245,9oC.

An NMR spectrum (CDCl3) consistent with the proposed structure.

Mass spectrum (FAB):

Calculated: C26H38N2O2: m/e 411;

Found: 411.

Elemental analysis for C26H38N2O2H2O:

Calculated,%: C 72,82; H 9,40; N TO 6.58;

Found,%: C 73,21; H 9,20; N 6,25.

Example 15. Synthesis of 17- (N-1-adamantanecarbonyl)-4-Aza-5 - androst-1-EN-3-one

In 2.0 ml of dry THF suspended 200.0 mg of 4-H-dipyridamole Aza-steroid spolu syringe at room temperature under nitrogen atmosphere. After a few minutes, received a clear yellow solution, and after 0.5 h the formed precipitate. The reaction mass was kept in an atmosphere of nitrogen overnight, diluted with methylene chloride, washed twice in 10% sodium hydroxide solution, twice with water, and then twice 10% hydrochloric acid and again twice with water and twice with a saturated solution of sodium chloride.

The organic layer was dried with magnesium sulfate, filtered, evaporated in vacuum and the obtained product is an NMR spectrum of which was consistent with the proposed structure. After recrystallization from ethyl acetate were received of 149.0 mg of product, so pl. 255-257oC (decomp.).

Mass spectrum (FAB):

Calculated: m/e 411;

Found: 411.

Example 16 Synthesis of 17- (N-2-adamantylidene)-4-Aza-5 - androstane-3-one

A mixture of 1.09 g of 17- (N-2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one (example 10), 150 ml of ethanol and 1.0 g of 30% Pd/C was first made during the night when shaken and at a pressure of 45 pounds per square inch. The suspension was filtered to separate the catalyst and the filtrate was evaporated to dryness, received the gray balance. This residue was chromatographically on the column with 200 mg of silica gel (eluent acetone/methylene chloride) was obtained 1.0 g of the solid product, so pl. 294-296oC.

Found %: C 76,23; H 9,86; N OF 5.92.

Mass spectrum (electron impact) M, weight 452.

Example 17. Synthesis of 17- (N-2-adamantylidene)-4-methyl-4-Aza-5 - androst-1-EN-3-one

A suspension of 500 mg of 17- (N-2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one obtained in example 16, 10 ml of DMF, dried over sieves and 140 mg of NaH was stirred at 170oC in nitrogen atmosphere for 18 hours was Cooled to room temperature and then added dropwise with stirring was added 0.4 ml under the conditions and the reaction mass was stirred at 50oC for 3 h Then the reaction mass was cooled to room temperature and was added 15 ml of water. The mixture was extracted with methylene chloride (3 x 20 ml). The organic layers were combined, washed with brine, dried and evaporated. Got a white crystalline residue. After recrystallization their mixture of ethyl acetate/methylene chloride was obtained pure white solid product, so pl. 246-248oC.

Elemental analysis for C30H44N2O20,3 H2O:

Calculated,%: C 76,65; H 9,56; N 5,96;

Found,%: C 76,50; H 9,75; N Of 5.84.

Mass spectrum: Molecular weight 464.

Example 18. Synthesis of 17- (N-2-adamantylidene)-3-oxo-4-methyl-4-Aza-5 - androstane

17- - (N-2-adamantylidene)-4-methyl-4-Aza-5 - androst-1-EN-tor hydrogenation). The suspension was shaken overnight under hydrogen pressure of 40 pounds per square inch. The suspension was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from hot ethyl acetate, was obtained a white crystalline product, so pl. 113-115oC.

Elemental analysis for C32H45N2O3of 0.5 EtOAc:

Calculated,%: C 75,25; H 9,86; N 5,48;

Found,%: C 75,07; H 9,52; N 5,28.

Mass spectrum: Molecular weight 466 (resolutional molecules).

Example 19. Synthesis of 17- (N-methyl-N-2-adamantylidene)-4-methyl-4-Aza-5 - androst-1-EN-3-one

17- (N-2-adamantylidene)-4-Aza-5 - androst-1-EN-3-one (5.0 g) and 1.5 g of sodium hydride in 100 ml dry DMF was stirred in a dry nitrogen atmosphere for 3 h at 40oC. the Reaction mass was cooled to room temperature and was added dropwise to approximately 4 ml under the conditions. Was stirred at room temperature for 1 h, the Reaction mass was then cooled in an ice bath was added a large amount of water is about 250 ml of Water the mixture was extracted with methylene chloride (3 x 100 ml), organic layers were combined, washed with water, brine, evaporated to dryness and was obtained as crude product. High-performance liquid chromatography obtained the IR(A) was identified as 4-methylated product of example 15. The second peak of the product (B) was identified as 4-methylated 17- (N-2-adamantylamine similar, then there is a necessary connection: so pl. 163-165oC.

Elemental analysis for C31H46N2O2:

Calculated,%: C to 77.77; H 9,68; N 5,86;

Found,%: C 77,29; H 9,79; N 5,77

Mass spectrum: Molecular weight 478.

Example 20. Synthesis of 17- (N-methyl-N-2-adamantylidene)-4-Aza-4-methyl-androstane-3-one

The crude reaction mixture of example 19 (4.6 g) was dissolved in 200 ml of ethanol containing 1.0 g of 30% Pd/C, and was first made when hydrogen pressure of 40-45 psi at room temperature overnight. The mixture was filtered, the residue washed with ethanol. The ethanol solution was evaporated to dryness and was obtained as crude product. After recrystallization from a mixture of methylene chloride/ diethyl ether/hexane received 800 mg of pure nanometrology ether androstanolone compound of example 16, so pl. 113 - 115oC. the Second and third outputs of the product obtained by recrystallization, was combined with the mother liquor and subjected to HPLC as in example 17. Received DIMETHYLPROPANE derivative of these compounds, so pl. 180 - 182oC.

Elemental analysis for C31H48N2O2:

Calculated,%: C 77,45 em.-butyl androst-3,5-diene-17 - carboxamide-3-carboxylic acid

(a) N-tert.-butyl androst-3,5-diene-3-bromo-17 - carboxamide

To a solution of oxalic acid (0,0011 mol, 0.1 g) and oxalylamino (0,0211 mol, 3 ml) in 15 ml of toluene, dried over molecular sieves, was added within 1 h 1 g (of 0.003 mol) androst-4-EN-3-one-17 - carboxylic acid. The reaction mass was stirred at room temperature for 2 h and then concentrated in vacuum. Excess oxalylamino was removed by azeotropic distillation with toluene under vacuum. The resulting brown oil was dissolved in toluene, cooled to 0oC and added dropwise within 15 min was added 10 ml of tert.-of butylamine (7.0 g) in 30 ml of toluene. After the addition, the reaction mass was stirred at 0oC for 15 min, and then kept at -20oC for 19 h Then the reaction mass was allowed to warm to room temperature and stirred it with the 25oC for another 1 h Volatile products were removed under vacuum. The residue was treated with a mixture of chloroform/water, was dissolved and the resulting layers were separated. The aqueous layer was twice extracted with chloroform. The chloroform extracts were combined, washed twice with water and dried with anhydrous magnesium sulfate. The crude product was purified by rapid chromatography on silica gel, eluent - 20% ethyl is (b) N-Tert.-butyl androst-3,5-Dien-17 - carboxamide-3-carboxylic acid

To a solution of N-tert.-butyl androst-3,5-diene-3-bromo-17 - carboxamide (0.5 g, 0,00115 mol) in 5 ml of tetrahydrofuran, cooled to -78oC (bath of dry ice/acetone) in an argon atmosphere, was added dropwise 1.5 ml (0,00375 mol) of a 2.5 M solution of ad-utility in hexane. The reaction mass was stirred at this temperature for 1 h and then for 45 min in the reaction mass was let in carbon dioxide through a column filled with concentrated sulfuric acid. The reaction mixture was allowed to warm to room temperature and was diluted with water, aqueous hydrochloric acid and chloroform. The mixture was shaken and the layers were then separated. The aqueous layer was extracted twice with chloroform. The combined organic extracts washed twice with water, once with brine and then dried with anhydrous magnesium sulfate. The solvent was evaporated in vacuum and received 0.6 g of crude solid product. The product is suspended in hexane, and provided a white solid product (0,43 g). After recrystallization from acetonitrile has been named connection, so pl. 247-250oC.

Part 2.

Example 1. Methyl 3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate

A suspension of methyl 3-oxo-4-Aza-5 - androstane-17-carboxylate (Rasmusson Johnston and Arth Pat. The clinical aspects was replaced with a distillation column and the mixture was slowly removed the water, formed during the reaction (2 hours). The solution was evaporated and received 198 g of wet sediment. The remainder in the form of a solution in dichloromethane washed with saturated aqueous NaHCO3and saturated NaCl solution, then dried and evaporated. Received 172,4, the product was chromatographically 2.56 kg of silica gel (eluent initially dichloromethane (5 l), and then a mixture of dichloromethane/acetone, 4:1). The desired product was washed 8 l and received at 53.4 g of product, which was washed with diethyl ether and dried, received a 49.5 g of the specified connection, so pl. 278 - 280oC.

Example 2. S-(2-pyridyl)-3-oxo-4-Aza-5 - androst-1-EN-17 - dicarboxylate

A suspension of 25.0 g of the above product of example 1 omilami with a solution of 12.5 g of KOH in 150 ml of a mixture methanol-water 5:1 boiling under nitrogen atmosphere for 4 hours the Mixture was cooled to 25oC and acidified to pH < 2. Under stirring was added 175 ml of water and got the precipitate, which was isolated and washed with water.

After drying, the product weight was 25 g, so pl. 313 - 315oC (decomp.).

Untreated dry acid (23,0 g) suspended in 210 ml of toluene and the resulting suspension was added triphenylphosphine (56,0 g) and 2,2'-piperidinedione (48,3 g) and the mixture was stirred at 24oC during the night Banglore, 1:1. Obtained after chromatography was carried out desired thioether was washed with ether, was obtained to 36.8 g of the named product, so pl. 232-235oC.

Example 3. 22-methyl-4-Aza-21-nor-5 - hole-1-ene-3,20-dione

< / BR>
To a solution of 7.2 g of S-(2-pyridyl)-3-oxo-4-Aza-5 - androst-1-ene-17 - dicarboxylate in 288 ml of tetrahydrofuran at -78oC was added to 33.6 ml of 1.3 M solution of S-butylacrylamide. After 30 min of incubation of the solution at -78oC the solution was allowed to warm to room temperature and treated with saturated aqueous solution of sodium chloride. The product was extracted with methylene chloride and washed with saturated aqueous sodium chloride, dried and concentrated. The residue was passed through a column of 430 g of silica gel (eluent methylene chloride/acetone, 9:1). Received 4.5 g of product, so pl. 246 - 249oC.

By repeating the reaction using reagents obtained product (see table)

Example 4. 22-methyl-4-Aza-21-nor-5 - hole-1-ene-3,20-dione

< / BR>
an alternative way

A solution of 22-methyl-4-Aza-21-nor-5 - Holan - 3,20-dione and 29,49 g benzamidenafil anhydride in 552 ml of chlorobenzene was heated with distillation of water for 4 h the Mixture was concentrated and the residue was dissolved in methylene chloride. The resulting solution was washed with 10% aqueous who left the house taking and evaporated. Received 45 g of a yellow residue. After chromatography was carried out on 1.5 kg of silica gel (eluent ethyl acetate) was obtained 10.6 g of product, so pl. 248 - 251oC.

When using as a starting compound 23-methyl-4-Aza-21-nor-5 - Holan-3,20-dione was obtained 23-methyl-4-Aza-21-nor-5 - hole-1-ene-3,20 - diode, so pl. 283 - 286oC.

Example 5. 17- (phenylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension of 43 g of S-(2-pyridyl)-3-oxo-4-Aza-5 - androst-1-ene-17 - dicarboxylate in 500 ml of anhydrous tetrahydrofuran (THF) at -78oC and with stirring was added a solution of 157 ml of 2 n solution of phenylmagnesium for 60 min and stirred at this temperature for another 60 minutes and Then the temperature of the mixture was raised to -30oC and the reaction was suppressed with 10% hydrochloric acid, keeping the temperature below -20oC. After the temperature of the mixture was raised to 0oC, to the mixture was added to 2000 ml of water and was extracted with 4000 ml of methylene chloride in several portions. Then the organic layer was washed successively with water, 1 N. a sodium hydroxide solution, water and saturated aqueous sodium chloride, then dried with magnesium sulfate and concentrated in vacuum. Got to 37.5 g of crude product. After recrystallization from a mixture of methyl-fortuneserver-4-Aza-5 - androst-1-EN-3-one

By repeating example 5 with p-performancebased as Grignard reagent received the specified connection, so pl. 315 - 315,5oC.

Example 7. 17- (cyclohexylcarbonyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension of 34.8 g dipyridamole ether of example 2 in 700 ml of anhydrous THF was added at -65oC 130 ml of 2 M ethereal solution of cyclohexylaniline within 20 minutes the Reaction mass was stirred at -70oC for 60 min, and then gave it to warm to -10oC and stirred at this temperature for another 60 minutes the Mixture was diluted with 500 ml of methylene chloride and then was added dropwise water. The resulting phases were separated and the organic layer was sequentially washed with water, 1 N. a sodium hydroxide solution, again with water and a saturated solution of sodium chloride. The organic layer was decolorized with activated charcoal, filtered and concentrated in vacuo, the obtained residue was recrystallized from ethyl acetate. Allocated to 28.2 g of the named compound, so pl. to 271.5 - 277oC.

Example 8. The compound of example 7 can also be obtained by the following method.

To a mixture of 150 g of methyl 3-oxo-4-Aza-5 - androst-1-ene-17 - carboxylate in 2800 ml of anhydrous THF under stirring pri PM After cooling to a temperature of less than 10oC the reaction mixture was acidified using 10% hydrochloric acid and was extracted with methylene chloride. The organic layer was washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried with anhydrous magnesium sulfate and evaporated. Received 163 g crude cyclohexylethane. After recrystallization from a mixture of methylene chloride/ethyl acetate was received 131 g of pure product, so pl. 269 - 270oC.

Elemental analysis:

Calculated, %: N 3,61; C 77,37; H 9,74;

Found,%: N 3,61; C 77,37; H 10,13.

Example 9. 17- (cyclopentanecarbonyl)-4-Aza-5 - androst-1-EN-3-one

By repeating the method of example 7 or 8 using as reagent cyclopentylamine received the specified connection, so pl. 272 - 273oC.

Elemental analysis:

Calculated, %: N 3,66; C 76,25; H 9,60;

Found,%: N 3,78; C 74,89; H 9,54.

Example 10. 17- (cyclobutanecarbonyl)-4-Aza-5 - androst-1-EN-3-one

By repeating the method of example 7 or 8 using as reagent cyclobutylamine received the specified connection, 288 - 289oC.

Elemental analysis:

Calculated, %: N 3,94; C 77,71; H 9,36;

Found,%: N 3,8 the x activated magnesium chips in 5 ml of dry THF was added 932 mg of 4-bromobiphenyl in 5 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at a temperature of 24 - 30oC. To a well stirred mixture was added dropwise 30 ml of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1-1 .5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was $ 4.0 mmol in 10 ml of dry THF.

The steroid from example 2 (205,0 ml, 0.5 mmol dipyridamole ether) suspended in 2 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (3.8 ml) for 5-10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere). The solution was diluted with 10.0 ml of methylene chloride and extinguished the reaction of a saturated aqueous solution of ammonium chloride to pH 4. The organic layer was separated, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and was evaporated in vacuo, got 156,2 mg crude product. Recrystallization from ethyl acetate gave 98,58 mg this product, so pl. 290-290,5oC.

Elemental analysis for C31H35NO2:

Calculated,%: N 3,09; C 82,08; H 7,78;

Found,%: N 3,06; C 81,84; H 8,01.

Maslansky)-4-Aza-5 - androst-1-EN-3-one

To a suspension 258,0 ml of dry activated magnesium chips in 8 ml dry THF was added 932 mg 3-bromobiphenyl in 2 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at 24-30oC. To a well stirred mixture was added dropwise 30 μl of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1-1 .5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was $ 4.0 mmol in 10 ml of dry THF.

The steroid from example 2 (205,0 ml, 0.5 mmol dipyridamole ether) suspended in 2 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (3.8 ml) for 5-10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere). The solution was diluted with 10.0 ml of methylene chloride and extinguished the reaction of a saturated aqueous solution of ammonium chloride to pH 4. The organic layer was separated, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and evaporated in vacuum. Received 122,84 mg of crude product, which was purified on a column of 20.0 g of silica gel (eluent chloroform/acetone 70: 30. Received 117,0 mg named,%: N 3,09; C 82,08; H 7,78;

Found,%: N 2,98; C 82,28; H 8,04.

Mass spectrum (FAB):

Calculated for C31H35NO2: 453;

Found: 453.

Example 13. Synthesis of 17- (4-methylthiophenyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension of 250.0 mg of dry activated magnesium chips in 8 ml dry THF was added 812 mg of 3-bromophenol in 2 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at 24-30oC. To a well stirred mixture was added dropwise 30 μl of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1-1 .5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was $ 4.0 mmol in 10 ml of dry THF.

The steroid from example 2 (205,0 ml dipyridamole ether) suspended in 2 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent per 5-10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere). The solution was diluted with 10 ml of methylene chloride and extinguished the reaction of a saturated aqueous solution of ammonium chloride to pH 4. The organic layer was separated, washed 3 times with water, 3 times with saturated solution of chloride of soda the obtained product was purified by TLC (one plate, 20 cm x 20 cm x 20 cm x 1000 ál of silica gel, eluent methylene chloride/acetone, 80:20). Crystallization from ethyl acetate received 105,0 mg this product, so pl. 286 - 287oC.

Mass spectrum (FAB):

Calculated for C26H33NO2S: 424;

Found: 424.

Example 14. Synthesis of 17- (4-methylsulfonylbenzoyl) and 17- (4-methylsulfonylbenzoyl)-4-Aza-5 - androst-1-EN-3-one

A. Oxidation.

In 2.5 ml of methylene chloride was dissolved of 19.91 mg methylthiopropionate of example 13, the solution was cooled to 0 - (-2oC) and treated with a solution of 9.6 mg m-chlormadinone acid in 1.0 ml of methylene chloride for 4 minutes Then the reaction mass was stirred at a temperature of 0 - (-2oC) for 1 h, diluted with 10 ml of methylene chloride. The organic layers were washed successively with 2.5% sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and evaporated in vacuum. Received 17 mg of product. After crystallization from ethyl acetate were received to 11.8 mg of the above compound in the form of a solid product with so pl. 313-313,5oC (decomp.).

Elemental analysis for C26N33NO3S 1/4 H2O

Calculated,%: N 3,15; C 70,31; H 7,60;

Found,%: N 3,00; C 70,47; H 7,70.

Mass with the As a by-product of the reaction using chromatography allocated 15% of the corresponding sulfone - 17- (4-methylsulfonylbenzoyl)is derived. After recrystallization from ethyl acetate were obtained solid product with so pl. 279-279,5oC.

Elemental analysis for C26N33NO4S 1/4 H2O

Calculated,%: C 67,87; H 7,28; N 3.04 FROM;

Found,%: C 67,96; H 6,72; N 2,95.

Example 15. Synthesis of 17- (4-acetoxybenzoic)-4-Aza-5 - androst-1-EN-3-one

Dissolved 165 μl triperoxonane anhydride 780 μl of acetic anhydride and kept for 5 h at room temperature.

To 300 μl of the above solution mixture of anhydrides with stirring was added 34,15 mg of pure sulfoxide of example 14. After a few minutes was added 54,0 μl of 2,6-lutidine and the resulting reaction mass was stirred 17 h at room temperature in a nitrogen atmosphere.

Liquid anhydrides were removed in vacuo and the resulting residue was extracted with chloroform 4 times. Chloroform extracts were washed with diluted hydrochloric acid, three times with 5% sodium bicarbonate solution, three times with water and finally with saturated sodium chloride solution, then dried with magnesium sulfate and the solvent was evaporated to dryness. Got to 42.1 mg of crude product.

The crude product from step A was purified by chromatography connection in the form of a crystalline product, so pl. 235 - 236oC (decomp.).

Elemental analysis for C28H35NO4S 1/4 H2O:

Calculated,%: C 68,57; H 7,40; N 2,86;

Found,%: C 69,02; H 7,39; N 2,73.

Mass spectrum (FAB): calculated for C28H35NO4S:

Found: 482.

An NMR spectrum consistent with proposed structure.

Example 16. Synthesis of 17- (4-mercaptobenzyl)-4-Aza-5 - androst-1-EN-4-it

In 3.0 ml of isopropanol suspended 40,0 mg acetoxymethyl-derivative of example 15. The reaction mixture for several minutes was purged with nitrogen and evacuated. To the prepared mixture was added with a syringe 40,0 mg of potassium carbonate in 2.0 ml of water (free of oxygen), then gave the temperature of the reaction mixture to rise to 80oC at a light boil in a small reduced pressure for 10 min, and then in a nitrogen atmosphere for 1 h After 1 h, the reaction mass became a clear yellow solution. After cooling to a temperature of 0-5oC the reaction mass was treated with 2,5 N. hydrochloric acid (nitrogen atmosphere) and 4 times were extracted with methylene chloride. The organic layers were washed 4 times with water, 3 times with saturated brine, dried with magnesium sulfate and evaporated in vacuum to dryness. Ali using preparative HPLC on silica gel (eluent methylene chloride/acetone, 60:40). Was led from ethyl acetate, got 20,7 mg of pure titled compound, so pl. 285 - 286oC.

Elemental analysis for C25H31NO2S 1/2 H2O:

Calculated,%: C 72,19; H of 7.69; N 3,24;

Found,%: C 71,82; H 7,43; N 3,26.

Mass spectrum: found 410.

Example 17. Synthesis of 17- (4-dimethylaminobenzoyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension 291,0 mg of dry activated magnesium chips in 8 ml dry THF was added 800 mg of 4-bromo-N, N-dimethylaniline in 2 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at 24-30oC. To a well stirred mixture was added dropwise 30 μl of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1-1 .5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was $ 4.0 mmol in 10 ml of dry THF.

The steroid from example 2 (205,0 ml dipyridamole ether) suspended in 2 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (3.8 ml, 3 equivalents) for 5-10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere). The solution was diluted with 10.0 ml mi, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and was evaporated in vacuo, got 115,3 mg crude product. Crystallization from ethyl acetate received 124,5 mg this product, so pl. 268,5 - 269oC.

Mass spectrum (FAB):

Calculated for C27H36N2O2421;

Found 421.

Range PMR (CDCl3) consistent with the proposed structure.

Example 18. A General method of obtaining silylamine derivatives

The phenol or its derivatives (1.0 mol) or alcohol (1.0 mol) was added to 1.5 l of dry methylene chloride. To the resulting clear solution was added to 3.0 mol of imidazole (nitrogen atmosphere). The solution was cooled to 0oC and was added dropwise to 2.0 mol of tert.-butyldimethylchlorosilane in 300 ml of dry methylene chloride. At the end of the adding reagent was observed sediment. The reaction mass was stopped to cool and kept at room temperature in a nitrogen atmosphere over night. Was filtered, washed precipitate with cold methylene chloride, the solvent was evaporated in vacuum and obtained the crude product. The resulting product was easily purified by filtration through silica gel (eluent methylene chloride, based on 1 g of the nd purity.

Example 19. Range of 17- (4-hydroxybenzoyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension of 1.22 g of dry activated magnesium chips in to 20.0 ml of dry THF was added 5.6 g of 1-bromo-4-(tert.-butyldimethylsiloxy)benzene (obtained from p-bromophenol according to the General procedure described above) in 2 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at a temperature of 24-30oC. To a well stirred mixture was added dropwise 150-200 μl of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1-1 .5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent is 19.5 mmol 30.0 ml of dry THF.

The steroid from example 2 (1,02 g, 2.49 mmol) suspended in 20 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (3.8 ml, 3 equivalents) for 5-10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere). The solution was diluted with 10.0 ml of methylene chloride and extinguished the reaction of a saturated aqueous solution of ammonium chloride to pH 4. The organic layer was separated, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Phil is named product, so pl. 248-249oC.

Elemental analysis for C31H45NO3Si

Calculated,%: C 73,32; H 8,93; N 2,75;

Found,%: C 73,27; H 8,99; N 2,75.

Mass spectrum (FAB):

Found 508;

Calculated 508.

Century Dailyroutine.

The product from step A (1.3 g) was dissolved in of 20.0 ml of dry THF. The resulting solution was cooled to -5oC and added 437 μl glacial acetic acid (nitrogen atmosphere). To a cold solution (-5oC) using a syringe dropwise added 3.0 ml of Tetra-ad-butylamphetamine (nitrogen atmosphere). The reaction mass was stirred under these conditions for 0.5 - 2 h, then poured it into a 2-phase mixture of ethyl acetate/saturated sodium bicarbonate solution, cooled to 0oC. the Aqueous layer was separated and additionally were extracted with ethyl acetate (3 times) and methylene chloride (2 times).

The organic layers were combined, washed 3 times with water, 1 time a saturated solution of sodium chloride and dried with magnesium sulfate, filtered and evaporated to dryness. The product was recrystallized from ethyl acetate, got 842,3 mg this product, so pl. 296-297oC.

Elemental analysis for C25H31NO31/3 H2O

Calculated,%: C 75,15; H 7,98; N 3,51;

Found,%: C 75,13; H benzoyl)-4-Aza-5 - androst-1-EN-3-one

A. obtaining a Grignard reagent.

To a suspension of 260 mg of dry activated magnesium chips in 6.0 ml of dry THF was added 628,0 g of 1-bromo-3,5-dimethyl-4-(tert.-butyl-dimethylsiloxy)benzene (obtained from 4-bromo-2,6-dimethylphenol according to the General procedure described above) in 4 ml dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at 24-30oC. To a well stirred mixture was added dropwise 150 - 200 ál 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1 to 1.5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was 2.0 mmol in 10.0 ml of dry THF.

The steroid from example 2 (205,0 mg, 0.5 mmol) suspended in 3 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (7.5 ml, 1.5 equivalent) for 5 - 10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at a temperature of -10oC (nitrogen atmosphere).

Extinguished the reaction of 1 N. hydrochloric acid and then diluted with chloroform. The organic layers were combined, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and evaporated in VI in a mixture of chloroform/acetone, 70:30, was filtered through a Teflon (Acrodisk CR) and purified using preparative HPLC on silica gel (eluent chloroform/acetone 70:30).

The main product was recrystallized from ethyl acetate, was received with 52.0 mg of product, so pl. 245 - 245,5oC.

Elemental analysis for C33H49NO3Si

Calculated, %: C 73,96; H 9,23; N 2,61;

Found, %: C 74,06; H 9,23; N 2,64.

Mass spectrum (FAB):

Found 536;

Calculated 536.

B. removing the silyl protection.

Dissolved 54.0 per mg of product from step A in 1.3 ml of dry THF. The clear solution was cooled to 0oC and added 29 μl of glacial acetic acid with a syringe (nitrogen atmosphere). Then the prepared solution with a syringe was added dropwise 172 μl of Tetra-ad-butylamphetamine (nitrogen atmosphere). The reaction mass was kept under these conditions for 1.5 h, then poured it into a mixture of ice/saturated sodium bicarbonate solution/ethyl acetate and stirred for a few minutes. The layers were separated, the aqueous layer was extracted 3 times with ethyl acetate and 3 times with chloroform.

The combined organic extracts were washed 3 times with water and then 3 times with saturated sodium chloride, dried with magnesium sulfate, filtered and evaporated the DOS is and 22.5 mg of the compounds, so pl. 305 - 306oC.

Elemental analysis for C27H35NO3H2O:

Calculated, %: C 73,77; H 8,49; N 3,10;

Found, %: C 73,62; H Of 7.90; N 3,44.

Mass spectrum (FAB):

Found 422;

Calculated 422.

Example 21. Synthesis of 17- (4-methoxybenzoyl)-4-Aza-5 - androst-1-EN-3-one

To a suspension 258.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 748,0 mg of n-bromoanisole in 2 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath for 24 - 30oC. To a well stirred mixture was added dropwise 30 μl of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1 to 1.5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was $ 4.0 mmol in 10.0 ml of dry THF.

The steroid from example 2 (205,0 mg, 0.5 mmol) suspended in 2 ml of dry THF, cooled to -78oC and the resulting suspension with a syringe was added previously obtained Grignard reagent of (3.75 ml, 14 milliequivalents) for 5 - 10 min (nitrogen atmosphere). The reaction mass was kept at -80oC (nitrogen atmosphere) for 1 h and then a further 1 h at -10oC (nitrogen atmosphere).

The reaction mass was diluted with chloroform and extinguished the reaction of 1 N. hydrochloric acid and satiata magnesium. Was filtered and was evaporated in vacuo, the obtained product was washed with ether, was led from ethyl acetate, provided 110 mg of product, so pl. 305 - 306oC.

Further purification was performed using TLC (plate, 20 cm x 20 cm x 1000 μm), eluent chloroform/acetone 70:30. After recrystallization from ethyl acetate received 78,56 mg this product, so pl. 305 - 306oC (decomp. ).

Mass spectrum (FAB):

Found 408;

Calculated 408.

Example 22. Synthesis of 17- (3-hydroxybenzoyl)-4-Aza-5 - androst - 1-EN-3-one

A. Grignard Reagent.

To a suspension 230,0 mg of dry activated magnesium chips in 2.0 ml of dry THF was added 722,4 mg 1-bromo-3-(tert. -butyldimethylsiloxy)benzene (obtained from 3-bromophenol according to the General procedure described above) in 8 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath at a temperature of 24 - 30oC. To a well stirred mixture was added dropwise 20 ml of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 1 to 1.5 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was 2,52 mmol in 10.0 ml of dry THF.

The steroid from example 2 (205 mg, 0.5 mmol) suspended in 2 ml of dry THF, cooled to -78oC and the TA) 5 - 10 min (nitrogen atmosphere). The reaction mass was kept for another 1 h at -10oC (nitrogen atmosphere). The reaction mass at 0 - -5oC extinguished 1 N. hydrochloric acid and diluted with chloroform. The organic layer was washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and was evaporated in vacuum, received the product, which was purified on a column of silica gel, eluent chloroform/acetone 70:30. Received 58,0 mg silyl derivative, 17- (3-tert.-butyldimethylsilyloxy) -4-Aza - 5 - androst-1-EN-3-one.

B. Dailyroutine.

Silyl derivative of 57.6 g) was dissolved in 3.0 ml of dry THF. The resulting solution was cooled to 0oC and with a syringe was added 20 ml of glacial acetic acid (nitrogen atmosphere). To a cold solution (-5oC) using a syringe was added dropwise 130,0 μl of Tetra-ad-butylamphetamine (nitrogen atmosphere). The reaction mass was stirred under these conditions for 1 h then poured it into a mixture of ethyl acetate/saturated sodium bicarbonate solution, cooled to 0oC.

The organic layers were combined, washed 3 times with water, 1 time a saturated solution of sodium chloride and dried with magnesium sulfate, filtered and evaporated to dryness, received goform/acetone, 70: 30. Got to 44.5 mg of the named compound. After recrystallization from ethyl acetate received 29,30 mg of product, so pl. 279 - 280oC.

Elemental analysis for C25H31NO38H2O:

Calculated, %: C 73,60; H of 8.06; N 3,43;

Found, %: C 73,26; H By 8.22; N 3,28.

Mass spectrum (FAB):

Found 394;

Calculated 394.

Example 23. Synthesis of 17- (4-hydroxymethylbenzene)-4-Aza-5 - androst-1-EN-3-one

A. obtaining a solution of the Grignard reagent

To a suspension of 100.0 mg (4 mmol) of dry activated magnesium chips in 5.0 ml of dry THF was added 753,0 mg 1-bromo-4-(tert.butyldimethylsilyloxy)benzene (obtained from 4-bromophenol according to the General procedure described above) (nitrogen atmosphere). The reaction was carried out in an ultrasonic bath for 24 - 30oC. To a well stirred mixture was added dropwise 20 ml of 1,2-dibromethane (nitrogen atmosphere). The reaction mass was kept for 2 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was 2.5 mmol in 5.0 ml of dry THF.

B. Reaction of Grignard

The steroid from example 2 (205 mg, 0.5 mmol) suspended in 2 ml of dry THF, cooled to -78oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (3.0 ml, 3,7 and nitrogen). Transparent reaction mass at a temperature of 0 - (-5oC) put a saturated solution of ammonium chloride and diluted with methylene chloride. The organic layer was separated and washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and was evaporated in vacuum, received the product, which was led from ethyl acetate, yield similarvideo product 137 mg.

Mass spectrum (FAB):

Calculated for C30H41NO3Si: 521,75;

Found 522.

C. Dailyroutine

The product from step B (23,67 mg) was dissolved in 0.5 ml of dry THF and 0.5 ml of methanol and cooled to 0oC (nitrogen atmosphere). To the cooled solution was added 10 μl of concentrated sulfuric acid (98%) and was stirred for 45 min at 0oC in nitrogen atmosphere. To a cold solution (0oC) was slowly added to a saturated solution of sodium bicarbonate and chloroform. The reaction mass was extracted with chloroform three times. The organic layers were washed 3 times with water, 3 times with saturated solution of sodium chloride and dried with magnesium sulfate, filtered and evaporated to dryness, got 10,18 mg crude product. After purification by TLC on plates, eluent chloroform/acetone, 1:1 and the product crystallize the I C26H33NO31/3 H2O:

Calculated, %: C 75,41; H 7,94; N 3,38;

Found, %: C 75,61; H To 7.84; N 3,12.

Mass spectrum (FAB):

Found 408;

Calculated 408.

Example 24. Synthesis of 17- (4-carboxybenzoyl)-4-Aza-5 - androst-1 - EN-3-one

A. Oxidation

In 2,63 ml of glacial acetic acid was dissolved by 90.2 mg of the product of example 23 and to the resulting clear solution was added 69,0 mg CrO3(pre-dried over P2O5at room temperature in vacuum for 2 days). The reaction mass was stirred overnight, diluted with water and left in the refrigerator over night. Then the reaction mass was filtered and the filtrate and washing liquid were extracted overnight using extractor, liquid-liquid (water-ethyl acetate) in boiling. The organic layer was dried with magnesium sulfate, filtered and evaporated in vacuum. The obtained residue was dissolved in hot methanol, filtered and evaporated in vacuo, got 32,0 mg of product.

Mass spectrum (FAB):

Found 422;

Calculated for C26H33NO4422.

B. Cleanup.

The above acid was purified by dissolving the product in 1 to N. the sodium hydroxide solution. A clear solution of EC is Yu was added dropwise under stirring to pH 4. The reaction mass was kept for aging for 1 h at 0oC, then filtered and the residue washed with cold water. Was dried over night at 100oC in vacuum (less than 0.2 mm).

The output of the named product - free acid - totalled 9.85 mg

Mass spectrum (FAB):

Found 422;

Calculated for C26H33NO4422.

C. Sodium salt of the specified acid.

of 4.9 mg of the acid obtained above B was dissolved in 2.0 ml of hot methanol. To the clear solution was added to 11.6 μl of 1 N. aqueous sodium hydroxide solution. To the resulting solution, after evaporation of the methanol under vacuum was added water to achieve a pH 7,21. The aqueous solution was dried by freezing, received 6,3 mg sodium salts of the specified acid.

Example 25. Synthesis of 17- (4-hydroxyethylbenzene)-4-Aza-5 - androst-1-EN-3-one

A. obtaining a solution of the Grignard reagent

To a suspension of 252 mg of dry activated magnesium chips in 10.0 ml of dry THF was added 1.26 g (4 mmol) of 1-bromo-4-(tert.-butyldimethylsilyloxy)benzene (obtained from 2-(n-bromophenyl)ethanol by the General procedure described above) (nitrogen atmosphere). The reaction was carried out with an ultrasonic vibrator. K mix well the mixture dropwise we use the tell a 3.5 - 4 h (nitrogen atmosphere). The concentration of the Grignard reagent was 4 mmol in 10.0 ml of dry THF.

B. The Grignard Reaction.

The steroid from example 2 (205 mg, 0.5 mmol) suspended in 2 ml of dry THF, cooled to -80oC and the resulting suspension with a syringe was added previously obtained Grignard reagent of (3.75 ml, 1.5 milliequivalent) for 5 - 10 min (nitrogen atmosphere). The reaction mass was kept at a temperature of -80oC for 1 h and 1 h at -10oC (nitrogen atmosphere). Transparent reaction mass at a temperature of 0 - (-5oC) put a saturated solution of ammonium chloride and diluted with methylene chloride. The organic layer was separated and washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and evaporated in vacuum to dryness, the obtained product, which was led from ethyl acetate, yield milirovannie product 152 mg, so pl. 233 - 234oC.

Elemental analysis for C33H49NO3Si1/4 H2O:

Calculated, %: C to 73.55; H 9,18; N 2,59;

Found, %: C 73,45; H To 8.94; N Is 3.21.

Mass spectrum (FAB):

Calculated for C30H41NO3Si 521,75;

Found 522.

C. Dailyroutine

The product from step B (70,8 mg) was dissolved in 1,4 is with a syringe 29 μl of concentrated sulfuric acid and was stirred for 45 min under nitrogen atmosphere. The reaction mass at 0oC carefully extinguished saturated sodium bicarbonate solution and was extracted three times with methylene chloride. The organic layers were washed 3 times with water, then with saturated sodium chloride solution and dried with magnesium sulfate, filtered and evaporated in vacuo, got 43,0 mg crude product. The resulting product was applied on a column of silica gel and was suirable a mixture of acetone/methylene chloride, 1: 1. The isolated product was led anhydrous methanol, received 20.0 mg of the named compound, so pl. 292 - 293oC (decomp.).

Elemental analysis for C27H35NO31/4 H2O

Calculated, %: C 75,31; H 8,25; N 3,25;

Found, %: C 75,49; H 8,29; N 3,45.

Mass spectrum (FAB):

Found 422;

Calculated 422.

Example 26. Synthesis of 17- (4-carboxybenzoyl)-4-Aza-5 - androst-1-EN-3-one

A. Oxidation.

In 1 ml of glacial acetic acid was dissolved at 13.0 mg of the product of example 25 and to the resulting clear solution was added 10.0 mg CrO3(pre-dried over P2O5at room temperature in vacuum for 2 days). The reaction mass was stirred overnight at room temperature, and then 48 h at 0oC. was Added to 7.0 ml of water and left reactioni was dried in vacuum at 110oC (pressure less than 1 mm).

The dried product was dissolved in 1 N. the sodium hydroxide solution and the basic solution was extracted 3 times with methylene chloride. The organic layer was separated and the aqueous basic solution was cooled and acidified with 1.5 N. hydrochloric acid. The precipitate was filtered, washed with water and dried over night at 100oC in vacuum (<0.1 mm). The output of the named product was 7.0 mg

Mass spectrum (FAB):

Found 436;

Calculated for C27H33NO4436.

Example 27. Synthesis of 17- (3,4-dihydroxybenzyl)-4-Aza-5 - androst-1-EN-3-one

A. Reaction of Grignard

To a suspension 258,5 mg of dry activated magnesium chips in 10.0 ml of dry THF was added 482 mg of 1-bromo-1,2-methylenedioxybenzene (original product commercially available Aldrich Chemical).

The reaction was carried out in an ultrasonic water bath for 24 - 30oC. To a well stirred mixture was added dropwise 40 ml of 1,2-dibromethane (nitrogen atmosphere) as a catalyst for the reaction. The reaction mass was kept for 1.5 - 2 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was 3.75 mmol in 10.0 ml of dry THF.

The steroid from example 2 (410 mg, 1.0 mmol) suspended in 4 m is ctiv Grignard (8.0 ml, 3.04 from milliequivalent) for 5 - 10 min (nitrogen atmosphere). The reaction mass was kept at -80oC for 1 h and 1 h at -10oC (nitrogen atmosphere). The reaction mass was diluted with methylene chloride and extinguished 1 N. hydrochloric acid.

The organic layers were separated, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated in vacuum to dryness, the obtained product, which was purified by 50.0 g of silica gel, eluent methylene chloride/acetone, 1:1. Received 347 mg of product.

Mass spectrum (FAB):

Calculated 422;

Found 422.

After crystallization of the resulting product from ethyl acetate received is 11.39 mg of product, so pl. 324 - 325oC.

Elemental analysis for C26H31NO43/4 H2O

Calculated, %: C 71,78; H 7,53; N 3,22;

Found, %: C 71,90; H Rate Of 7.54; N 3,25.

Mass spectrum (FAB):

Calculated for C26H31NO4422;

Found 422.

B. Splitting methylenedioxyphenol group

In 25 ml of 1,2-dichloroethane was dissolved 70.0 mg of the product of stage A (room temperature, nitrogen atmosphere). The solution was cooled to -10oC and was added dropwise to 1.03 ml BBr3(1.0 M solution in dichloromethane). The reaction mass UP>C and extinguished 10.0 ml of methanol for 10 min at 0oC, then the temperature was gradually raised to room. The reaction mass was evaporated to dryness in vacuum. The residue was extracted three times with ethyl acetate. The organic layers were washed three times with water, twice with saturated sodium bicarbonate solution and finally with a solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated in vacuum. The crude product was purified by chromatographytandem on 2 plates with silica gel (20 cm x 20 cm 20 cm x 250 μm), eluent acetone/methylene chloride, 1:1. After recrystallization from ethyl acetate received 5.0 mg of the named product, so pl. 222 - 222,5oC.

Elemental analysis for C25H31NO41/2 H2O

Calculated, %: C 71,78; H 7,66; N 3,35;

Found, %: C 71,71; H 7,71; N 3,33.

Mass spectrum (FAB):

Calculated for C25H31NO4410;

Found 410.

Example 28. Synthesis of 17- (2-methoxybenzoyl)-4-Aza-5 - androst-1-EN-3-one

A. The Reaction Of The Grignard Reagent.

To a suspension 258.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 771,0 mg on-bromoanisole in 2.0 ml of dry THF (nitrogen atmosphere). The reaction was carried out in an ultrasonic water bath at a temperature of 24 - 30oC. To mix well the th mass was kept for 2 h at 28oC (nitrogen atmosphere). The concentration of the Grignard reagent was 4 mmol in 10.0 ml of dry THF.

The steroid from example 2 (205 mg) suspended in 8 ml of dry THF, cooled to -79oC and the resulting suspension with a syringe was added previously obtained Grignard reagent (4.0 ml, 1.6 milliequivalents) for 5 - 10 min (nitrogen atmosphere). The reaction mass was kept at -80oC for 1 h and 1 h at a temperature of -10oC (nitrogen atmosphere). The reaction mass was diluted with methylene chloride and extinguished 1 N. hydrochloric acid.

The organic layers were separated, washed 3 times with water, 3 times with saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and evaporated in vacuum to dryness, the obtained product, which was led from ethyl acetate. Received 124,5 mg of product, so pl. 228 - 230oC. After purification on a column of silica gel, eluent chloroform/acetone 70:30, got 83,0 mg of pure compound, so pl. 241 - 241,5oC.

Elemental analysis for C26H33NO3< / BR>
Calculated,%: C 76,91; H 8,19; N 3,45;

Found,%: C 76,36; H Compared To 8.26; N 3,35.

Mass spectrum (FAB):

Calculated for C26H33NO3406;

Found 406.

B. Splitting metoxygroup

In 5.0 ml of dry meth is UP>C dropwise with a syringe was added 50 μl (1 mmol/ml) BBr3in methylene chloride. The reaction was rapidly stirred at room temperature overnight. The next day got a transparent yellow solution. Then the reaction mass was cooled to 0-2oC and added water to hydrolyze the excess BBr3. The organic phase is washed three times with dilute sodium hydroxide solution, three times with water and three times with diluted hydrochloric acid, and then washed three times with water, three times with saturated sodium chloride solution, dried with magnesium sulfate. Was filtered and the filtrate was evaporated in vacuum to dryness. The crude product was led from ethyl acetate, got 7,0 mg of pure 17- (2-hydroxymethylene)-4-Aza-5 - androst-1-EN-3-one.

Mass spectrum:

Calculated for C25H31NO2394;

Found 394.

Example 29. 17b-(- hydroxybenzyl)-4-Aza-5 - androst-1-EN-3-one

Suspended 570 mg 17 - benzoyl-4-Aza-5 - androst-1-EN-3-one (obtained from dipyridamole ester of example 2 and commercially available phenylmagnesium by the method similar to the method of example 5, to obtain the 17 - benzoylpropionic, so pl. 295 - 296oC, crystallization from ethyl acetate) in 80 ml of anhydrous isopropanol. To Ali 20 ml of dry THF thus, that the reaction mixture became a transparent solution. The reaction mass was kept at room temperature during the night. Then the reaction was carefully stopped with 1 N. hydrochloric acid, and stirred in a nitrogen atmosphere at room temperature for another 1 h Then the reaction mass was diluted with water, was extracted three times with chloroform. The organic extracts were combined, washed three times with water, three times with saturated sodium chloride solution and dried with sodium sulfate, filtered and evaporated. Got a white solid product, 495,0 mg.

The crude product was led from ethyl acetate, got 349,5 mg of product. Additional purification on a column of silica gel, eluent chloroform/acetone 70:30, gave the pure titled compound, 221 mg, so pl. 296 - 297oC.

Elemental analysis for C25H33NO2< / BR>
Calculated,%: C 79,17; H 8,78; N 3,70;

Found,%: C 79,24; H Cent To 8.85; N 3,48.

Mass spectrum (FAB):

Calculated for C25H33NO2380;

Found: 380.

Example 30. 17 - hydroxymethyl-4-Aza-5 - androst-1-EN-3-one

In 40 ml of dry THF at room temperature under nitrogen atmosphere was dissolved 500.0 mg S-2-pyridyl-3-oxo-4-Aza-5 - androst-1-EN-3-one (example 2). The solution was cooled in the range of dibutylaniline in THF. The reaction mass is kept at (-76) - (-78)oC 0.5 hours, the Temperature is gradually raised to room temperature and was further stirred for 2 to 2.5 hours the Reaction was stopped using 2 N. hydrochloric acid at a temperature of 0 to 5oC, and then was diluted with chloroform. The organic layers was separated, washed with water three times, then with a saturated solution of sodium chloride, dried with magnesium sulfate. Was filtered and was evaporated in vacuo, got 216,0 mg crude product.

The crude product was purified on a column of 20.0 g of silica gel, eluent chloroform/acetone 70:30.

Received 126,3 mg of pure titled compound, so pl. 271 - to 271.5oC.

Mass spectrum (FAB):

Calculated for C19H29NO2304;

Found 304.

An NMR spectrum in CDCl3consistent with the proposed structure.

Example 31. 17 - formyl-4-Aza-5 - androst-1-EN-3-one

In a dry flask to 100.0 ml downloaded 1.3 ml of oxalicacid (2 M solution in methylene chloride) and 50 ml dry methylene chloride (nitrogen atmosphere). The resulting solution was cooled to -78oC and with a syringe was added dropwise 338 μl of DMSO. The mixture was stirred under these conditions for 30 min with a syringe was added in advance the resulting solution of the alcohol of example 15, 17 - hydroxym the Ali at -78oC for 1 h, then added quickly dry triethylamine. The reaction temperature slowly with stirring was raised to room temperature, the yellow solution was poured into a 50.0 ml of cold water. The organic layer was washed with a saturated solution of sodium bicarbonate, then saturated sodium chloride solution was dried with magnesium sulfate, evaporated in vacuo, got 172,4 mg crude product. After purification on a column with 60,0 g of silica gel, eluent chloroform/acetone 70:30, got a clean product. After crystallization from ethyl acetate were received of 37.7 mg of the named compound, so pl. 258 - 259oC.

Example 32. Synthesis diastereomeric 17-(- hydroxybenzyl)-4-Aza-5 - androst-1-EN-3-ones

Dissolved 26,3 mg previously obtained formyl derivative (example 31) in 7.0 ml of dry THF (nitrogen atmosphere). The resulting solution was cooled to -78oC and added dropwise with a syringe was added 131 ál phenylmagnesium (Aldrich) (0,393 milliequivalent) in dry THF. The reaction mass was kept for 1 h at a temperature of -78oC and then 1 h at room temperature.

The reaction was stopped with the help of 2.5 N. hydrochloric acid at 0 to 5oC, and then was diluted with chloroform. The organic layer was separated, washed three times Vogue dry. Got to 28.6 mg of crude product. These NMR spectrum and HPLC data indicate that the resulting product is a mixture of two diastereomers. The crude product was filtered through a Teflon and were HPLC purified on a column of WHitman Portisil 10, eluent chloroform/acetone 70: 30. Mass spectrum (FAB) contains peaks M++1 for both isomers, and mass unit corresponds to 380. The isomer is eluted faster, so pl. 289 - 289,5oC, was led from acetic acid ethyl ester was obtained pure product containing according to TLC one connection.

Elemental analysis for C25H33NO21/4 H2O

Calculated,%: C 78,39; H 8,81; N 3,65;

Found,%: C 78,11; H 8,65; N To 3.58.

The isomer is eluted more slowly, so pl. 300 - 301oC, according to TLC also contained a single connection. The NMR spectrum (CDCl3) isomer, aliremove faster, observed the signal of the protons of CH3-group at C-18, which is shifted in a weaker field (0,89 M. D.) in comparison with the corresponding signal of another isomer (0,69 memorial plaques). Benzyl proton of the first isomer is also shifted (4,5 M. D. relatively 4,95 memorial plaques). The signal of the olefinic proton at C-1 is also shifted for the first isomer (for 6.81 M. D. ) in comparison with the signal of the proton of the other isomer (6,62 memorial plaques ). Of these tx2">

Example 1. Getting 4-(2-(11-carboxymethylamino)phenoxy)butane acid

Stage A: Ethyl-4-(2-nitrophenoxy)butyrate (3)

To a solution of 2-NITROPHENOL (1.4 g, 10 mmol) and ethyl-4-bromobutyrate (2.1 g, of 1.57 ml, 11 mmol) in 35 ml dry acetone was added with stirring 2 g (14.5 mmol) of anhydrous powdered potassium carbonate. The obtained colored mixture was heated in a nitrogen atmosphere and heated until then, until he disappeared coloration, due to the phenolate-ion, and the mixture became yellow. The mixture was cooled, filtered and evaporated, got the oil, which was purified by rapid chromatography (silica gel), eluent ethyl acetate/hexane or methylene chloride) was obtained 2.4 g (96%) of compound (3) as oily liquid.

When using substituted ortho-NITROPHENOL instead of 2-NITROPHENOL and using instead 4-bromobutyrate other halogen-esters were obtained the corresponding 2-nitrophenoxyacetic.

Stage B: Ethyl 4-(2-aminophenoxy)butyrate (4)

A solution of compound 3 (1.27 g, 5.0 mmol) in 15 ml of ethyl acetate containing 200 mg of 5% palladium on coal, was kept in an atmosphere of hydrogen (40 psi) at room temperature until cessation of hydrogen absorption. Then the mixture was filtered and privacyPolicy)dodekanisa acid (6)

A mixture of 12-bromododecane acid 5 (0,558 g, 2.0 mmol) and isopropylmalate sodium (1.1 g, 11.1 mmol) in 1,2-dimethoxyethane was wearisomely (nitrogen) and heated to 85oC (bath temperature). Held at this temperature for 72 h, the Reaction mixture was cooled and filtered. The precipitate was dissolved in water and filtered. The resulting solution under stirring was acidified with diluted hydrochloric acid, was kept for aging, filtered, and the obtained residue was washed well with water and dried. Received connection 6 (0.54 g) as a white solid product.

When using other galocilata instead of 2-bromododecane acid, the corresponding (isopropylthio)-acid.

Similarly, when you use other mercaptane instead isopropylmalate sodium obtained other relevant (alkylthio)alcamovia acid.

Examples of acids that are obtained by this procedure include, but are not limited to: 8-(isopropylthio)octanoic acid, 10-(isopropylthio)cekanova acid, 10-(ethylthio)cekanova acid, 11-(tert.-butylthio)undecanoate acid, 14-(n-propylthio)tetradecanoic acid, 9-(methylthio)novanova acid.

Stage D: Ethyl 4-(2-(12-(isopropyl) in dry methylene chloride (10 ml) at room temperature was added 4-dimethylaminopyridine (0,122 g, 1.0 mmol) and then was added over 1 min a solution of N,N-dicyclohexylcarbodiimide (0,22 g, 1.06 mmol) in methylene chloride (1 ml). After 2 days the mixture was filtered and evaporated in vacuo, the residue was purified by rapid chromatography on silica gel, eluent 15 - 20% solution of ethyl acetate in hexane. Received connection 7 (0,22 g) in the form of an oil which rapidly crystallized.

Stage E: 4-(2-(12-(isopropylthio)dodecanolide)phenoxy)butane acid (8)

To a solution of the ester (7) (0.124 g, 0,258 mmol) in methanol (10 ml) was added under stirring and at room temperature in a nitrogen atmosphere for 2.5 n sodium hydroxide solution (0.6 ml). Methanol (2 x 2 ml) was used to obtain a clear mixture, after which the reaction was kept up until TLC data testified to the presence of unreacted ester. The mixture was filtered, evaporated in vacuo, the resulting residue was mixed with 30 ml of water. After aging the mixture was filtered (sediment consisted of a sodium salt of the product (100 mg), the filtrate with stirring, acidified with diluted hydrochloric acid, was kept, was filtered, washed with water, received 8 product (0.02 g) as a white solid product, so pl. 82 - 84oC, start softening at 66oC.

Treatment with the AC connection 8 m-chlormadinone acid, as in stage Ibwill give the corresponding sulfon.

Stage F: 4-(2-(12-(isopropylthio)dodecanolide)phenoxy)butyramide (9)

To a solution of compound 7 (20 mg, 0,041 mmol) in methanol (10 ml) under stirring was added methanol saturated with ammonia (5 ml), and stirred at room temperature until completion of reaction (TLC data, no or a small number of compounds (D). After evaporation of the reaction mass and preparative TLC (silica gel, eluent of 3% methanol/methylene chloride) was obtained compound 9 (11 mg) as a waxy solid product.

Stage G: Ethyl 4-(2-aminophenylthio)butyrate (11)

To a deaerated (nitrogen) solution of 2-aminothiophenol 10 (1.25 g, 10 mmol) and ethyl 4-bromobutyrate (2.1 g, 11 mmol) in 40 ml of dry 1,2-dimethoxyethane under stirring were added to 8.3 g of solid powdered anhydrous potassium carbonate, the resulting mixture was wearisomely three times with nitrogen and stirred at room temperature until completion of reaction (TLC data). The mixture was filtered, the filtrate was evaporated and the obtained residue was purified by rapid chromatography on silica gel (85 g), eluent: 15% ethyl acetate/hexane, received 1.8 g of compound (11) in the form of a light beige oil.

Stage H: Ethyl 4-(2-(10-(isopropylthio)d is inane 11 and 10 (isopropylthio)decanoas acid was obtained connection 12.

Stage I: 4-(2-(10-(isopropylthio)decanoylamino)phenylthio)butane acid (13)

When the hydrolysis conditions described in stage E, the received connection 13.

Stage J: 4-(2-(11-(ethylsulfinyl)undecanoate)phenoxy)butane acid

When processing esters or acids metaperiodate sodium (stage Ja) in a suitable solvent (for example, in a mixture of acetone/water) received appropriate sulfoxidov. Processing metacompetencies acid (stage Jb) leads to the corresponding sulfone. For example, if ethyl 4-(2-(11-(ethylthio)undecanoate)phenoxy)butyrate 14 (of 0.045 g, 0.1 mmol) in acetone (10 ml) is reacted with metaperiodate sodium (0,072 g, 0.33 ml) in water (2 ml) at room temperature was obtained the corresponding sulfoxide 15. The hydrolysis according to the method stage of E leads to the connection 16, which represents an unpainted solid product. In addition, the process of joining 14 m-chlormadinone acid leads to sulfone 17, which on hydrolysis under conditions of stage E gives acid 18.

The method of obtaining new compounds of the present invention already described for the General case, can be further illustrated by the trail of the CLASS="ptx2">

Example 1. Synthesis of 4-(2-(11-carboxyphenoxy)phenoxy)butane acid (8)

(7)

A. Ethyl 4-(2-benzyloxyphenyl)butyrate (3)

To a solution of 2-benzyloxyphenol 1 (4.0 g, 20 mmol) and ethyl 4-bromobutyrate 2 (5.6 g, 28.7 mmol) in dry acetone (100 ml) under stirring was added powdered anhydrous potassium carbonate (6.0 g, 44 mmol) and the resulting mixture was heated in a nitrogen atmosphere until the end of the reaction (TLC data). The reaction mass was filtered, the filtrate was evaporated and the residue was purified by rapid chromatography (silica gel, eluent: 15% ethyl acetate/hexane), was obtained 3.0 g of product 3 as a clear oil.

When replacing 4-bromobutyrate other galoperai received the corresponding ether-esters. Similarly, when using instead of the specified in the methodology of phenol other substituted 2 - benzyloxyphenol, received the appropriate 2-substituted esters. When replacing 2-benzyloxy or 2 - benzylthio-thiophenol 2-hydroxyacetophenone received appropriate thioether-ethers.

B. Ethyl-4-(2-hydroxyphenoxy)butyrate (4)

A mixture of compound 3 (1,57 mg, 7% mmol), ethanol (50 ml), glacial acetic acid (7 drops) and 10% palladium on coal was kept at room temperature in hydrogen atmosphere (40 psi) to the next.

C. Ethanol 4-(2-(11-carbomethoxy)undecanoate)butyrate (6)

When interacting compounds 4 (0,224 g, 1.0 mmol) and methyl 12-bromododecane 5 (0.32 g, 1.1 mmol) with potassium carbonate in acetone according to the method of example a received connection 6 (0.3 g) as a colourless oil.

When using this method instead of methyl 12 - bromododecane other halo-ethers received the corresponding diesters.

D. 4-(2-(11-carboxyphenoxy)phenoxy)butane acid (7)

With stirring to a solution of compound 6 (is 0.102 g, 0.23 mmol) in methanol (4 ml) and water (3 drops) was added dropwise a 2.5 N solution of sodium hydroxide (0,55 ml, 1.37 mmol), was added 2 ml of methanol to obtain a clear solution. Upon completion of the reaction (TLC data, 2% methanol in methylene chloride (10 ml) with the addition of 4 drops of glacial acetic acid) methanol was evaporated in vacuo, the residue was stirred with water (10 ml) and the resulting solution was filtered, the filtrate was acidified using 2 N. hydrochloric acid. The precipitate was filtered, washed with water and dried. Received connection 7 (88 mg) as a white solid product, so pl. connections with 95oC, melting at 105oC (not exactly; A. O. Spencer Hot Stage).

Elemental analysis for C22H34O6< / BR>

4-(2-(11-carboxyphenoxy)phenylsulfonyl)butane acid

When processing thioethers, for example, compounds 7A in the circuit C in the form of ester or acid, metaperiodate sodium in a suitable solvent received the corresponding sulfoxide. Similarly, when interacting with tieferen with m-chlormadinone acid was obtained corresponding sulfon. For example, in the interaction of 4-(2-(11 - carboxyphenoxy)phenylthio)butane acid 7A (0,41 g, 1.9 mmol) in acetone (25 ml) with metaperiodate sodium (to 0.72 g, 3.3 mmol) in water at room temperature was obtained sulfoxide 7B. When processing the same connection with excess m-chlormadinone acid in methylene chloride was received appropriate sulfon.

The NMR spectra and mass spectra of all compounds 3-16 consistent with the proposed structure.

Example 1. Getting 4-(2-(11-carboxymethylamino)phenoxy)butane acid

Stage A: Ethyl-4-(2-nitrophenoxy)butyrate (3)

To a solution of 2-NITROPHENOL 1 (1.4 g, 10 mmol) and ethyl-4-bromobutyrate (2.1 g, of 1.57 ml, 11 mmol) in 35 ml dry acetone was added with stirring 2 g (14.5 mmol) of anhydrous powdered potassium carbonate. The obtained colored mixture was heated in a nitrogen atmosphere and heated until then, until ischezali, got the oil, which was purified by rapid chromatography (silica gel, eluent ethyl acetate/hexane or methylene chloride) was obtained 2.4 g (96%) of compound (3) as oily liquid.

Stage B: Ethyl-4-(2-aminophenoxy)butyrate (4)

A solution of compound 3 (1.27 g, 5.0 mmol) in 15 ml of ethyl acetate containing 200 mg of 5% palladium on coal, was kept in an atmosphere of hydrogen (40 psi) at room temperature until cessation of hydrogen absorption. Then the mixture was filtered and was evaporated in vacuum, received 1.0 g of compound 4 in the form of oil/low-melting solid product.

Stage C: Dodecandioic acid onomatology ether

Diethyldodecanamide 5 (34.4 g, 0.12 mmol) was treated with octahydrate of barium hydroxide (19.2 g, 0.06 mmol) in methanol (240 ml) by the method described in the article J. Org. Syn. Coll. Vol. 111, p. 635, got 24.8 g of compound 6 as a white solid product.

Stage D: Dodecandioic acid onomatology ether monochlorohydrin (7)

A mixture of monocellate 6 (10 g, 0,041 mol) and thionyl chloride (12.1 g, 0,166 mol) was heated 5 hours, the excess thionyl chloride was removed in vacuo, dissolving several times in benzene and pariva dry, obtained 10.8 g of the named compound 7 in the form of a waxy product.

Stage E:amine 4 and dry triethylamine (1.2 ml) in dry ether (40 ml) under stirring was added dropwise over 4 min a solution of the carboxylic acid 7 (1.04 g, of 4.6 ml) in 20 ml dry ether. The resulting mixture was stirred with cooling for 20 min and then at room temperature overnight. The reaction mass was filtered from chlorohydrate of triethylamine, the ether filtrate was evaporated in vacuo, the obtained residue was chromatographically on a column with 82 g of silica gel, eluent 20% ethyl acetate/hexane, got 1,49 g (yield 85%) of compound 8 in the form of a waxy product.

In this reaction, the ether/triethylamine can be replaced by methylene chloride/pyridine. The same connection can be obtained for a direct connection acid 6 with the same amine using known binding reagents, such as dicyclohexylcarbodiimide, N,N-dimethylaminopyridine etc.

Stage F: 4-(12(11 carboxymethylamino)phenoxy)butane acid (9)

To a solution of compound 8 (1.0 g, 2.22 mmol) in methanol (100 ml) under stirring was added 1 ml of water, and then was added dropwise a solution of 2.5 n sodium hydroxide solution (4.0 ml). The walls of the reaction flask was rinsed with 10 ml of methanol and the resulting mixture was stirred under nitrogen atmosphere until the end of the reaction (disappearance of the mono - or diapir, TLC data). The methanol was evaporated in vacuo, the residue was treated with 100 ml of water under stirring, fil is added dropwise. The precipitate was filtered, washed with water twice and dried. Received 0.87 g (yield 96%) of compound (9) in the form of a chalk-like product. According to TLC (silicagel, eluent 10 ml of 2% methanol in methylene chloride containing 4 drops of glacial acetic acid) product contain one connection, so pl. 128,5-130oC.

Elemental analysis:

Calculated,%: C 64,84; H 8,16; N 3,44;

Found, %: C 64,90; H A 8.34; N 3,33.

Stage G: Ethyl 4-(2-amino-3-methylphenylthio)butyrate (11)

To a deaerated (nitrogen) solution of 2-aminothiophenol 10 (1.25 g, 10 mmol) and ethyl 4-bromobutyrate (2.14 g, 11 mmol) in dry 1,2-dimethoxyethane (40 ml) under stirring was added to 8.3 g of solid powdered anhydrous potassium carbonate, the resulting mixture was variavle three times with nitrogen and stirred at room temperature until completion of the reaction (TLC data). The mixture was filtered and concentrated, the obtained residue was subjected to rapid chromatographicaliy on silica gel (85 g) using 15% ethyl acetate in hexane as eluent. Received 1.8 g of compound (11) in the form of a light beige oil.

Stage H: 4-(2-(11-carboxymethylamino)phenylthio)butane acid (13)

When the acylation of amine 11 with the acid chloride of the acid 7 on metodio)phenylthio)butyrate 12) at stage I by the method of stage F received a named connection 13, so pl. 113,5-115oC.

The following compounds of this series were further obtained by the method described above:

14) 4-(2-(9-carboxyaniline)phenoxy)butane acid, so pl. 121,5-124,5oC.

15) 4-(2-(10-carboxymethylamino)phenoxy)butane acid, so pl. 110-111,5oC.

16) 4-(2-(12-carboxymethylamino)phenoxy)butane acid, so pl. 116-119oC.

17) 4-(2-13-(carboxyhaemoglobin)phenoxy)butane acid, so pl. 128-129,5oC.

18) 4-(2-(15-carboxymethylamino)phenoxy)butane acid, so pl. 121-125oC.

19) 4-(2-(11-carboxymethylamino)phenoxy)valeric acid, so pl. 112-113,5oC.

20) 4-(2-(11-carboxymethylamino)-3-methylphenoxy)butane acid, so pl. 134,5 to 136.5oC.

21) 4-(2-(11-carboxymethylamino)-4-methylphenoxy)butane acid, so pl. of 99.5-100,5oC.

22) 4-(2-(11-carboxymethylamino)-5-methylphenoxy)butane acid, so pl. 109,5-113oC.

Stage I: Benzyl 2-nitrophenyloctyl ether (23)

When the interaction of 2-NITROPHENOL 1 benzylbromide under the conditions described in stage A, has been named connection in the form of oil is Golden in color.

Stage K: Benzyl 2-AMI is svodnyy ammonia, was stirred in nitrogen atmosphere (pressure of 40 pounds per square inch) in the presence of Raney Nickel (2 g) to the end of the reaction (TLC data, the disappearance of the original nitro compounds). The mixture was filtered and using dry nitrogen was otdovali from an excess of ammonia. After removal of ethanol at room temperature by vacuum distillation was obtained 1.0 g of compound 24 in the form of highly colored residue, which was used without further treatment in the next reaction. The same compound can be obtained by careful restoration in ethanol or ethyl acetate using a catalyst of palladium on charcoal, but this process is accompanied by a slight excess recovery.

Stage L: N-TRIFLUOROACETYL-2-benzyloxyaniline (25)

To a mixture of amine 24 (5.0 mmol) and dry diethyl ether (30 ml) under stirring was added anhydrous sodium carbonate (6.9 g, 57 mmol) and the resulting mixture was cooled in an ice bath. To the cooled mixture dropwise over 2 min was added triperoxonane anhydride (1.5 ml, 10.6 mmol), the reaction mixture became yellow-red. After 2 h, removed the cooling bath and the reaction mass was stirred at room temperature overnight, then filtered, the filtrate conc the howling colouring on the edges).

Stage M: N-methyl-2-benzyloxyaniline (27)

A well-stirred solution of compound 25 (0,295 g, 1.0 mmol), under the conditions (0.25 ml, 4.0 mmol) and anhydrous acetone (5.0 ml) was placed in an oil bath, preheated to 59oC, and held at this temperature for 2 minutes and Then in one portion was added a powder of anhydrous potassium hydroxide (0,225 g, 4.0 mmol), the bath temperature was raised to 65oC. was Observed clumping certain amount of KOH. After 15 min the reaction mass was removed from the bath, cooled and removed volatile components. With stirring to the resulting residue N-methyl-N-TRIFLUOROACETYL-2-benzyloxyaniline 26 was added methanol (7 ml), then water (1 ml) and then methanol (1 ml) (for washing walls). After stirring over night at room temperature the methanol was evaporated in vacuo, the residue was treated with ether and water, salts were separated, the organic layer was washed with water, saturated sodium chloride solution and dried with sodium sulfate. After filtration the ether solution was evaporated and obtained a named connection 27 (0,212 g) as oil. According to the NMR spectra, mass spectrum and TLC the product contained a small amount of dimethyl derivative.

Stage N: N-(11-(carbomethoxy)undec is inflorida (10 ml), containing anhydrous pyridine (0.3 ml) with stirring dropwise within 1 min was added compound 7 (0.27 g, 1,03 mmol) in 5 ml of methylene chloride (a small amount of methylene chloride used for washing). After stirring for 30 min the mixture was allowed to warm to room temperature to complete the reaction. Then the reaction mass was washed 1 time 1 N. hydrochloric acid, dried with sodium sulfate and filtered. After a quick chromatography (silica gel, eluent 20% ethyl acetate/hexane) of the obtained residue was allocated a named connection 28 (0.3 g) as a colourless oil.

Stage A: N-(11-(carbomethoxy)undecanoyl)-N-methyl-2 - hydroxyanisol (29)

A solution of compound 28 (0.11 g, 0.25 mmol) in methanol (11 ml) containing 10% palladium on coal (30 mg) was shaken in an atmosphere of hydrogen (pressure of 40 pounds per square inch) before the end of the reaction (TLC data, the absence of Y). The filtered solution was concentrated in vacuum, has been named connection 29, which is immediately used at the stage of P.

Stage P: Ethyl 4-(2-N-(11-carbomethoxyamino)-N-methylamino)phenoxy)butyrate (30)

To a solution of compound 29 (0,087 g, 0.25 mmol) and ethyl 4-bromobutyrate (0,1145 ml, 0.80 mmol) in anhydrous acetone (10 ml) with stirring up the atmosphere of nitrogen for 24 hours The mixture was cooled, filtered, evaporated and subjected to rapid chromatographicaliy (silica gel, eluent 20% ethyl acetate/hexane), was obtained 80 mg of the named compound 30 as a colorless oil.

Stage Q: 4-(2-N-(11-carbomethoxyamino)-N-methylamino)phenoxy)butane acid (31)

When the hydrolysis of compound 30 (by 0.055 g, amount of 0.118 mmol), analogously to its N-demetrova analogue (stage F), followed by acidification and extraction of the resulting oil with methylene chloride, has been named connection 31 (51 mg) as a colourless oil.

Stage R: Ethyl 4-(2-(11-bromoundecanoic)phenoxy)butyrate (32)

To a solution of compound 4 (2,60 g, 11 mmol) 11-bromoundecanoic acid (2.65 g, 10 mmol) in anhydrous methylene chloride (90 ml) was added 4-(dimethylamino)pyridine (1.22 g, 10 mmol) and then N,N-dicyclohexylcarbodiimide (2.3 g, 11 mmol) (wash 4 x 5 ml of methylene chloride). Sediment dicyclohexylamine appeared after 4 minutes At the end of the reaction (TLC data) and the mixture was filtered, the filtrate was concentrated in vacuo and the residue was extracted with ether. The combined extracts were washed once with 1 N. hydrochloric acid, 1 time with saturated sodium chloride solution, dried with sodium sulfate and evaporated, or ether, or with chloride metrenome 32 (2.35 g) in the form of oil, which is easily turned into a waxy product.

Attempts to clean the column chromatography described above (silica gel, eluent 20% ethyl acetate/hexane) resulted in the receipt of contaminated product, with a significant reduction of the output.

Stage S: Diethyl-10-(N-((2-(3-carboethoxy)propyloxy)phenyl)carboxamido)decylphosphonic (33)

A mixture of compound 32 (0,252 g, 0.5 mmol) and triethylphosphite (TEF) under stirring was kept in nitrogen atmosphere at 180oC (bath temperature) for 8 h, cooled, removed excess Teff in vacuum and the residue was subjected to rapid chromatographicaliy (silica gel, eluent ethyl acetate). Received connection 33 (0,13 g) as a colourless oil.

Stage T: the Splitting of the phosphonate ester 33 using bromotrimethylsilane (method - J. C. S. Chem. Comm. 1979, p. 139) led to 10-(N-((2-(3-carboethoxy)phenoxy)phenyl)carboxamido)decylphosphonic acid 34.

Stage U: Further hydrolysis of compound 34 by the method of example G was brought to the corresponding di-acid, 10-(N-((2-(3-carboxy)phenoxy)phenyl)carboxamido)decylphosphonic acid 35.

Stage V: 10-(N-((2-(3-carboethoxy)propyloxy)phenyl)carboxamido)mechanizations bromide (36)

A solution of compound 3 is ary conditions, described for stage W. After evaporation of the reaction mixture has been named connection 36 (containing a small amount of thiourea), which slowly crystallized upon standing. Rubbing with dry chloroform and subsequent filtration and concentration gave the product as a thick wax.

Stage W: 10-(N-((2-(3-carboethoxy)propyloxy)phenyl)carboxamido)dementiazoloft sodium (37)

To a solution of compound 32 (0,047 g, 0.1 mmol) in ethanol (2.0 ml) under stirring was slowly added water (10 drops), and then sodium thiosulfate (0.035 g, 0.14 mmol) and the reaction mass was heated in nitrogen atmosphere in an oil bath (bath temperature approximately 90oC) before the end of the reaction (TLC data). The mixture was cooled and ethanol was evaporated and water. Got the white balance, the extraction of which chloroform and filtered from inorganic impurities led to 37 product (49 mg) in the form of a glaze, which eventually turned into a waxy solid product. The resulting product had good solubility in water.

Oxidation of compound 36 or 37 by the method described Kovallam D. S. and others - J.Org. Chem. - 1962, 27, p.2853, or C. Ziegler and others J.Org. Chem. - 1951, p.621, led to the corresponding acid is utrata 2 and 2-nitro-3-pyridinol 39 according to the method of stage A. After a quick chromatography (silica gel, eluent 1.5% methanol/methylenchlorid) to remove traces of the original phenol necessary washing the ether solution with dilute sodium bicarbonate solution. Received connection 40 in the form of a light yellow oil, yield 76%.

Stage V: Ethyl 4-(2-aminopurin-2-yloxy)butyrate (41)

This compound was obtained when reconnecting 40 according to the method described for stage B. Amin 41 was obtained in the form of a waxy solid product.

Stage Z: Ethyl 4-(2-(11-carbomethoxyamino)peril-3-yloxy)butyrate (42)

When interacting compounds 41 and 7 according to the method described for stage E, has been named connection 42, the hydrolysis of which leads to the corresponding decollete 4-(2-(11-carboxymethylamino)pyrid-3-yloxy)butane acid 43.

Stage AA: N-(11-carbomethoxyamino)-2-hydroxyanisol (44)

To a mixture of 2-aminophenol (0.24 g, 2.2 mmol) and anhydrous methylene chloride (25 ml) under stirring was added dry pyridine (0,66 ml) and the resulting mixture was cooled in an ice bath. Within 1 min was added to a solution of compound 7 (0,525 g, 2.0 mmol) in methylene chloride (2 ml) (wash 2 x 1.5 ml of methylene chloride) and the mixture was stirred while cooling. Che is voitel was evaporated in vacuum and the residue was pumped to remove traces of pyridine. Compound 44 was used without additional processing at the next stage.

Stage BB: 4-(2-(11-carbomethoxyamino)phenoxy)butyronitrile (45)

When interacting compounds 44 and 4-bromobutyronitrile according to the method described for stage A, the received connection 45 in the form of a waxy solid product. When communicating connection 44 with ethyl 4-bromobutyrate methodology stage A received connection 8.

Stage CC: 4-(2-(11-carbomethoxyamino)phenoxy)butyramide (46)

To a solution of compound 45 (11 mg, or 0.027 mmol) in methylene chloride (3 ml) was added under stirring activated dioxide, magnesium (100 ml) and the resulting suspension was stirred at room temperature. A few days later the reaction mixture was added some additional amount of methylene chloride and oxide of magnesium (100 mg) to complete the reaction. The operation was repeated once again. Upon completion of the reaction (TLC data, the absence of the original nitrile), the reaction mass was filtered, the catalyst was well washed with pure methylene chloride, the filtrate was concentrated, received the specified product 46 in the form of a waxy solid product.

The above new net connection had NMR spectra and mass-span are accurate.

Part 4

Example 1. 17 - benzoyl-androst-3,5-diene-3-carboxylic acid

This compound obtained by the reaction of 17 - carbomethoxy-androst-3,5-diene-3-protected carboxylic acid, for example, in THF with phenylmagnesium in the standard conditions of the Grignard reaction. Got a named connection, so pl. 222 - 225oC,

Reference example 1. Synthesis of 4-(4-isobutylbenzene)-2,3-dimethylbenzaldehyde

< / BR>
A mixture of 4-hydroxy-2,3-dimethylbenzaldehyde (220 mg), 4-isobutylbenzene (341 mg), potassium carbonate (1.38 in) and ethylmethylketone (10 ml) was boiled for 6 hours After cooling the reaction mass was diluted with ethyl acetate, the solution was washed with diluted hydrochloric acid, water, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent hexane/ethyl acetate, 10:1), has been named the compound (383 mg) having the following physical properties:

TLC: Rfof 0.48 (hexane/ethyl acetate 5:1);

An NMR spectrum, memorial plaques: to 7.64 (1H, d), 7,32 (1H, d), 7,16 (1H, d), 5,12 (2H, s), 2,60 (3H, s), 2,48 (2H, d), 2,24 (3H, s), 1,94 and 1.80 (1H, m) of 0.90 (6H, d).

Reference example 2. Synthesis of 4-(4-isobutylbenzene)-2,3-dimethylbenzoic acid

< / BR>
A solution of the aldehyde obtained in reference example 1 (380 mg) in acetone (5 ml) and ohlord the temperature. The reaction was stopped by adding isopropyl alcohol. The crystalline residue was washed with hexane, dried and purified column chromatography on silica gel (eluent hexane/ethyl acetate), was obtained the titled compound (328 mg) having the following physical properties.

TLC: Rfof 0.36 (hexane/ethyl acetate, 2:1).

An NMR spectrum, M. D.: 7,80 (1H, d), 7,33 (1H, d), to 7.15 (1H, d). make 6.90 (1H, d), 5,09 (2H, s), 2,58 (3H, s), 2,48 (2H, d), and 2.26 (3H, s) of 0.91 (6H, d).

Reference example 3. Synthesis 4-[2-[4-(4-isobutylbenzene)-2,3-dimethylbenzylamine]phenoxy]butane acid ethyl ester

< / BR>
Oxalicacid (2 ml) was added dropwise to a solution of carboxylic acid obtained in reference example 2 (325 mg) in methylene chloride (2 ml). The resulting solution was stirred for 1 h and evaporated. To ice a mixture of ethyl 4-(2-aminophenoxy)butanoate (232 mg), pyridine (1 ml) and methylene chloride (15 ml) with stirring was added dropwise and the solution so obtained. The mixture was stirred 30 min at the same temperature and 1 h at room temperature. The reaction mass was washed with water, dried and evaporated. The residue was purified column chromatography on silica gel (eluent hexane/ethyl acetate 5: 1), has been named the compound (383 mg) having the following physical,34 (1H, d), 7,16 (1H, d), 7,08-of 6.96 (2H, m), 6,09-to 6.80 (2H, m), 5,07 (2H, s), 4,14-of 3.96 (4H, m), 2.49 USD (2H, d), 2,48 (2H, d), is 2.44 (3H, s) of 1.18 (3H, t) 0,91 (6N, e).

Reference example 4. Synthesis 4-[2-[4-(4-isobutylbenzene)-2,3-dimethylbenzylamine]phenoxy]butane acid

< / BR>
To a solution of the ester obtained in reference example 3, (380 g) dimethoxyethane (8 ml) was added 1 n solution of lithium hydroxide (3 ml). The mixture was stirred for 30 min at 50oC, on the end of the reaction the solution was neutralized with diluted hydrochloric acid and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was recrystallized from hexane, received the specified compound (317 mg) having the following physical properties:

TLC: Rfof 0.26 (hexane/ethyl acetate, 1:1), so pl. 143oC.

Reference example 5. By the method similar to the methods of examples 1, 2, 3 and 4 received 4-[2-[4-[1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzylamine] phenoxy]butane acid of the following formula

< / BR>
where substituent R is a residue of the formula

< / BR>
Reference example 6. (-)-4-[2-[4-[1-(4-isobutylphenyl)ethoxy)- 2,3-dimethylbenzylamine]phenoxy]butane acid

The compound obtained in the previous reference example 5, (403 mg) and cinchonidine (2,36 g) was dissolved in nirvanacassanouv from acetone four times. The obtained white crystals were dissolved in chloroform. The solution was washed with diluted hydrochloric acid. The oily layer was washed with water, dried and evaporated, has been named the connection with the following physical properties:

Appearance: white crystals:

The angle of optical rotation: []-39,6(c=1, CHCl3).

Reference example 7. Sodium salt(-)-4-[2-[4-[1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzylamine] phenoxy]butane acid

The compound obtained in reference example 6, was dissolved in methanol and added a molar equivalent of sodium hydroxide solution was evaporated and received the specified connection with the following physical properties:

IR-spectrum: 3050, 1750, 1580, 1560, 1510, 1445, 1260, 1090, 1020, 740 cm-1.

Prescription example. The following components were mixed in the usual ways and formed of 100 tablets, each containing 50 mg of active ingredient, g:

4-[2-[4-[1-(4-isobutylphenyl] ethoxy)-2,3-dimethylbenzylamine]phenoxy]butane acid - 5

Calcium gluconates (dezintegriruetsja tool) - 0,2

Magnesium stearate (lubricant) - 0,1

Microcrystalline cellulose - 4,7

Examples of pharmaceutical compositions

positions for oral administration, containing the compound of the invention, 1 mg terazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 2. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 2 mg terazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 3. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg terazosin 5 mg finasteride (17- -(N-tert.- butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 4. Composition for oral administration

Example 5. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg doxazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 6. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 3 ml of doxazosin and 5 mg finasteride (17 - N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 7. Composition for oral administration.

As a specific ins and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose, to get the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 8. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 8 mg doxazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 9. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg doxazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 10. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 2 mg doxazosin and 2.5 mg finasteride (17- (N - tre which returns the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 11. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 4 mg doxazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 12. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg prazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 13. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg of prazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to the 4. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 10 mg prazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 15. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 20 mg of prazosin 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 16. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg prazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose, to get the total to the La oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg of prazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 18. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 10 mg of prazosin and 2.5 finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 19. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg of alfuzosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill a solid W is a specific variant of implementation of the composition for oral administration, containing the compound of the present invention, 7.5 mg of alfuzosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 21. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the present invention, 10 mg of alfuzosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo- -4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 and 590 mg to fill hard gelatin capsules size 0.

Example 22. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 2.5 mg of alfuzosin and 2.5 mg finasteride (17- (N-tert. -butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 23. Compositing reception containing the compound of the invention, 5 mg of alfuzosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 24. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg indoramin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 25. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg indoramin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 26. Composition for oral administration of the compound of the invention, 10 mg indoramin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 27. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 20 mg of indoramin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 28. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 40 mg indoramin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 29. Composition for oral administration.

As specifically the Mina and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose, to get the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 30. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg indoramin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 31. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 10 mg indoramin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 32. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 20 mg of indoramin and 2.5 mg finasteride (17- (N-tre which returns the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 33. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg bunazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 34. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg bunazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 35. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 10 mg bunazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose that the floor is 6. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 20 mg bunazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 37. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 40 mg bunazosin and 5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3 - oxo-4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 38. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 1 mg bunazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total is I for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 5 mg bunazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN - 3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 40. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 10 mg bunazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo - 4-Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill hard gelatin capsules size 0.

Example 41. Composition for oral administration.

As a specific variant of implementation of the composition for oral administration containing a compound of the invention, 20 mg bunazosin and 2.5 mg finasteride (17- (N-tert.-butylcarbamoyl)-3-oxo-4 - Aza-5 - androst-1-EN-3-one) was combined with enough powdered lactose to obtain the total amount of 580 to 590 mg to fill the firmness of the second gland, characterized in that it includes the introduction of about 5 mg / day of the inhibitor of 5 - reductase inhibitor selected from the group consisting of 17 - substituted 4-azasteroid, 17 - substituted aazastrida, 17-acyl-3-carboxyester-3,5-dienes derived benzylaminopurine acid, condensed Benz(thio)amides, cinnamamide, aromatic 1,2-diesters or thioethers, aromatic areallyuniquename acids, rotationally-acylaminopenicillins acids or their pharmaceutically acceptable esters or salts, in combination with 1 - 10.0 mg per day blocker1-adrenergic receptor.

2. The method according to p. 1, characterized in that the inhibitor of 5-reductase, is a 4-17-substituted-azasteroid formula I

< / BR>
where the dotted line represents a double bond, if present;

the substituents R1and R3independently from each other hydrogen, methyl or ethyl;

R2is a hydrocarbon radical selected from among linear or branched substituted or unsubstituted alkyl, cycloalkyl, or aralkyl with 1 to 12 carbon atoms or a monocyclic aryl may contain 1 or more lower alkyl substituents with 1 to 2 carbon atoms and/or one or Bo is adored, or methyl,

and its pharmaceutically acceptable salts or esters.

3. The method according to p. 1, characterized in that the inhibitor of 5-reductase, is a 4-azasteroid formula

< / BR>
where the dotted line represents a double bond, if present in the molecule;

R is selected from hydrogen, methyl and ethyl;

R2represents (a) a monovalent radical selected from among linear or branched alkyl or cycloalkyl containing 1 to 12 carbon atoms which may be substituted by one or more C1-C2-alkilani or halogen atoms; (b) Uralkaliy radical selected from benzyl or Venetia; (C) polycyclic aromatic radical, which may be substituted by one or more OH groups, groups defending the OH-group, group-OC1-C4-alkyl, C1-C4-alkilani, halogen atoms or nitro groups; (d) a monocyclic aromatic radical, which may be substituted by one or more substituents from among: (1) - OH, -OC1-C4-alkyl, C1-C4-alkyl, -(CH2)mOH, -(CH2)n, COOH, including group protecting the OH-group, where m = 1 to 4, and n = 1 to 3, provided that C1-C; 2) - SH, -SC1-C4-alkyl, -SOC1-C4-alkyl, -SO2N(C1-C4-alkyl)2C1-C4-alkyl -(CH2)mSH, -S-(CH2)n-O-COCH3where m = 1 to 4, n = 1 to 3, provided that C1-C4-alkyl is only present when you have one of these serosoderjaschei radicals;

(3) N(R3)2group which may be protected, where the substituent R3represents H or C1-C4-alkyl, when monetarily radical can also be substituted C1-C4-alkyl, and (d) heterocyclic radicals selected from 2 - or 4-pyridyl, 2-pyrrolyl, 2-furil or thiophenyl;

the substituents R', R" and R"' are each chosen from a hydrogen atom and methyl,

and their pharmaceutically acceptable salts.

4. The method according to p. 1, characterized in that the inhibitor of 5-reductase is not azasteroid formula

< / BR>
where in the ring And holds up to two double bonds;

rings b, C and D contain the optimal double bond, which is indicated by the dashed line, provided that ring a, b and C do not contain adjacent double bonds and the D ring does not contain C16-C17-double bond, when the substituent R3PR is slowiy, Deputy Z - (CH)nif he is in the adjacent position to the double bond;

X represents H, Cl, F, Br, J, CF3or C1-C6-alkyl;

Y represents H, CF3, Cl, F, or CH3provided that substituent Y represents hydrogen, if there is no C5-C6- double bond;

R1- H or C1-C8-alkyl;

R2if it is present, is H or CH3provided that the substituent R2is absent when the carbon atom to which it is attached is unsaturated;

R3represents a

(1) hydrogen atom, or hydroxyl group, or-acetoxy and/or (a) a group of the formula

< / BR>
W is a bond or C1-C12-alkyliden;

R4represent (I) hydrogen, (II) a hydroxy-group, (III) C1-C8-alkyl, (IV) hydroxy - C1-C8-alkyl, (V) C1-C8-alkoxy, (VI) NR5R6where R5and R6each independently from each other selected from hydrogen, C1-C8-alkyl, C3-C6-cycloalkyl, phenyl; or the substituents R5and R6together with the nitrogen atom to which they are attached, form a 5 - to 6-membered saturated ring, (VII) OR7where R7- water is B>-alkyliden, R8represents (I) phenyl - C1-C6-alkylsulphonyl, (II) C5-C10-cycloalkylcarbonyl, (III) benzoyl, (IV) C1-C8-alkoxycarbonyl, (V) aminocarbonyl or C1-C8-alkyl substituted aminocarbonyl, (VI) hydrogen atom or (VII) C1-C8-alkyl;

(2) = CH-W-COR4or = CH-W - COR8, where W is the relationship C1-C12alkylidene, R4and R8accept these values, and R8is hydrogen or C1-C20-alkylcarboxylic group;

(3) a group of the formula

< / BR>
where broken link replaces the 17-hydrogen atom;

(4) is a hydrogen atom or a group HNCOR9where R9- C1-C12-alkyl or N R5R6group, where R5and R6take these values;

(5) is a hydrogen atom or a cyano,

(6) is a hydrogen atom, or tetrazolyl, or

(7) ketogroup;

or their pharmaceutically acceptable salt, with the exception of compounds in which:

(I) the ring b contains C5- C6-double bond, R1- CH3and R3is catography, methoxycarbonyl or acetyl; or

(II) ring-Nord contains C3-C4- double bond, and R3- acetoxy or acetyl;3-C4- double bond, and R1is methyl; or

(V) ring b contains C3-C4- double bond, and R3is a hydroxy-group.

5.Sposobov.1,otlichayushiesya,CTO-acyl-3-carboxy-androst-3,5-diene is a compound of the formula

< / BR>
where R1represents (a) C1-C6- linear or branched alkyl, C3-C12-cycloalkyl, which may be substituted C1-C4-alkoxygroup or C1-C4-linear/branched alkyl, C7-C12-aryl or C7-C13-aralkyl, which can be substituted by one or more substituents from among-OH, -OC1-C4-alkyl, C3-C4-alkyl, -(CH2)mOH, -(CH2)n, COOH, including protected OH group, where m = 1 to 4, and n = 1 to 3; (b) C1-C6- linear or branched alkyl, C3-C12-cycloalkyl, which may be substituted C1-C4-alkoxygroup or C1-C4-linear/branched alkyl, C6-C12-aryl or C7-C13-aralkyl, which can be substituted by one or more substituents from among-OH, -OC1-C4-alkyl, C1-C4-alkyl, -(CH2)mOH; -(CH2)n,

.

6. The method according to p. 1, characterized in that the derivative benzoylaminopyrazolin acids are compounds of the formula

< / BR>
where R' is a hydrogen atom or alkyl containing from 1 to 4 carbon atoms;

And is oxygen, sulfur or alvilda (SO) group;

R1both are methyl or chlorine, or both R1and the carbon atoms of the benzene ring to which are attached two Deputy R1together form a cyclopentane, cyclohexane or benzene ring;

R2represents the remains of formulas

< / BR>
< / BR>
or

< / BR>
where is oxygen, sulfur or a residue of the formula NR11where R11is hydrogen or alkyl containing 1 to 4 carbon atoms;

R3- R8independently from each other - alkyl containing 1 to 4 carbon atoms, halogen, triptoreline or cyclobutylmethyl group;

m = 0 or 1;

n = 1 to 5;

R9is hydrogen, alkyl containing 1 to 5 carbon atoms, or a group of the formula

< / BR>
< / BR>
or

< / BR>
where R12- R15independently from each other hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, triptoreline or cyclobutylmethyl group, and 1 = 1 - 4, integer;

R10represents a group of formula

< the, halogen, triptoreline or cyclobutylmethyl group;

l1= 1 - 4, integer;

and their non-toxic salts.

7. The method according to p. 1, characterized in that the specified cinnamoned represents the connection formulas

< / BR>
where R2and R3each independently from each other or a methyl group, provided that (I) if the substituent R2represents a methyl group, R3is hydrogen, (R1)nrepresents a group selected from the group comprising 3-pentelow, 4-pentelow, 4-neopentylene group, 4-(2-ethylbutyl)-4-(2-were), or (II) if R2is hydrogen, R3is a methyl group, R1)n- 3-pencilina group,

and their non-toxic salts.

8. The method according to p. 1, characterized in that the condensed benzo(thio)amide is a compound of the formula

< / BR>
where a represents a single bond or a group selected from methylene, ethylene, trimethylene, tetramethylene, vinylene, propylene, butylene, butadiene or ethynylene, possibly substituted by one, two or three linear or branched alkyl groups containing 1 to 10 carbon atoms and/or phenyl (s) group(s);

In a 4 - to 8-membered Goethe is Yes, nitrogen and sulfur, such ring may be substituted by substituents of oxo, thioxo - and/or hydroxy groups, including rings formulas

< / BR>
T is oxygen or sulfur;

R1represents the balance formulas

< / BR>
< / BR>
< / BR>
(IV) a linear or branched alkyl, alkenyl or quinil containing 1 to 20 carbon atoms,

where the substituents R5and R6independently from each other hydrogen or halogen, or a branched or linear alkyl, alkenyl or quinil containing 1 to 20 carbon atoms which may be unsubstituted or substituted by one, two, three, four or five carbon atoms with atoms of oxygen, sulfur, halogen, nitrogen, benzene rings, thiophene rings, naphthalenamine rings, carbocyclic ring containing 4 to 7 carbon atoms, carbonyl groups, carbonyloxy, hydroxyl groups, carboxypropyl, sidegroups and/or nitro groups;

R2is hydrogen or a linear or branched alkyl containing 1 to 6 carbon atoms;

R3is hydrogen, halogen, a hydroxy-group, the nitro-group, a group of the General formula COOR7where R7is hydrogen or a linear or branched alkyl containing 1 to 6 atoms of carbon is dstanley group of General formula

-V-(CH2)n-COO R8< / BR>
< / BR>
or

< / BR>
V is oxygen or sulphur;

R8is hydrogen or a linear or branched alkyl containing 1 to 6 carbon atoms;

n and m = 1 to 10

p and q = 0 or 1 to 10, an integer,

and their non-toxic salts.

9. The method according to p. 1, characterized in that the specified areallyuniquename acid formula

< / BR>
where a is a 1,2-disubstituted aromatic ring selected from among: (a) benzene; 1,2-substituted naphthalene; (b) a 5 - to 6-membered heteroaromatic ring containing 1 to 2 nitrogen atom, 1 sulfur atom or oxygen, or a combination thereof; D and E independently of one another are - COOH, -CONH2, -CONHRin, COORin, SO2OH, SO3(OH), SO2NH2, -SSO2ASO, -PH(O)(OH), -P(O)(OH)2;

X is O, S, SO or SO2;

R is hydrogen, C1-C4-alkyl, phenyl or substituted phenyl, halogen atom, halogenated the hydroxy-group, carboxyl group, cyano, C1-C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylsulfonyl group,

C1-C4-alkylsulfonyl group, the nitro-group, amino group, C1-C4-mono - or di-alkylamino;

R' and R" independently of the other is the group where fragments CH-R' or CHR" in the formula become a group- (C=0;

Randrepresents H or C1-C4-alkyl;

Hb- C1-C12-alkyl, phenyl or phenyl C1-C4-alkyl;

y = 1 - 6;

z = 6 - 20;

(CH)y- R' and (CH)zR" can independently from each other represent substituted or unsubstituted alkyl radicals or alkeneamine radicals containing at least one alanovoy communication;

and their pharmaceutically acceptable salts and esters.

10. The method according to p. 1, characterized in that the specified rotationalvibrational acid is a compound of the formula

< / BR>
where A - 1,2-disubstituted aromatic ring;

D - OH, NH2, OTHERwithORwith;

X IS O, S, SO, SO2;

R is hydrogen or C1-C4-alkyl, phenyl or substituted phenyl, halogen, haloalkyl, the hydroxy-group, carboxyl group, cyano, C1-C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylsulfanyl group, C1-C4-alkylsulfonyl group, the nitro-group, amino group, C1-C4- mono - or di-alkylamino;

R' and R" independently from each other hydrogen, halogen, C1-C
Rand- H or C1-C4-alkyl;

Rband Rcindependently from each other - C1-C12-alkyl, phenyl, phenyl-C1-C4-alkyl;

n = 0 - 2;

y = 1 - 6;

z = 6 - 20;

fragments (CH)y-R' and (CH)Z- R" can independently from each other represent substituted or unsubstituted alkyl radicals or alkeneamine radicals containing at least one alanovoy communication;

and their pharmaceutically acceptable salts and esters.

11. The method according to p. 1, characterized in that the aromatic fluids or thioether is a compound of the formula

< / BR>
where a is a 1,2-disubstituted aromatic ring;

D - OH, NH2, OTHERcORc;

X IS O, S, SO, SO2;

R is hydrogen, C1-C4-alkyl, phenyl or substituted phenyl, halogen, haloalkoxy, carboxyl group, cyano, C1-C4-alkoxygroup, C1-C4-allylthiourea, C1-C4-alkylolamides group, C1-C4-alkylsulfonyl group, the nitro-group, amino group, C1-C4- mono - or di-alkylamino,

R' and R" independently from each other hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxygroup, amino H, or C1-C4-alkyl;

Rband Rcindependently from each other - C1-C12-alkyl, phenyl, phenyl - C1-C4-alkyl;

n = 0 - 2;

y = 1 - 6;

z = 6 - 20;

(CH)yand (CH)Z- R" can independently from each other represent substituted or unsubstituted alkyl or alkeneamine radicals containing at least one alanovoy communication;

and their pharmaceutically acceptable salts and esters.

12. The method according to p. 1, characterized in that the blocker1-adrenergic receptor selected from the group consisting of terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin.

13. The method according to p. 8, characterized in that the blocker1-adrenergic receptor is a terazosin.

14. The method according to p. 1, characterized in that the above-mentioned inhibitor of 5-reductase is finasteride and above the blocker1-adrenergic receptor is terazosin.

15. Pharmaceutical composition for the treatment of benign prostatic hyperplasia, including a 2.5 - 5.0 mg of inhibitor of 5-reductase inhibitor selected from the 17-substituted 4-azasteroid, 17-substituted aazastrida, 17-acyl-3-carboxymethylamino, aromatic 1,2-diesters, aromatic areallyuniquename acids, portatilmovilintercentrino acids or their pharmaceutically acceptable salts and esters, and 0.5 - 10 mg blocker1-adrenergic receptor in a pharmaceutically acceptable carrier.

Priority points:

20.03.91 on PP.1, 3, 4, 6, 8, 10, 12 - 15;

11.03.92 on PP.2, 5, 7, 9 and 11.

 

Same patents:

The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases

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;)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

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

The invention relates to medicine, specifically to pharmacology
The invention relates to pharmaceutical industry and relates to the creation of new dosage forms in the form of ointments with photosensitizers that may be used in medical practice, in particular when conducting photodynamic therapy

The invention relates to the compound of formula (I):

< / BR>
where

Ar is chosen from the group including

(a) phenyl, naphthyl and diphenyl, each of which optionally contains from one to three substituents selected from the group including:

C1-4alkyl, C1-4halogenated, C1-4hydroxyalkyl, C1-4alkoxy, C1-4halogenoalkane, C2-4alkoxyalkane, C1-4alkylthio, hydroxy, halogen, cyano, amino, C1-4alkylamino, di (C2-8) alkylamino, C2-6alkanolamine, carboxy, C2-6alkoxycarbonyl, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group or halogen, phenoxy, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halog is selected from the group including C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen;

(b) furyl, benzo (b) furyl, thienyl, benzo/b/thienyl, pyridyl and chenail, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, halogen, C1-4alkoxy, hydroxy, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano or halogen, phenoxy group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications

The invention relates to derivatives of 2, 3, 4, 5-tetrahydro - 1,4-benzothiazepine, containing pharmaceutical compositions, and methods for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means to prevent such painful conditions as paralysis
The invention relates to medicine, Nephrology

The invention relates to the class of pyrimidine compounds, which are suitable for the treatment of diseases and disorders of the Central nervous system (CNS), for example to prevent cerebral ischemic lesions, containing their pharmaceutical compositions and to methods for their preparation

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases
The invention relates to medicine, surgery may be used in the treatment of acute pancreatitis
Up!