Inhibitors of testosterone 5-reductase inhibitor, pharmaceutical composition and method of inhibiting the activity of the testosterone 5- reductase

 

(57) Abstract:

Describes inhibitor testosterone 5-reductase, having a molecular formula I, where the dotted line represents an optional PI bond; R4denotes hydrogen or methyl, but is not hydrogen if there is no specified optional PI bond; R6denotes hydrogen; R7denotes hydrogen; R17denotes hydrogen or lower alkyl and R17stands WITH1-C7is an alkyl or aryl tertiary amino group or1-C7is an alkyl or aryl aminogroup. New inhibitors can be used in the treatment of androgen-sensitive diseases, which can be slowed by inhibition of activation of androgen receptors. Also describes the composition with compounds of the formula I and a method of inhibiting the activity of the testosterone 5-reductase. 8 S. p. f-crystals., 8 Il., 13 table.

This invention relates to active compounds, pharmaceutical compositions and methods for the treatment of androgen-mediated disorders, and this composition contains new activity inhibitors of testosterone 5-reductase. Inhibitors possess a good combination of young incarnations, antiandrogenna activity. More specifically, some specific embodiments of the invention relate to derivatives of 4-Aza-androstenone or 4-Aza-androstenone.

Background of the invention

Previously known inhibitor of 5-reductase fail to provide the combination of (1) lack of androgenic activity and (2) the ability to inhibit both forms of testosterone 5-reductase ("5-reductase").

5-reductase is the enzyme that catalyzes the conversion of androgen - testosterone - in a much stronger androgen dihydrotestosterone (DHT). DHT is a more active idrogeno in many target organs (Andersson and Liao. Nature 219:277-279, 1968). The same enzyme catalyzes the conversion of Androstenedione in androstendion. Inhibitors of 5-reductase inhibit the biosynthesis of products, the formation of which is catalyzed by 5-reductase.

5-reductase was rejected on various wdah (Liang et al. Endocrinology 117: 571-579, 1985). His isolation and structure and expression of cDNA encoding it, have been described (Andersson and Russell. Proc. Natl. Acad. Sci. 87:3640-3644, 1990).

Recent data have demonstrated the presence of at least two different genes expressing 5-reductase in humans. 5-reductase type is ductase type II is the predominant enzyme isoform in these tissues (Andersson et. al., Nat. 354, 159-161, 1991).

Blockade of 5-reductase emanated from the point of view of the pharmaceutical development of medicines for the treatment of diseases such as prostate cancer. In European patent application N EP 285383 Ramusson et al. describe the treatment of prostate carcinoma using 17-N-monosubstituted carbonyl-4-Aza-5-androst-1-EN-3-ones. Diseases which were also investigated inhibitor of 5-reductase, include inflammation of the sebaceous glands, baldness (Rittmaster et. al. J. Clin. Endocrinol. Metab. 65:188-193, 1987) and benign hyperplasia of the prostate (Metcalf et al. 10:491-495, 1989).

It was proved that 4-Aza-steroid N, N-diethyl-4-methyl-3-oxo-4-Aza-5-androstane-17-carboxamide, 4-M, are useful for inhibiting the formation of DHT from testosterone in the prostate of rats in vitro and in vivo (Brooks et al., Endocrinology 109: 830-836, 1981), thus reducing the testosterone-induced increase in the weight of prostate cancer in these animals. It was discovered that another 4-Aza-steron, MK-906 (PROSCAR), causes a decrease in the concentration of DHT in the prostate and 25-30% reduction in the size of the prostate in humans (Imperato-McGinley et al., Proc. 7ist Ann. the meet. Endocr. Soc. p. 332, abst 1639, 1989). However, it is reported that Proscar is a strong inhibitor of the enzyme type II, but a weak inhibitor of the enzyme type I (Andersson et al., Nature 354, 159-161, 1991). Such weak inhibitory AK is not capable of lowering serum levels of dihydrotestosterone below 25-35% of control, thus keeping a very significant concentration of circulating androgens (Vermeulen et al., The Prostate 14, 45-53, 1989). The inhibitory effect of drugs on prostate volume in humans remains limited to the level of 25-35% over the period of time of 6 months (Stoner, J. Steroid Biochem. Mol. Biol. 37, 375-378, 1990). Therefore, you must create compounds that can effectively inhibit both type I and type II 5-reductase and, thus, to cause a more complete suppression of circulating levels of dihydrotestosterone.

In U.S. patent N 4317817, Belgium patent N 883091 and the United Kingdom patent N 2048888 Blohm and Metcalf consider the application of certain diazo-steroids as inhibitors of 5-reductase. Metcalf et al. describe the synthesis of closely related structure compounds in Tetrahedron Lett. 21, 15-18, 1980.

In the publication EP N 343954, publication EP N 375347, U.S. patent N 4882319, U.S. patent N 4937237 and J. Med. Chem. 33:937-942, 1990, Holt et al. consider using some of the A-ring aryl steroid derivatives as inhibitors of steroid-5-reductase.

In the publication EP N 289327 and publication EP N 42734, on the one hand, and in J. Steroid Biochem. 34, 571-575, 1989, Biochemistry 29: 2815-2824, 1990, on the other hand, Holt and Levy consider accordingly the use of androsten - and pregnen-3-carboxylate getting substituted phosphoric acid steroids as inhibitors of testosterone 5-reductase.

In the publication EP N 271219, publication EP N 314199 and publication EP N 155096 Rasmusson and Reynolds are considering getting a 17-substituted-4-Aza-5-androstenone as inhibitors of steroid-5-reductase.

Brooks et al. (Steroid 47: 1-19, 1986; Prostate 9: 65-76, 1986) reported inhibitory 5-reductase and androgen - suppressive activities of some 4-Aza-steroid.

Rasmusson et al. consider some Aza-steroids as inhibitors of 5-reductase in the prostate of rats (J. Med. Chem. 27:1960-1701, 1984; the same authors, 29:2298-2315, 1986, J. Biol. Chem. 259: 734-739, 1984).

In the publication EP N 277002 Holt et al. consider the 17-substituted-4-Aza-5-androstane-3-ones.

In the publication EP N 271220 Carlin et al. consider getting 17-(N-monosubstituted carbarnoyl)-4-Aza-5 - androstane-3-ones.

In the publication EP N 200859 Carlin et al. consider getting some 4-Aza-steroidprednisone that, as installed, are inhibitors of steroid-5-reductase.

In the international patent application N WO 91/12261 Panzeri et al. consider obtaining derivatives of 17 - substituted-4-Aza-5-androstane-3-ones.

In U.S. patent 4396615, Steroids 38:121-140, 1981 and Steroid Biochem. 19: 1491-1502, 1983; Petrow et al. consider some derivatives of 6-medienproduktion that, as installed, are inhibitors smusson et al. consider some 17-substituted-4-Aza-5-androstane (including their acylamino-substitution) as inhibitors of steroid-5-reductase.

In the publication EP N 052799 Alig et al. consider some D-Domostroy as inhibitors of steroid-5-reductase.

In U.S. patent 4191759 Johnston and Arth consider N-substituted-17-carbarnoyl-androst-4-EN-3-ones as inhibitors of steroid-5-reductase.

In Belgium patent 855992 Benson and Blohm consider steroid inhibitors of testosterone 5-reductase for the treatment of skin diseases.

In the patent Canada 970692 Voight and Hsia consider compounds that inhibit the activity of 5-reductase.

In French patent 1465544 Jolly and Warnant consider 4-Aza-aromatic steroid derivatives as inhibitors of steroid-5-reductase.

In U.S. patent 4087461 Robinson examines some of allene steroids as inhibitors of testosterone 5-reductase.

In the publication EP N 414529 Metcalf examines some of 17-substituted steroid acids as inhibitors of testosterone 5-reductase (see, e.g., abstract). See also Holt et al., publication EP N 427434.

In the publication EP N 298652 Bhattacharya considers the synthesis of 4-Aza-1-steroids.

< / the 3-oxo-4-Aza-androst-1-ene-17-ketones.

In the patent application U.S. N 5061803 Steinberg and Rasmusson consider getting a 17-aminobenzoyl-4-Aza-5/ -androst-1-EN-3-ones as agents for benign prostatic hypertrophy.

Lan-Hargest et al. consider the synthesis of A bridge ring steroids as inhibitors of 5-reductase (Tetrahedron Lett. 28: 6117-6120, 1987).

Weintraud et al. (J. Med. Chem. 28: 831-833, 1985) consider getting a 20-hydroxymethyl-4-methyl-4-Aza-2-oxa-5-pregnan-3-one as inhibitors of testosterone 5-reductase.

Kadohama et al. (Cancer Res. 44:4947-4954, 1984) consider inhibition with sodium 4-methyl-3-oxa-4-Aza-5-pregnan-20 (S) carboxylate 5-reductase inhibitor prostate cancer.

MacIndoe et al. in Steroid Biochem. 20: 1095-1100, 1984; see 5-reductase inhibitory activity of some 6-meilensteine in the cells of MCF-7 breast cancer man.

Liang et al. (J. Biol. Chem. 256: 7998-8005 1981) consider 17-N, N-diethylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one as a reversible inhibitor of 5-reductase.

Salomons and Doorenbos (J. Pharm. Sci. 63: 19-23, 1974) and Doorenbos et al. (J. Pharm. Sci. 60: 1234-1235, 1971; the same authors 62: 638-640, 1973; Chem. and Ind.; 1322, 1970) consider the synthesis of 17-amino-4-Aza-steroid.

Nakayama et al. (J. Antibiotics XLII: 1221-1229; the same authors, 1230-1234, 1989; the same authors, 1235-1240, 1989) consider the promotional and publication EP N 294035 Nakai et al. consider obtaining respectively cinnamamide derivatives and derivatives ((benzoylamine)phenoxy)butane acid as an inhibitor of 5-reductase.

U.S. patent 5026882 and publication EP N 375349 refer to certain compounds steroid-3-phosphoric acid for use as inhibitors of testosterone 5-reductase. These patents also contain in their descriptions of numerous related compounds identified as inhibitors of 5-reductase prior art. See, for example, table 1 of U.S. patent 5026882 and discussion of prior art in this patent.

Publication EP N 435321 refers to a derivative of A non-steroid-3-carboxylic acid, which reportedly shows the ability to inhibit 5-reductase.

In international publication N WO 91/13060 and in the publication EP N 458207 Okada et al. consider getting indole derivatives as inhibitors and testosterone 5-reductase.

Salle et al., "17-acylurea Derivatives of 4-Azasteroids as Inhibitors of Testosterone 5-Reductase", for studies examining the effect of 5-reductase new series 17-alluriazone derivatives.

U.S. patent 5053403 describes the use of some agents that suppress androgen receptors vlez, excessive polosatosti and baldness in men.

It is inconceivable that the previously known inhibitors of 5-reductase completely inhibited both forms of 5-reductase without symptoms or stimulate unwanted androgenic or other hormonal activity.

The invention

In the treatment of certain diseases, the development of which is stimulated by activation of androgen receptors, it is desirable to reduce the activation of these receptors. This can be done by

reduced availability of "agonists", for example, natural androgens and other compounds able to activate the receptor, or by reducing the availability of receptors and/or by blocking access to the receptor of compounds, which would otherwise activate them. The latter can be achieved by the introduction of "antagonist", compounds with affinity for the receptor that binds to a receptor and blocks the access of agonist. In the case of androgen receptor androgen antagonist ("antiandrogen") may preferably bind the androgen receptor without activating the receptor. His physical presence will block access to the natural receptor or other androgens, which, reaching the receptor, ry testosterone 5-reductase inhibitor used in the treatment of androgen-sensitive diseases, which can be slowed by inhibition of activation of androgen receptors. Compounds of the invention inhibit the activity of 5-reductase, which catalyzes the synthesis of a strong androgen dihydrotestosterone. It is therefore desirable to reduce the ability of DHT to activate androgen receptors.

It is important to achieve this desirable reduction activity of 5-reductase without stimulating unwanted effects with the main goal of suppressing the activation of androgen receptors. Therefore, even if the compound inhibits the activity of 5-reductase, its therapeutic effect is reduced if the most inhibitor inherent androgenic properties as that inhibitor activates the same receptors, activation of which should be reduced. In addition, the inhibitor must be resistant to transformation in vivo androgenic compound.

On the contrary, however, the inhibitor of 5-reductase with antiandrogenna properties, exhibits two rather than one, the desired effect in the treatment of androgen-mediated diseases. First, it inhibits the enzymatic conversion of testosterone to dihydrotestosterone, thereby reducing the amount the range of androgen receptors, protecting them from activating any androgens, including any dihydrotestosterone, which can be synthesized in spite of the inhibitor.

Thus, inhibitors of the activity of 5-reductase preferably exhibit a combination of desirable qualities, including (A) the ability to exercise inhibition activity of 5-reductase (preferably both types of 5-reductase) and (B) significantly reducing androgenic activity (and resistance to transformation in vitro androgen). It is also desirable that the inhibitors had antiandrogenna properties. With the aim of getting rid of unwanted side effects is the preferred inhibitor of 5-reductase, in addition, have significantly reduced glucocorticoid characteristics.

Thus, an object of the present invention are superior inhibitor of 5-reductase, which more effectively inhibit the activity of 5-reductase and preferably inhibit the activity of both known types of human 5-reductase.

Another object of the present invention are pharmaceutical compositions containing an inhibitor of 5-reductase, possessing little inherent androgenic activity and minor sclerostegia object of the present invention is a method of treating androgen-mediated diseases, the development of which contributes to the activation of androgen receptors. Such diseases include, for example, prostate cancer, prostatic hyperplasia and sexual disorders and can be treated this way, lower the activity of 5-reductase.

Treatments include use of an inhibitor of 5-reductase in this invention either alone or in combination with another active ingredient, such as antiandrogens, as part of combination therapy.

The above and further objectives can be implemented using pharmaceutical compositions containing an inhibitor of 5-reductase, proposed here, together with pharmaceutically acceptable carriers or diluents. These pharmaceutical compositions are administered to a patient suffering from those diseases, which were discussed above, the development of which contributes to the activation of androgen receptors.

In one embodiment of the invention features a pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5-reductase, having a molecular fog or methyl;

where R6denotes hydrogen or C1-C3saturated or unsaturated hydrocarbon;

where R7selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6callproperty, C3-C6abaxially and their ninasimone analogues;

where R17denotes hydrogen or lower alkyl and

where R17denotes tertiary amino or aminogroup.

In another implementation of the invention, a pharmaceutical composition characterized in that it contains a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line indicates the optional PI bond;

where R4denotes hydrogen or methyl;

where R6denotes hydrogen or C1-C3saturated or unsaturated hydrocarbon;

where R7selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6cyclopropylamine C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6cyclopropylethyl, C3-C6abaxially and their unsaturated analogs; and

where R17denotes hydrogen, hydroxy or Deputy, transformed in vivo into hydroxy.

The next implementation of the invention, a pharmaceutical composition characterized in that it contains a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line indicates the optional PI bond;

where R4denotes hydrogen or methyl;

where R6denotes hydrogen or C1-C3saturated or unsaturated hydrocarbon;

where R7selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6cyclopropylethyl, C3-C6abaxially and their unsaturated analogs;

where denotes hydrogen or lower alkyl and

where R17selected from the group consisting of acyl, carboxamide, Tr is the position differs it contains pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line indicates the optional PI bond;

where R4denotes hydrogen or methyl;

where R6denotes hydrogen or C1-C3saturated or unsaturated hydrocarbon;

where R7selected from the group consisting of C2-C6alkyl, C2-C6hydroxyalkyl, C2-C6haloalkyl, C2-C6carbonylethyl, C3-C6cyclopropylethyl, C3-C6abaxially and their unsaturated analogs;

where R17denotes hydrogen or lower alkyl and

where R17selected from the group consisting of acyl, carboxylic, tertiary amino or tertiary amido.

The next implementation of the invention the pharmaceutical composition is characterized in that the inhibiting activity testesteron 5-reductase it contains a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of 5-reductase formula

< / BR>
where the dotted line indicates the optional PI bond;

g the th or unsaturated hydrocarbon;

where R7selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6callproperty, C3-C6abaxially and their unsaturated analogs;

where Raselected from the group consisting of lower alkyl, cycloalkyl and radical, which together with Rband a nitrogen atom, represented by R17is a 5-7-membered heterocyclic ring having one heteroaromatic nitrogen atom; and

where Rbselected from the group consisting of the radical, which together with Raand a nitrogen atom, represented by R17is a 5-7-membered heterocyclic ring having one heteroaromatic nitrogen atom; -CORC, -CONRCRD, -CSNRCRD, -SO2RC, -PO3RCRD(RCand RDare hydrogen, lower alkyl or lower haloalkyl).

Can also be used capsule containing an inhibitor of 5-reductase discussed here. The inhibitors and compositions containing them are used in accordance with the invention to reduce the activity of 5-reductase and of treating diseases which are caused aktivacii gland, seborrhea, abnormal hairiness, androgenic alopecia and the like.

A detailed description of the preferred embodiments

When some, but not all, implementations azasteroid kernel have a substituent (i.e. non-hydrogen), at least 4, 6, or 7 positions, such as 4-methyl and/or 6 lower alkyl, and/or 7-lower alkyl.

In some implementations, the substituent R17is a tertiary amine, such as-N(R19)(R20), where R19denotes lower alkyl or haloalkyl and R20is lower alkyl. In other implementations, R17is tradicionalna Deputy, for example, acylamino substituents, such as-N(R25)C(O)R26where R26denotes hydrogen or lower alkyl and R25represents C1-C6saturated or unsaturated hydrocarbon, such as cyclopropyl, cyclohexyl, butyl or isobutyl.

As used here, the term "tertiary amine or tertiary amido" refers to the amino or amidoamines, where the nitrogen of the amino or amido is not vodorazdelny. Preferred substituents for the nitrogen include, but are not limited to, acyl or lower alkyl.

For at least one of the two Deputy was hydrogen, hydroxy or Deputy, who converted to hydroxy in vivo (for example, benzoyloxy, acetoxy).

Hydrocarbon substituents can be saturated or unsaturated. Unsaturated substituents are believed particularly useful when the provisions of R7and R17. In some implementations, R7denotes Deputy C2-C6alkyl, alkenyl or quinil.

In some realizations, especially when R17denotes hydrogen, hydroxyl (or its ether derivatives), R17represents C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C2-C6carbonylethyl, C3-C6abaxially or their unsaturated analogs. Preferred unsubstituted analogues include, for example, halo, or hydroxy quinil or alkenyl deputies, especially when halo or hydroxy-group is at the end of the Deputy, that is the furthest away from the Aza-steroid D-ring. Preferable unsaturated 17-substituent at 1, 2 or 3 position.

Except as provided in other cases, the substituents can have - or-stereochemistry. Optional PI bond indicated by the dotted lines in mo is OUTSTA one does not depend on the presence or absence of the other, if the valence does not require interdependence. Compounds considered here, can enter into the composition in the form of their salts. Atoms azasteroid cores, which is not shown Deputy may be optionally further substituted (as valence allows) to such an extent, as the Deputy has no adverse effect on the ability of the compound to inhibit the activity of 5-reductase and does not make the connection much more androgenic.

As used here, the term "lower" when described chemical radical, means the radical having 8 or less atoms. For example, "lower alkyl" means C1-C8alkyl. Any radical of more than two atoms can be straight - or razvetvlennoy, unless otherwise stated.

As discussed in more detail later, carriers, or diluents include solid or liquid. New pharmaceutical compositions according to the invention can be used for treatment of androgen-mediated diseases. The systematic introduction by injection, for example, in the treatment of prostate cancer, benign prostate hyperplasia and other diseases, mainly not acting on the skin, using conventional diluents or neiteler saline, water, water, alcohol or oil. When the inhibitors according to the invention is used for treatment of androgen-mediated diseases, such as inflammation of the sebaceous glands, seborrhea, abnormal hairiness, androgenic alopecia, inhibitors preferably given together with commonly used carrier or diluent such as a mixture of ethanol and propylene glycol. In normal use, it is preferable that the diluent or carrier did not promotional transdermal penetration of the active ingredients into the blood stream or other tissues, where they may cause undesirable systemic effects. When the composition is prepared not for immediate use, typically include well-known experts preservatives (e.g. benzyl alcohol).

When the connection is appointed with media skin or outer route of administration, the carrier can be any known in the cosmetic or medical practice by the media, such as any gel, cream, lotion, ointment, liquid or not liquid carrier, an emulsifier, solvent, liquid diluent, or other similar solvent that does not exert any harmful effects on the skin or other living tissue of an animal. Examples under langille, water, liquid amides, liquid esters, liquid lanolin and lanolin derivatives, and similar materials. The alcohols include mono and polyhedrality, including ethanol, glycerol, sorbitol, isopropanol, diethylene glycol, propylene glycol, ethylene glycol, hexyleneglycol, mannitol and methoxyethanol. Typical carriers may also include ethers, such as diethyl and DIPROPYLENE ether, methoxypolyethylene, karbowski, polyethylenglycol, polyoxyethylene and sorbitol. Typically the carriers for topical use include both water and alcohol in order to achieve maximum hydrophilic and lipophilic solubility. Typical media will contain 75% ethanol or isopropanol and 15% water.

Carrier for external application may also include various ingredients used in ointments and lotions and is well known in the cosmetic and medical fields. For example, can be represented flavors, antioxidants, fragrances, gelatinous agents, thickening agents such as carboxymethyl cellulose, surfactants, stabilizers, softeners, coloring agents and other agents.

As illustrated in the examples given below, the compositions of the present the Oia creams, lotions, gels and ointments that are dermatologically acceptable and non-toxic. The composition can be applied in the form of a gel, cream, ointment, lotion and the like.

Can be used dry to deliver the system as described in U.S. patents NN 3742951, 3797494 or 4568343.

To facilitate transdermal penetration, when the desired systemic effects, can also be used solvents or tools, as described in U.S. patents NN 5064654, 5071644 or 5071657.

The connection may also be introduced oral route. The compound of the present invention may typically be part of a conventional pharmaceutical excipient, for example, dried spray dried lactose and Starata magnesium, in the form of tablets or capsules for oral administration. Of course, in the case of oral input forms can be added to enhance the taste of the substance. When the desired capsules for oral administration, any pharmaceutical capsules can be filled by an inhibitor of 5-reductase according to the invention with or without additional solvents and other additives discussed here.

The active substance may be placed in tablets or in the core drops by mixing with solid ismelda as polyvinylpyrrolidone, gelatin or cellulose derivatives, possibly with the addition of also lubricants such as magnesium stearate, sodium lauryl sulfate, Carbowax or polyethylene glycol.

As further forms you can use sealed capsules, for example, hard gelatin, and closed soft gelatin capsules containing a softener or plasticizer, such as gelatin. Sealed capsules contain the active substance preferably in the form of a granulate, for example, in a mixture with fibers, such as lactose, sucrose, mannitol, starches such as potato starch or amylopectin, cellulose derivatives or highly dispersed silicic acid. In soft gelatin capsules the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oil or liquid polyethylene glycols.

The following non-limiting examples describe the obtaining of a typical cream, lotion, gel or ointment, respectively. In addition to these solvents, the technician can choose other solvents in order to adapt to specific dermatological needs.

Example A.

Typical lotion contains (Phnom gel contains (by weight) 5% of active compound, 5% propylene glycol, and 0.2% Carbomer 940 (available in the form of Carbomer 940 R from B. F. Goodrich), 40% water, 0.2% triethanolamine, 2% PPG-12-Buteh-16 (available in the form of Ucon R fluid 50 from Union Carbide), 1% hydroxypropyl and 46.8% ethanol (95% ethanol-5% water).

Example C.

Typical ointment contains (by weight) 5% active compounds, 13% of propylene glycol, 79% petroleum butter, 2.9 percent glycerylmonostearate and 0.1% polyparaben.

Example D.

A typical cream contains (by weight) 5% of active compound, 0.2% propylene glycol, 5% lanolin oil, 7.5% of sesame oil, 5% cetyl alcohol 2% glycerylmonostearate, 1% triethanolamine, 5% propylene glycol, 0.1% of Carbomer 940 R and 69.2% of water.

Inhibitors of 5-reductase according to the invention is preferably included in pharmaceutical compositions in the normal concentrations for inhibitor of 5-reductase. The doctor may choose to change the concentration and/or dosage to meet the specific dose response in each patient.

When the inhibitor activity of 5-reductase are appointed in accordance with the present invention, they preferably are appointed by the oral or parenteral. Dosage preferably ranges from about 1 mg to about 1000 mg of the active part of the lo 500 mg per day per 50 kg of body weight.

The concentration of the active component varies famous by depending on the method of administration of the pharmaceutical composition. The composition is suitable for oral administration may preferably include at least one inhibitor of the activity of 5-reductase in the total concentration of all such inhibitors in the specified pharmaceutical composition from 1% to 95% by weight of the composition and preferably from about 5% to about 20%. Pharmaceutically acceptable diluent is preferably starch or lactose (with or without tetrazine).

In the case of parenteral administration, the inhibitor is preferably added at a concentration of between about 2.0 mg/ml and about 50 mg/kg (preferably from about 5.0 mg/ml to about 20 mg/ml) to the medium, preferably selected from the group consisting of saline, water, ethanol and oil.

In some alternative implementations of a pharmaceutical composition according to the invention may be part of the permanent release according to known technique. The compositions of the constant release of preferably receive a known manner, appropriate or for oral, intramuscular or subcutaneous injection.

In the case of the Tav with the carrier, selected from the group consisting of propylene glycol, ethanol, isopropanol and water, in concentrations varying from 0.5% to 10% of the total weight of the pharmaceutical composition. The composition for external use can be prepared, for example, in the form of an ointment, gel, cream or lotion to apply on the affected skin surfaces if necessary, twice a day.

In some implementations of the invention, an inhibitor of 5-reductase according to the invention are used in combination with another active ingredient as part of combination therapy. For example, new inhibitors can be used in conjunction with special antiandrogens, which may be part of the same pharmaceutical composition as the inhibitor of 5-reductase, or may be introduced separately. The active compound may have as antiandrogenna and inhibitory 5/ -reductase activity and may be supplemented by another connection for amplification of each of both of these activities (for example, another antiandrogen or another inhibitor of 5-reductase). Combination therapy may also include processing one or more compounds that inhibit the production of testosterone or its predecessor.

When ancient genom maybe for example:

< / BR>
Antiandrogen is included in the composition at normal concentrations and is entered when the conventional dosages, for example, when the same concentrations and doses as defined above for an inhibitor of 5-reductase.

Antiandrogen flutamide is commercially available from Schering Corp. (New Jersey). Antiandrogen EAT-248 may be synthesized as follows (see diagram 1).

Connection b.

To a solution of testosterone I (288,43 g, 1.0 mol) in glacial acetic acid (3.5 l) add acondition (85 ml, 1.01 mol) and boron TRIFLUORIDE (800 ml) at 10oC. the Mixture is stirred at this temperature for 1 hour and poured onto ice (2 kg). From this aqueous phase is separated white solid product and is harvested by filtration, washed with water (2 x 2 l) and dried in air. Crystallization from methanol gives pure compound "b". Output: 328,28 g (90%).

Connection c.

Solution b (182,3 g, 0.5 mol) in dry dichloromethane (1.5 l) is added dropwise to a solution of chloramine pyridinium (150 g, 0.7 mol), molecular sieves 3A (200 g) and sodium acetate (25 g) at room temperature. After completion of the addition the mixture is stirred for 16 hours and then diluted with diethyl ether (2 l) and filtered through silica gel in vorone with getting a clean connection "c". Output: 158,7 g (87%).

Connection d.

2-(3-Butenyloxy)tetrahydro-2H-Piran (112,5 g, advanced 0.729 mol) is added dropwise to a solution of metallyte (500 ml of 1.4 M MeLi in ether, 0.70 mol) in 1 l of anhydrous THF at -30oC in argon atmosphere in a 5-liter round bottom flask. After completion of addition, the cooling bath removed and the solution allowed to stand at room temperature for 4 hours. The solution is again cooled to -30oC and added dropwise to the solution "c" (75 g, 0,207 mol) in 2.5 l of anhydrous THF. After addition the cooling bath is removed and the mixture is left to stand at room temperature for 16 hours. To this mixture was added 100 ml of salt solution and the solution is diluted with ethyl acetate, washed with salt solution and dried over anhydrous MgSO4. The solvent is evaporated, and after a short period of time crystallized solid precipitate. To complete the planting add hexane. The solid product is filtered and washed with hexane. The connection used in the next stage without further purification. Output: 95,8 g (90%).

Connection e.

A mixture of compound d (30 g, 0,058 mol) and under the conditions (65 ml, 1 mol) in 96% methanol (750 ml) is heated under reflux for 16 hours. The solvent from the shat over anhydrous MgSO4. After evaporation of the solvent the solid residue was washed with diethyl ether, filtered on a funnel with steklovata and washed again with diethyl ether. This connection can be used in the last stage without further purification. Yield: 65%.

17-(chlorbutanol)-17-hydroxy-4-androsten-3-one (f, EAT 248).

A mixture of compound d (15 g, 0.04 mol), triphenylphosphine (21 g, 0.08 mol) and carbon tetrachloride (9.3 g, 0.06 mole) is heated under reflux in 1 l of anhydrous dichloromethane for 10 hours. After evaporation of the solvent the crude mixture adsorb on silica gel and chromatographic on silica gel (flash) diethyl ether : hexane (70:30). The connection is then purified by crystallization from diethyl ether. Yield: 85%.

Combination therapy including an inhibitor of 5-reductase inhibitor and antiandrogen, has a successful effect of inhibiting activation of androgen receptors by two distinct mechanisms without significant lower levels of testosterone, which can cause unwanted side effects in some patients. In appropriate cases, that is, when prostate cancer or other androgen-mediated diseases do not respond sufficiently to treatment, magiceskaja or chemical castration, for example, the introduction of LHRH agonists or antagonists, known to specialists).

Inhibitors of testosterone 5-reductase formula

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include, but are not limited to, are presented in table. I.

Inhibitors of testosterone 5-reductase formula

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includes, but is not limited to, are presented in table. II.

Inhibitors of testosterone 5-reductase formula

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include, but are not limited to, listed in the table. I and II, as well as connections, are presented in table. III.

Except as stated otherwise cases, the inhibitor of 5-reductase determined by the following method. Use tablets with 24 holes each. In each recess is placed 100,000 cells from the cell line DU 145 carcinoma metastasized prostate man (ATS # NTV 81) in MEM containing 2% calf serum, processed dextranomer coal (dextran charcoal-treated) 1% penicillin, 1% streptomycin and 1% nieznanych amino acids. 24 hours later the medium is removed and again placed in 2.5 ml medium MEM containing 2% calf serum, processed dextranomer coal (dextran charcoal-treated), 10 mm titiraupenga 4-androsten-3,20-dione and 1% ethanol. Each recess has a different concentration of the test inhibitorsmedical environment then removed, centrifuged at 1000 RPM for 10 minutes and decanted into vials for research. These investigated the tubes, add 100 l of ethanol containing 25 g of androstendione, 25 g of 4-androstendione, 25 g of dihydrotestosterone and 25 g of testosterone. Then extracted steroids from a mixture of the two extraction with 2 ml diethyl ether. Phase separation is achieved by freezing the aqueous phase. The organic phase is then evaporated, the thus obtained steroid residue is dissolved in a few drops of methylene chloride and applied the stain on the plate for TLC (Whatman WH 4420222). After developing twice with a mixture of benzene-acetone (9:1) spots show with UV and gaseous iodine, cut out, placed in a separate tube for each steroid and extracted for 15 minutes with 1 ml of ethanol. After adding 10 ml of scintillation cocktail (NEN 989) tubes are shaken out and cheated.

The activity of 5-reductase is the sum of the transformations of 4-Androstenedione in androstendion and conversion of testosterone to dihydrotestosterone. Define the transformation titiraupenga 4-androstene-3,20-dione with other steroids in the presence of different concentrations of inhibitor and a constant concentration of radioactive 4-androstendione 5-reductase) to calculate the Ki values for the inhibition of each compound according to Cheng and Prusoff (Biochem. Pharmacol. 22, 3099-3108, 1973).

The following examples are not limiting examples of methods of synthesis of an inhibitor of 5-reductase inhibitor for use according to the present invention. The specialist can easily modify these syntheses known methods for other inhibitors of 5-reductase according to the invention.

Examples of syntheses of preferred inhibitors of the activity of steroid-5-reductase.

Example 1.

Getting 17-(N-n-butyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one (11, R1= C4H9EM 347).

The synthesis is depicted in figure 1.

Getting 17-hydroxy-5-oxo-A-nor-3,5-secondrate-3-OIC acid (1). To a stirred mixture of testosterone acetate (Steraloids Inc. Wilton NH USA) (200 g, 0,605 mol) in tert-butyl alcohol (2 l) add a solution of sodium carbonate (96,3 g, 0,908 mol) in 460 ml of water. The mixture is subjected to boiling under reflux and slowly (1 hour) add a solution of periodate sodium (893,8 g 4,176 mol) and potassium permanganate (70,8 g, 0,448 mol) in warm water (75oC) while maintaining the boiling point of the solution. The reaction is cooled to 30oC and after 15 minutes, the solids removed by filtration. The solid residue was washed with water (800 ml) and the combined filtrates concenteredon cooled and acidified to pH 3.0 with concentrated hydrochloric acid. The aqueous solution is extracted with methylene chloride (4 x 800 ml) and the combined organic phase washed with water, dried and concentrated to dryness. The thus obtained solid product is subjected acetate hydrolysis by boiling under reflux with NaOH (34.3 g, 0,857 mol) in methanol (2.0 l) for 12 hours. The reaction mixture is concentrated to 400 ml, diluted with water (600 ml) and acidified to pH 3. The solid product was filtered, washed with water and dried. The filtrate is extracted with methylene chloride (3 × 1.0 l) and the combined organic phases are concentrated to a syrup. And sediment, and the syrup is treated with boiling EtOAc and cooled at 0oC during the night to obtain 125 g (yield 67%) of colorless crystals; so pl. 205-207oC.

Getting 17-hydroxy-4-Aza-androst-3-one (3). In the tube Slinka (Schlenk) in a mixture of SECO acid 1 (8.0 g, 25,974 mmol) in ethylene glycol (80 ml) at room temperature and bubbled MeNH2before saturation. The clear yellowish solution is heated gradually (3oC/min) to 180oC and kept at this temperature for 1 hour. The reaction mixture is cooled to 10oC with stirring, water (80 ml). The solid product was filtered, washed with water (20 ml) and dried with getting 6,1 g 3 (81%); so pl. 181-183ois th acid (99.9%, the 130 ml) hydronaut in the presence of platinum oxide (600 mg) at 45 psi (pound per square inch), starting from room temperature and heating to 60oC over 12 hours. The reaction mixture is cooled and filtered. The catalyst is washed with acetic acid (30 ml) and the combined filtrates are concentrated to a solid (5.5 g, 91%); so pl. 178-180oC.

4-Methyl-4-Aza-5-androstane-3,17-dione (7). The following method is illustrative. To a stirred solution of compound 5 (of 7.3 g, 25 mmol) in methylene chloride (260 ml) is added, pyridine chlorproma (8,1 g, 37 mmol) and the mixture is stirred at room temperature for 3 hours. The content is passed through Florisil (30-60 mesh) to remove the precipitate and the filtrate washed with water (2 x 200 ml) and dried. The resulting residue is purified column flash chromatography with getting dione 7 (4.4 g, 61%); so pl. 126-128oC.

Getting 17-(N-butyl)amino-4-methyl-4-Aza-5 - androstane-3-one (9, R1= C4H9). The following method is illustrative. To a mixture of the dione 7 (0,150 g, 0,495 mmol) and n-butylamine (0,040 g, 0.54 mmol) in 1,2-dichloroethane add triacetoxyborohydride sodium (0.156 g, of 0.74 mmol) and then acetic acid (0.03 g, 0.49 mmol) in argon at room temperature. After 16 hours the reaction mixture R is, the tub and the solvent is removed to obtain the crude product, which was purified flash column-chromatography with getting 17-N-butyl derivative (0,110 g, yield 61%).

Getting 17-(N-n-butyl-N-formamido)-4-methyl-4-Aza-5 of 0.66 (s, 3H), 0.74 and-of 1.42 (m, 11H), 1,2-2,08 (m, 19H), 2,37-2,48 (m, 2H), 2,87 (s, 3H), 3.04 from (DD, 1H, J=4,13 Hz), 3,2-3,4 (m, 3H), 8,17 (s, 0,8 H), 8,24 (s, 0,2 H);

13C NMR (CDCl3): 170,56; 164,54; 162,97; 68,59; 65,52; 51,99; 51,71; 44,11; 36,85; 36,40; 34,12; 32,88; 30,64; 29,68; 29,04; 28,96; 25,20; 24,37; 22,86; 20,55; 20,21; 13,77; 12,34; HRMS: calculated for C24H40N2O2388,3089; found 388, 3147.

Example 2.

17-(N-n-Amyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one (11, R1= C5H11EM 401).

The synthesis is depicted in figure 1.

Getting 17-(N-n-amyl)amino-4-methyl-4-Aza-5-androstane-3-one (9, R1= C5H11). To a mixture of the dione 7 (3.4 g, and 22.6 mmol) and n-pentylamine (1.07 g, 12.3 mmol) in 1,2-dichloroethane add triacetoxyborohydride sodium (3.5 g, and 16.7 mmol) and then acetic acid (0.68 g, and 11.2 mmol) in argon at room temperature. After 16 h, the reaction mixture was diluted with methylene chloride (150 ml) and washed with 1 N. aqueous sodium hydroxide (2 x 200 ml), then a salt solution (200 ml), dried and the solvent is removed to obtain the crude product, which was purified column of flash is)-4-methyl-4-Aza-5-androstane-3-one (11, R1= C5H11EM 401. To a solution of formic acid (0,504 g, made 13.36 mmol) in chloroform (37 ml) is added dropwise disclocation (DCC) (2,75 g, made 13.36 mmol) in chloroform (37 ml) at 0oC. After 5 min to the above solution was added compound 9 (2.5 g, of 6.68 mmol) in pyridine (20 ml). The mixture was then stirred for 1 hour at room temperature. Evaporation of the solvent followed by the addition of ether gives dicyclohexylamine, which is removed by filtration, and the solid product washed with ether. The combined filtrate is concentrated and purified flash column-chromatography to obtain compound (11), R1= C5H11(EM 401) (2.5 g, 93%). Analysis of NMR spectroscopy gives a mixture (4:1) two conformers, so pl. 149-151oC;

1H NMR (CDCl3): of 0.67 (s, 3H), 0,86 (s, 3H), 0,82 - 1,19 (m, 6H), 1,21 - of 1.42 (m, 11H), 1.56 to 1.57 in (m, 2H), 1,69 is 1.91 (m, 4H), 1,92 - 1,9 (m, 3H), 2,38 is 2.43 (m, 2H), 2,89 (s, 3H), of 3.00 ( DD, 1H, J = 3.2, and to 12.4 Hz), 3,21 of 3.28 (m, 3H), to 8.14 (s, 0,8 H), and 8.2 (s, H 0,2);

13C NMR (CDCl3): 170,56, 164,8, 162,97, 68,54, 65,58, 61,98, 51,66, 51,24, 46,69, 44,28, 37,24, 36,8, 36,37, 34,07, 32,83, 32,12, 29,64, 29,13, 29,04, 28,8, 28,19, 25,15, 24,33, 23,22, 22,84, 22,36, 20,51, 13,94, 12,73, 12,32. HRMS: calculated for C25H42O2N2402,3245; found 402,3242.

Example 3.

By methods similar to those described in example 1,UB>= CH3). The product is obtained with a yield of 78%, and the analysis of the NMR shows a mixture of two conformers, so pl. 194-196oC;

1H NMR (CDCl3): 0,74 (c, H 2,4 in), 0.75 (s, 0,6 H) to 0.88 (s, 0,6 H) to 0.89 (s, 2.4 H), 0,78 - to 1.14 (m, 3H), 1.26 in to 1.47 (m, 6H), 1.60 - to 1,90 (m, 7H), 2,01 - 2,07 (m, 2H), 2,41 is 2.46 (m, 2H), 2,90 (s, 3H), of 2.92 (s, 3H), 3,02 - of 3.07 (DD, 1H, J = 12,58, and 3.2 Hz), 3,32 (t, 0,8 H, J = 9.6 Hz), is 4.21 (t, 0,2 H, J = 10 Hz), 8,15 (s, 0,8 H), 8,18 (C, H 0,2);

13C NMR (CDCl3): 170,45, 164,20, 163,32, 68,95, 65,43, 61,36, 51,82, 51,37, 51,12, 45,50, 44,21, 37,10, 36,66, 36,26, 33,87, 33,58, 32,70, 29,59, 29,51, 28,92, 28,83, 25,04, 23,03, 22,84, 22,74, 21,49, 20,35, 13,20, 12,61, 12,21; HRMS: calculated for C21H34N2O2346,2620; found 346,2645.

EM 336: 17-(N-Cyclopropyl-N-formamido)-4-methyl-4-Aza-5 of 0.39 to 0.44 (m, 0,4 H), and 0.61 - of 0.85 (m, 10H), 0,86 - 1,17 (m, 2H), 1.18 to 1.41 for (m, 7H), 1,42 - of 1.56 (m, 1H), 1,57 - to 2.06 (m, 6H), 2,35 (DD, J = 4,5, and 9.4 Hz, 2H, 1H), 3,24 (t, J = 8,7, 8,9 Hz, 0,4 H) 4,0 (t, J = 9,2, 9.5 Hz, 0,6 H) of 8.27 (s, 0,4 H), with 8.33 (s, 0,6 H).

13C NMR (CDCl3): 170,6, 165,4, 163,5, 69,9, 65,6, 64,4, 51,9, 51,8, 51,3, 45,7, 44,2, 37,9, 37,5, 36,4, 34,2, 29,3, 29,7, 29,1, 29,0, 28,8, 25,3, 22,2, 20,7, 13,6, 12,3, 9,9, 8,1, 6,4, 6,2, MCBP HRMS: calculated for C23H36N2O2372,2796; found 372,2820.

EM 337: 17-(N-Cyclohexyl-N-formamido)-4-methyl-4-Aza-5 0,70 (s, 1.5 H) of 0.77 (s, 1.5 H) to 0.85 (s, 1.5 H) of 0.87 (s, 1.5 H), 0,81 - of 1.41 (m, 12H), 1,44 of - 1.83 (m, 13H), 1,90 - 2,04 (m, 2H), 2.40 a (DD, J = 4,6, and 9.3 Hz, 2H), 2,90 (s, 3H), 2,99 (DD, J = 3,2, and 12.4 Hz, 1H), and 3.16 (t, J = 9,7, 9.9 Hz, 0.5 H), 3,70 - 3,82 (m, 0.5 H), 4,28 (t, J = 9,6, ,2, 36,8, 36,5, 34,2, 34,1, 33,7, 32,9, 30,9, 30,6, 29,8, 29,7, 29,3, 29,1, 29,0, 27,9, 26,9, 26,2, 26,0, 25,4, 25,3, 23,2, 22,9, 20,7, 20,5, 13,0, 12,6, 12,4;

HRMS: calculated for C26H42N2O2414,3246; found 414,3270.

EM 402: 17-(N-Hexyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one (11, R1= C6H13). The product is obtained with a yield of 70%.

Analysis of the NMR shows a mixture of two conformers, so pl. 101-103oC;

1H NMR (CDCl3): of 0.68 (s, 3H), 0,86 (s, 3H), 0.77 - a of 1.09 (m, 6H), 1,22 - of 1.42 (m, 10H), 1,43 - of 1.57 (m, 2H), 1.60 - to is 1.82 (m, 5H), 1,89 - 2,03 (m, 4H), 2,38 is 2.43 (m, 2H), 2,89 (s, 3H), 2,97 - 3,03 (DD, 1H, J = 12,4, a 3.2 Hz), 3,18 of 3.28 (m, 2,4 H) 4,12 (t, 0,2 H, J = 10 Hz), 8,14 (s, 0,8 H), and 8.2 (s, H 0,2);

13C NMR (CDCl3): 170,57, 164,49, 162,97, 68,55, 65,58, 61,99, 51,95, 51,66, 51,26, 46,72, 45,66, 44,32, 44,22, 37,24, 36,8, 36,37, 34,07, 32,83, 32,43, 31,32, 29,64, 29,19, 29,04, 28,95, 28,47, 26,64, 26,35, 25,15, 24,34, 23,23, 22,84, 22,49, 20,51, 13,92, 12,32; HRMS: calculated for C26H44O2N2416,3382; found 416,3355.

EM 405; 17-(N-ISO-Amyl-N-formamido)-4-methyl-4-Aza-5 of 0.67 (s, 3H), 0.77 - a of 1.06 (m, 12H), 1,21 - of 1.57 (m, 10H), 1,71 and 1.80 (m, 4H), 1,82 - of 1.97 (m, 3H), 2,38 is 2.43 (m, 2H), 2,89 (s, 3H), 2,97 - a 3.01 (DD, 1H, J=12,4, 3,2 Hz), 3,20 - 3,29 (m, 1.8 H), 4,16 (t, 0,2 H, J = 10 Hz), 8,13 (s, 0,8 H), and 8.2 (s, H 0,2);

13C NMR (CDCl3): 170,57, 164,46, 162,91, 68,49, 65,58, 51,92, 51,63, 44,19, 42,72, 37,19, 36,80, 36,35, 34,07, 32,81, 29,64, 29,19, 29,04, 28,93, 26,28, 25,92, 25,15, 24,27, 22,84, 22,43, 20,51, 12,77, 12,32; HRMS: calculated for C25H42O2N2402,3245; Nai 2H), only 2.91 (s, 3H), 2,99-3,1 (m, 1,7 H), 3,95 (t, 0,3 H, J = 10 Hz), 8,24 (s, 0,3 H), 8,48 (s, 0,7 H);

13C NMR (CDCl3): 170,60, 163,88, 163,46, 66,28, 65,74, 65,62, 63,81, 52,85, 52,02 51,89, 51,77, 44,94, 43,17, 37,24, 36,39, 34,22, 32,89, 29,75, 29,66, 29,07, 29,01, 28,89, 28,56, 28,47, 26,19, 25,32, 25,22, 23,25, 23,05, 22,98, 20,78, 13,25, 13,07, 12,36, 11,79, 11,44, 10,62; HRMS: calculated for C25H42O2N2402,3246; found 402,3265.

EAT 422: 17-(N-ISO-Butyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one (11, R1= ISO-C4H9). The product is obtained with a yield of 90%, and the analysis of the NMR shows a mixture (4:1) two conformers, so pl. 52-54oC.

1H NMR (CDCl3): 0,67 (c, 3H), of 0.85 (s, 3H), 0,68 - of 1.15 (m, 9H), 1,21 - to 1.38 (m, 6H), 1.5 to to 1.79 (m, 6H), 1,81 of 1.99 (m, 3H), 2,38 - to 2.42 (m, 2H), 2,88 (s, 3H), 2,94 - to 3.02 (DD, 1H, J = 12,4, 3,3 Hz), 3.1 to 3.15 in (DD, 0,2 H, J = 13,2, 5.7 Hz), 3,23 (t, 0,8 H, J = 0.8 Hz), 3,32 - 3,39 (DD, 0,8 H, J = 13,2, and 6.6 Hz), of 4.05 (t, 0,2 H, J = 10 Hz), 8,15 (C, 0,2 H), 8,29 (s, 0,8 H );

13C NMR (CDCl3): 170,57, 164,66, 162,82, 69,57, 52,26, 51,89, 51,83, 51,23, 45,99, 44,25, 37,16, 36,34, 32,81, 29,04, 28,92, 28,03, 27,12, 26,76, 25,12, 24,94, 23,05, 22,81, 20,17, 19,93, 19,78, 12,84, 12,33; HRMS: calculated for C24H40N2O2388,3089; found 388,3069.

EM 423: 17-(N-n-propyl-N-formamido)-4-methyl-4-Aza-5 0,65 (c, 3H), or 0.83 (s, 3H), 0,69 is 1.13 (m, 6H), 1,19-of 1.81 (m, 13H), of 1.86 to 2.0 (m, 3H), 2,35-2,4 (m, 2H), 2,86 (s, 3H), 2,94 to 3.0 (DD, 1H, J = 12,4, a 3.2 Hz), 3,10 of 3.28 (m, 1,82 H), 4,1 (t, 0,18 H, J = 10 Hz), 8,11 (C 0,82 H), 8,17 (with, of 0.18 H);

13C NMR (CDCl3): 170,51, 164,43, 162,99, 68,51, 65,52, 51SUB>O2374,2933; found 374,2903.

EM 436; 17-(N-Benzyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one (11, R1= CH2C6H5). The product is obtained with a yield of 80%. Analysis of the NMR shows a mixture of (4,88:1) two conformers, so pl. 89-91oC; IR cm-1(KBr): 1640, 1610;

1H NMR (CDCl3): 0,74, (s, 3H), of 0.85 (s, 3H), 2,37-to 2.42 (m, 2H), 2,87 (s, 3H), 2.95 points to 3.0 (DD, 1H, J = 12,5, 3,4 Hz), or 3.28 (t, 0,8 H, J = 9.8 Hz), 4,28 (t, 0,2 H, J = 9.7 Hz), 4,4 (l, 0,8 Ha, J = 15,5 Hz), and 4.5 (d, 0,4 H, J = 3.8 Hz), 4,79 (l, 0,8 Hb, J = 15,5 Hz), a 7.1 to 7.3 (m, 5H), of 8.28 (s, 0,2 H), 8,42 (s, 0,8 H);

13C NMR (CDCl3): 170,38, 165,17, 162,93, 138,76, 137,38, 128,55, 128,34, 127,27, 126,93, 125,93, 68,01, 65,42, 62,27, 51,80, 51,63, 51,20, 50,36, 47,28, 45,81, 44,11, 37,39, 37,06, 36,29, 34,04, 32,75, 29,61, 29,49, 28,87, 25,04, 24,65, 23,29, 22,72, 20,54, 12,95, 12,41, 12,23; HRMS: calculated for C27H38N2O2422,2933; found 422,2924.

Example 4.

Getting 17-(N-methyl-N-formamido)-4-methyl-4-Aza-5-androst-1-EN-3-one (17).

Obtaining presented in figure 3.

Getting 17-(N-methyl-N-formamido)-4-methyl-4-Aza-5-androst-1-EN-3-one (17, R1= CH3EM 314). The following method is illustrative. To a mixture of formamide 11, R1= CH3(EM 316) (0.10 g, 0,289 mmol) is added under nitrogen atmosphere bis (trimethylsilyl)triptorelin (0,305 g 1,185 mmol) and 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (of 0.066 g, 0,289 mmol) in docstor mix poured into a mixture of methylene chloride (6 ml) and 1% aqueous solution of sodium bisulfite (1.8 ml). The heterogeneous mixture is filtered. Dark red organic layer was washed with 2 ml of HCl, then the solution of salt, dried and concentrated. The crude mixture was purified column chromatography to obtain 41 mg of product 17, R1= CH3(EM 314) (41%);

1H NMR (CDCl3): to 0.72 (s, 3H (78%)), of 0.74 (s, 3H(22%)), 0,85-2,15 (m, 15H), to 0.89 (s, 3H(22%)), of 0.91 (s, 3H(78%)), 2,89 (s, 3H), of 2.93 (s, 3H), 3.27 to to 3.36 (m, 2H), of 5.82-to 5.85 (m, 3H), of 6.65 (d, 1H, J = 11 Hz), 8,14-8,24 (m, 1H); HRMS: calculated for C21H32N2O2344,2463; found 344,2426.

Example 5.

By methods similar to those described in example 4, synthesize compounds 16 (i.e. EATING 420) using as initial products of formamide 10 or ureas 12 and 13.

Example 6.

Poluchenie-N-(1N-cyclopropyl-2N-phenylurea)-4-methyl-4-Aza-5-N-(1N-cyclopropyl-2N-phenylurea)-4-methyl-4-Aza-5 0,74 - 1,11 (m, 6H), 0.8 a (s, 3H), 0,86 (s, 3H), 1,23 - to 2.06 (m, 14H), 2,34 - to 2.65 (m, 4H), 2,9 (s, 3H), 2,99 (DD, 1H, J = 4,13 Hz) 4,06 (t, 1H, J = 9.5 Hz), 7,07 - 7,42 (m, 5H);

13C NMR (CDCl3): 170,72, 157,19, 139,09, 128,81, 122,77, 119,49, 65,63, 52,04, 51,10, 45,57, 38,08, 36,35, 34,22, 32,79, 29,70, 29,02, 27,79, 25,244, 23,43, 23,05, 20,79, 13,73, 12,35, 12,01, 9,96.

Example 7.

By methods similar to those described in example 6, synthesize the following compounds.

EM 373: 17-N-(1N-cyclopropyl-2N-methylurea)-4-methyl-4-Aza-5 0,71 (c, 3H), 0,82 (c, 3H), and 1.9 (s, 3H), 2.95 and - a 3.01 (DD, 1H, J = 12,5, 3,4 Hz), 3,9 (t, 1H, J = 10 Hz), from 5.29 (q, 1H, J = 5 Hz);

13C NMR (CDCl3): 170,66, 160,86, 67,74, 65,58, 52,01, 51,05, 45,16, 37,98, 36,31, 34,16, 32,75, 29,66, 28,96, 27,37, 25,21, 23,32, 22,94, 20,68, 13,61, 12,29, 11,43, 9,51; MS:me (% Rel. int.) 344 (M57).

EM 392: 17-N-(1N-cyclopropyl-2N-ethylurea)-4-methyl-4-Aza-5 0,70 (c, 3H), 0,81 (s, 3H), of 1.08 (t, 3H, J = 7 Hz), was 1.94 (DD, 1H, J = 12,4, a 3.2 Hz), 2,25 - 2,31 (m, 1H), 2,36 (DD, 1H, J = 9,5, 4,8 Hz), 2,42 - to 2.57 (q, 1H, J = 10 Hz), of 2.86 (s, 3H), 2.95 and - 3,19 (DD, 1H, J = 12,5, 3,4 Hz), 3,20 is 3.23 (m, 2H), 3,9 (t, 1H, J = 10 Hz), 5,27 (t, 1H, J = 5 Hz);

13C NMR (CDCl3): 170,60, 160,03, 67,50, 65,55, 51,95, 50,96, 45,31, 37,95, 36,26, 35,27, 34,10, 32,70, 29,61, 28,92, 27,18, 25,17, 23,28, 22,90, 20,64, 15,47, 13,58, 12,26, 11,64, 9,57; HRMS: calculated for C25H41N3O2415,319; found 415,318.

EM 408: 17-N-(1N-methyl-2N-phenylurea)-4-methyl-4-Aza-5-androsten-3-one (13, R1= CH3, R2= C6H5). The product is obtained with a yield of 87%;

1H NMR (CDCl3) to 0.73 (s, 3H), 0,86 (s, 3H), 2,4 (DD, 2H, J = 9,5, a 4.7 Hz), 2,90 (s, 3H), 2,96 (s, 3H), 2,96 - 3,0 (DD, 1H, J = 12,5, 3,4 Hz), 4,24 (t, 1H, J = 10 Hz), 6,53 (s, 1H), 6,98 (t, 1H, J = 7 Hz), 7,24 (t, 2H, J = 7 Hz), was 7.36 (d, 2H, J = 7 Hz);

13C NMR (CDCl3): 170,66, 156,37, 139,24, 128,69, 122,70, 119,79, 65,55, 63,96, 51,92, 51,17, 44,91, 37,35, 33,92, 32,75, 31,58, 29,66, 29,03, 28,95, 25,19, 23,11, 20,50, 13,10, 12,30; HRMS: calculated for C27H39N3O2437,2804; found 437,2823.

Example 8.

Getting 17-N-(1N-cyclopropyl-2N-me="ptx2">

Obtaining presented in figure 4.

Getting 17-allyl-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one (21, R3= C3H5EM 322). The following method is illustrative. To a solution of compound 7 (see scheme 2) (0.1 g, 0,328 mmol) in THF (10 ml) add allylanisole (394 l, 0,394 mmol) at -78oC. After the addition the contents stirred for 1 hour and subjected to normal processing emitting crude product, which was purified column chromatography to obtain the pure product EM 322 (77 mg, 67%);

1H NMR (CDCl3): 0,68 - 1,0 (m, 2H), 0,84 (s, 6H), 1,14 - of 1.66 (m, 11H), 1,77 - to 2.06 (m, 5H), 2,14 - 2,2 (m, 1H), 2,28 - of 2.36 (m, 1H), 2,42 - 2,48 (m, 2H), 2,86 (s, 3H), 2,94 - to 2.99 (DD, 1H, J = 4,13 Hz), 5,14 (DD, 1H, J = 17.2 in Hz), and 5.2 (DD, 1H, J = 13,2 Hz), 5,91 - the 6.06 (m, 1H);

13C NMR (CDCl3): 170,70, 134,85, 118,99, 82,13, 65,70, 51,91, 50,13, 46,33, 41,75, 36,45, 35,14, 34,78, 32,94, 31,63, 29,95, 29,03, 25,31, 23,55, 20,77, 14,55, 12,37; HRMS: calculated for C22H35NO2345,2658; found: 345,2658.

Example 10.

Getting 17-propyl-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one (21, R3= C3H7EM 378). The same receipt as the formation of compounds 21 in example 9, but using PROPYLENEIMINE instead of allylanisole as a reagent.

Example 11.

Getting 17-propyl-17-hydroxy-I 21 in example 9, but using compound 6 as the original product.

Example 12.

Synthesis of 17-(4-bromobutyryl)-17-hydroxy-4-Aza-5-androstane-3-one (24, x = 2, P = Br, EM 465) (scheme 5).

Obtaining presented in scheme 1 and scheme 4.

Getting 17-hydroxy-4-Aza-androst-5-ene-3-one (2). First, according to the scheme 1 in the apparatus for high pressure propulsive NH3before saturation in the mixture SECO acid 1 (6.0 g, 18 mmol) in ethylene glycol (60 ml) at room temperature. The clear yellowish solution is gradually heated (3oC/min) to 180oC and kept at this temperature for 1 hour. The reaction mixture is cooled to 10oC and add water (80 ml) under stirring. The solid solution is filtered, washed with water (20 ml) and dried to obtain 4.5 g of the substance 2.

Getting 4-Aza-5-androstane-3,17-dione (6). A solution of compound 2 (160 g, 0.5 mmol) in acetic acid (500 ml) hydronaut at 60 psi using PtO2(15 g) as a catalyst at 60oC within 60 minutes After cooling and filtration, the catalyst was washed with acetic acid and the solvent is removed. The residue is dissolved in methylene chloride, washed with 1 N. sulfuric acid, a salt solution, saturated sodium bicarbonate and the solution Lucetta/hexane gives crystalline compound, which is treated with 3% methanolic sodium hydroxide by boiling under reflux for 90 minutes. After normal processing of the obtained residue is dissolved in acetone (500 ml), cooled to 0oC and added dropwise Jones reagent (Jones) (solution 8 N. chromic acid, 65 ml). After 15 minutes add isopropanol and the mixture was concentrated in vacuo. Water is added and the mixture extracted with ethyl acetate. The organic layers are washed with salt solution, dried and evaporated to dryness. The chromatography was carried out of the residue on silica gel with ethyl acetate/hexane as eluent gives Ashkelon 6 (152 g), the structure of which the balls are determined by spectroscopy.

17-(4-tetrahydropyranyloxy)-17-hydroxy-4-Aza-5-androstane-3-one (22, x = 2). According to scheme 5 to anhydrous THF (140 ml) at -60oC add motility (1.4 M, 100 ml) and a solution of 4-tetrahydropyranyloxy (21,6 g, 140 mmol). To this mixture, warmed to room temperature, stirred for 2 hours and cooled to -60oC, is added dropwise a solution of the above azaceta (9.6 g, 30 mmol) in THF (350 ml) and the mixture is heated to room temperature and stirred for 16 hours. After normal processing of compound 22 (x = 2) purify by chromatography and its structure octamethyl-4-Aza-5-androstan-3-one (23, x = 2).

17-(4-bromobutyryl)-17-hydroxy-4-Aza-5-androstane-3-one (24, P = Br, x = 2, EM 465). To a solution of azadiya 24 (P = OH) (179 mg, 0.5 mmol), obtained by acid hydrolysis of compound 22, and triphenylphosphine (262 mg, 1 mmol) in methylene chloride (15 ml) at 0oC add CBr4(249 could, 1 mmol) and the mixture is stirred for 2 hours at room temperature. The solvent is removed and the connection 24 (P = Br, x = 2, EM 465) purified flash chromatography and the structure to be installed using spectroscopy. Similarly receive 17-(4-bromobutyryl)-17-hyroxy-4-methyl-4-Aza-5-androstane-3-one (25, P = Br, EM 321).

Poluchenie-(4-iodobutyl)-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one (25 P = 1, EM 320). To a mixture of 17-(4-bromobutyryl)-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one (25, x = 2, P = Br, EM 321) (200 mg, 0,471 mmol) in acetone (16 ml) is added sodium iodide (92 mg, 0,6132 mmol) and the mixture refluxed for 12 hours. Remove acetone and normal processing result to the crude product, which was purified by colocinni chromatography to obtain the pure product (EM 320) (137 mg, 60%);

1H NMR (CDCl3): or 0.83 (s, 3H), 0.88 to (s, 3H), 2,41 is 2.46 (m, 2H), and 2.83 (t, 2H, J = 6,84 Hz), 2.91 in (s, 3H), 3.0 to a 3.06 (DD, 1H, J = 3,4, 12,5 Hz), 3,24 (t, 1H, J = 3,4, 12,5 Hz), 3,24 (t, 2H, J = 7,1 Hz), HRMS : calculated for C23H34INO2

Example 14.

Getting 17-(N-n-butyl-N-formamido)-4,6-dimethyl-4-Aza-5-acetoxy-6-methyl-4-androsten-3-one (30). Testosterone (50 g) (Schering A. G., Germany) treated with diethylene glycol in toluene in the apparatus, equipped with a distillation head Dean-stark, in the presence of catalytic amount of p-toluensulfonate acid by boiling under reflux for 16 hours. The resulting ketal 26 oxidize the magnesium salt monoperoxyphthalic acid (Aldrich Chem. Comp. Inc. Milwaukee Wis USA) in isopropanol at 50oC for 1 hour. After removal of the solvent and crystallization of the mixture of epoxide 27 is heated under reflux with a large excess of methylmagnesium in tetrahydrofuran within 8 hours. 6-metalmetal 28 is subjected to removal of the protective group during curing overnight at room temperature with a mixture of acetone/water (9:1). Thus obtained hydroxyketone 29 monteserrat by heating in a mixture of 0.1 G. of sodium hydroxide in methanol and 17-hydroxyl will acetimidoyl in the usual way (acetic anhydride/pyridine). Thus obtained 6-methylene is-N-formamido)-4,6-dimethyl-4-Aza-5-(N-alkyl-N-formamido)-4-methyl-7-hydroxyalkyl-4-Aza-5-androstane-3-one (34).

The synthesis is presented in scheme 7.

The following method is illustrative. Commercial 17-acetoxy-4,6-androstadien-3-one 32 (Steraloids Inc. Wilton, NH, USA) treated with 1.5 excess TBDMSO(CH2)xCu(ON)Li (obtained from TBDMSO(CH2)xI, tert-BuLi and CuCN) in ether or tetrahydrofuran in the presence of tributyltinchloride at -78oC. the Mixture is heated to room temperature and subjected to normal processing. The compound obtained 33 turn 17-(N-alkyl-N-formamido)-4-methyl-7-hydroxyalkyl-4-Aza-5-androstane-3-one (34) by a method similar to the method described in example 1. The last stage is the removal of the protective silyl group.

Example 16.

Getting alkylamino, alkylsulfonates and alkylphosphines derivatives of 17 - N-alkyl-4-methyl-4-Aza-5-androstane-3-one.

The synthesis is presented in scheme 8.

Compound 8 or 9, obtained in accordance with scheme 1, is treated at room temperature with acylchlorides in tetrahydrofuran using a 2-fold excess powder K2CO3as the base. After normal processing of receive connections 35 or 36. Using sulphonylchloride instead of acylchlorides network in the same conditions, respectively, the connection 37 or is atamido)-4-methyl-4-Aza-5 of 0.67 (s, 1,95 H) 0,74 (with, of 1.05 H) of 0.80 to 1.0 (m, 9H), 1,07 was 1.69 (m, 12H), 1,71 is 1.91 (m, 5H), 1,99-2,07 (m, 1H), 2,12 (with, of 1.05 H), and 2.14 (s, 1,95 H), 2,42 at 2.45 (m, 2H), 2,84-3,0 (m, 0,35 H), 2.91 in (s, 3H), 3,0 was 3.05 (DD, 1H, J = 12,5, a 3.2 Hz), 3,11-3,18 (m 0,65 H), 2,24-to 2.29 (m, 0,65 H), 3,68-3,71 (m, 0,7 H), 4,49 (t, 0,65 H, J = 9.9 Hz).

13C NMR (CDCl3): 171,43, 171,14, 170,54, 67,29, 65,53, 62,27, 51,05, 46,36, 45,55, 44,55, 44,34, 37,10, 36,31, 33,96, 33,01, 32,75, 30,87, 29,67, 29,22, 28,98, 28,94, 25,18, 24,59, 23,65, 23,17, 22,70, 22,33, 20,49, 20,34, 20,04, 13,66, 12,94, 12,73, 12,29; HRMS; calculated for C25H42N2O2402,3246; found 402,3234.

Additional examples of farbkomposition (17-20) are presented in tables V-VIII.

The terms and descriptions used herein are the preferred implementation, are presented to illustrate, but are not considered as limiting many of the modifications, which, as is clear to the specialist that are possible with the implementation of the present invention, presented in the claims.

EM 396

17-[N-cyclopropyl-N-(N'-isopropyl)carbarnoyl]-4-methyl-4-Aza-5 0,66 (m, cyclopropyl), to 0.72 (s, 3H, 18-CH3), or 0.83 (s, 3H, 19-CH3), to 1.11 to 1.12 (2D, 6H, J = 6.5 Hz, CH(CH3)2), of 2.38 (DD, 2H, J = 9,5, 4,7 Hz, 2-H2), is 2.88 (s, 3H, N-CH3), 2,98 (DD, 1H, J = 12,5, 3,4 Hz, 5-H), 3,99 (septet, 1H, J = 6.5 Hz, CH(CH3)2), 5,11 (d, 1H, J = 7 Hz, NH);

13C-NMR (CDCl3): 170,7, 159,4, 67,4, 65,6, 53,8, 52, 51, 45,5, 42,1, 38, 36,3, 34,44 (53), 329 (100), 315 (30); mass spectrometry high resolution: calculated for C26H43N3O2429,3355 found 429,3363.

EM 394

17-[N-cyclopropyl-N-(N'-butyl)carbarnoyl]-4-methyl-4-Aza-5 0,66 (m, cyclopropyl), to 0.72 (s, 3H, 18-CH3), or 0.83 (s, 3H, 19-CH3), to 0.88 (t, 3H, J = 7 Hz, NH(CH2)3CH3), 1,26 of 1.46 (m, 4H, NHCH2CH2CH2CH3), of 2.38 (DD, 2H, J = 9,5, 4,7 Hz, 2-H2), 2,87 (s, 3H, N-CH3), of 2.97 (DD, 1H, J = 12,5, 3,4 Hz, 5-H), 3,2 (m, 2H, NHCH2CH2CH2CH3), of 3.96 (t, 1H, J = 10 Hz, 17-H), 5,31 (t, 1H, J = 5 Hz, NH);

13C-NMR (CDCl3): 170,7, 160,1, 67,6, 65,6, 52, 51, 45,3, 40,3, 38, 36,3, 34,1, 32,8, 32,3, 29,7, 29, 27,2, 25,2, 23,3, 22,9, 20,7, 20,1, 13,7, 13,6, 12,3, 11,6, 9,5; MS (electron ionization), m/Z (relative intensity) 443 (18), 428 (12), 360 (15), 360 (15), 344 (45), 329 (100), 315 (30); mass spectrometry high resolution: calculated for C27H45N3O2443,3511 found 429,3530.

EAT 409

17-[N-methyl-N-(N'-methyl)carbarnoyl] -4-methyl-4-Aza-5-androstane-3-one (6a). Yield: 63%. So pl. 240oC; IR (KBr) 3375, 1647, 1534 cm-1;

1H-NMR (CDCl3): of 0.67 (s, 3H, 18-CH3), is 0.84 (s, 3H, 19-CH3), 2,39 (DD, 2H, J = 9,5, was 4.76 Hz, 2-H2), 2,77 (s, 3H, N-CH3), 2,78 (d, 3H, J = 5 Hz, NH-CH3), 2,89 (s, 3H, N-CH3), 3 (DD, 1H, J = 12,5, of 3.53 Hz, 5-H), 4,19 (t, 1H, J = 10 Hz, 17-H), of 4.45 (q, 1H, J = 5 Hz, NH);

13C-NMR (CDCl3is its intensity) 375 (25), 318 (16), 287 (13), 249 (15); mass spectrometry high resolution: calculated for C22H37N3O2375,2885 found 375,2836.

< / BR>
EM 450

17-(N-butyl)-2'-chloroacetamido-4-methyl-4-Aza-androstane-3-one (EM 450).

Connection EM 450 (0.12 g, 53% yield) was prepared from 17-N-butylamino connection (0.20 g, 0.52 mmol), NMR analysis showed the presence of a mixture of two conformers (1,27: 1). So pl. 181-183oC. IR (KBr, cm-1) 2924, 2882, 1634, 1442, 1412, 1296, 1228, 1102, 1028.

1H-NMR (CDCl3): 0,69 - 0,81 (m, 4H), 0,86 - 1,0 (m, 8H), 1,02 - to 1.63 (m, 12H), 1,65 - 2,03 (m, 6H), 2,43 (DD, J = 4,3, and 9.2 Hz, 2H), 2,92 (s, 3H, 4-NCH3), 2,81 - to 3.02 (m, 0,56 H), 3,03 (DD, J = 3,4, 12.3 Hz, 1H, 5-H), 3,14 - 3,24 (m, 0,56 H), 3,61 is 3.76 (m, 0,44 H) to 3.99 (d, J = 11.8 Hz, 0,56 H), 4,14 (d, J = 11,9 Hz, 0,56 H), 4.26 deaths (d, J = 12.1 Hz, 0,44 H, 17-H), of 4.44 (t, J = A 9.4, 9.5 Hz, 0,56 H, 17-H).

13C-NMR (CDCl3): 170,8, 168,1, 77,2, 67,1, 65,7, 63,2, 52,0, 51,7, 51,2, 46,2, 45,7, 45,0, 42,0, 37,5, 37,2, 36,4, 34,0, 32,9, 30,2, 29,8, 29,1, 29,0, 25,3, 24,5, 23,5, 23,2, 22,9, 20,6, 20,1, 13,7, 13,0, 12,7, 12,4. MS with electron ionization, m/s (relative intensity) 436 (M+, 4), 387 (17), 371 (6), 358 (9), 343 (8), 329 (6), 315 (18), 291 (13), 287 (21), 188 (79), 154 (43), 140 (50), 124 (45), 112 (100), 93 (26), 70 (90). Mass spectrometry high resolution: calculated for C25H41O2N2Cl1436,2856; found 436,2826. Elemental analysis (C25H41O2N2Cl1): C, H, n

3), to 0.89 (s, 3H, 19-CH3), of 0.91 - 0.99 (m, 3H), 1,23 - and 1.54 (m, 9H), 1,55 - of 1.74 (m, 5H), 1,92 (DQC, J = 3,6, and 9.1 Hz, 2H), 2,04 (DD, J = 6,6, 13.1 Hz, 2H), 2,14-2,19 (m, 1H), 2,42 (t, J = 6,7 Hz, 2H, 3'-H), a 2.36-2,44 (user. s, 1H, 17-OH), 3.04 from (DD, J = 3,9, and 12.6 Hz, 1H, 5-H), 3,51 (t, J = 6.5 Hz, 2H, 5'-H), 6,02 (user.s, 1H, 4-NH).

13C-NMR (CDCl3): 172,2, 84,9, 84,0, 79,7, 60,7, 51,0, 50,0, 47,0, 39,1, 35,8, 35,7, 33,4, 32,4, 31,4, 29,2, 29,1, 28,6, 27,3, 23,0, 20,8, 17,5, 12,9, 11,3. MC with electron ionisation, m/s (relative intensity) 437 (M++2, 19), 435 (M+, 18), 422 (77), 424 (79), 402 (8), 377 (4), 356 (51), 342 (7), 329 (57), 314 (18), 248 (100), 243 (48), 188 (34), 124 (56), 98 (96), 81 (92), 70 (36). Mass spectrometry high resolution: calculated for C23H34O2N1Br1435,1773; found 435,1781.

EM 448

17-Hydroxy-17-(4'-headbuttin-1'-yl)-4-Aza-5-androstane-3-one (EM 448). EM 448 (0.10 g, 86% yield) was obtained from(4'-brambati-1'-yl)-derivative (0.10 g, 0.24 mmol). So pl. 197-199oC. IR (KBr, cm-1) 3460-3122 (OSiR.), 2908, 2840, 1638, 1436, 1348, 1224, 1046.

1H-NMR (CDCl3): or 0.83 (s, 3H, 18-CH3), 8,89 (s, 3H, 19-CH3), 0,97-1,03 (m, 1H), 1,10-of 1.43 (m, 8H), 1,50-of 1.74 (m, 4H), 1.85 to 1,99 (m, 3H), of 2.21 (DDD, J = 5,3, 9,3, 18.5 Hz, 1H), 2,39 (t, J = 4.4 Hz, 2H), 2,82 (t, J = 7,0 Hz, 2H, 3'-H), 3.04 from (DD, J = 3,6, and 12.5 Hz, 1H, 5-H), 3,24 (t, J = 6.9 Hz, 2H, 4'-H), 4,21 (user. s, 1H, 17-OH), 5,99 (user.S., 1H, 4-NH).

13C-NMR (CDCl3): 172,2, 85,7, 84,6, 79,3, 60,6, 50,8, 49,8, 47,0, 38,8, 35,6, 35,2, 33,3, 32,5, 29,0, 28,5, 27,2, 23,9, 22,9, 20,8, 12,8, 12,3, 224 (34), 119 (27), 105 (46), 93 (44), 79 (57), 69 (100). Mass spectrometry high resolution: calculated for C22H32O3N1I1469,1479; found 469,1474.

EM 471

17-Hydroxy-17-(5'-identi-1'-yl)-4-Aza-5-androstane-3-one (EM 471). EM 471 (0.11 g, 99% yield) was obtained from bromide EM 358 (0.10 g, 0.23 mmol). So pl. 175-177oC. IR (KBr, cm-1) 3486-3122 (OSiR.), 2902, 2826, 1642, 1446, 1342, 1266, 1112, 1062.

1H-NMR (CDCl3): of 0.82 (s, 3H, 18-CH3), of 0.87 (s, 3H, 19-CH3), 0,89-1,08 (m, 1H), 1,16-1,50 (m, 9H), 1,59-of 1.73 (m, 4H), to 1.86 (DD, J = 3,0 and 13.5 Hz, 2H), 1,97 (t, J = 6,8 Hz, 2H), and 2.14 (DD, J = 9,9, to 15.8 Hz, 2H), and 2.26 (t, J = 6.5 Hz, 2H, 3'-H), 2,23-2,39 (m, 2H), 3,05 (DD, J = 3,4, and 12.2 Hz, 1H, 5-H), 3,29 (t, J = 6.6 Hz, 2H, 5'-H), 6,11 (user. s, 1H, 4-NH).

13C-NMR (CDCl3): 172,3, 85,1, 83,8, 79,7, 60,7, 53,8, 50,1, 47,1, 39,7, 35,7, 33,4, 32,7, 31,9, 29,6, 29,2, 28,6, 27,2, 22,9, 20,8, 19,9, 12,9, 11,3, 5,4. MC with electron ionisation, m/s (relative intensity) 438 (M+, 8), 468 (75), 450 (5), 420 (6), 386 (4), 356 (56), 342 (19), 329 (52), 268 (26), 248 (88), 234 (44), 148 (34), 124 (53), 112 (76), 98 (78), 81 (100), 69 (51). Mass spectrometry high resolution: calculated for C23H34O2N1I1483,1636 found 483,1625.

Table. X presents at the end of the description.

EM 352

17-Hydroxy-17-propyl-4-Aza-5-androstane-3-one (EM 352). A General method. To a stirred solution of 17-hydroxy-17-allyl-4-Aza-5-androstane-3-one (0.1 to the Panov was connected with the cylinder, filled with hydrogen (99,99%), was added palladium on activated carbon (palladium content of 10%, 0.02 g). The flask was pumped (2933 PA) and three blew strong jet of hydrogen. The mixture was stirred at room temperature for 3 hours. After the reaction was carried out thin-layer chromatography. The reaction mixture was filtered through CeliteR521 to remove the catalyst and washed Celite with ethyl acetate. The solution in ethyl acetate is evaporated under vacuum. The crude product was passed through a short column for flash chromatography with silica gel with eluent (C6H14: CH3COCH37:3) to obtain the compound EM 352 (0.10 g, 97% yield). So pl. 208-210oC. IR (KBr, cm-1) 3484-3228 (user. ), 3164, 2914, 2842, 1642, 1435, 1392, 1346, 1294, 1216, 1104, 1002.

1H-NMR (CDCl3): 0,81 (s, 3H, 18-CH3), of 0.87 (s, 3H, 19-CH3), to 0.89 (t, J = 7,0 Hz, 2H, 3'-CH3), 1,13-1,25 (m, 3H), 1,27-of 1.55 (m, 14H), of 1.66 (DD, J = 2,9, 10.1 Hz, 2H), 1,68-1,89 (m, 2H), 2,11 (user.d, J = 2.5 Hz, 1H, 17-OH), was 2.34 (DD, J = 4,3, 9.5 Hz, 2H), 2,96 (DD, J = 3,6, and 12.4 Hz, 1H, 5-H), 6,64 (user. s, 1H, 4-NH).

13C-NMR (CDCl3): 172,4, 83,1, 60,6, 51,2, 49,9, 46,4, 39,0, 35,8, 35,5, 34,0, 33,3, 32,4, 31,3, 29,3 (2C), 28,5, 27,0, 16,6, 14,8, 14,4, 11,2. MC with electron ionisation, m/s (relative intensity) 333 (M+, 402), 454 (7), 420 (3), 342 (64), 324 (26), 315 (8), 300 (6), 290 (57), 272 (12), 248 (100), 234 (47), 220 (24), 180 (5), 161 (7), >
333,2749 found 333,2727.

Table. XI presents at the end of the description.

EM 435

17-[N-(3,3'-dimethylbutyl)formamido] -4-methyl-4-Aza-5 - androstane-3-one. 17-[N-(3,3'-dimethylbutyl)formamido] connection EM 435 (0.12 g, 66% yield) was prepared from 17-[N-(3,3'-dimethylbutyl)amino]-4-methyl-4-Aza-5 0,66 (s,

3H, 18-CH3), of 0.82 (s, 0,62 H, 19-CH3), 0,84 (2,38 H, 19-CH3), of 0.87 (s, 9H, 3', 3', 4'-CH3), 0,96-of 1.05 (m, 2H), 1,20 to 1.47 (m, 7H), 1,48-of 1.64 (m, 3H), 1,88-of 1.81 (m, 4H), of 1.92 (t, J=9.7 Hz, 2H), 1,89-of 1.95 (m, 1H), of 2.38 (DD, J= 4,6, and 10.5 Hz, 2H), 2,87 (s, 3H, 4-NCH3), of 2.97 (DD, J=3,5, and 12.6 Hz, 1H, 5-H), 3,18-to 3.34 (m, 3H), 8,10 (C, H 0,80, 17-NCHO), 8,17 (s, 0,20 H, 17-NCOH);

13C-NMR (CDCl3): 170,5, 164,6, 162,8, 68,4, 65,5, 62,4, 51,8, 51,5, 46,7, 44,1, 43,8, 41,4, 40,5, 36,7, 36,3, 34,0, 32,8, 29,7, 29,6, 29,1, (3C), 29,0, 28,9, 25,1, 24,1, 22,8, 20,5, 12,3 (2C); MC electronic ionisation, m/s (relative intensity) 416 (M+, 20) 401 (11), 387 (7), 371 (5), 345 (53), 331 (11), 315 (13), 287 (18), 260 (21), 246 (16), 168 (100), 140 (34), 124 (39), 112 (52), 84 (28), 70 (81). Mass spectrometry high resolution: calculated for C26H44O2N2416,3382; found 416,3316. Elemental analysis (C26H44O2N2) : C, H, n

EM 346

17-(N-methylformamide)-4-methyl-4-Aza-5-androst-1-EN-3-one (EM 346). Characteristic is the following method. Three-neck round bottom flask (250 ml), equipped with an opening for entry of argon, reverse holodilny the portions under stirring was added 3.0 g (8,66 mmol) 17 -(N-methylformamide)-4-methyl-4-Aza-5-androstane-3-one. To this suspension was added to portions of 1.9 g (8,66 mmol) 2,3 dichlor-5,6-dicyan-1,4-benzoquinone (DDQ); the flask was pumped (2933 PA) three times and blew a strong stream of argon. To this stirred suspension was added bis(trimethylsilyl)triptorelin (BSTFA, 9,14 g, 35,50 mmol) via a dropping funnel at a speed of 5 ml/min. and the Temperature was slowly increased from 22 to 25oC for 30 min, at least as a large part of the solid phase was dissolved during this period with the formation of a transparent solution. The solution was stirred for 18 hours at 22oC (the time after which by using thin-layer chromatography was observed the formation of two diastereomeric adducts). Then to this solution was added 0.08 g cyclohexane-1,3-dione and the reaction mixture was stirred at 22oC additionally for 3 hours to completely decompose the remainder of DDQ. Then the solution was heated on an oil bath so as to maintain a very low boil (bath temperature 120oC, the internal temperature of 108oC). After boiling under reflux for 16 hours watched the full decomposition of the adducts and the formation of the final product. The reaction mixture was cooled to 22oC and poured in was parameterically, to remove the precipitated hydroquinone. Dark red organic layer was separated and washed 6 N. HCl solution (20 ml) and then saturated NaCl solution, dried and evaporated. The crude residue was then purified using chromatography on silica gel (C6H14:CH3COCH3, 95:5-70:30) to give the desired product (2.14 g, 72% yield). NMR analysis showed the presence of a mixture of two conformers (3,6:1). So pl. 176-178oC. IR (KBr, cm-1) 2918, 2846, 2820, 1645, 1590, 1420, 1388, 1205, 1042;

1H-NMR (CDCl3): 0,73 (2,34 H, 18-CH3), to 0.74 (s, 0,66 H, 18-CH3), of 0.90 (s, 0,67 H, 19-CH3), of 0.91 (s, 2,33 H, 19-CH3), 0,99-1,20 (m, 2H), 1,24-of 1.41 (m, 4H), of 1.57 (DD, J=3,8, 12.9 Hz, 1H), 1,73-1,89 (m, 6H), 1,91-of 2.15 (m, 2H), 2,89 (2,34 H, 4-NCH3), 2,90 (with, of 0.66 H, 4-NCH3), to 2.94 (s, 3H, 17-NCH3), and 3.31 (t, J=9.5 Hz, 0,78 H, 17-H), to 3.35 (DD, J=3,7, and 6.6 Hz, 1H, 5-H), 4,22 (t, J= 9.5 Hz, 0,22 H, 17-H), of 5.82 (DD, J=3,2, 8,1 Hz, 0,22 H, 2-H), of 5.84 (DD, J= 3,2, 8,2 Hz, 0,78 H, 2-H), of 6.65 (d, J=9.9 Hz, 1H, 1-H), 8,15 (C 0,78 H, 17-NCHO), 8,24 (C 0,22 H, 17-NCHO);

13C-NMR (CDCl3): 165,7, 164,5, 163,6, 149,1, 148,8, 122,9, 122,8, 69,2, 63,7, 51,4, 51,2, 47,9, 44,4, 39,5, 37,1, 36,7, 34,3, 33,8, 30,2, 29,4, 27,6, 24,2, 22,9, 20,7, 13,3, 12,7, 12,1; MC with electron ionisation, m/s (relative intensity) 344 (M+, 83), 329 (25), 285 (8), 270 (13), 259 (23), 246 (22), 150 (7), 137 (42), 124 (100), 108 (12), 98 (47), 70 (59), 57 (23); mass spectrometry high resolution: calculated for C21H32O2N2344,2464; ) in the end of the description.

1. Inhibitor testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line represents an optional PI bond;

R4denotes hydrogen or methyl, but is not hydrogen if there is no specified optional PI bond;

R6denotes hydrogen;

R7denotes hydrogen;

R17denotes hydrogen or lower alkyl;

R17stands WITH1- C7is an alkyl or aryl tertiary amino group or1- C7is an alkyl or aryl alluminare.

2. Inhibitor testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line represents an optional PI bond;

R4denotes hydrogen or methyl;

R6denotes hydrogen;

R7denotes hydrogen;

R17denotes hydrogen or lower alkyl;

R17stands WITH1- C7tertiary alkyl or the aryl amino group WITH3-C13- allcritical amino.

3. Inhibitor testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line represents an optional PI bond;

R4denotes hydrogen regroupe, include1- C6-alkyl, C1- C6-hydroxyalkyl,1- C6-halogenated,2- C6-carbonylethyl,3- C6-cyclopropylethyl,3- C6-epoxyethyl and their unsaturated analogs;

R17denotes hydrogen or hydroxy.

4. Inhibitor testosterone 5-reductase, having a molecular formula

< / BR>
where the dotted line represents an optional PI bond;

R4denotes methyl;

R6denotes hydrogen or C1- C3-hydrocarbons;

R7denotes hydrogen;

Randselected from the group comprising lower alkyl or cycloalkyl;

Rinselected from the group comprising-CORwith, -CONRWITHRD, -CSNRWITHRD, (RWITHand RDare hydrogen, lower alkyl and lower halogenation).

5. Inhibitor testosterone 5-reductase inhibitor is selected from the group consisting of

< / BR>
17-(N-n-amyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one;

< / BR>
17-(N-n-butyl-N-formamido)-4-methyl-4-Aza-5

17-(N n-hexyl-N-formamido)-4-methyl-4-Aza-5-androstane-3-one;

< / BR>
17-allyl-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one;

< / BR>
17-propyl-17-hydroxy-4-methyl-4-Aza-5-androstane-3-one;


< / BR>
where the dotted line represents an optional PI bond;

R4denotes hydrogen or methyl;

R6denotes hydrogen;

R7denotes hydrogen;

R17denotes hydrogen or lower alkyl;

R17denotes a tertiary amine or tertiary acylamino,

as defined in paragraph 1.

7. The pharmaceutical composition inhibiting testosterone 5-reductase containing a pharmaceutically acceptable diluent or carrier and an active component, characterized in that in contains as an active ingredient a therapeutically effective amount of an inhibitor of testosterone 5-reductase specified in any of paragraphs.1-5.

8. A method of inhibiting the activity of the testosterone 5-reductase, which includes the use of an inhibitor of 5-reductase inhibitor, wherein the inhibitor used, specified in any of paragraphs.1-5, or farbkomposition specified in paragraph 6 or 7, in an effective amount.

 

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< / BR>
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< / BR>
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