Oestrogen receptor ligands and methods of using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely urology, and can be used for treating advanced prostate cancer in male individuals. That is ensured by administering a therapeutically effective amount of a compound of formula IV or its isomer, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate or any combination thereof.

EFFECT: method provides treating effectively, inhibiting, reducing an incidence, relieving a severity or inhibiting advanced prostate cancer, as well as conducting the palliative treatment of advanced prostate cancer.

12 cl, 21 ex, 20 tbl, 23 dwg

 

The SCOPE of the INVENTION

The present invention relates to a method of reducing testosterone levels by reducing levels of luteinizing hormone (LH) or regardless of the levels of LH in the male subject and to methods for treating, suppressing, reducing the incidence of, reducing severity of, or inhibiting the widespread prostate cancer and palliative treatment of advanced cancers of the prostate gland.

PRIOR art

Estrogens are a group of endogenous and synthetic hormones, which are important and are used to maintain tissue and bone. Estrogens are endocrine regulators of cellular processes involved in the development and maintenance of the reproductive system. It is generally accepted role of estrogen in reproductive biology, prevention of postmenopausal hot flashes and prevention of postmenopausal osteoporosis. The most important endogenous human estrogen is estradiol, and it is found in women as well as men.

In the manifestation of the biological actions of estrogens and antiestrogens are two different subtypes of intracellular receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Usually endogenous estrogens are potent activators of both receptor subtypes. For example,estradiol acts as an agonist of ERα in many tissues, including the breast tissue, bone, cardiovascular and Central nervous systems. Usually selective modulators of estrogen receptors (SERM) in different tissues are different. For example, a SERM can be an ERα antagonist in the breast, but may be a partial agonist of ERα in the uterus, skeletal and cardiovascular systems. Accordingly, compounds that act as ligands of estrogen receptors, are useful in treating a number of conditions and disorders.

Prostate cancer is one of the most commonly diagnosed types nekoneko cancer in men in the United States and the second most common cause of death from cancer, and this year we expect more than 180000 new cases and almost 29000 deaths. Patients diagnosed with widespread cancer of the prostate is subjected antiandrogenna therapy (ADT), usually either by agonists releasing factor, luteinizing hormone (LHRH) or through bilateral blindness. In the antiandrogenna therapy decreases not only testosterone, but also reduced levels of estrogen, because estrogen is obtained by aromatization of testosterone, the levels of which are depleted in the ADT. Estrogen deficiency induced antiandrogenna therapy causes significant side effects, which include PR is the Livs, gynecomastia and mastalgia, loss of bone mass, deterioration of the quality and strength of the bones, osteoporosis and life-threatening fractures, adverse changes in lipids and more frequent cases of cardiovascular disease and myocardial infarction, depression and other mood changes. It is believed that many of the side effects of ADT, due to a lack of estrogen, mediated by ERα.

Leuprolide acetate (Lupron®) is a synthetic nonapeptide similar natural gonadotropin-releasing hormone (GnRH or LH-RH). Leuprolide acetate is superagonist LH-RH, which ultimately suppresses the secretion of LH that occurs in the pituitary gland. Leuprolide acetate acts as a potent inhibitor of gonadotropin secretion, causing suppression of ovarian and testicular steroidogeneza. Introduction leuprolide acetate people first causes an increase in levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the bloodstream, leading to a temporary increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in women premenopausally period). However, the continuous introduction of leuprolide acetate leads to a decrease in the levels of LH and FSH. In men, testosterone is reduced to levels appropriate medical castration (nige ng/DL). Women in premenopausally period estrogen content is reduced to postmenopausal levels. Testosterone is a known stimulus for malignant prostate cells. Thus, the suppression of testosterone secretion or inhibition of action of testosterone is a necessary component of therapy for prostate cancer. Leuprolide acetate in the treatment of prostate cancer can be used for suppression of LH, resulting in the reduction and reduced levels of testosterone in the serum to levels appropriate medical castration.

Before you enter the LHRH agonists, reached levels of testosterone, relevant medical castration, enhancing estrogenic activity at the pituitary by estrogens, mainly of diethylstilbestrol (DES). Equally DES was effective as of LHRH agonist of the suppression of testosterone to levels appropriate medical castration. In patients treated with DES, no tides or bone loss, but it was reported gynecomastia in more than ADT using LHRH agonists. Unfortunately, the use of highly pure estrogen, like DES and estradiol, very often associated with a high risk of serious cardiovascular and thromboembolic complications, which limit their clinical application.

The compounds of this invention reduce the levels of testosterone to levels appropriate medical castration, which can be useful for the treatment of prostate cancer, at the same time preventing an increased risk of thrombotic events and not causing bone loss, hot flashes and/or gynecomastia.

The INVENTION

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula I-XII, which is set forth in the description below.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula I-XII, which is set forth in the description below, such a decrease in total testosterone in serum occurs by reducing the levels of luteinizing hormone in serum.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount is tion of the compounds of formula I-XII , which is set forth in the description below, such a decrease in the total serum testosterone does not depend on reducing levels of luteinizing hormone in serum

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula I-XII , which is set forth in the description below, where the specified input of the above mentioned compounds of formula I-XII prevents or causes to treatment side effects associated with antiandrogenna therapy (ADT), with the specified subject has prostate cancer.

In one of the embodiments according to this invention, a method antiandrogenna therapy for a subject, comprising introducing a therapeutically effective amount of the compounds of formula I-XII, which is set forth in the description below. In another embodiment of the specified subject has prostate cancer.

In one of the embodiments according to this invention, a method for treating, suppressing, reducing the incidence of, reducing severity of, or inhibiting the widespread prostate cancer, comprising introducing a therapeutically effective amount of the compounds of formula I-XII, which is proposed in this description below.

In one of the embodiments according to this invention, a method of palliative treatment of advanced lung cancer, prostate cancer, comprising introducing a therapeutically effective amount of the compounds of formula I-XII, which is set forth in the description below.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Recognized by the invention the object is defined specifically and clearly stated in the final part of this description. However, the invention, as to organization and mode of action, together with its objectives, characteristics and advantages may best be understood with reference to the following detailed description when viewed together with the accompanying graphic materials, in which:

in Fig.1 presents the levels of testosterone (continuous line) and androgens in General (dotted line) in the blood serum of intact male monkeys after daily oral (p/o) introduction of Compound IV at a dose of 30 mg/kg (first dose at 0 days) (see Example 8);

in Fig.2 presents the levels of testosterone in intact rats treated with Compound IV (0,3; 1; 10; 30 mg/kg).Imeans P<0,05 compared with intact controls, treated with solvent. The BLOQ values (below the limit of quantitation) is represented graphically with a limit of quantitation of 0.08 ng/ml (the m Example 9);

in Fig.3 shows the inhibitory effect of Compound IV on the activity of the enzyme 17β-HSD5 (see Example 12);

in Fig.4 presents the aggregation of human platelets in vitro in the presence of DES, 17β-estradiol (E2) and Compound IV. Platelet-rich plasma (PRP) was incubated with diluent, E2, DES, or Compound IV within 30 seconds, after which induced aggregation, using 0.3 units of thrombin. Monitoring of the aggregation was performed for 5 minutes and expressed as a percentage of control - diluent (see Example 13);

Fig.5. A typical scheme of synthesis for the preparation of Compounds II-XII (see Example 1);

Fig.6. Scheme of synthesis for the preparation of Compound IV (see Example 2);

Fig.7. Scheme of synthesis for the preparation of Compound VI (see Example 3);

Fig.8. Scheme of synthesis for the preparation of Compounds IX and X (see Example 5);

in Fig.9 presents the levels of testosterone in intact rats treated with Compound IV at doses of 3 mg/kg, 10 mg/kg and 300 mg/kg, 24 h, 72 h and 168 h (see Example 9);

in Fig.10 shows the levels of LH (Fig.10A), the levels of FSH (Fig.10), the levels of testosterone (Fig.10C), the levels of mass of the prostate gland (Fig.10D), the levels of the weight of the seminal vesicles (Fig.10E) and mass levator (Fig.10F) in the intact and orientirovannyh (ORX) rats treated with Compound IV at doses of 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kgImeans P<0.05 V is compared to intact controls, treated with diluent.Omeans P<0,05 compared to ORX controls, treated with solvent. The BLOQ values are presented graphically with the limit of quantitation 0.08 ng/ml (see Example 9);

in Fig.11 presents the size of the prostate gland in intact and subjected ORX rats after administration of Compound IV (Fig.11A) and DES (Fig.11B) in different dosages (see Example 15);

in Fig.12 presents the differences between the DES and the Compound IV; DES gives cross-react with the glucocorticoid receptor (GR), while Compound IV does not (Fig.12A); DES gives cross-react with the androgen receptor (AR). He weakly stimulates and weakly inhibits the action of AR (i.e., is a partial agonist/antagonist), while Compound IV does not (Fig.12V); DES eliminates the transactivation of receptor, related to the estrogen receptor, (ERR), while Compound IV does not (Fig.12C) (see Example 15);

in Fig.13 shows the effect of Compound IV in doses of 5 mg/kg, 10 mg/kg, 15 mg/kg and 30 mg/kg on the weakening of the tides in the model cancellation of morphine. N=7 animals per group. 17β-E2 was used in a dose of 5 mg/kg in 100% Ohm DMSO (dimethyl sulfoxide) (see Example 14);

in Fig.14 shows a dose-dependent decrease in body weight (kg) macaques (~20% at a dose of 100 mg/kg) after administration of Compound IV for 91 days. Observed no signs of gyno or hyperestrogenemia (see Example 16);

in Fig.15 shows dose-dependent decrease in the level of testosterone in blood serum (ng/ml) in macaques after daily oral administration of Compound IV in comparison with positive control (LHRH agonist). The dashed line indicates the level of testosterone in chemically castrated patients, and the thick dashed line indicates the level of testosterone in surgically castrated monkeys (see Example 16);

in Fig.16 shows the dependence of the level of the antigen of the prostate (PSA) (ng/ml) dose in monkeys after administration of Compound IV in the initial moment, and on the 28th day. Treatment of Compound IV was significantly reduced PSA levels (see Example 16);

in Fig.17 shows the dependence of the volume of the prostate measured with the use of transrectal ultrasonography (TRUS), the dose in macaques compared with positive control (LHRH agonist) after administration of the Compounds IV, for 6 weeks (see Example 16);

in Fig.18 shows the dependence of the mass of organs (prostate, seminal vesicles and testes) of the dose in monkeys after administration of Compound IV as a percentage of the control at 90 days (Fig.18A). The weight of the prostate in macaques at the opening on the 13th day after daily oral administration of Compound IV (Fig.18V) (see Example 16);

in Fig.19 shows the dependence of the medium is equal total testosterone (nmol/l) dose-dependent people in the period between the 1-th and 11-th day after injection of Compound IV (100 mg, 300 mg, 600 mg and 1000 mg) (see Example 17);

in Fig.20 shows the dependence of the average levels of LH (IU(international units)/l) dose-dependent people in the period between the 1-th and 10-th day after injection of Compound IV (100 mg, 300 mg, 600 mg and 1000 mg) (see Example 17);

in Fig.21 shows the dependence of the average levels of free testosterone (PG/ml) dose-dependent people in the period between the 1-th and 10-th day after injection of Compound IV (100 mg, 300 mg, 600 mg and 1000 mg) (see Example 17);

in Fig.22 shows the dependence of the average levels of PSA (µg/l) dose-dependent people in the period between the 1-th and 10-th day after injection of Compound IV (100 mg, 300 mg, 600 mg and 1000 mg) (see Example 17);

in Fig.23 shows the dependence of the levels of testosterone (ng/ml) dose in intact rats after 14 days of recovery after administration of Compound IV.Imeans P<0,05 compared with intact controls (see Example 10).

It should be borne in mind that for simplicity and clarity of illustration, elements shown in the graphic materials do not necessarily have to be represented in the scale. For example, the dimensions of some elements may be exaggerated compared to other elements for clarity. In addition, where appropriate, the item numbers to indicate corresponding or similar elements may be repeated among graphic materials.

DETAILED description of the INFUSION IS HIS INVENTIONS

In the following further detailed description set forth numerous specific details in order to ensure full understanding of the invention. However, experts in this field it is clear that the present invention can be implemented in practice without these characteristic details. In other cases, details are not described well-known methods, techniques and components, in order not to overload the present invention.

In one embodiments, the compounds described herein, and/or compositions containing these compounds, can be used to reduce levels of total testosterone in the blood serum of the subject of the male sex.

In one embodiments, the compounds described herein, and/or compositions containing these compounds, can be used to reduce levels of total testosterone in the blood serum of the subject is male, and this decrease in the total serum testosterone is by reducing the levels of luteinizing hormone (LH) in serum.

In one embodiments, the compounds described herein, and/or compositions containing these compounds, can be used to reduce levels of total testosterone in the blood serum of the subject is male, and this decrease in the total serum testosterone is not the head of the Sith from the reduction in levels of luteinizing hormone in serum.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the structure formula I:

where

Y represents C(O) or CH2;

R1, R2independently represent hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3N(R)2, sulfonamide, SO2R, alkyl, halogenated, aryl, O-Alk-NRaRe, or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, aromatic possible;

R3, R4independently represent hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, halogenated, aryl, or a protected hydroxyl;

R represents alkyl, hydrogen, halogenoalkane, dihalogenoalkane, trihalogen, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, NO2or HE;

R5and R6independently represent hydrogen, phenyl, alkyl group of 1-6 atom is in carbon, 3-7-membered cycloalkyl, 3-7-membered heterocycle, 5-7-membered aryl; or R5and R6form a 3-7-membered ring together with nitrogen atom;

j and k are independently equal to 1-4;

Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbon atoms or cyclic alkyl of 3-8 carbon atoms.

In additional embodiments of the methods described herein, the compound of formula I is represented by formula IA:

where R1, R2, R3, R4, j and k are such as defined for formula I.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of formula II:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any and the combination represented by the compound of formula III:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutical product, pharmaceutically acceptable salt, polymorph, hydrate or any combination thereof, represented by the compound of formula IV:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of the formula V:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of the formula I:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of formula VII:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of formula VIII:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in serum by reducing the levels of luteinizing hormone (LH) in a male subject having prostate cancer, comprising introducing a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any and the combination represented by the compound of formula IX:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of the formula X:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of formula XI:

.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the compound of formula XI:

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the male subject has prostate cancer. In another embodiment, the total testosterone in serum is reduced to less than about 100 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 50 ng/DL. In another embodiment, the concentration of total testosterone in serum is reduced to less than about 25 ng/DL.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and such reduced total serum testosterone is by reducing the levels of luteinizing hormone (LH) in serum. In another embodiment the subject is uiskogo floor has prostate cancer. In another embodiment, the total testosterone in serum is reduced to less than about 100 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 50 ng/DL. In another embodiment, the concentration of total testosterone in serum is reduced to less than about 25 ng/DL.

In one of the embodiments according to this invention, a method for reducing levels of free testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and such reduction of free testosterone in serum occurs by reducing the levels of luteinizing hormone (LH) in serum. In another embodiment, the male subject has prostate cancer.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and such reduction in total testosterone in savor is de not depends on reducing the levels of luteinizing hormone (LH) in serum. In another embodiment, the male subject has prostate cancer. In another embodiment, the total testosterone in serum is reduced to less than about 100 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 50 ng/DL. In another embodiment, the concentration of total testosterone in serum is reduced to less than about 25 ng/DL.

In one of the embodiments according to this invention, a method for reducing levels of free testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and such reduced levels of free testosterone in serum does not depend on reducing levels of luteinizing hormone in serum. In another embodiment, the male subject has prostate cancer.

In one of the embodiments according to this invention proposed methods of reducing levels of total testosterone in serum or blood levels of free testosterone in the blood serum of the subject is male, with the specified subject male has prostate cancer. In another embodiment of the specified subject has als is wounded prostate cancer.

In one of the embodiments of the decrease in concentration of testosterone in serum is reversible and after treatment with the compounds according to the invention there is a return to the levels of the original time.

In another embodiment the concentration of testosterone in blood serum are reversible after treatment with Compound IV according to Fig.23 and Example 10.

In one of the embodiments according to this invention proposed methods of reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the total testosterone in serum is reduced to less than about 100 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 50 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 25 ng/DL. In another embodiment, the total testosterone in serum is reduced to less than about 75 ng/DL. In another embodiment, the total testosterone in serum is reduced to approximately in the range of 75 ng/DL to 100 ng/DL. In another embodiment, the total testosterone in serum is reduced approximately to the level of d is apatone from 50 ng/DL to 75 ng/DL. In another embodiment, the total testosterone in serum is reduced to approximately in the range from 40 ng/DL to 50 ng/DL. In another embodiment, the concentration of total testosterone in serum is reduced to approximately in the range from 25 ng/DL to 50 ng/DL. In another embodiment, the total testosterone in serum is reduced to approximately in the range from 40 ng/DL to 60 ng/DL.

Testosterone levels in serum can be measured in terms of levels of "free" (i.e. bioavailable and unbound) or in the form of "total" testosterone (including the percentage of testosterone associated with protein and unavailable). Men older than 40 years who do not have prostate cancer, show low testosterone levels corresponding to the levels of total testosterone less than 250 ng/DL (<to 8.7 nmol/l) or the level of free testosterone less than 0.75 ng/DL (<0.03 nmol/l).

In one of the embodiments include methods according to this invention, a method for reducing levels of total and/or free testosterone in serum regardless of the reduction of the levels of luteinizing hormone (LH) or by reducing the levels of LH in the male subject having prostate cancer. In another embodiment changes in the levels of testosterone will be reduced relative to the level before treatment. In another embodiment the level of the total testosterone in serum is reduced to a value smaller than 100 ng/DL. In another embodiment, the total testosterone in serum are reduced to a level less than 50 ng/DL. In another embodiment, the total testosterone in serum is reduced to levels less than 25 ng/DL. In another embodiment, the level of free testosterone is reduced to a value smaller than 2 ng/DL. In another embodiment, the level of free testosterone is reduced to a value smaller than 1 ng/DL. In another embodiment, the level of free testosterone is reduced to a value smaller than 0.5 ng/DL. In another embodiment, the level of free testosterone is reduced to a value smaller than 0.25 ng/DL.

Methods for determining levels of free testosterone in serum levels of total testosterone in serum include monitoring levels of testosterone in the continuation of the treatment period by conducting a blood test. Total testosterone is a combination circulating in the bloodstream testosterone, associated with protein-carriers (albumin, SHBG (globulin that binds sex hormones (from the English. sex hormone-binding globulin), interacted, transferrin), and the free/unbound hormone. The levels of total testosterone can be affected by various factors, including the level of protein in the blood, which transports this hormone in the body, age, the presence of obesity and interference associated with commonly used test methods.

Methods suitable to measure the free testosterone (FT), can be complex (equilibrium dialysis and the calculation of free testosterone (CFT) or simple (a commercially available kit for determination FT "Coat-A-Count") using the same labeled substances. In another embodiment the measurement of the levels of total testosterone and free testosterone in serum can be achieved by simultaneous measurement of total testosterone and SHBG (for example, using the set of counting results Immunoradiometric analysis (from the English. immunoradiometric assay) Irma-Count from DPC (Diagnostic Products Corporation) and then calculate free testosterone (CFT). In another embodiment, the measurement of total testosterone and free testosterone within the competence of the specialist in this field.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in serum or blood levels of free testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of a combination of one or more than one other form of ADT and the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the decline in the total or free testosterone in serum occurs by reducing the level of luteinizing hormone (LH) in the blood serum. In another embodiment the reduction in levels of total or free testosterone in the serum does not depend on reducing levels of luteinizing hormone in serum.

Methods according to this invention includes the introduction of a combination of other forms of ADT and compounds according to the invention. In one of the embodiments other forms of ADT include the use of LHRH agonist. In another embodiment of the LHRH agonist is leuprolide acetate (Lupron® (US 5480656; US 5575987; 5631020; 5643607; 5716640; 5814342; 6036976; all of them are included in this description by reference) or goserelin acetate (Zoladex®) (US 7118552; 7220247; 7500964; they are all included in this description by reference). In one of the embodiments other forms of ADT include the use of LHRH antagonist. In another embodiment of the LHRH antagonist is degarelix. In one of the embodiments other forms of ADT include the use of anti-androgens. In another embodiment the anti-androgens are bikalutamid, flutamide, finasteride, dutasteride, MDV3100, nilutamide, chlormadinone or any combination thereof.

In one of the embodiments of the methods according to this invention includes the introduction of a therapeutically effective amount of antiandrogen and compounds according to the invention. In one of the embodiments of the methods according to this invention includes the introduction of a therapeutically effective amount of an LHRH agonist, and compounds according to the invention. In one of the embodiments of the ways in which d is nomu invention includes the introduction of a therapeutically effective amount of antiandrogen, the LHRH agonist, and compounds according to the invention.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone and/or levels of free testosterone in serum by reducing the levels of luteinizing hormone (LH) or independently from the reduction in levels of luteinizing hormone in the male subject having prostate cancer, with the purpose of antiandrogenna therapy (ADT), including the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII. In another embodiment this connection is the connection IV.

In another embodiment according to this invention, a method antiandrogenna therapy (ADT) of a subject, comprising introducing a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the specified subject has prostate cancer. In another embodiment this connection is the connection IV.

In another embodiment of the ADT is used to treat prostate cancer, to slow the progression of prostate cancer or for the prevention and/or treatment of prostate cancer recurrence.

In one of the embodiments according to the invention p is idlogin a method of treating prostate cancer, slowing the progression of prostate cancer, prevention and/or treatment of prostate cancer recurrence, comprising introducing the compound according to the invention. In another embodiment, the introduction of the compounds according to the invention in combination with LHRH analogues, reversible anti-androgens (such as bikalutamid or flutamide), antiestrogen, anti-cancer drugs, inhibitors of 5-alpha-reductase, aromatase inhibitors, progestins, selective modulators androgenetic receptors (SARM) or agents acting through other nuclear receptors of hormones.

In one of the embodiments according to the present invention, a method for treating prostate cancer and reduce the levels of total testosterone in serum and/or free testosterone in serum by reducing the levels of LH or independently from the reduction in LH levels, including the introduction of the compounds of formula IA, I-XII. In another embodiment, comprising introducing the Compound IV.

In the antiandrogenna therapy decreases not only testosterone, but also reduced levels of estrogen, because estrogen is obtained by aromatization of testosterone. Estrogen deficiency induced antiandrogenna therapy causes significant side effects, which include hot flashes, incomes the Oia, the mastalgia, loss of bone mass, deterioration of the quality and strength of the bones, osteoporosis, osteopenia and life-threatening fractures, adverse changes in lipids and more frequent cases of cardiovascular disease and myocardial infarction, loss of libido, impotence, loss of muscle mass (sarcopenia), fatigue, cognitive dysfunction and depression and other mood changes.

In other embodiments according to the present invention, a method for treatment of any disease, disorder or symptom associated with ADT. In other embodiments according to the present invention, a method for treatment of any disease, disorder or symptom associated with the loss of testosterone. Every disease, disorder or symptom represents a separate embodiment of the present invention.

In one of the embodiments according to this invention, a method for reducing levels of total testosterone in the blood serum of the male subject, comprising the introduction of a therapeutically effective amount of the compounds of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, where the aforementioned introduction of the compounds of formulas IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product polymorpha, hydrate or any combination thereof prevents or causes a prevention, inhibition, reduction of frequency, inhibition or treatment of adverse effects associated with conducting antiandrogenna therapy (ADT), with the specified subject has prostate cancer. In another embodiment the reduction of the levels of total or free testosterone in serum is realized by decreasing the levels of LH or independently from the reduction in LH levels.

In one of the embodiments of the introduction of the compounds according to the invention leads to the suppression, reduction of frequency, inhibition or treatment of the typical side effects associated with traditional antiandrogenna therapy (ADT). In another embodiment the subject has prostate cancer. Such prevention and/or reduction of side effects is relatively placebo or control group. In one of the embodiments of the typical side effects associated with traditional antiandrogenna therapy (ADT), include hot flashes, gynecomastia, reduced bone mineral density and an increased tendency to fracture. In another embodiment, the introduction of the compounds according to the invention prevents the occurrence of hot flashes, which can be detected using the traditional forms antiandrogenna therapy (ADT). Another is lewinii introduction of the compounds according to the invention prevents gyno, which can be detected using the traditional forms antiandrogenna therapy (ADT). In another embodiment, the introduction of the compounds according to the invention prevents decreased bone mineral density (BMD), which can be detected using the traditional forms antiandrogenna therapy (ADT). In another embodiment, the introduction of the compounds according to the invention prevents an increased tendency to fracture, which can be detected using the traditional forms antiandrogenna therapy (ADT). In another embodiment an increased tendency to fracture is a pathological fractures, nontraumatic fractures, fracture of the spine, nevertebralnah fractures, new morphometric fractures, clinical fracture or a combination of both.

In one of the embodiments, the term "traditional antiandrogenna therapy" refers to blindness (surgical castration), when the surgeon removes the testicles. In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction analogues releasing factor, luteinizing hormone (LHRH); these medicines lower the amount of testosterone produced by the testes. Examples of LHRH analogues, the public in the United States of America, include leuprolide (lupron, viadur (viadur), eligard), goserelin (Zoladex), tript relin (trelstar) and histrelin (vantas). In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction of anti-androgens; antiandrogens block the body's ability to use any androgens. Even after blindness or during treatment with LHRH analogues, the adrenal glands is still a small amount of androgens. Examples antiandrogenna medicines include flutamide (eulexin), bikalutamid (casodex) and nilutamide (nilandron). In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction of the antagonists releasing factor, luteinizing hormone (LHRH), such as abarelix (plenaxis); degarelix (firmagon) is a new antagonist of LHRH, which in 2008 was approved by the FDA (office of quality control of food, drugs and cosmetics) for use for the treatment of disseminated prostate cancer. In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction of inhibitors of 5α-reductase such as finasteride (proscar) and dutasteride (avodart), inhibitors of 5α-reductase blocks the body's ability to convert testosterone into a more active androgen 5α-dihydrotestosterone (DHT). In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction of inhibitors of the biosynthesis of testoster is on, such as ketoconazole (nizoral). In another embodiment, the term "traditional antiandrogenna therapy" refers to the introduction of estrogens, such as diethylstilbestrol or 17β-estradiol.

In one of the embodiments, the term "flushing" refers to a sudden feeling of heat in the upper body or whole body, reddening of the face and neck, red spots appearing on the chest, back, and hands, intensive sweating, cold chills, and so on

In one of the embodiments, the term "gynecomastia" refers to benign enlargement of the mammary glands in males resulting from a proliferation of the glandular component of the breast that may be associated or may not be associated with pain. Clinically gynecomastia determined by the presence of an elastic or solid tumors, concentrically extending from the nipple. The condition known as pseudogynecomastia or lipomastia, characterized by fat deposition without glandular proliferation. Although usually gynecomastia is bilateral, it can be one-sided.

In one of the embodiments of the methods according to this invention relate to the treatment of men diagnosed with prostate cancer or common prostate cancer by reducing the level of testosterone, in addition does not cause bone loss, and tides. In another in which the glassing in the methods according to this invention using Compounds IA, I-XII, and these compounds have the ability to reduce the level of testosterone, the primary causes of cancer of the prostate, also without causing some side effects such as bone loss and hot flashes, which are usually observed in the modern antiandrogenna therapy (ADT) in the treatment of cancer of the prostate.

In another embodiment in the following Table 8 (Example 11) demonstrated a decrease in the amount of testosterone, also does not cause loss of bone mass resulting from the introduction of Compound IV.

In one of the embodiments of the methods according to this invention relate to reducing the levels of testosterone, which then leads to cure advanced cancers of the prostate, by introducing the compounds of formula IA, I-XII. In one of the embodiments of the methods according to this invention relate to reducing the levels of testosterone, which then leads to the suppression, reducing the incidence, reducing the severity or the inhibition of advanced lung cancer, prostate cancer, by introducing the compounds of formula IA, I-XII. In one of the embodiments of the methods according to this invention relate to reducing the levels of testosterone, which further provides palliative treatment of advanced lung cancer, prostate cancer, by introducing the compounds of formula IA, I-XII.

In one of the of oplasty methods according to this invention relate to the treatment of widespread prostate cancer. In one of the embodiments of the methods according to this invention are suppressing, reducing the incidence, reducing the severity or the inhibition of the spread of prostate cancer. In one of the embodiments of the methods according to this invention relate to palliative treatment of advanced cancers of the prostate. In another embodiment of the methods according to this invention using Compounds IA, I-XII. In another embodiment this invention relates to the treatment of widespread prostate cancer. In another embodiment this invention relates to the suppression of widespread prostate cancer. In another embodiment this invention relates to reducing the incidence of advanced cancers of the prostate. In another embodiment this invention relates to a weakening of gravity widespread prostate cancer. In another embodiment this invention relates to the inhibition of the spread of prostate cancer.

The term "common prostate cancer" refers to metastatic cancer that occurs in the prostate gland and giving metastasized beyond the prostate, such as in the surrounding tissue, covering the seminal vesicles, lymph nodes, or bone of pelvic region or other parts of the ate. Pathological condition of the prostate cancer are classified according to the Gleason score from 1 to 5 in order of increasing malignancy. In another embodiment of this definition should be included patients with a significant risk of progressive disease and/or death from prostate cancer, and every such patient with cancer beyond the prostate and is characterized by such stages of the disease, as IIB and worse, apparently has a "common" disease.

In one of the embodiments of the methods proposed in this description and/or in which the compounds are applied as proposed in this description, effective in providing feedback in the hypothalamic-pituitary-testicular axis (NRT axis). Feedback refers to the ability of a substance produced in one organ or tissue to regulate the activity of another organ or tissue, which affects its own activity. In one of the embodiments of the feedback in the hypothalamic-pituitary-testicular axis (NRT axis) leads to the reduction of LH levels. In one of the embodiments of the feedback in the hypothalamic-pituitary-testicular axis (NRT axis) leads to a decrease in the levels of total testosterone in serum. In one of the embodiments of the feedback in the hypothalamic-pituitary-testicular axis (NRT axis)leads to a decrease in the levels of free testosterone in serum. In one of the embodiments of the feedback in the hypothalamic-pituitary-testicular axis (NRT axis) leads to decreasing levels of androgens in serum, tissues or tumors.

The hypothalamic-pituitary-testicular (NRT) axis refers to the physiological endocrine system, which regulates levels of hormones in the hypothalamus, pituitary gland and the testes. LHRH (releasing factor, luteinizing hormone) released by the hypothalamus and stimulates the pituitary gland for the synthesis and secretion of LH and FSH (gonadotropins). Next, LH and FSH act on the testes, stimulating the production of testosterone and sperm. Then testosterone has a direct negative impact on the type of feedback on the hypothalamic secretion of LHRH and indirect negative impact on the type of feedback on the production of LH and FSH in the pituitary gland. Estrogens, androgens and whey proteins (for example, inhibin) also have a negative effect on the secretion of LHRH and secretion of LH and FSH.

The pituitary gland is one of the glands that regulates the level of testosterone in the body. When the testosterone level is reduced, the pituitary gland releases luteinizing hormone (LH). This hormone induces the production of more testosterone in the testes. The level of testosterone increases during puberty. The highest testosterone level is reached at the age of 20-4 years and then gradually decreases in older men. In the body of women, the amount of testosterone greatly reduced in comparison with men. However, testosterone plays an important role for the entire body of both men and women. It affects the brain, bone and muscle mass, distribution of fat, vascular system, energy levels, fabric (exterior) of the genital organs and sexual function. Most testosterone in the blood is bound to protein, referred to as globulin that binds sex hormones, (SHBG) or other serum protein called albumin. Testosterone that is not bound (or "free"), you can also define clinically.

In another embodiment the lower levels of total testosterone in serum or blood levels of free testosterone in serum, independent of a decrease in the levels of luteinizing hormone in serum, is due to the increase of globulin that binds sex hormones, (SHBG). In another embodiment, the reduced levels of free testosterone, independent of a decrease in the levels of luteinizing hormone in serum, is due to the increase of globulin that binds sex hormones, (SHBG). In another embodiment the lower levels of total testosterone in serum or free testosterone in serum, independent of the reduction level is th luteinizing hormone (LH) in serum, occurs as a consequence of inhibiting the production or secretion of testosterone by the Leydig cells in the testes. In another embodiment the lower levels of total testosterone in serum or free testosterone in serum, independent of a decrease in the levels of luteinizing hormone (LH) in serum is due to the decrease steroidogeneza in the adrenal glands.

In one embodiments of the compounds described herein, and/or compositions containing these compounds, can be used to reduce the levels of luteinizing hormone (LH). In another embodiment of the compounds and/or compositions of this invention can be used to reduce the level of endogenous sex hormones.

The members of the family of hydroxysteroid-dehydrogenases (HSD) involved in the conversion of circulating in the bloodstream of steroids. 17β-HSD5 converts Androstenedione to testosterone and estrone to estradiol. In addition, she is also involved in the synthesis of prostaglandins. In one embodiments of the compounds according to the invention inhibit HSD specifically inhibit 17β-hydroxysteroid-dehydrogenase 5 (17β-HSD5). Such inhibition may be useful for ADT, preventing peripheral/vneconomy the synthesis of testosterone, which may go out of control NRT axis and lead to insufficient reduction of the total or free the underwater testosterone in serum or make possible the presence of locally elevated intracellular levels of testosterone, in both cases, may be adversely with ADT.

Antiandrogenna therapy (ADT), provide therapy with LHRH agonists, i.e., the introduction of agonists releasing factor, luteinizing hormone (LHRH) or their analogues, first stimulates the release of gonadotropin from the pituitary gland and the production of testosterone from the testicles (the so-called "acute reaction" (from the English. flare reaction), then the reduction in the release of gonadotropin and reduced levels of both testosterone and estrogen. This "acute reaction" caused by therapy with LHRH agonists, has a negative impact on the prostate cancer treatment as a result of increased levels of androgens/testosterone. In addition, LHRH therapy associated with an increased risk of diabetes and cardiovascular disease (Smith (2008) Current Prostate Reports. 6: 149-154).

To overcome the acute effects of LHRH therapy proposed antiandrogenna monotherapy (bikalutamida, flutamide, chlormadinone), approaches combined with LHRH/antiandrogenna therapy and the use of LHRH antagonists (degarelix) (Suzuki et al., (2008) Int. J. Clin. Oncol. 13; 401-410; Sharifi, N. et al., (2005) JAMA. 294(2): 238-244). Antiandrogenna monotherapy does not reduce levels of androgens in the subject. It was shown that antiandrogenna monotherapy bikalutamida less effective than ADT for patients with prostate cancer with bone metast the tears. Moreover, the adverse effects observed during treatment with bikalutamida include pain and suffering (gynecomastia and mastodynia) mammary glands. (Suzuki et al., ibid.). The additional risk associated with antiandrogenna therapy includes increasing the level of liver transaminases (Sharifi et al., ibid.).

In one of the embodiments according to the present invention proposed a reduction of LH levels and thereby reducing levels of total testosterone in serum and/or free testosterone in the serum, not causing "acute" effect and at the same time overcoming the adverse effects associated with estrogen deficiency caused by low levels of testosterone when using the traditional methods of ADT. Methods/applications of the compounds which are the object of the invention involve the manifestation of timeselection estrogenic activities that ensure the maintenance of bone tissue (agonistic effects on bone tissue), reduced clotting capacity and/or tides and/or less strong or neutral effect on breast tissue compared with estradiol or diethylstilbestrol.

In one of the embodiments of the Compound IV shows agonistic, but not antagonistic effects (Examples 6 and 7), the use of the Compounds IV will not lead to increases the levels of gonadotropins and testosterone.

In one of the embodiments of the Compound IV shows agonistic activity (Examples 8-11), demonstrating a strong pharmacological response in the form of lower hormone levels of serum testosterone and androgens in General.

In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, effective to reduce or eliminate resorptive effects in bone tissue, caused by a decrease in the level of LH when using traditional forms of ADT. In one of the embodiments of the methods proposed in this description and/or apply the composition proposed in the present description, effective to reduce or eliminate resorptive effects in bone tissue, due to reduced levels of testosterone when using traditional forms of ADT. In one of the embodiments of the methods proposed in this description, in which the use of the composition proposed in the present description, effective to reduce or eliminate resorptive effects caused by declining estrogen levels by decreasing the level of LH. In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, prevent resorptive effects in bone tissue, associated with the mind what Ishenim level LH when using traditional forms of ADT. In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, prevent bone loss associated with reduced levels of endogenous LH, testosterone and/or estradiol using traditional forms of ADT. In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, increase bone density (BMD), while the decrease in the level of LH. In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, increase the percentage of bone volume, while reducing the levels of endogenous LH, testosterone and/or estradiol.

In some embodiments according to this invention, a method for preventing and/or attenuating thromboembolism by introducing the compounds according to the invention or its isomer, pharmaceutical product, polymorph, hydrate or any combination thereof.

In one of the embodiments of the methods proposed in this description, in which the use of the compounds and/or compositions proposed in this description, effective in breast tissue. In one of the embodiments of the methods proposed in this description, which used the t compounds and/or compositions, in the present description, provide a decrease in LH with simultaneous prevention of gynecomastia associated with decreased levels of LH, resulting traditional ADT.

In one of the embodiments, in Example 13, the results of special studies of toxicity, and in vitro studies on human platelets showed that Compound IV had a much lower protagonizada activity than DES. Thus, Compound IV, ER-selective agonist, in the treatment of cancer of the prostate may provide useful effect of DES with a reduced risk of thrombotic events than DES, as well as to provide the beneficial effect of an agonist or antagonist of LHRH, without causing bone loss, tides or unfavorable lipid profiles.

Therapy one diethylstilbestrol (DES) or in conjunction with other ADT showed that the use of DES to prevent bone resorption in patients with a diagnosis of prostate cancer. Although the use of DES implemented as a therapy for prostate cancer, it is considered that the effects of DES on angiogenesis and cancer mediated by metabolites DES, not its effects through the estrogen receptor. In addition, the levels of dosage DES entered for therapeutic applications, give numerous adverse side effect the points, including vascular disease, cardiovascular complications, thrombotic complications due to toxicity, gynecomastia, erectile dysfunction and decreased libido (Scherrand Pitts, ibid, and Presti, J. C. Jr. (1996) JAMA. 275(15): 1153-6).

In one of the embodiments of the present invention overcomes the negative side effects of treatment with agonists or antagonists of LHRH used individually or in combination with anti-androgens or DES. In another embodiment the methods of the invention under examination include the implementation antiandrogenna therapy without adverse side effects associated with loss of estrogen, such as adverse conditions associated with bone tissue, and without the adverse side effects associated with stimulation of estrogen, such as gynecomastia. In another embodiment the methods of the present invention include reduction of LH levels and thereby reducing levels of total and/or free testosterone in serum, without causing "acute" effect while overcoming the adverse effects associated with estrogen deficiency, caused a decrease in LH, and overcoming the adverse effects associated with a General increase in the level of estrogen agonists observed in the treatment with DES. Methods/application of the connection, is the located object of the invention, provide for the manifestation of timeselection estrogenic activities, thereby ensuring the maintenance of bone tissue (agonistic effects on bone tissue), reduced clotting potential and neutral effects on breast tissue.

Antiestrogenic effects of traditional selective modulators of estrogen receptors (SERM) such as tamoxifen, toremifene and raloxifene, at the hypothalamic level, expressed in increased levels of gonadotropins or increase of LH levels in men and thus potentially lead to increased levels of testosterone in serum (Tsouri et al., 2008, Fertility and Sterility doi: 10.1016). Conversely, methods filed with the invention, including the introduction of the compounds of formula IA, I-XII, include reduction of the level of LH in the male subject.

Additional embodiments of the compounds of formula I

In one of the embodiments of the methods according to this invention Y in the Compound of formula I represents S(O). In another embodiment Y represents CH2. In another embodiment R1and R2in the Compound of formula I or IA independently represent O-Alk-NR5R6or O-Alk-heterocycle. In another embodiment of Alk in these groups, O-Alk-heterocycle, O-Alk-NR5R6, -Alk-heterocycle and Alk-NR5R6as outlined in the description above, is a linear Ala is l from 1-7 carbon atoms, branched alkyl of 1-7 carbon atoms or cyclic alkyl of 3-8 carbon atoms. In another embodiment alkyl is an ethylene (-CH2CH2-). In another embodiment Alk represents a methylene (-CH2-). In another embodiment Alk represents a propylene (-CH2CH2CH2-). In another embodiment Alk represents a 2-methylpropene (-CH2CH(CH3)CH2-).

In one of the embodiments of the methods according to this invention R1in the Compound of formula I or IA is in the para-position. In one of the embodiments of the methods according to this invention R1and R2in the Compound of formula I or IA are different. In another embodiment of the methods according to this invention R1and R2in the Compound of formula I or IA are the same. In another embodiment of the methods according to this invention R1in the Compound of formula I or IA is a. In another embodiment of the methods R1in the Compound of formula I or IA is a hydroxyl. In another embodiment of the methods R1in the Compound of formula I or IA is an alkoxy. In another embodiment of the methods R1and R2independently represent hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3N(R)2, sulfonamide, SO2R, alkyl, halogenated, aryl, O-Alk-NR5R6 or O-Alk-heterocycle, where the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, aromatic possible. In another embodiment of the methods R1and R2in the Compound of formula I or IA independently represent halogen, hydroxyl, alkoxy, cyano, nitro, CF3N(R)2, sulfonamide, SO2R, alkyl, halogenated, aryl, O-Alk-NR5R6or O-Alk-heterocycle, where the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, aromatic possible. In another embodiment of the methods R2in the Compound of formula I or IA is a halogen. In another embodiment of the methods R2in the Compound of formula I or IA is an F. In another embodiment of the methods R2in the Compound of formula I is a Cl. In another embodiment of the methods R2in the Compound of formula I or IA is a Br. In another embodiment of the methods R2in the Compound of formula I or IA is a I. In another embodiment of the methods R2in the Compound of formula I or IA is a hydroxyl. In another embodiment of the methods R1and/or R2is a CF3. In another embodiment R1and/or R2represents CH3. In another embodiment R1and/or R2represents a halogen. In another waples the NII R 1and/or R2represents F. In another embodiment R1and/or R2represents Cl. In another embodiment R1and/or R2represents Br. In another embodiment R1and/or R2represents I. In another embodiment R2in the Compound of formula I is in the para-position.

In one of the embodiments of the methods according to this invention R3and R4in the Compound of formula I or IA are the same. In another embodiment of the methods according to this invention R3and R4in the Compound of formula I or IA are different. In another embodiment of methods j and k in the Compound of formula I or IA independently represent 1. In another embodiment of the methods R3and R4in the Compound of formula I or IA independently represent halogen, halogenated, hydroxyl or alkyl. In another embodiment of the methods R3and R4in the Compound of formula I or IA independently represent F. In another embodiment of the methods R3and R4in the Compound of formula I or IA independently represent Br. In another embodiment of the methods R3and R4in the Compound of formula I or IA independently represent Cl. In another embodiment R4located in the para-position. In another embodiment R3located in the ortho-position. In another embodiment R3located in the meta-position. In other the second embodiment R 3and/or R4is a CF3. In another embodiment R3and/or R4represents CH3.

In one of the embodiments of the methods according to this invention R5and R6in the Compound of formula I or IA form a 3-7-membered ring together with the nitrogen atom. In another embodiment the ring is a saturated or unsaturated ring. In another embodiment the ring is a substituted or unsubstituted ring. In another embodiment of the methods according to this invention R5and R6in the Compound of formula I or IA form piperidine ring together with nitrogen. In another embodiment of the methods R5and R6in the Compound of formula I or IA form pyrazinone ring together with nitrogen. In another embodiment of the methods R5and R6in the Compound of formula I or IA form pieperazinove ring together with nitrogen. In another embodiment of the methods R5and R6in the Compound of formula I or IA form morpholine ring together with nitrogen. In another embodiment of the methods R5and R6in the Compound of formula I or IA form a pyrrole ring together with nitrogen. In another embodiment of the methods R5and R6in the Compound of formula I or IA form pyrrolidin. In another embodiment of the methods R5and R6in the Compound of formula I or IA form a pyridine ring with the nitrogen. Another is lewinii this ring is substituted with halogen, the alkyl, alkoxy, alkylene, hydroxyl, cyano, nitro, amino, amidon, COOH or aldehyde.

In another embodiment of the methods according to this invention R1in the Compound of formula I or IA and R2in the Compound of formula I or IA independently represent O-Alk-heterocycle or OCH2CH2-heterocycle. In another embodiment, the term "heterocyclic" group refers, in one of the embodiments, the ring structure containing in addition to carbon atoms, sulfur atoms, oxygen, nitrogen, or any combination thereof, as part of the ring. In another embodiment, the heterocycle is a 3-12-membered ring. In another embodiment, the heterocycle is a 6-membered ring. In another embodiment, the heterocycle is a 5-7-membered ring. In another embodiment, the heterocycle is a 4-to 8-membered ring. In another embodiment of the heterocyclic group can be unsubstituted or can be substituted with halogen, halogenoalkanes, hydroxyl, alkoxy, carbonyl, amido, alkylamino, dialkylamino, cyano, nitro, CO2N, amino, alkylamino, dialkylamino, carboxyla, thio and/or thioalkyl. In another embodiment of the heterocyclic ring may be condensed with another saturated or unsaturated cycloalkyl or heterocyclic 3-8-membered ring. In another embodiment of the heterocyclic ring, not only is em a saturated ring. In another embodiment of the heterocyclic ring is an unsaturated ring. In another embodiment, the heterocycle is a piperidine. In another embodiment, the heterocycle is a pyridine. In another embodiment, the heterocycle is a piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazin, piperazine or pyrimidine.

The term "cycloalkyl" refers to non-aromatic monocyclic or polycyclic ring containing carbon atoms and hydrogen. Cycloalkyl group can contain one or more than one carbon-carbon double bond in the ring provided that the ring does not become aromatic due to their presence. Examples cycloalkyl groups include, but are not limited to, (C3-C7)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and saturated cyclic and bicyclic terpenes, and (C3-C7)cycloalkenyl groups, such as cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl and cycloheptenyl and unsaturated cyclic and bicyclic terpenes. Cycloalkyl group can be unsubstituted or may be substituted by one or two substituents. Preferably, cycloalkyl group is a monocyclic ring or bicyclic ring.

The term "alkyl" refers, in the bottom of the embodiments, to the saturated aliphatic hydrocarbon, including groups with a straight chain, branched chain and cyclic alkyl groups. In one embodiments the alkyl group contains 1-12 carbon atoms. In another embodiment the alkyl group contains 1 to 7 carbon atoms. In another embodiment the alkyl group contains 1-6 carbon atoms. In another embodiment the alkyl group contains 1-4 carbon atoms. In another embodiment, the cyclic alkyl group contains 3 to 8 carbon atoms. In another embodiment, the cyclic alkyl group contains 3 to 12 carbon atoms. In another embodiment branched alkyl represents an alkyl, substituted alkyl side chains containing 1-5 carbon atoms. In another embodiment branched alkyl represents an alkyl, substituted halogenoalkane side chains containing 1-5 carbon atoms. The alkyl group can be unsubstituted or can be substituted with halogen, halogenoalkanes, hydroxyl, alkoxy, carbonyl, amido, alkylamino, dialkylamino, nitro, amino, alkylamino, dialkylamino, carboxyla, thio and/or thioalkyl.

The term "Alchemilla" group refers, in another embodiment, the unsaturated hydrocarbon, including groups with a straight chain, branched chain and cyclic alkyl groups containing one or more double bonds. Elke the ilen group may have one double bond, two double bonds, three double bonds, etc. In another embodiment Alchemilla group contains 2-12 carbon atoms. In another embodiment Alchemilla group contains 2-6 carbon atoms. In another embodiment Alchemilla group contains 2-4 carbon atoms. Examples alkenyl groups are ethynyl, propenyl, butenyl, cyclohexenyl etc. Alchemilla group can be unsubstituted or can be substituted with halogen, hydroxy, alkoxy, carbonyl, amido, alkylamino, dialkylamino, nitro, amino, alkylamino, dialkylamino, carboxyla, thio and/or thioalkyl.

The term "aryl" group refers to an aromatic group containing at least one carbocyclic aromatic group or heterocyclic aromatic group which may be unsubstituted or may be substituted by one or more groups selected from halogen, halogenoalkane, hydroxy, alkoxy, carbonyl, amido, alkylamino, dialkylamino, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl. Non-limiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl and the like. In one of the embodiments of the aryl group represents a 4-8-membered ring. In another embodiment the aryl group submitted is a 4-12-membered ring(a). In another embodiment the aryl group is a 6-membered ring. In another embodiment the aryl group represents a 5-membered ring. In another embodiment the aryl group represents a system of 2-4 condensed rings.

The term "aldehyde" group refers, in one of the embodiments, the alkyl or alkenyl, substituted formyl group, where the alkyl or alkenyl such as defined above. In another embodiment of the aldehyde group is an aryl or phenyl group, substituted formyl group, where the aryl as defined above. Examples of aldehydes are formyl, acetal, propanal, butanal, pentanal, benzaldehyde. In another embodiment of the aldehyde group is a formyl group.

The term "halogenoalkane" group refers, in another embodiment, the alkyl group as defined above that is substituted by one or more than one halogen atom such as F, Cl, Br or I.

The term "hydroxyl" group refers, in another embodiment, the group HE. Specialists in this field it is clear that when R1, R2or R3in the compounds of the present invention are'OR, R is not HE.

In one of the embodiments, the term "halogen" or "halogen" refers to a halogen, such as F, Cl, Br or I.

In another embodiment, the term "phenol" is tositsa to any derivative of benzene, having an alcohol group (OH).

The link to the protected hydroxyl, in some embodiments, includes the introduction of a substituent linked to the oxygen group of the benzene ring, the Deputy can be easily removed. In some embodiments the protective group of the phenol can include the groups: simple methyl ether (methoxy), simple Olkiluoto ether (alkoxy) benzyl ether (Bn), simple methoxymethyl (MOM) ether, simple benzoyloxymethyl (CMV) ether, benzil, carbobenzoxy, simple methoxyethoxymethyl (MEM) ether, a simple 2-(trimethylsilyl)ethoxy-methyl (SEM) ether, simple methylthiomethyl (MTM) ether, simple phenylthiomethyl (RTM) ether, simple azidomethyl ether, simple cyanomethylene ether, simple 2,2-dichloro-1,1-diferetiable ether, a simple 2-hloretilova ether, a simple 2-bromatologia ether, simple tetrahydropyranyl (TNR) ether, a simple 1-ethoxyethyl (EE) ether, simple ventilago ether, a simple 4-bromination ether, simple cyclopropylmethanol ether, simple allyl ether, simple propargilovyh ether, simple isopropyl ether, simple cyclohexylamino ether, simple tert-butyl ether, simple 2,6-dimethylbenzyl ether, a simple 4-methoxybenzylthio ether, simple is-nitrobenzyl ether, simple 2,6-dihlorbenzilovy ether, simple 3,4-dihlorbenzilovy ether, a simple 4-(dimethylamino)carbonintensive ether, a simple 4-methylsulfanyl-benzyl ether, a simple 4-untilmarriage ether, a simple 4-Pikalyovo ether, getattr-p-tolyl, simple titrator-4-piridinovogo ether, simple trimethylsilyl (TMS) ether, simple tert-butyldimethylsilyl (TBDMS) ether, simple tert-butyldiphenylsilyl (TBDPS) ether, simple triisopropylsilyl (TIPS) ether, uriformat, arylacetic, killavullen, arelevant, allantoin, aryl-9-fluorenecarboxylic, arylmethylidene, 1-substituted-carbonate, tert-BUTYLCARBAMATE, 4-methylsulfonylbenzoyl, 2,4-dimethylpent-3-ylcarbonyl, aryl-2,2,2-trichlorethylene, allansilberman, arylcarbamoyl, complex dimethylphosphino ether (Dmp-OAr), complex dimethylphosphorodithioate ether (Mpt-OAr), complex diphenylphosphino-tinylogo ether (Dpt-OAr), arellanobond, uritolocalfile or aryl-2-formylbenzenesulfonic.

In one of the embodiments of the methods according to this invention using N,N-bis(4-hydroxyphenyl)-4-propylbenzamide (II) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 4,4'-(2,3-dimethyl-benzyladenine)of the WPPT, the al (III) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 3-fluoro-N-(4-forfinal)-4-hydroxy-N-(4-hydroxyphenyl)benzamide (IV) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using N,N-bis(4-hydroxyphenyl)-2,3-dimethylbenzamide (V) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using N,N-bis(4-hydroxyphenyl)-2-naphthylamide (VI) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (VII) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 4-((4-forfinal)(4-hydroxybenzyl)amino)phenol (VIII) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods on this invented what Yu use 4-fluoro-N-(4-hydroxy-phenyl)-N-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-2-trifluoromethyl-benzamide (IX) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention use cleaners containing hydrochloride salt of compound IX (HCl salt of compound (IX) or hydrochloride 4-fluoro-N-(4-hydroxy-phenyl)-N-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-2-trifluoromethyl-benzamide (X) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzene (XI) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment of the methods according to this invention using 3-fluoro-N,N-bis-(4-hydroxy-phenyl)-2-methyl-benzamide (XII) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination of them.

In one of the embodiments of the methods according to this invention use a "pharmaceutically acceptable salts" of the compounds that can be obtained by the interaction of the compounds according to the invention with acid or base.

Suitable pharmaceutically acceptable salts of amine compounds according to the methods of this invention can be derived from inorganic acids or organic is eskay acid. In one of the embodiments, examples of inorganic salts of amines are bisulfate, borates, bromides, chlorides, hemisulfate, hydrobromide, hydrochlorate, 2-hydroxyethansulfonate (hydroxyethanesulfonic), Iodate, iodides, isothionate, nitrates, persulfates, phosphates, sulphates, sulfamate (sulfamates), sulfanilate, salts of sulfonic acids (alkyl sulphonates, arylsulfonate, halogensubstituted alkyl sulphonates, halogensubstituted arylsulfonate), sulfonates and thiocyanates.

In one of the embodiments of the examples of organic salts of amines can be selected from classes of aliphatic, cycloaliphatic, aromatic, alifaticheskih, heterocyclic, carboxylic and organic sulfonic acids, examples of which include acetates, residues, aspartate, ascorbate, adipate, anthranilate, alginate (algenates), alkane-carboxylates, substituted alkane-carboxylates, alginates, bansilalpet, benzoate, bisulfate, butyrate, bicarbonates, bitartrate, carboxylates, citrates, camphorate, camphorsulfonate, cyclohexylsulfamate, cyclopentane-propionate, edetate calcium, camsylate, carbonates, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfate, dihydrochloride, decanoate, enanthate, econsultancy, edetate, edisylate, estolate, esylate, fumarate, formate, fluoride, galacturonase, gluconate, glutamate, glycol is s, glucarate, glucoheptonate, glycerophosphate, gluceptate, glycopyrrolate, glutamate, glutamate, heptanoate, hexanoate, hydroxylate, salts of hydroxycarboxylic acids, hexylresorcinol, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactates, lactobionate, laurate, malate, maleate, methylenbis(beta xinafoate), malonate, mandelate, mesylates, methansulfonate, methylbromide, methylnitrate, methylsulfate, monoclonality, Makati, monocarboxylate, nitrates, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, napsylate, N-methylglucamine, oxalates, octanoate, oleates, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalates, pectinate, phenylpropionate, palmitate, Pantothenate, polygalacturonate, pyruvate, salt Hinn acid, salicylates, succinate, stearates, sulfanilate, subacetate, tartratami, theophyllinate, p-toluensulfonate (tozilaty), triptoreline, terephthalate, tannate, teoclate, trichloracetate, triethiodide, tricarboxylate, undecanoate and valerate.

In one of the embodiments of the examples of inorganic salts of carboxylic acids or phenols can be selected from salts of ammonium, alkali metals including lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminium, zinc, barium, Kalinov, Quaternary ammonium.

In another embodiment approx the market of organic salts of carboxylic acids or phenols can be selected from salts of arginine, organic amines, including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathine, tert-butylamine, benethamine (N-benzylpenicillin), dicyclohexylamine, diethylamine, diethanolamine, ethanolamines, ethylendiamine, geranamine, imidazoles, lisini, methylamines, meglumine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, pikolines, piperazines, procaine, Tris(hydroxymethyl)methylamines, triethylamine, triethanolamines, trimethylamine, tromethamine and urea.

In one of the embodiments, such salts can be formed by conventional methods, e.g. by bringing in product interaction in the form of a free base or free acid with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging ions available salt to another ion on a suitable ion exchange resin.

In one of the embodiments of the methods according to this invention is applied pharmaceutically acceptable salt of the compounds according to this invention. In one of the embodiments of the methods according to this invention used the pharmaceutically acceptable salt of Compounds of formula IA, I-XII. In one of the embodiments in the methods of this invention employ an amine salt of Compounds of formula IA, I-XII of this invention. In one of the embodiments of the methods according to this invention apply salt of the phenol Compounds of formulas IA, I-XII of this invention.

In one of the embodiments of the methods according to this invention is used, the compound of formula IA, I-XII or its isomer, pharmaceutical product, hydrate, polymorph or their combination in the form of a free base, free acid, in the uncharged form or in the form of not forming a complex.

In some embodiments of the present invention the compounds according to the invention contain three phenyl groups, which are held together by amide linkages. In one embodiments of the compounds according to the invention are uncharged structure. In another embodiment of the compounds according to the invention represent patterns in free base form. In another embodiment of the compounds according to the invention represent structures in the form of the free acid. In another embodiment of the compounds according to the invention are not forming complexes patterns. In another embodiment of the compounds according to the invention are reinsuance patterns. In another embodiment of the compounds according to the invention are pharmaceutically acceptable salts. In the other is the embodiment of some compounds according to the invention are salts of hydrochloride (HCl).

In one of the embodiments of the methods according to this invention is applied isomer of Compounds of formula IA, I-XII. In one of the embodiments of the methods according to this invention used in the pharmaceutical product of the Compound of formula IA, I-XII. In one of the embodiments of the methods according to this invention is applied hydrate the compounds of formula IA, I-XII. In one of the embodiments of the methods according to this invention apply polymorph the compounds of formula IA, I-XII. In one of the embodiments of the methods according to this invention is applied metabolite of the Compounds of formula IA, I-XII. In another embodiment of the methods according to this invention using a composition containing a Compound of formula IA, I-XII, as described herein, or, in another embodiment, a combination isomer, metabolite, pharmaceutical product, hydrate, polymorph the compounds of formula IA, I-XII.

In one of the embodiments, the term "isomer" includes the optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like, but is not limited to.

In one of the embodiments, the term "isomer" includes the incorporation into optical isomers of the compounds. In one of the embodiments, the term "isomer" includes the incorporation in its stereoisomers of the compounds. In the compounds according to the invention include amide bond, which can be characterised by its CIS - or Tr is the na-isomerization. It should be understood that the present invention covers any optically active or stereoisomeric form, or mixtures thereof, and it is believed that their use for any application is within the scope of this invention.

In another embodiment, the invention also includes hydrates of the compounds. In one of the embodiments, the term "hydrate" refers to the hemihydrate, monohydrate, dihydrate, trihydrate, or other forms known in the art.

The synthesis methods

The compounds of formula I or IA can be obtained, for example, as a result of interaction of the substituted diphenylamine with benzoic acid or benzoylchloride in the presence of a base to obtain benzamide. In one embodiments the base is pyridine. In another embodiment of benzoylchloride represents a benzoyl chloride. In another embodiment of the hydroxyl Deputy protect during the reaction between diphenylamine and benzoic acid or benzoylchloride. In another embodiment of the protective group of the hydroxyl possibly removed at the last stage. Cm. the publication of the application U.S. No. 2009/00624231, which is incorporated in its entirety by reference.

For example, the Compound of formula IA:

,

where R1, R2, R3and R4, j and k, as described above,

may b the th received by way including bringing in interaction

with

obtaining

; and

bringing in the interaction of diphenylamine (3)

in the presence of a base to obtain

,

where if R1, R2, R3and R4independently represent IT, O-Alk-R5R6or O-Alk-heterocycle, R1', R2', R3', R4'represents a protected hydroxyl group, and the protective group is removed to obtain the free hydroxyl, or perhaps with subsequent interaction with Cl-Alk-heterocycle or Cl-Alk-NR5R6obtaining the compounds of formula IA:

where if R1, R2, R3and R4independent groups are not HE, O-Alk-NR5R6or O-Alk-heterocycle, R1', R2', R3'and R4'are R1, R2, R3and R4respectively.

Another example of the method of obtaining the compounds of formula IA:

,

where R1, R2, R3and R4such as described above, includes bringing in interaction

with

in the presence of a base is getting

,

where if R1, R2, R3and R4independently represent IT, O-Alk-R5R6or O-Alk-heterocycle, R1', R2', R3'and R4'represents a protected hydroxyl group, where the protective group is removed to obtain the free hydroxyl, or perhaps with subsequent interaction with Cl-Alk-heterocycle or Cl-Alk-NR5R6obtaining the compounds of formula IA:

,

where if R1, R2, R3and R4independent groups are not HE, O-Alk-NR5R6or O-Alk-heterocycle, R1', R2', R3'and R4'are R1, R2, R3and R4respectively.

In one example Compound II receive in accordance with Example 1 and Fig.5.

In another example, the Compound III receive in accordance with Example 1 and Fig.5.

In the following example, the compound of formula IV:

can be obtained by interaction

with

in the presence of a base to obtain

with the subsequent destruction of the protected group to obtain Compound IV:

,

where R and R' represent the same is e or different protective groups. In one of the examples of Compound IV receive in accordance with Example 2 and Fig.6.

In another example, the Connection V receive in accordance with Example 1 and Fig.5.

In the following example, the Connection VI receive in accordance with Example 3 and Fig.7.

In another example, the Compound VII receive in accordance with Example 1 and Fig.5.

In another example, the Compound VIII receive in accordance with Example 4 and Fig.5.

In another example, the Connection IX receive in accordance with Example 5 and Fig.8.

In another example, the hydrochloride of Compound X receive in accordance with Example 5 and Fig.8.

In another example, the Connection of the XI receive in accordance with Example 1 and Fig.5.

In another example, the Compound XII receive in accordance with Example 1 and Fig.5.

Suitable protective groups include hydroxyl, such as a group of simple methyl ether (methoxy) benzyl ester (benzyloxy), simple methoxymethyl (MOM) ether, simple benzoyloxymethyl (CMV) ether, benzil, carbobenzoxy, simple methoxyethoxymethyl (MEM) ether, a simple 2-(trimethylsilyl)ethoxy-methyl (SEM) ether, simple methylthiomethyl (MTM) ether, simple phenylthiomethyl (RTM) ether, simple azidomethyl ether, simple cyanomethylene ether, simple 2,2-dichloro-1,1-diferetiable ether, a simple 2-hloretilova ether, simple 2-bromet the gross ether, simple tetrahydropyranyl (TNR) ether, a simple 1-ethoxyethyl (EE) ether, simple ventilago ether, a simple 4-bromination ether, simple cyclopropylmethanol ether, simple allyl ether, simple propargilovyh ether, simple isopropyl ether, simple cyclohexylamino ether, simple tert-butyl ether, simple benzyl ether, simple 2,6-dimethylbenzyl ether, a simple 4-methoxybenzylthio ether, simple on-nitrobenzyl ether, simple 2,6-dihlorbenzilovy ether, simple 3,4-dihlorbenzilovy ether, a simple 4-(dimethylamino)carbonintensive ether, simple 4-methylsulfanyl-benzyl ether, a simple 4-untilmarriage ether, a simple 4-Pikalyovo ether, getattr-p-tolyl, simple titrator-4-piridinovogo ether, simple trimethylsilyl (TMS) ether, simple tert-butyldimethylsilyl (TBDMS) ether, simple tert-butyldiphenylsilyl (TBDPS) ether, simple triisopropylsilyl (TIPS) ether, uriformat, arylacetic, killavullen, arelevant, allantoin, aryl-9-fluorenecarboxylic, arylmethylidene, 1-substituted-carbonate, tert-BUTYLCARBAMATE, 4-methylsulfonylbenzoyl, 2,4-dimethylpent-3-ylcarbonyl, aryl-2,2,2-trichlorethylene, allansilberman, arylcarbamoyl, complex dimethylphosphino ether (Dmp-OAr), complex dimethylphosphine tinylogo ether (Mpt-OAr), complex diphenylphosphino-tinylogo ether (Dpt-OAr), arellanobond, uritolocalfile or aryl-2-formylbenzenesulfonic.

Methods according to this invention include the use of compounds IA, I-XII, the method of preparing compounds according to the invention includes bringing in the interaction of diphenylamine with benzoyl chloride in the presence of a base. Suitable bases include, for example pyridine, triethylamine, K2CO3Cs2CO3, Na2CO3, methylamine, imidazole, benzimidazole, histidine, tributylamine or any combination of them. In one of the embodiments of the base is a pyridine.

Methods according to this invention include the use of Compounds IA, I-XII, the method of preparing compounds according to the invention includes the removal of the protected hydroxyl. In another embodiment of the deletion criteria will depend on the protective group. In some embodiments of stage removal protection includes hydrogenation in the presence of Pd/C. In another embodiment, the removal of protection includes interaction with BBr3. In another embodiment of the stage of removal protection includes interaction with acid.

In the following examples, Compounds IA, I-XII protect in accordance with Fig.5-8 and Examples 1-5.

The pharmaceutical composition

In some embodiments according to this invention proposed how PR is changing, which include the introduction of compositions containing the described compounds. As used herein, "pharmaceutical composition" means therapeutically effective amount" of the active ingredient, i.e., compounds according to the invention together with a pharmaceutically acceptable carrier or diluent. The term "therapeutically effective amount", as used herein, refers to that amount which provides a therapeutic effect for a given condition and mode of administration.

As it is used in this description, the term "introduction" refers to bringing a subject in contact with the connection of the present invention. As used in this description, the introduction can be performed in vitro, i.e., in vitro or in vivo, i.e. in cells or tissues of living organisms, for example humans. In one of the embodiments of the present invention encompasses the introduction of the compounds of the present invention the subject of male sex.

According to this invention proposed, in other embodiments, the pharmaceutical products of the compounds set forth in this description. The term "pharmaceutical product" refers, in other embodiments, to compositions suitable for pharmaceutical applications (pharmaceutical compositions), for example, described in this specification.

Connection to izopet the tion can be entered by themselves or as an active ingredient of the composition. Thus, the present invention also includes pharmaceutical compositions of Compounds of formula I containing, for example, one or more pharmaceutically acceptable carriers.

There are a huge number of standard references, which describe methods of preparation of various compositions suitable for administration of the compounds according to the invention. Examples of possible compositions and preparations contain, for example, in the Handbook of Pharmaceutical Excipients American pharmaceutical Association, current edition); Pharmaceutical Dosage Forms: Tablets (editors Lieberman, Lachman and Schwartz, current edition, published by Marcel Dekker, Inc.), and Remington''s Pharmaceutical Sciences (editor Arthur Osol), 1553-1593 (current edition).

The route of administration and dosage forms are closely associated with therapeutic amounts of the compounds or compositions that are desirable and effective for a given therapeutic application.

Suitable dosage forms include those for oral, rectal, sublingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, intrabronchial, lymphatic and intrauterine injection and other dosage forms for systemic delivery of active ingredients, but the mi is not limited. Preferred compositions suitable for oral administration.

To prepare such pharmaceutical dosage forms, the active ingredient can be mixed with a pharmaceutical carrier according to conventional methods of mixing pharmaceuticals. The media may be available in a wide variety of forms depending on the form of preparation is needed for injection.

In the manufacture of compositions in the composition of the oral dosage form can be any of the usual pharmaceutical media. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, corrigentov, preservatives, dyes and the like. For solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to the ease at their introduction of tablets and capsules represent the most preferred standard oral dosage form. If it is desired, using standard methods on tablets can be coated in sugar or intersolubility floor.

For parenteral compositions is Sitel will usually contain sterile water, although there may be included other ingredients such as ingredients that promote solubility or conservation. You can also prepare input injection solutions, in this case, you can use the corresponding stabilizers.

In some cases it may be advantageous to use the active agent in a "vectorized" form, as for example, by encapsulating the active agent in a liposome or other encapsulating the environment or by "fixing" active agent, for example, covalent bonding, chelation, or education associative coordination bonds, on a suitable biological molecule such as a molecule selected from proteins, lipoproteins, glycoproteins and polysaccharides.

The treatment methods of the present invention with the use of formulations suitable for oral administration may be presented in different ways with the use of the individual units, such as capsules, pills, tablets or lozenges, each containing a predetermined amount of the active ingredient in the form of, for example, powder or granules. Perhaps that may be used in suspension in an aqueous solution or non-aqueous liquid such as a syrup, an elixir, an emulsion or a hood.

A tablet may be made by compressing or molding or wet granulation, in which you can together with one or more than one auxiliary ingredient. Molded tablets may be made by molding in a suitable machine the active compound is in free flowing form such as powder or granules, which may be mixed, for example, with the binder, baking powder, lubricant, inert diluent, surface-active agent or bleaching agent. Molded tablets, consisting of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.

The syrup can be made by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, to which may be added any accessory ingredient(s). Such accessory ingredient(s) may include corrigentov, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as polyhydric alcohol, such as glycerol or sorbitol.

Preparations suitable for parenteral administration may include sterile aqueous composition of active compounds, which preferably is isotonic with the blood of the recipient (e.g., saline). Such drugs may include suspendresume agents and thickening agents and lipo is ohms or other systems, consisting of microparticles, which are designed to implement the directed delivery of the compound to blood components or one or more organs. Such medications may be presented in a single dosage form or dosage form for repeated administration.

Parenteral administration may refer to any suitable form of system delivery. The introduction may be, for example, intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intra-abdominal (e.g., intraperitoneal), and so on, and can be achieved by infusion pumps (external or implantable) or any other suitable means corresponding to the desired method of administration.

Nasal compositions and other compositions for administration by sputtering on the mucous membranes (for example, inhalation form) can contain purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Preferably, the pH and isotonic condition such compositions were summed to values that are compatible with nasal or other mucous membranes. Alternatively, they can be in the form of fine solid powders suspended in a gaseous medium. Such compositions can be delivered using any suitable means or method, in the example, through the nebulizer, atomizer, metering pump or the like.

Compositions for rectal injection can be presented in the form of a suppository with a suitable carrier such as cacao butter, hydrogenated fats or hydrogenated fatty carboxylic acid.

The transdermal compositions can be prepared by introducing an active agent into a thixotropic or gel-like media, such as cellulose, such as methylcellulose or hydroxyethylcellulose, with the resulting composition is then placed in a transdermal device, adapted to guarantee dermal contact with skin of the user.

In addition to the aforementioned ingredients, the compositions of this invention may additionally include one or more than one auxiliary ingredient(s) selected from, for example, diluents, buffers, corrigentov, binders, disintegrating agents, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.

The compositions of the present invention may have a profile immediate release, continuous release, release with delay action, or any other profile release, well-known specialist in this field.

One is of the embodiments according to this invention proposed methods (a) reduce levels of total testosterone in serum; b) a decrease in the levels of free testosterone in serum by decreasing luteinizing hormone (LH) or regardless of the decrease of the hormone LH in the male subject having prostate cancer, comprising the introduction of oral compositions containing a Compound of formula IA, I-XII. In additional embodiments of the methods according to this invention applied oral composition comprising a Compound of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII.

In one of the embodiments according to this invention, a method for treating prostate cancer by reducing the levels of LH or regardless reduction of LH levels in a male subject having prostate cancer, comprising the introduction of oral compositions containing a Compound of formula IA, I-XII, In additional embodiments according to this invention methods of treating prostate cancer by reducing the levels of LH or regardless reduction of LH levels in a male subject having prostate cancer, comprising the introduction of an oral composition containing the Compound of the formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII.

You should understand, is that the invention encompasses any embodiment of the compounds which is set forth in this description and which in some embodiments referred to as "compound of the invention".

In one of the embodiments of the methods according to this invention may include the introduction of compounds according to the invention in various dosages. In one of the embodiments of the compound according to the invention is administered at a dosage 1-1500 mg per day. In additional embodiments of the compound according to the invention is administered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg / day 50-100 mg / day 50-200 mg / day 150-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 150-500 mg / day, 200-1000 mg per day, 300-1500 mg / day or 100 to 1000 mg per day.

In one of the embodiments of the methods according to this invention may include the introduction of compounds according to the invention in various dosages. In one of the embodiments of the compound according to the invention is administered at a dose of 3 mg In additional embodiments of the compound according to the invention is administered at a dose of 10 mg, 30 mg, 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg or 1500 mg

In one of the embodiments of the methods according to this invention may include the introduction of compounds according to the invention in various dosages. In one of the embodiments of the compound according to the invention is administered in a dosage of 0.1 mg/kg/day. In additional embodiments of the compound according to the invention is administered in a dosage of from 0.2 to 30 mg/kg/day and 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day or 30 mg/kg/day.

In one of the embodiments of the methods according to this invention proposed for use, and pharmaceutical compositions containing the Compound of formula IA, I-XII. In additional embodiments of the methods according to this invention proposed for use, and pharmaceutical compositions containing the Compound of the formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII.

In some embodiment the pharmaceutical composition is a solid dosage form. In another embodiment the pharmaceutical composition is a tablet. In another embodiment the pharmaceutical composition is a capsule. In another embodiment the pharmaceutical composition is a solution. In another embodiment the pharmaceutical composition is a transdermal patch.

In one of the embodiments of the application of the compounds according to the invention or a composition containing this compound will be used in the inhibition, suppression, enhancement or stimulation of the desired response in the subject, which is obvious to the person skilled in the art. In another embodiment the composition may also contain additional active ingredients, the activity to which that useful for a particular application, for which impose the connection according to the invention.

With the introduction of mammals, and particularly humans, it is expected that the physician will determine the actual dosage and duration of treatment that will be most suitable for the individual and can vary depending on age, weight, heredity and/or answer specific individual.

In some embodiments of any of the compositions of this invention will contain the connection according to the invention in any form or by any embodiment described in this specification. In some embodiments the composition of any of the compositions of this invention will include a connection according to the invention in any form or by any embodiment described in this specification. In some embodiments the compositions of this invention will consist essentially of the compounds according to the invention in any form or by any embodiment described in this specification. In some embodiments, the term "contain" refers to the inclusion of the indicated active agent, such as a connection according to the invention, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc. such that known in the pharmaceutical industry. In some embodiments, the term "consisting essentially of" relative is raised to the composition, the active ingredient of which is only specified active ingredient, but may include other compounds intended for stabilization, preservation, etc. of this song, but not involved directly in therapeutic effect of said active ingredient. In some embodiments, the term "consisting essentially of" may refer to the components that contribute to the release of the active ingredient. In some embodiments, the term "consisting" refers to a composition that contains an active ingredient and a pharmaceutically acceptable carrier or excipient,

It should be understood that any use of any of the Compounds described herein, can be used in the treatment of any disease, disorder or condition described herein, and it represents the embodiment of the present invention. In one embodiments of the compounds represent a connection in the form of a free base, free acid, in the uncharged form or in the form of not forming a complex.

The following examples are presented to more fully illustrate the preferred embodiments of the invention. They in no way be construed as limiting the broad scope of the invention.

EXAMPLES

EXAMPLE 1

General procedure for the synthesis of the of soedinenii formulas II-XII and synthetic intermediates

Organic solvents, surfactants, antioxidants, etc. that can be used in the compositions described herein, are generally available from commercial sources. For example, PEG-300, Polysorbate 80, Captex™ 200, Capmul™ MCM C8 can be obtained, for example, Dow Chemical Company (Midland, Ml), ICI Americas, Inc. (Wilmington, DE) or Abitec Corporation (Janesville, WI).

The ligands of estrogen receptors described herein, can be obtained in different ways, well known to specialists in this field. For example, ligands of estrogen receptors described herein, can be obtained by the synthesis methods described in application for U.S. patent No. 2009/0062341; thus the description of each of them is included in its entirety by reference.

Total synthesis of derivatives of N,N-bis-aniversario

Total synthesis of diarylamino (Fig.5). Arylamine (1.5 equivalent), allided (1 equivalent), K2CO3(2 equivalent), CuI (0.1 equivalent) and L-Proline (0.2 equivalent) were mixed together and dissolved in anhydrous DMSO at room temperature. Then the reaction mixture was stirred and heated to 90°C for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. In order to carry out the separation of the solution was added EtOAc. EtOAc-containing layer was separated, washed with brine and dried over anhydrous MgSO4. actuarial was removed under reduced pressure. The solid residue was purified column flash chromatography (silica gel) using a mixture of 5% EtOAc/hexane as eluent, which allowed to obtain the appropriate diarylovely.

Bis-(4-methoxyphenyl)amine (1A): pale yellow solid, yield 73%. So pl. 98,6-99,0°C.1H NMR (CDCl3, 300 MHz) δ 6.93-6.81 (m, 8H), 5.37 (s, br, 1H), 3.78 (s, 6H). MS m/z 228,4 (M-H)+.

N-(4-Methoxyphenyl)-phenylamine (1b): pale yellow solid, yield 70%. So pl. 106,3-to 106.5°C.1H NMR (CDCl3, 300 MHz) δ 7.24-7.18 (m, 3H), 7.08-7.06 (m, 2H), 6.92-6.84 (m, 4H), 5.61 (s, br, 1H), 3.79 (s, 3H). MS m/z 200,1 (M+H)+.

N-(4-Forfinal)-N-4-methoxybenzylamine (1C): pale yellow solid, yield 54%. So pl. 60,6-61,0°C.1H NMR (CDCl3, 300 MHz) δ 7.01-6.83 (m, 8H), 3.78 (s, 3H). MS m/z 217 (M)+.

N-(4-Benzyloxyphenyl)-N-4-methoxybenzylamine (1d): pale yellow solid, yield 54%. So pl. 108,0-108,4°C.1H NMR (CDCl3, 300 MHz) δ 7.34-7.08 (m, 5H), 6.90-6.81 (s, 3H), 3.78 (s, 3H). MS m/z 306 (M+N)+.

Total synthesis of benzamides. Kilanerin (1 equivalent), benzoyl chloride (1.3 equivalents) and pyridine (6 equivalents) were mixed together and dissolved in anhydrous THF (tetrahydrofuran) at room temperature. The mixture was stirred and boiled under reflux for 24 hours. The reaction solution was cooled to room temperature and hydrolyzed by adding 2 n HCl solution. The solution was extracted with ethyl acetate. The organic layer about ivali saturated aqueous NaHCO 3to remove excess acid, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified column flash chromatography using EtOAc/hexane (3/7 vol./vol.), allowing connection of appropriate benzamido.

3-Fluoro-N-(4-forfinal)-4-methoxy-N-(4-methoxyphenyl)benzamide (2A): yellow solid. So pl. 54-56°C.1H NMR (CDCl3/TMS (tetramethylsilane was)) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H). MS (ESI (electrospray ionization) m/z 370,1 [M+H]+.

4-Fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2b): colorless oil, yield 84.2 per cent.1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m/z 442,1 (M+Na)+.

4-Methoxy-N-(4-methoxyphenyl)-N-(4-forfinal)-benzamide (2C): white solid, yield 97%. So pl. 133,5-134,5°C.1H NMR (CDCl3, 300 MHz) 6 8.11-6.66 (m, 15H), 3.74 (s, 3H), 3.73 (s, 3H). MS m/z 384 (M+H)+.

N-(4-Patoxetine)-N-(4-benzyloxyphenyl)-2-naphthylamide (2d): white solid, yield 58%. So pl. 174,9-175,5°C.1H NMR (CDCl3, 300 MHz) δ 8.04 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.61 (m, 1H), 7.51-7.43 (m, 4H), 7.40-7.31 (m, 4H), 7.13-7.10 m, 4H), 6.88-6.78 (m, 4H), 4.99 (s, 2H), 3.74 (s, 3H). MS m/z 460 (M+H)+.

4-Fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2): colorless oil, yield 84.2 per cent.1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), .71 (s, 3H). MS m/z 442,1 (M+Na)+.

A General method demethylation derivatives benzamido using BBr3. Connection methoxybenzamide was dissolved in anhydrous CH2Cl2. Was added dropwise BBr3(1.0 M solution in CH2Cl2) at 0°C. the Reaction solution was slowly heated to room temperature and left to mix overnight at room temperature. The mixture was cooled to 0°C in an ice bath and hydrolyzed by adding water. In order to carry out the separation of the solution was added EtOAc. The organic layer was separated; the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified column flash chromatography using CH3HE/CH2Cl2(about 1/9./vol.), allowing for connection of the corresponding phenols.

4-Fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)benzamide (3A): white solid, yield of 92.5%.1H NMR (DMSO-d6, 300 MHz) δ 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.18 (d, 2H, J=8.7 Hz), 6.93 (d, 4H, J=8.7 Hz), 7.03 (d, 2H, J=8,4 Hz), 6.78 (d, 2H, J=8.7 Hz), 6.57 (d, 2H, J=8.7 Hz). MS m/z 392,1 (M+H)+.

The following compounds were synthesized, as described herein above defined characteristics and results are summarized in Table 1: N,N-bis(4-hydroxyphenyl)-4-propylbenzamide (II); 3-fluoro-N-(4-Fortini is)-4-hydroxy-N-(4-hydroxyphenyl)benzamide (IV); N,N-bis(4-hydroxyphenyl)-2,3-dimethylbenzamide (V); 3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (VII); 3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzene (XI); and 3-fluoro-N,N-bis(4-hydroxyphenyl)-2-methylbenzamide (XII).

General methods of dibenzylamine benzyloxyphenyl-benzamido. The compound was dissolved in EtOH in the vessel for the hydrogenation capacity of 250 ml To the solution was added a powder of Pd/C (5 mol%). The reaction vessel was installed in the apparatus for hydrogenation under pressure of the hydrogen gas 20 psig (138 kPa). Over the course of the reaction was monitored using TLC (thin layer chromatography) until the disappearance of the original substance. Then the solvent was removed under reduced pressure. The residue was purified column flash chromatography using hexane/EtOAc (about 3/2./vol.), that allowed to obtain the desired product.

The following compounds were synthesized, as described herein above defined characteristics and results are summarized in Table 1: N,N-bis(4-hydroxyphenyl)-2-naphthylamide (VI).

General methods of recovery benzamido without protection. Connection benzamide was dissolved in 20 ml anhydrous THF at room temperature. With a syringe at room temperature in an argon atmosphere was added N3(SMe2). The reaction solution was stirred and heated to a temperature of reflux distilled for 6 hours. Then the reactions is extinguished, adding 10 ml of the Meon at 0°C. the Solvent was removed under reduced pressure. The residue was subjected to column flash chromatography (silica gel, CH2Cl2/Meon=9/1.vol.), that allowed to obtain the desired product.

The following compounds were synthesized, as described herein above defined characteristics and results are summarized in Table 1: 4,4'-(2,3-dimethylbenzylidene)diphenol (III); 4-((4-forfinal)(4-hydroxybenzyl)amino)phenol (VIII).

Total synthesis of O-(2-piperidine-1-ylethoxy)-benzamido and analogues. To a solution of similar hydroxyphenylacetamide benzamide (1 equivalent) in acetone was added K2CO3(3 equivalent) and hydrochloride salt of N-chloroethylamine (1.2 equivalent). The solution was heated to the temperature of reflux distilled for 6 hours. The solution was evaporated to dryness. The residue is hydrolyzed by adding water, and then extracted with ethyl acetate. The organic layers was separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified flash chromatography using methylene chloride/methanol (9/1 vol/vol.), to give the desired compound. Salt is the hydrochloride was obtained by adding HCl in Et2O to a methanol solution of compounds with subsequent evaporation of solvent.

The following compounds were synthesized as outlined in the description above, was determined by ha is acteristic and the results were summarized in Table 1: 4-fluoro-N-(4-hydroxyphenyl)-N-(4-(2-(piperidine-1-yl)ethoxy)phenyl)-2-(trifluoromethyl)benzamide (IX); and 4-fluoro-N-(4-hydroxyphenyl)-N-(4-(2-(piperidine-1-yl)ethoxy)phenyl)-2-(trifluoromethyl)benzamide hydrochloride (X), which is the HCl salt of compound IX.

TABLE 1.
The physical characteristics of the compounds of formulas II-XII
No. Conn.StructurePhysical characteristics
II1H NMR (DMSO-d6, 300 MHz) δ 9.46 (s, 2H, 2×OH), 7.27-7.26 (m, 2H, ArH), 7.06-7.04 (m, 2H, ArH), 6.99-6.97 (m, 4H, ArH), 6.66-6.65 (m, 4H, ArH), 2.50 (s, 2H, CH2, overlapping with DMSO peak), 1.53-1.52 (m, 2H, CH2), of 0.82 (t, J=7,33 Hz, 3H, CH3). m/z 346,0 (M-N)-.
IIIReddish-brown foam, yield 41%. So pl. 147-150°C.1H NMR (DMSO-d6, 300 MHz) δ 8.92 (s, 2H), 7.07 (d, J=7,33 Hz, 1 H), 7.00-6.94 (m, 2H), 6.76-6.72 (m, 4H), 6.63-6.59 (m, 4H), 4.72 (s, 2H), 2.23 (s, 3H), 2.16 (s, 3H). m/z 320,2 (M+H)+.
IVReddish-brown solid, yield 92%. So pl. 110-112°C.1H NMR (DMSO-d6, 300 MHz) δ 10.14 (bs, 1H),9.71 (bs, 1H) 7.26-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J=8,61 Hz, 2H), 6.68 (d, J=8,68 Hz, 2H). m/z 364,1 (M+Na)+.
V1H NMR (DMSO-d6, 300 MHz) δ 9.47 (bs, 2H, 2×OH), 7.18 (d, J=8,30 Hz, 2H, ArH), 7.06 (d, J=7,08 Hz, 1H, ArH), 7.00-6.92 (m, 4H, ArH), 6.78 (d, J=8,30 Hz, 2H, ArH), 6.51 (d, J=of 8.06 Hz, 2H, ArH), 2.22 (s, 3H, CH3), 2.15 (s, 3H, CH3). m/z 334,3 (M+N)+.
VIWhite solid, yield 70%. So pl. 264,3-265,2°C (decomposition).1H NMR (DMSO-d6, 500 MHz) δ 9.46 (s, 2H), 7.98 (s, 1H), 7.85-7.75 (m, 2H), 7.75-7.73 (m, 2H), 7.54-7.48 (m, 2H), 7.45-7.43 (m, 1H), 7.05 (s, 4H), 6.66 (s, 4H). m/z 356 (M+N)+.
VII1H NMR (DMSO-d6, 300 MHz) δ 10.25 (bs, 1H, HE), 9.48 (bs, 2H, 2×OH), 7.12-6.95 (m, 6H, ArH), 6.80-6.65 (m, 5H, ArH). m/z 338,0 (M-N)-.
VIIIYellow oil, yield 92%.1H NMR (DMSO-d6, 500 MHz) δ 9.29 (s, 1H), 9.24(s, 1H), 7.09 (d, 2H, J=8,3 Hz), 6.98 (d, 2H, J=9.0 Hz), 6.94-6.91 (m, 2H), 6.73 (d, 2H, J=9.0 Hz), 6.68-6.64 (m, 4H), 4.70 (s, 2H). m/z 307,8 (M-N)-.
IX and X (HCl salt of compound (IX)Bel is e solid, output 57,7%.1H NMR (DMSO-d6, 300 MHz) δ 9.57 (s, 1H), 7.71-7.68 (m, 2H), 7.47-7.44 (m, 1 H), 7.28 (d, 1H, J=9.0 Hz), 7.18 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8,4 Hz), 6.97 (d, 1H, J=9.0 Hz), 6.80-6.76 (m, 2H), 6.57 (d, 1H, J=8.7 Hz), 4.06 (t, 1 H, J=6.0 Hz), 3.93 (t, 1H, J=6.0 Hz), 2.66 (t, 1 H, J=5.7 Hz), 2.55 (t, 1H, J=5.4 Hz), 2.44 (s, 2H), 2.36 (s, 2H), 1.49-1.37 (m, 6H). m/z 501,0 (M-N)-.
XI1H NMR (DMSO-d6, 300 MHz) δ 9.95 (bs, 1H, HE), 9.47 (bs, 2H, 2×OH), 7.02-6.95 (m, 6H, ArH), 6.75-6.72 (m, 1H, ArH), 6.68-6.66 (m, 4H, ArH). m/z 324,0 (M+H)+.
XIIPale red solid. Output 72,0%. So pl. > 240°C.1H NMR (DMSO-d6, 300 MHz) δ 9.50 (bs, 2H), 7.19-6.79 (m, 7H), 6.61 (d, J=8,93 Hz, 2H), 6.53 (d, J=7,79 Hz, 2H), 2.23 (s, 3H). m/z 336,0 (M-H)-.

EXAMPLE 2

The synthesis of the compounds of formula IV (Fig.6)

Stage 1: synthesis of 4-fluoro-N-(4-methoxyphenyl)aniline (1C)

4-Ftoranila (78,63 g; 0,708 mol), 4-iadanza (138,00 g; 0,590 mol), anhydrous K2CO3(122,23 g; 0,884 mol), CuI (11,23 g; 58,96 mmol) and L-Proline (of 13.58 g; amount of 0.118 mol) was mixed together in a dried three-neck round bottom flask with a capacity of 1 l, equipped with a rod for stirring, reflux condenser and inlet for argon. Added anhydrous DMSO (300 ml) at room temperature. React the mixture was stirred and heated to 90°C for 20 hours in an argon atmosphere. Then the mixture was cooled to room temperature and hydrolyzed with water (300 ml). In order to carry out the separation of the solution was added EtOAc (200 ml). EtOAc-containing layer was separated. The aqueous layer was extracted with 100 ml EtOAc. EtOAc-containing layers were combined, washed with brine (2×100 ml) and dried over anhydrous MgSO4(50 g). The solvent was removed under reduced pressure. The remainder in the form of a brown oil was purified column flash chromatography (silica gel, hexane/EtOAc=9/1.vol.), that allowed us to get the product 4-fluoro-N-(4-methoxyphenyl)aniline (1C) as a yellow solid (99,70 g); output 77,8%. So pl. 46-48°C. MS (ESI) m/z 218,1 [M+H]+.1H NMR (DMSO-d6, 300 MHz) δ 7.77 (bs, 1H), 7.03-6.98 (m, 4H), 6.93-6.82 (m, 4H), 3.70 (s, 3H).

Stage 2: synthesis of 3-fluoro-N-(4-forfinal)-4-methoxy-N-(4-methoxyphenyl) benzamide (2A)

4-Fluoro-N-(4-methoxyphenyl)aniline (1C) (90,78 g; 0,418 mol) and 3-fluoro-4-methoxybenzophenone (94,55 g; 0,501 mol) were mixed together and dissolved in anhydrous THF (200 ml) in a dried three-neck round bottom flask with a capacity of 1 l, equipped with a rod for stirring, reflux condenser and inlet for argon. With a syringe at room temperature in an argon atmosphere was added anhydrous pyridine (132,22 g; 1,672 mol). The reaction mixture was stirred and heated to a temperature of reflux distilled during the night. Then the reaction mixture ohla is given to room temperature and was filtered to remove pyridine salts. The solution was concentrated to remove the THF solvent. The remainder in the form of oil was washed with 200 ml of 2 n HCl solution and was extracted with ethyl acetate (2×200 ml). The combined organic layer was washed with a saturated aqueous solution of Na2CO3(150 ml) to remove excess of benzoyl chloride and acid, dried over MgSO4(50 g), filtered and concentrated under reduced pressure, obtaining oil. The residue was purified column flash chromatography using silica gel and CH2Cl2/acetone (about 50/1./vol.), that allowed us to obtain a pure compound corresponding benzamide as a yellow solid. So pl. 54-56°C. MS (ESI) m/z 370,1 [M+H]+.1H NMR (CDCl3/TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).

Stage 3: synthesis of 3-fluoro-N-(4-forfinal)-4-hydroxy-N-(4-hydroxyphenyl)benzamide (IV)

The compound 3-fluoro-N-(4-forfinal)-4-methoxy-N-(4-methoxyphenyl)-benzamide (2A) (138,0 g; 0,374 mol) was dissolved in anhydrous CH2Cl2(600 ml) at room temperature (RT) in an argon atmosphere. Dropwise via syringe with stirring was added BBr3(374,75 g; 1,496 mol) at 0°C in an ice bath in an argon atmosphere. The reaction solution was allowed to mix at room temperature over night. Then the solution was poured into 1 l of ice water with stirring. This suspension was stirred at whom atoi temperature for 2 hours. The white precipitate was filtered, washed with water (2×100 ml) and dried under vacuum. Layer CH2Cl2was separated, dried over anhydrous MgSO4(50 g), filtered and concentrated under reduced pressure to dryness. A white precipitate and the residue from the solution of CH2Cl2were combined and purified flash column-chromatography (silica gel, CH2Cl2/acetone/Meon=90/7/3 about./about./vol.), getting a lighter-reddish-brown solid, which is recrystallized twice from hot EtOAc solution/hexane, which allowed us to obtain a white crystalline solid (104,0 g); yield of 81.6%. So pl. 110-112°C. MS (ESI) m/z 364,1 [M+Na]+.1H NMR (DMSO-d6) δ 10.14 (bs, 1H),9.71 (bs, 1H), 7.25-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 2H).

EXAMPLE 3

The synthesis of compounds of formula VI (Fig.7)

Synthesis of 4-(benzyloxy)-N-(4-methoxyphenyl)aniline (1d) 4-Benzyloxyaniline (16.6 g; 83,31 mmol), 4-iadanza (15.0 g; 64,09 mmol), K2CO3(17,72 g; 128,18 mmol), CuI (1.22 g; 6,41 mmol) and L-Proline (1.48 g; 12,82 mmol) were mixed together and dissolved in anhydrous DMSO (120 ml) at room temperature. Then the reaction mixture was stirred and heated to 90°C for 48 hours. The mixture was cooled to room temperature and hydrolyzed with water. In order to carry out the separation of the solution was added EtOAc. EtOAc-containing layer was separated, washed with brine, dried over anhydrous MgSO4. actuarial was removed under reduced pressure. The solid residue was purified column flash chromatography (silica gel) using EtOAc/hexane (about 1/9./vol.), that allowed to obtain the appropriate diarylovely in the form of a yellow solid (9.8 g); yield 50%. So pl. 108,0-108,4°C.1H NMR (CDCl3, 300 MHz) δ 7.34-7.25 (m, 5H), 6.90-6.81 (m, 8H), 5.02 (s, 2H), 3.78 (s, 3H). MS m/z 306 (M+H)+.

Synthesis of N-(4-benzyloxyphenyl)-N-(4-methoxyphenyl)-2-naphthalide(2d) One equivalent of 4-(benzyloxy)-N-(4-methoxyphenyl)aniline (0,80 g; 2,62 mmol) was mixed with 1.5 equivalents of 2-nafolklore (0.75 g; 3.93 mmol) and 4 equivalents of pyridine (PY) (0,83 g; 10,48 mmol) in dried three-neck round bottom flask equipped with a magnetic rod for stirring and a reflux condenser. The mixture was dissolved in anhydrous THF (30 ml) and was heated to the temperature of reflux distilled for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified column flash chromatography using silica gel and EtOAc/hexane (3/7 vol./vol.), that allowed us to obtain a pure compound corresponding naphthalide in the form of a white solid (0,70 g); yield 58%. So pl. 174,9-175,5°C.1H NMR (CDCl3, 300 MHz) δ 8.04 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.61 (m, 1H), 7.51-7.43 (m, 4H), 7.40-7.31 (m, 4H), 7.13-7.10 (m, 4H), 6.88-6.78 (m, 4H), 4.99 (s, 2H), 3.74 (s, 3H). MS m/z460 (M+H)+.

Synthesis of N,N-bis(4-hydroxyphenyl)-2-naphthylamide (VI)

The compound N-(4-Benzino Setenil)-N-(4-methoxyphenyl)-2-naptime (2d) (0.50 g; of 1.09 mmol) was dissolved in anhydrous CH2Cl2(30 ml) at room temperature. Dropwise via syringe with stirring was added BBr3(3,26 ml of 1.0 M solution in CH2Cl2; 3,26 mmol) at room temperature. The reaction solution was left to mix overnight at room temperature. The mixture was cooled to 0°C in an ice bath and hydrolyzed by adding water. In order to carry out the separation of the solution was added EtOAc. The organic layer was separated; the aqueous layer was twice extracted with EtOAc. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified column flash chromatography using silica gel and CH3HE/CH2CH2(about 1/9./vol.), that allowed us to obtain the desired pure compound phenol as a white solid (0.27 g); yield 70%. So pl. 264,3-265,2°C (decomposition).1H NMR (DMSO-d6, 500 MHz) δ 9.46 (s, 2H), 7.98 (s, 1H), 7.85-7.75 (m, 2H), 7.75-7.73 (m, 2H), 7.54-7.48 (m, 2H), 7.45-7.43 (m, 1H), 7.05 (s, 4H), 6.66 (s, 4H). MS m/z356 (M+H)+.

EXAMPLE 4

The synthesis of the compounds of formula VIII

Synthesis of 4-((4-forfinal)(4-hydroxybenzyl)amino)phenol (VIII)

The compound N-(4-forfinal)-4-hydroxy-N-(hydroxyphenyl)benzamide (0,30 g; 0,93 mmol) was dissolved in 20 ml anhydrous THF at room temperature. With a syringe was added N3(SMe 2) (of 1.86 ml of 2 M solution in THF; 3,71 mmol) at room temperature in argon atmosphere. The reaction solution was stirred and heated to a temperature of reflux distilled for 6 hours. Then the reaction was suppressed by adding 10 ml of the Meon at 0°C. the Solvent was removed under reduced pressure. The residue was subjected to column flash chromatography (silica gel, CH2Cl2/MeOH=9/1.vol.), getting a yellow oil (0.26 g); yield 92%.1H NMR (DMSO-d6, 500 MHz) δ 9.29 (s, 1H), 9.24 (s, 1H), 7.09 (d, 2H, J=8,3 Hz), 6.98 (d, 2H, J=9.0 Hz), 6.94-6.91 (m, 2H), 6.73 (d, 2H, J=9.0 Hz), 6.68-6.64 (m, 4H), 4.70 (s, 2H). MS m/z 307,8 (M-H)-.

EXAMPLE 5 Synthesis of compounds of formulas IX and X (Fig.8)

Synthesis of diarylamino. Arylamine (1.5 equivalent), allided (1 equivalent), K2CO3(2 equivalent), CuI (0.1 equivalent) and L-Proline (0.2 equivalent) were mixed together and dissolved in anhydrous DMSO at room temperature. Then the reaction mixture was stirred and heated to 90°C for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. In order to carry out the separation of the solution was added EtOAc. EtOAc-containing layer was separated, washed with brine, dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The solid residue was purified column flash chromatography (silica gel) using EtOAc/hexane (3/7 vol./about.) as a solvent, which allowed us to obtain the appropriate diary is aniline. Bis-(4-methoxyphenyl)amine (1A): pale yellow solid; yield 73%.1H NMR (CDCl3, 300 MHz) δ 6.93-6.81 (m, 8H), 5.37 (s, br, 1H), 3.78 (s, 6H). MS m/z 228,4 (M-H)+.

Synthesis of 4-fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2F)

Mixing 1 equivalent of bis-(4-methoxyphenyl)amine (1A) (0.73 g; 3,18 mmol) with 1.2 equivalent of 4-fluoro-2-triftormetilfullerenov (0.87 g; 3,82 mmol) and 6 equivalents of pyridine (1.51 g; 19,08 mmol) in dried three-neck round bottom flask equipped with a magnetic rod for stirring and a reflux condenser. The mixture was dissolved in anhydrous THF (20 ml) and was heated to 90°C for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified column flash chromatography using silica gel and EtOAc/hexane (3/7 vol./vol.), that allowed us to obtain a pure compound corresponding benzamide as a colorless oil (1.12 g); output 84,2%.1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m/z 442,1 (M+Na)+.

Synthesis of 4-fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)benzamide (3A)

The compound 4-fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2E) (1,00 g; of 2.38 mmol) was dissolved in anhydrous CH2Cl2(30 ml) at room temperature. With a syringe was added dropwise BBr3(10 ml,0 M solution in CH 2Cl2; 10.0 mmol) at room temperature. The reaction solution was left to mix overnight at room temperature. The mixture was cooled to 0°C in an ice bath and hydrolyzed by adding water. In order to carry out the separation of the solution was added EtOAc. The organic layer was separated; the aqueous layer was twice extracted with EtOAc. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified column flash chromatography using silica gel and CH3HE/CH2Cl2(about 1/9./vol.), that allowed us to obtain the desired pure compound phenol as a white solid (0,86 g); yield of 92.5%.1H NMR (DMSO-d6, 300 MHz) 59.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.18 (d, 2H, J=8.7 Hz), 6.93 (d, 4H, J=8.7 Hz), 7.03 (d, 2H, J=8,4 Hz), 6.78 (d, 2H, J=8.7 Hz), 6.57 (d, 2H, J=8.7 Hz). MS m/z 392,1 (M+H)+.

Synthesis of 4-fluoro-N-(4-hydroxyphenyl)-N-[4-(2-piperidine-1-yl)-ethoxy)phenyl]-2-(trifluoromethyl)benzamide (IX)

To a solution of 4-fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)benzamide (3A) (0,61 g; 1.56 mmol) in acetone was added K2CO3(1.29 g; 9,36 mmol) and hydrochloride salt of N-chloroethylamine (0.34 g; of 1.87 mmol). The solution was heated to the temperature of reflux distilled for 20 hours. The solution was evaporated to dryness. The residue was purified flash chromatography (silica gel; methylene chloride/methanol=9/1.vol.), receiving a wish is a connection in the form of a white solid (0.45 g); output 57,7%.1H NMR (DMSO-d6, 300 MHz) δ 9.57 (s, 1H), 7.71-7.68 (m, 2H), 7.47-7.44 (m, 1H), 7.28 (d, 1H, J=9.0 Hz), 7.18 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8,4 Hz), 6.97 (d, 1H, J=9.0 Hz), 6.80-6.76 (m, 2H), 6.57 (d, 1H, J=8.7 Hz), 4.06 (t, 1H, J=6.0 Hz), 3.93 (t, 1H, J=6.0 Hz), 2.66 (t, 1H, J=5.7 Hz), 2.55 (t, 1H, J=5.4 Hz), 2.44 (s, 2H), 2.36 (s, 2H), 1.49-1.37 (m, 6H). MS m/z 501,0 (M-N)-.

The hydrochloride salt of the compound (X) was obtained by adding HCl in Et2O to a methanol solution of the compounds, with subsequent evaporation of solvent.

EXAMPLE 6

The affinity of binding with receptor for estrogen agonistic and antagonistic activity

The binding affinity of compounds to ER was determined using analysis of competitive binding of radioactive ligand in vitro using natural high affinity ligand ER [2,4,6,7-3H(N)]-estradiol ([3H]E2) and bacterial expressed, fused with GST protein containing the ligand-binding domain (LBD) of the receptor ER-α or ER-β.

Method

Recombinant ER-α or ER-β combined with [3H]E2to determine the equilibrium dissociation constants (Kd) [3H]E2. Protein was incubated with [3N]E2in increasing concentrations in the presence and in the absence of unlabeled E2in high concentrations at 4°C for 18 h to determine total and nonspecific binding. Data on non-specific binding of the calc is Tali and K dfor E2(ERα: 0,71 nm; ERβ: 1,13 nm) was determined using the method of nonlinear regression. In addition determined the concentration of [3N]E2required for saturation of the ER-α and ER-β LBD, which was equal to 4-6 nm.

Compounds in increasing concentrations (range: 10-11-10-6M) were incubated with [3N]E2(5,7 nm) and ER-LBD in the above-described conditions. After incubation, the material of the tablets were collected using filters, GF/B, using the harvester Unifilter-96 (PerkinElmer) and washed three times with cooled in ice buffer (50 mm Tris; pH of 7.2). Filter plates were dried at room temperature, then to each well was added 35 μl of the cocktail Microscint-O and filter plates tightly closed, using TopSeal-A. Radioactivity was counted on a scintillation counter for microplate TopCount® NXT using the installation options for the3H, cocktail Microscint (PerkinElmer).

Specific binding of [3H]E2for each concentration of the compound was determined by subtracting the data for non-specific binding of [3N]E2(as determined by incubation with unlabeled E2at a concentration of 10-6M) and expressing it in percentage of specific binding in the absence of the test compound. Determined concentration of the compounds, which leads to the reduction of specificationsimage [ 3N]E250% (IC50). Next was calculated equilibrium binding constant (Kifor connections: Ki=Kd×IC50/(Kd+L), where Kdrepresents the equilibrium dissociation constant of [3H]E2(ER-α=0,71 nm; ER-β=1,13 nm), and L represents the concentration of [3H]E2(ER-a: 5,7 nm; ER-β is 5.7 nm).

Results

Analyses of the binding was confirmed that the ligands are associated with ER-α and ER-β in various concentrations in the range of 3.75 nm to more than 1000 nm, and a selectivity varies from compounds, which are selective to the isoforms, to not selective to the isoforms. Results for representative compounds are listed in Table 2.

Table 2.
The results of binding to the individual connections
CONNECTIONKi(nm) for ER-αKi(nm) for ER-β
3,7581,6
3,816,44
21,715,2
7,1335,9
972
the 6.0676,92
1319
14,79646,32
1557
15,1225,02

Compound IV binds to ERα and ERβ. The binding affinity of Compound IV with ER were determined using analysis of competitive binding of radioactive ligand in vitro using natural high affinity ligand ER - [2,4,6,7-3H(N)]-estradiol ([3H]E2) and bacterial expressed, fused with GST protein containing the ligand-binding domain (LBD) of the receptor ER-α or ER-β. According to this analysis, affinned the binding (the value of K i) Compound IV with ERα and ERβ was 21,7±1,7 nm (n=3) and 15.2±4,1 nm (n=3), respectively. After binding to ER Compound IV initiates a complex series of molecular events leading to translational expression or repression of target genes associated with pharmacological response. In tests with temporary transfection of Compound IV behaves as an agonist of ERα and ERβ, demonstrating higher efficiency in relation to the stimulation of ERα-mediated transcriptional activation compared to ERβ. While estradiol activates ERα and ERβ, showing 5.1 times greater selectivity for ERα, Compound IV demonstrates in 49,0 times greater selectivity for ERα. Thus, the relative transactivation efficiency (normalized to the values for estradiol) Compound IV is characterized by 9.7 times higher selectivity for ERα compared to ERβ. In addition, under the action of Compound IV at concentrations up to 10 μm inclusive observed no antagonistic effects against stimulated by estradiol (1 nm) transcriptional activation. Despite the fact that many steroid ligands to cross-react with other nuclear receptors of hormones, the effect of Compound IV is specific ERα and ERβ. In the analysis of transcriptional activation were screened for the subject as the local reactivity as agonistic, and antagonistic activity of the Compounds IV in respect of the isoforms of the glucocorticoid receptor (GR), receptor mineralocorticoids (MR), progesterone receptor (PR), androgen receptor (AR) rats and isoforms farnesoid X-receptor (FXR), liver X receptor (LXR), receptor-activated proliferation peroxisome (PPAR-α and PPAR-γ) and retinoid X receptor (RXR-α) person. Compound IV did not show any agonistic or antagonistic activity in any of these analyses, which confirms the conclusion that Compound IV does not have a functional cross-reactivity against members of this superfamily of nuclear receptors of hormones.

EXAMPLE 7

Transactivation under the action of the individual compounds

To determine whether the compound is an agonist, antagonist or partial agonist or antagonist, conducted analyses of the development on the subject of agonistic and antagonistic manner.

Method

Estrogen receptors (ER-α and ER-β) rats were cloned from cDNA ovarian rats in the backbone plasmid vector PCR3.1. To establish the absence of any mutations was performed sequencing. Cells of SOME 293 (human embryo kidney) were scattered in the amount of 100,000 cells per well in 24-hole tablet in minimum support environment Dulbecco (DMEM), updat the United 5% purified on charcoal fetal calf serum (csFBS). The cells were transfusional using lipofectamine (Invitrogen, Carlsbad, CA) together with 0.25 µg ERE-LUC (design of the estrogen response element and luciferase; from the English. estrogen response element-luciferase), 0.02 μg CMV-LUC (design (promoter) cytomegalovirus and luciferase (luciferase coral Renilla) and 12.5 ng of ER-α in rats or 25 ng of ER-β in rats. At 24 h after transfection cells were treated with compounds at various concentrations, or a combination of compounds and estradiol to determine the antagonistic activity. The luciferase assays were performed 48 h after transfection.

Results

Screening of compounds according to this invention in the system for TRANS-activation analysis revealed that the compounds belonged to all three classes, i.e. agonists, antagonists and partial agonists. An example of the agonist and antagonist are shown in Table 3. Results for development in very good agreement with the results by linking the object selectivity in respect of the isoforms.

Table 3 shows the values of EC50and IC50obtained in the analysis of development for some of the individual compounds according to this invention.

Table 3.
The results of the analysis of development (for both the agonist and antag NIST) under the action of the individual Compounds according to the invention
CONNECTIONEU50(nm) for ER-αEC50(nm) for ER-βIC50(nm) for ER-αIC50(NM)for ER-β
0,6540,4>1000>1000
>1000>10002,207145

EXAMPLE 8

Suppression of testosterone in cynomolgus macaques

Intact in relation to the sex glands of male cynomolgus macaques at the age of two (n=2) were included in the study in accordance with guidelines established by the USDA (Department of agriculture United States Department of Agriculture)) with free access to food for primates and water (except for fasting before oral dose). Animals once a day for 7 successive days orally via a stomach tube had a dose of the Compounds of formula IV (30 mg/kg) in the form of a microemulsion in the diluent tween 80/deionized water. Samples of blood to obtain serum was collected by venipuncture before oral introduction the receiving doses at 0-s (starting point), 2nd, 3rd, 4th, 5th and 6th day. The levels of testosterone and androgens in General was measured quantitatively using the method enzyme immunoassay (EIA), combined or not with HPLC (high performance liquid chromatography), respectively. After treatment with Compound of formula IV for 6 days it became obvious gramasevaka decrease levels of testosterone and androgens in General (testosterone/dihydrotestosterone). The compound of formula IV suppressed testosterone levels by 58% and 64% for animal 1 and animal No. 3, respectively, relative to the original values (see solid lines in Fig.1, Table 4). Similarly, the level of androgens in General was suppressed by 56% in both animals # 1 and # 3 (see dotted lines in Fig.1, Table 4) compared with the original values.

Consistent with the presence of estrogen feedback in the pituitary-testicular axis in individuals of the male sex, these results demonstrate reliable pharmacological response in relation to the suppression of hormones serum (testosterone and androgens in General) in the intact Primate, non-human (cynomolgus macaques) after repeated administration of oral doses (30 mg/kg) of Compounds of formula IV.

Table 4.
Levels test is sterone and androgens in General, serum intact male macaques with daily oral administration of the compounds of formula IV (30 mg/kg; first dose at 0 days)
TestosteroneAndrogens in General
Level in serum (PG/ml)Level in serum (PG/ml)
DayAnimal 1Animal 3Animal 1Animal 3
0
(source point)112061718681643
29374791178847
37844371078786
4552415988924
403276966664
6474221819726
The percentage decrease from the starting pointThe percentage decrease from the starting point
DayAnimal 1Animal 3Animal 1Animal 3
0
(source point)100100100100
216223748
330294252
451/td> 334744
564554860
658645656

EXAMPLE 9

Suppression of LH levels and the hormone testosterone in rats

To assess the effect of Compound IV on the suppression of LH in intact and orientirovannyh (ORX) male rats was performed to investigate the dependence of the effect is dose-dependent in vivo. In the intact and subjected ORX animals Compound IV in doses S10 mg/kg per day significantly inhibited the LH levels compared with the corresponding controls. (A similar pattern of suppression was observed for levels of FSH.) Suppression of LH resulted in a sustained decline of testosterone levels below the limit of quantitation (BLOQ), which is 0.08 ng/ml, and the reduced mass of the prostate gland, seminal vesicles and muscle mass levator, because they are highly androgen-dependent organs. In the intact animals was marked dose-dependent decrease in the mass of these organs, while the weight of the seminal vesicles and muscle mass levator reached level controls, soo the relevant medical castration. Although the mass of the prostate gland in intact animals was significantly decreased, these values did not reach the level of controls appropriate medical castration. The results are summarized in the following Table 6.

Materials and methods

Male rats Sprague-Dawley weighing approximately 200 g were supported in cycle mode light/dark 12 h with unlimited access to feed (feed for rodents with a protein content of 16% Teklad Global 2016, Harlan, Madison, WI) and water. The Protocol works with animals was reviewed and approved by the bioethics Committee of the University of Tennessee.

Tested in this study, the product was weighed and dissolved in 10% wage DMSO (Fisher), diluted PEG (Acros Organics, NJ), to obtain compositions with appropriate doses. For this study, sixty (60) male rats Sprague-Dawley distributed randomly on body weight and was ranked as one of the twelve subjected to treatment groups (n=5 animals/group). Subjected to the treatment group are listed in Table 5. Animals were kept in groups of 2-3 animals per cage. Control groups (intact and orientirovannym (ORX)) daily injected with a diluent. Compound IV was administered by subcutaneous injection (200 μl) at doses of 0.3, 1, 3, 10 and 30 mg/kg/day animals as intact and subjected ORX groups.

After injection mode within 14 days animals amarsul is whether under anesthesia (ketamine/xylazine, 87:13; mg/kg) and record the weight. In addition, we have extracted the ventral portion of the prostate gland, seminal vesicles and levator, cleaned of extraneous tissue and weighed separately. The body mass normalized to body weight and expressed as a percentage of the intact control. Under anesthesia with isoflurane were selected blood from the abdominal aorta and left to coagulate. The serum was separated by centrifugation and stored at -80°C until determination of hormone levels. Concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum were determined using the Luminex analysis for the determination of hormones by the pituitary gland of the rat (the Rat Pituitary Luminex Assay) (Millipore, Billerica, MA) according to the manufacturer's instructions. The lower limit of quantitation (LLOQ) for this analysis was 3.2 PG/ml for LH and 32 PG/ml for FSH. Testosterone was measured using EIA for determination of testosterone (Alpco Diagnostics, Salem, NH) with LLOQ 0.08 ng/ml Levels of hormones in the blood serum below the lower limit of quantitation (BLOQ) were discarded in the analysis of average values within the group. Therefore, the reported value for LH and T (testosterone) in groups with samples BLOQ, will be higher than the true values. This method of analysis gives a conservative estimate of the suppression of LH and So For comparison of groups receiving individually the e dose with intact groups and subjected to ORX control groups treated with the diluent used test Fisher to determine statistically significant differences. Statistical significance was defined a priori as P value<0,05.

Table 5.
Subjected to the treatment group
GroupGonadal statusDose (mg/kg/day)Test product
1The intact-Thinner
2ORX-Thinner
3The intact0,3Compound IV
4The intact1Compound IV
5The intact3Compound IV
6 The intact10Compound IV
7The intact30Compound IV
8ORX0,3Compound IV
9ORX1Compound IV
10ORX3Compound IV
11ORX10Compound IV
12ORX30Compound IV

The levels of luteinizing hormone in intact and subjected ORX rats (table 6)

The LH levels (mean ± SD (standard deviation) in the intact and subjected ORX control groups treated with the diluent, were 1.46±0,64 and 11.1±3.9 ng/ml, respectively. Compound IV dose-dependent manner reduced the levels of LH in intact animals with obtaining statistically significant reductions in the use of daily doses ≥ 3 mg/kg, UB is neither LH in intact treated with Compound IV animals were 0,863±0,384, 0,704±0,530, 0,395±0,302, 0,226±0,165 and 0,236±0,176 ng/ml after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The LH levels in exposed ORX males also significantly decreased in the treatment with Compound IV. The subject ORX animals LH levels were 15,4±2,9, 13,5±2,2, 6,5±5,6, 0,425±0,135 and 0,368±0,119 ng/ml after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The results are presented graphically in Fig.10A.

The levels of follicle-stimulating hormone in intact and subjected ORX rats (table 6)

FSH levels in serum in intact and subjected ORX control groups treated with the diluent, was 20.9±8,5 and 93.5±13,8 ng/ml, respectively. In the intact animal the Compound IV dose-dependent manner reduced the levels of FSH with obtaining statistically significant reductions observed at doses ≥ 10 mg/kg/day. FSH levels in the intact treated with Compound IV animals were 17,3±6,4; 15,7±7,3; 18,4±7,7; 9,2±4,0 and 6.3±1.8 ng/ml after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The subject ORX animals LH levels were 115±17, 114±22, 65,2±31,9, 27,6±8,2 and 15.1±4.1 ng/ml after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The results are presented graphically in Fig.10V.

Testosterone levels in intact and subjected ORX rats

The levels of testosterone in the blood serum of intact treated with the diluent control groups was 2.4±,1 ng/ml The lower limit of quantitation for T was 0.08 ng/ml Values less than 0.08 ng/ml are considered as values below the limit of quantitation (BLOQ). In the intact animal the Compound of formula IV dose-dependent manner reduced the levels of T with a significant decrease observed at doses ≥ 3 mg/kg per day. Testosterone levels in intact animals treated with Compound of formula IV, was 2,6±1,7, 1,6±1,0, 0,7±0,4, BLOQ and BLOQ ng/ml after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg per day, respectively. The subject ORX animals the levels of T were BLOQ for all groups treated with Compound IV, and group treated with diluent. Results for intact animals are represented graphically in Fig.10C (and Fig.2) (for graphic purposes BLOQ values represented by the limit of quantitation).

Rapid and effective suppression of testosterone in the blood serum of intact male rats measured after administration of Compound IV in doses of 3 mg/kg, 10 mg/kg and 300 mg/kg after 24 h, 72 h and 168 h, shown in Fig.9.

Mass bodies (table 6)

Mass of the prostate gland, seminal vesicles and muscle mass of levator was measured to confirm the suppression of So Masses of the bodies (mean ±SD) is shown in Fig.10D, 10E and 10F, respectively. Dose-dependent reduction of weight of the prostate gland, seminal vesicles and muscle the assy of levator was observed in intact animals, treated with Compound IV. The mass of the prostate gland in intact animals was 84,0±19,2, 75,2±20,7, 68,2±8,1, 45,1±20,0 and 43.6±8,8% after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. Mass prostate cancer in exposed ORX animals were 19,0±4,2, 17,4±3,4, 19,6±6,7, 22,9±5,4 and 20.6±2.1 per cent after the introduction of the doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The weight of the seminal vesicles in intact animals was 76,2±7,8, 66,3±27,2, 51,8±28,5, 19,1±7,0 and 17.9±3.3 percent after the introduction of the doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. The weight of the seminal vesicles have been subjected ORX animals were 12,2±1,3, 16,6±5,4, 16,5±4,8, 13,3±1,9 and 12.9±2.1 per cent after the introduction of the doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively. Mass levator in the intact animals was 86,9±10,0, 82,1±12,1, 65,2±4,4, 57,8±11,2 and to 58.1±4.7% after the introduction of the doses of 0.3, 1,3, 10 and 30 mg/kg/day, respectively. Mass levator the subject ORX animals were 54,5±6,6, 49,6±7,0, 53,6±10,0, 51,1±4,9 and 49.2±4,2% after administration of doses of 0.3, 1, 3, 10 and 30 mg/kg/day, respectively.

Data on suppression of LH and reduce the mass of bodies are summarized in Table 6.

Table 6.
The effect in vivo of the Compounds of formula IV for hormones serum and weight of organs
Gonadal statusThe connection is s Dose (mg/kg per day)LH (ng/ml)FSH (ng/ml)Prestat. iron (% of intact.)Seminal vesicles (% of intact.)Levator (% of intact.)
Intact.Thinner-Average SD1,46b
0,642
20,9b
8,49
100,0b
28,6
100,0b
the 13.4
100,0b
equal to 4.97
ORXThinner-Average SD11,1a
a 3.87
93,5a
13,8
13,7a
2,56
14,0a
2,93
58,8a
6,62
Intact.Compound IV0,3Average SD0,863b
0,384
17,3a
6,44
84,0b
19,2
76,2a,b
7,83
86,9a,b
10
Intact.Compound IV1Average SD0,704b
0,53
15,7b
7,26
75,2b
20,7
66,3a,b
27,2
82,1a,b
12,1
Intact.Compound IV3Average SD0,395a,b
0,302
18,4b
7,72
68,2a,b
8,12
51,8a,b
28,5
65,2a
4,35
Intact.Compound IV10Average SD0,226a,b
0,165
9,25a,b
3,97
45,1a,b
20
19,1a
6,98
57,8a
11,2
Intact.Compound IV30Average SD 0,236a,b
0,176
6,25a,b
1,82
43,6a,b
8,75
17,9a
3,33
58,1a
4,71
ORXCompound IV0,3Average SD15,4a
2,94
116a
17,2
19,0a,b
4,19
12,2a
1,31
54,5a
6,56
Gonadal statusConnectionDose (mg/kg per day)LH (ng/ml)FSH (ng/ml)Prestat. iron (% of intact.)Seminal vesicles (% of intact.)Levator (% of intact.)
ORXCompound IV1Average SD13,5a
2,18
114a
22,3
17,4a
3,4
16,6a
are 5.36
49,6a
? 7.04 baby mortality
ORXCompound IV3Average SD6,5
5,63
65,2a
31,9
19,6a
to 6.67
16,5a
4,82
53,6a
10
ORXCompound IV10Average SD0,425a,b
is 0.135
27,6b
8,16
22,9a,b
5,44
13,3a
1,91
51,1a
4,88
ORXCompound IV30Average SD0,368a,b
0,119
15,1b
4,11
20,6a,b2,0812,9a
2,14
49,2a,b
4,21
andP<0.05 compared to non-treated, treated with the diluent.bP<0.05 compared with subjected ORX treated with the diluent.

EXAMPLE 10

Restoring testosterone levels after the suppression under the action of the Compounds is s IV in rats and macaques

Investigated the reversibility of chemical castration under the action of the Compounds IV.

Materials and methods

Thirty-five (35) male rats Sprague-Dawley weighing approximately 200 g were supported in cycle mode light/dark 12 h with unlimited access to feed (feed for rodents with a protein content of 16% Teklad Global 2016, Harlan, Madison, WI) and water. The Protocol works with animals was reviewed and approved by the bioethics Committee of the University of Tennessee.

Tested in this study, the product was weighed and dissolved in PEG (100%) (Acros Organics, NJ) to obtain compositions with appropriate doses. Animals were randomly assigned them to one of the ten exposed treatment groups (n=5 animals/group). Subjected to the treatment group are listed in Table 7. Animals were kept in groups of 2-3 animals per cage. Animals of group 1 were killed in the beginning of the study (1st day) to determine the baseline levels of testosterone in intact animals. Animals of groups 2-7 orally via a stomach tube received daily doses of 1, 3 or 30 mg/kg (~200 ál) for three days. Animals of groups 2, 3 and 4 were killed on the 4th day to measure the maximum suppression of testosterone. Animals in groups 5, 6 and 7 were left to recover during the washout period (14 days) without the introduction of drugs.

Table 7.
Subjected to the treatment group
GroupCompound IV, p/o doseProcessing
Group 1-The starting point
Group 21 mg/kg for 3 daysWithout recovery
Group 33 mg/kg for 3 daysWithout recovery
Group 430 mg/kg for 3 daysWithout recovery
Group 51 mg/kg for 3 daysRecovery within 14 days
Group 63 mg/kg for 3 daysRecovery within 14 days
Group 730 mg/kg for 3 daysRecovery within 14 days

Results

The levels of testosterone in the blood serum of intact rats was 6.4±3.1 ng/ml (mean C is Uchenie ± SD) at the origin. Compound IV, administered at doses of 3 and 30 mg/kg over three days, significantly inhibited the levels of serum testosterone to 1.47±0.26 and of 1.62±0.49 ng/ml, respectively. No significant suppression was not observed in animals that received Compound IV at a dose of 1 mg/kg for three days. Most importantly, the levels of testosterone in serum was 3.3±1,92, 3,00±1,06 and 3.8±1,72 ng/ml in animals that within three days received Compound IV at a dose of 1, 3 or 30 mg/kg, respectively, based on the measurement results after 14 days of recovery period, and there were no statistically significant differences from testosterone concentrations in serum at the origin in the intact rats that shown in Fig.23.

This study confirms previous results showing that Compound IV is quickly suppressed testosterone levels in the blood serum of intact male rats. The inventors have observed suppression of testosterone levels in the serum in the groups receiving a dose of ≥ 3 mg/kg/day for 3 days. A significant decrease in testosterone levels in the serum were not observed for the group with a dose of 1 mg/kg However, after 14 days of recovery, the levels of serum testosterone returned to the level of intact controls. This study shows that the pharmacological castration in rats under the action of the m Compound IV is reversible.

The effect of Compound IV on the suppression and recovery of testosterone levels in intact male macaques were evaluated in combination with oral pharmacokinetic study. Three processed, not previously subjected to experiments to male cynomolgus macaques (aged 2-3 years) orally via a stomach tube during the subsequent 7 days daily injected with a Compound IV at a dose of 30 mg/kg blood Samples were collected and divided to obtain serum and plasma for the quantitative measurement of testosterone and Compounds IV, respectively. The results show that daily introduction oral doses of Compound IV was significantly reduced levels of circulating androgens (mainly testosterone and dihydrotestosterone) in all three male macaques by up to 47% compared to baseline levels (levels that make up 1591±72,5, 997±104 and 852±136 ng/ml, respectively for the starting point on the 2nd day and the 6th day of treatment (mean ± SEM (standard error of the mean))). After 18-day recovery period without the introduction of drugs levels of androgens had returned to normal and did not significantly differ from baseline levels before treatment (1757,7±369,5 ng/ml after recovery).

EXAMPLE 11

Preservation of bone mass despite reduced levels of LH and testosterone in rats (table 8)

Studies which followed an effect on bone tissue, caused by processing the Compound of the formula IV. Oral entered the Compound of formula IV is completely prevented the loss of bone mass associated with suppression of LH in intact male rats. A significant reduction in the level of LH was induced by the Compound of formula IV in the intact animals at dose levels ≥ 10 mg/kg per day. Although the dose of 1 mg/kg per day of the Compound of formula IV is not significantly reduced the level of LH, at this dose was obvious a significant decrease in the weight of the prostate gland, seminal vesicles and muscle mass levator, indicating that reduced levels of circulating testosterone were physiologically relevant in relation to those sensitive to androgens bodies. However, the introduction of the compounds of formula IV at a dose of 1 mg/kg per day maintained the volume of trabecular bone (measured in the distal part of the femur at the level of intact controls. At the doses of 10 and 30 mg/kg per day of the Compound of formula IV increased bone volume in the distal part of the femur is significantly longer than that of intact controls. These data show that Compound IV increases the mineral density of trabecular bone (BMD) and percentage bone volume at dose levels that reduce the levels of LH in intact rats. The data from this study are presented in Table 8.

Table 8.
The effect in vivo of the Compounds of formula IV bone mass of organs and hormonal parameters of blood serum in rats
Gonadal statusConnectionDose (mg/kg / day)Mineral. bone density (g/cm3)The percent bone volume (BV/TV) (%)Prestat. iron (% of intact.)Semen. bubbles (% of intact.)Levator (% of intact.)FSH (ng/ml)LH (ng/ml)
Intact.Thinner-AVG. SD0,274b
0,033
20,2b
3,57
100,0b
11,1
100,0b
15,9
100,0b
the 11.6
to 9.93b
2,94
0,781b
to 0.263
ORXThinner-AVG. SD0,224a
0,025
15,4a
2,6
14,8a
4,08
10,3a
0,767
59,4a
7,26
117a
40,2
22,0a
of 5.81
Intact.Compound IV1AVG. SD0,273b
0,04
20,0b
4,08
69,2a,b
13,5
44,6a,b
15,7
80,0a,b
6,69
14,1a,b
4,07
0,820b
0,392
Intact.Compound IV10AVG. SD0,326a,b
0,048
25,9a,b
4,76
30,7a,b
12,4
12,8a,b
0,886
58,1a
9,68
5,48a,b
1,97
to 0.060a,b
0,092
Intact.Compound IV30AVG. SD0,326a,b 0,04625,5a,b
4,49
30,1a,b
17,4
14.4Va,b
1,45
56,1a
4,67
6,32a,b
3,4
0,078a,b
0,114
andP<0.05 compared to non-treated, treated with the diluent.bP<0.05 compared with subjected ORX treated with the diluent.
BV/TV=ratio of the volume (trabecular) bone to the total volume (bone) (from the English. bone volume/total volume).

EXAMPLE 12

Effect on the activity of the enzyme 17β-hydroxysteroid-dehydrogenase type 5 (17β-HSD5)

Members of the HSD-family involved in the conversion of circulating steroids. 17β-HSD5 converts Androstenedione to testosterone and estrone to estradiol. In addition, she is also involved in the synthesis of prostaglandins. Here was demonstrated by the ability of some individual compounds according to the invention to inhibit the activity of 17β-HSD5.

Method

Human 17β-HSD5 cloned into the vector pGEX 4t1 and received purified protein. Purified protein was incubated together with a representative compound according to the invention,14With-Androstenedione and NADPH (reduced form of adenine dinucleotide phosphate) in the appropriate buffer. Synthesized testosterone was extracted, IP is by using ethyl acetate, dried in the air, put on a plate for thin-layer chromatography (TLC) and perform the separation. The TLC plate was exhibited on the screen of phosphoimager and the intensity of the band of testosterone was determined quantitatively. As a positive control (LHRH agonist) used indomethacin.

Results

Tested Compound IV had a partial inhibitory effect on the activity of the enzyme 17β-HSD5. Positive control indomethacin (LHRH agonist), as expected, showed a strong inhibition of this enzyme, as shown in Fig.3.

EXAMPLE 13

Toxicity studies

For comparison of the coagulation potential of Compounds IV and diethylstilbestrol (DES, a positive control) conducted a study using the analysis of aggregation of human platelets in vitro. This study used the blood of healthy donors male, because men are contingent, for which it was intended treatment of Compound IV (suppression of LH). Platelet-rich blood plasma pre-incubated with each of the following: estradiol (E2), DES, Compound IV or diluent for 30 seconds and then added thrombin (0.3 units) for the induction of platelet aggregation. The results show that pre-incubation with DES increases and doziruemoy thrombin platelet aggregation approximately 10 times. However, Compound IV and estradiol reduce aggregation in platelet-rich plasma. These data demonstrate that Compound IV reduces the reactivity of human platelets in vitro compared with DES, and suggest that the Compound IV may have a lower thromboembolic potential than DES (Fig.4).

EXAMPLE 14

The effect of Compound IV on "tides"

Conducted a study of the effect of Compound IV on "tides", using the morphine-dependent rat model (MD model), developed by Simpkins et al. (1983), which was shown several similarities with related to menopause "tides". In addition to similarities with human nature, this experimental animal model is characterized by short-term performance, which makes it a useful tool for high-throughput screening using measurements of the skin temperature of the tail (TST) to identify compounds that can relieve vasomotor symptoms. TST-sensors TA-40 (Data Sciences International, MN) was attached with tape to the base of the tails and carried out the registration of the initial temperature for 15 minutes. After 15 minutes, the animals were treated with naloxone (1 mg/kg, SQ) to undo the effects of morphine. During the experiment the temperature of the skin of the tail (TST) was measured within one hour after treatment with naloxone with frequency measurement 5 C. After sbordone was calculated moving average value of temperature, registered for every 60 seconds for each animal, and subjected to subsequent analysis. The source temperature was calculated as the average of 15 minutes prior to the injection of naloxone. The area under the curve (AUC) was calculated by subtracting all values after administration of naloxone from the original values using the linear trapezoid method.

Compound IV weakened the tides in the model cancellation of morphine (see Fig.13) with the best results for 10 mg of Compound IV. 17β-E2 was used at a concentration of 5 mg/kg in 100% Ohm DMSO.

EXAMPLE 15

Comparison of Compounds IV and DES rats

Before the introduction of LHRH agonists reached levels of testosterone, relevant medical castration, enhancing estrogenic activity at the pituitary by estrogens, mainly of diethylstilbestrol (DES). DES was as effective as LHRH agonists in suppressing testosterone to levels appropriate medical castration. In patients treated with DES, no tides or bone loss, but it was reported gynecomastia in more than ADT using LHRH agonists. Unfortunately, the use of highly pure estrogen, like DES and estradiol, very often associated with a high risk of serious cardiovascular and thromboembolic complications to the e limit their clinical application.

Was suggested, but not proved, the hypothesis that the increased risk of venous thromboembolic complications as a result of DES is associated with its cross-reactivity with other receptors of hormones. In vitro studies using human platelets showed that Compound IV has a much smaller protagonizada activity than DES. Thus, Compound IV, a selective agonist of ER-alpha in relation to prostate cancer may provide useful action DES and also provide beneficial effects of the LHRH agonist without causing osteoporosis or unfavorable lipid profiles.

Compound IV is as effective as DES in reducing the size of the prostate in rats (Fig.11A) and gives a modest increase in the size of the prostate have been subjected ORX rats (Fig.11B).

Differences between DES and Compound IV is shown in Fig.12A-12C, where it is seen that DES provides cross-react with the glucocorticoid receptor (GR) (Fig.12A) and the androgen receptor (AR) (Fig.12V), while Compound IV no. In addition, DES antagonisitic the transactivation of receptor, related to the estrogen receptor, (ERR), while Compound IV no. Compound IV does not show cross-reaction with any of the three isoforms ERR (ERR-α, ERR-β and ERR-γ), as shown in Fig.12C.

EXAMPLE 16

The study toxi who work in monkeys - 90 days

From Mauritius were obtained lived families cynomolgus macaques. We planned a prospective study to obtain the pharmacological and Toxicological evaluation of the results of oral administration of Compounds IV and positive control (LHRH agonist) in the 39 weeks to male cynomolgus macaque with an intermediate period of 13 weeks. A total of 39 adult male macaques aged 5-8 years were randomly divided into five groups before treatment. Groups included: 1) diluent as a control, 2) Compound IV at a dose of 1 mg/kg, 3) Compound IV at a dose of 10 mg/kg, 4) Compound IV at a dose of 100 mg/kg and 5) positive control (LHRH agonist). The drug was taken pills, using the introduction on the type of "cage-side" once a day for 39 weeks, were injected diluent as control (tween 80/PRANG™) for Groups 1 and 5 or the Compound IV in the diluent for Groups 2, 3 and 4. The dose levels of Compound IV were 1, 10 and 100 mg/kg/day for Groups 2, 3 and 4 respectively. The oral dose was delivered in the dose volume 10 ml/kg, calculated on the basis of the most recent measurement of body weight for each animal (Fig.14). Animals in Group 5 in addition received a once daily subcutaneous injection of the positive control (LHRH agonist) (constantly in a volume of 0.02 ml) during the study period 39 n the del. Daily noted and recorded the overall appearance and clinical symptoms. The standard evaluation and several other studies conducted as specified in the study Protocol. Sampling parameters include testosterone, the antigen of the prostate (PSA) and the volume and weight of the prostate, but not limited to.

Levels of total testosterone and PSA levels were quantitatively determined in samples of blood serum (following the standard procedure), using enzyme immunoassay (EIA) and chemiluminescent immunoassay (LIA, ALPCO Diagnostics, Salem, NH), respectively. Blood samples to assess the level of testosterone were collected from all animals (PCP) in the original time (i.e. before treatment) and on the 1st, 3rd, 7th, 14th, 28th, 64 and 90 days. Blood samples for determination of PSA were collected from all animals (PCP) in the source point and within 6 weeks. To discuss the results for samples with concentrations below the limit of quantitation (BLOQ) in the analysis of testosterone and PSA was taken into account in the form of ½ from the lower limit of quantitation (LLOQ) in the analysis and considered as "estimated final concentration". The data given in Tables 9-16, presented in the form of "only concentrations quantifiable" (i.e. the magnitude of the BLOQ excluded) in addition to the evaluation of the final con is intrateam" (i.e. samples with the BLOQ is included as ½ LLOQ analysis). The volume of the prostate was measured on live animals under anesthesia using procedures transrectal ultrasonography (TRUS) at the origin and on the 6th week. Register width and height of the prostate. The volume of the prostate was calculated as (width × width × height × π/6) and normalized to body weight. The wet weight of the prostate was detected at autopsy after cleaning fabric from the fat and extraneous tissue.

Results and discussion

The levels of testosterone in serum is shown in Fig.15 and in Tables 9-12. At the origin testosterone levels for all macaques in this study were within the range of normal for Mature adult male cynomolgus macaques. However, testosterone levels were significantly decreased in macaques receiving Compound IV at a dose of 100 mg/kg/day, and in macaques treated with the positive control (LHRH agonist). It was demonstrated biphasic changes of testosterone levels in the positive control group (LHRH agonist), first with a significant increase (i.e., "acute" reaction equal to 47.4% 547% (p<0,01) on the 1st and 3rd day, respectively, and then decrease 3,6%, 67%, 73%, 83% and 85% on the 7th, 14th, 28th, 64 and 90 days (see Fig.15 and Table 9-12). Similar acute reactions were not observed for any animal treated with Compound IV even with the relatively high doses (i.e., 100 mg/kg/day). Dose and duration of treatment were important for the pharmacological activity of a Compound IV, with a dose of 100 mg/kg/day inhibited the levels of testosterone in the blood serum on 60%, 51%, 42%, 79% and 92% on the 3rd, 7th, 14th, 28th and 64 days, respectively, relative to the size of the source point (See. Fig.15 and Table 9 and 10). After 90 days of treatment with Compound IV (100 mg/kg/day) testosterone levels in 6 of 10 macaques Group 4 was reduced to concentrations below the limit of quantitation of this analysis (reference to Table 11). The average testosterone level in the serum macaques Group 4 was reduced by 96% compared with the corresponding initial values (the"estimated final concentration", i.e. testosterone levels for 6/10 macaques with BLOQ values calculated as 50% of the LLOQ concentration, see Table 10). It is important to note that the 90 day Compound IV at a dose of 100 mg/kg/day reduced the levels of testosterone in the serum to significantly lower levels than the positive control (LHRH agonist) (p=0.013).

Table 9.
Average levels of testosterone in blood serum (ng/ml) in the intact male monkeys after daily oral administration of Compound IV;@estimated final concentration
DayControl - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control (LHRH agonist)
AverageSEMNAverageSEMNAverageSEMNAverageSEMNAverageSEMN
0 (Ref. point.)6,11,2107,31,06a 4.90,664,40,610a 4.90,97
1 8,01,710111,667,61,168,02,2107,20,87
38,22,3107,41,265,11,161,8*0,51032#$the 3.87
75,91,2106,70,867,71,962,2*0,79the 4.72,6 7
143,40,510the 3.80,467,11,662,60,991,6#0,27
28the 3.80,610the 4.70,969,42,160,9*0,2101,3#0,27
645,11,1104,30,66of 5.41,560,3* 0,190,8#$0,27
903,60,694,20,644,61,050,2*0,0100,8#$0,27
LLOQ in the analysis of testosterone=0,246 ng/ml;@the BLOQ values calculated as 0,123 ng/ml, half of the LLOQ.
*: Statistically significant (p<0.05) results for Compounds IV (100 mg/kg) in comparison with control diluent.
#: Statistically significant (p<0.05) results for the positive control (LHRH agonist) in comparison with control diluent.
$: Statistically significant (p<0.05) results for the positive control (LHRH agonist) in comparison with Compound IV (100 mg/kg).

Table 10.
Percentage change (%) average levels of testosterone is in the serum compared to the original point; @estimated final concentration
DayControl - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgWill believe. control
13144548247
3351,83,5-60547
7-3,2-8,157-51-3,6
14-44-4845-42-67
28-38-3592-79-73
64-16-41-92-83
90-42-42-5,5-95-85
LLOQ in the analysis of testosterone = 0,246 ng/ml;@the BLOQ values calculated as 0,123 ng/ml, half of the LLOQ.

7,4 0,6 LLOQ in the analysis of testosterone=0,246 ng/ml;λvalues BLOQ excluded.
Table 11.
Average levels of testosterone in blood serum (ng/ml) in the intact male monkeys after daily oral administration of Compound IV;λonly concentrations quantifiable
DayControl - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control (LHRH agonist)
AverageSEMNAverageSEMN AverageSEMNAverageSEMNAverageSEMN
0 (Ref. point.)6,11,2107,31,06a 4.90,664,40,610a 4.90,97
18,01,710111,667,61,168,02,2107,20,87
38,22,3101,265,11,161,80,51032the 3.87
75,91,2106,70,867,71,962,20,79the 4.72,67
143,40,510the 3.80,467,11,662,60,991,60,27
28the 3.810the 4.70,969,42,160,90,2101,30,27
645,11,1104,30,66of 5.41,560,30,190,80,27
903,60,694,20,644,61,050,20,040,80,27

-42
Table 12.
Percentage change (%) average levels of testosterone compared to the original point;λonly concentrations quantifiable
DayControl - thinnerCompound IV 1 mg/kgCompound IV 10 m g/kgCompound IV 100 m g/kgWill believe. control
13144548247
3351,83,5-60547
7-3,2-8,157-51-3,6
14-44-4845-67
28-38-3592-79-73
64-16-4111-92-83
90-42-42-5,5-95-85
LLOQ in the analysis of testosterone=0,246 ng/ml;λvalues BLOQ excluded.

The PSA levels in the serum also significantly suppressed by Compound IV four weeks after beginning treatment. A decrease in PSA 69% and 87% (on average) were reported for macaques receiving Compound IV at a dose of 10 mg/kg and 100 mg/kg for 4 weeks, whereas in the group of positive control (LHRH agonist) PSA levels were reduced by 60% (Fig.16 and Table 13-16).

Table 13.
Mean levels of PSA in blood serum (ng/ml) in the intact male monkeys after daily oral administration of the is mode IV; @estimated final concentration
Control - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control (LHRH agonist)
AverageSEMNAverageSEMNAverageSEMNAverageSEMNAverageSEMN
Before processing.1,10,2101,00,260,80,161,00,1101,0 0,17
4th week.1,00,2100,90,260,3*0,160,1&0,1100,4#$0,17
LLOQ in the analysis PSA=0,0575 ng/ml;@the BLOQ values calculated as 0,02875 ng/ml, half of the LLOQ.
*: Statistically significant (p<0.05) results for Compounds IV (10 mg/kg) in comparison with control diluent.
&: Statistically significant (p<0.05) results for Compounds IV (100 mg/kg) in comparison with control diluent.
#: Statistically significant (p<0.05) results for the positive control (LHRH agonist) in comparison with control diluent.
$: Statistically significant (p<0.05) results for the positive control (LHRH agonist) in comparison with Compound IV (100 mg/kg).

Table 14.
The percentage change is (%) average PSA levels compared with the original point; @estimated final concentration
ControlCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control (LHRH agonist)
4th week.-7,1-11-69-87-60
LLOQ in the analysis PSA=0,0575 ng/ml;@the BLOQ values calculated as 0,02875 ng/ml, half of the LLOQ.

Table 15.
Mean levels of PSA in blood serum (ng/ml) in the intact male monkeys after daily oral administration of Compound IV;λonly concentrations quantifiable
Control - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgP is a positive control (LHRH agonist)
AverageSEMNAverageSEMNAverageSEMNAverageSEMNAverageSEMN
Before processing.1,20,291,00,260,80,161,00,1101,00,17
4th week.1,10,190,90,260,30,150,30,1 40,40,17
LLOQ in the analysis PSA=0,0575 ng/ml;λthe BLOQ values in this table are excluded.

Table 16.
Percentage change (%) average PSA levels compared to the starting point;λonly concentrations quantifiable
ControlCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control
4th week.-7,1-11-64-72-60
LLOQ in the analysis PSA=0,0575 ng/ml;λthe BLOQ values in this table are excluded.

The volume of the prostate was measured periodically using TRUS throughout the study. The results obtained after six weeks of treatment, demonstrating the strong effect of the Compounds IV and positive control (agony is the LHRH) on the prostate gland macaques. Compound IV significantly, 25% and 45%, inhibited the volume of the prostate at dose levels of 10 mg/kg and 100 mg/kg, respectively, whereas in the group of positive control (LHRH agonist) the volume of the prostate was reduced by 28% (Fig.17 and Table 17 and 18).

Table 17.
The average volume of the prostate gland (in relative units) in male monkeys after daily oral administration of Compound IV
Control-thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control (LHRH agonist)
AverageSEMNAverageSEMNAverageSEMNAverageSEMNAverage SEMN
6th weeks.4387810468786327336242281031547

Table 18.
Percentage change (%) medium volumes of the prostate compared to the starting point
ControlCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kgThe positive control
6th weeks.06,8-25-45-28

Associated with Compound IV volume reduction of the prostate gland was confirmed by the result and estimate the mass of the prostate at autopsy. After thirteen weeks of treatment with Compound IV significantly, 24% and 21%, reduced average weight of the prostate gland in animals receiving 10 and 100 mg/kg/day, respectively (Fig.18V and Tables 19 and 20).

Table 19.
The average mass of the prostate gland (in grams) at autopsy in macaques with daily oral administration of Compound IV
Control - thinnerCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kg
AverageSEMNAverageSEMNAverageSEMNAverageSEMN
13th weeks.1,80,231,80,4 31,30,131,40,13

Table 20.
Percentage change (%) average mass of the prostate gland compared to the starting point
ControlCompound IV 1 mg/kgCompound IV 10 mg/kgCompound IV 100 mg/kg
13th weeks.01,7-24-21

No pronounced effects on platelet aggregation, prothrombin time (PT) or activated partial thromboplastin time (ART) were not observed.

EXAMPLE 17

Research Compound IV on the people

Conducted a study to determine the effect of Compound IV on men. Studies were performed on 12 subjects per group, using dosages of the Compounds IV 100, 300, 600 and 1000 mg. In Table 21 presents the average changes in the levels of LH, PSA, free testosterone and total testosterone in serum cu is VI men after administration of Compound IV at doses of 100, 300, 600 and 1000 mg. dose-dependent mean levels of total testosterone (nmol/l) in humans was measured between 1-th and 11-th day (Fig.19). Levels of total testosterone decreased 51.9% and 47.9% for doses of 600 mg and 1000 mg, respectively.

Dose-dependent mean levels of LH (IU/l) in humans was measured between 1-th and 10-th day (Fig.20). The LH levels were increased by 20.7%, 46.9% and 27,6% and 29.2% for doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

Dose-dependent average levels of free testosterone (PG/ml) in humans was measured between 1-th and 10-th day (Fig.21). Levels of free testosterone decreased by 17.0%, and 18.5%, 72,7% and 53.2% for doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

Dose-dependent mean levels of PSA (µg/l) in humans was measured between 1-th and 10-th day (Fig.22). The PSA levels decreased by 9.2%, or 24.4%, to 27.5% and 29.9% for doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively. There has been no changes to the doses of 10 and 30 mg

Table 21.
The average change from the starting point
100 mg300 mg600 mg1000 mg
PSA serumto-9.2%/td> -24,4%-27,5%-29,9%
LH20,7%46,9%27,6%29,2%
Free testosterone-17,0%is 18.5%-72,7%-53,2%
Total testosterone3,9%7,3%-51,9%-47,9%

EXAMPLE 18

The bioavailability of the Compounds IV

Compound IV is rapidly absorbed after oral administration to rats, dogs and makkam. Oral bioavailability of the Compounds IV to rats was in the range from 6% to 25% depending on the composition, in which the injected dose. Compositions prepared using polyethylene glycol 300 (PEG), generally had a larger impact than the microemulsion prepared in Tween 80, diluted with deionised water. Visual inspection of profiles "concentration in the plasma-time" on dogs allowed to make the assumption that Compound IV undergoes enterohepatic recirculation, as evidenced by the second peak in the final phase. It is important to note is, the impacts on the dogs in the group of males receiving oral dose of 30 mg/kg in PEG exceeded the exposure necessary to provide the maximum effect on reducing prostate cancer in a rat model of suppression of the LH. Preliminary pharmacokinetic studies on monkeys allowed to make the assumption that the oral bioavailability of this species is approximately equivalent to one or higher than that in dogs, which was confirmed by measuring concentrations of Compounds IV in plasma and suppression of testosterone levels in the serum for seven days. Overall, these data suggest that a sufficient effect by oral administration can be achieved in two species of animals that are not rodents, to obtain the desired pharmacological effect (based on AUC). Further, the data on the endocrine system in rats and monkeys suggest that the pharmacological effects of the Compounds IV are reversible (i.e., the concentration of testosterone in serum is returned to the starting point or normal levels after cessation of treatment with Compound IV).

EXAMPLE 19

Pharmacokinetics of Compound IV

Preliminary studies of metabolism in vitro (mouse, rat, dog, monkeys and man) and in vivo (rat) made the assumption that the joint part is their Connection IV, it gidrauxilirovannogo metabolite(s) and its N-dialkylamino metabolite contributes to the overall distribution of Compound IV in animals and humans. Results interspecific comparisons, though, are only qualitative, indicate that the overall metabolic profiles in species not participating in clinical trials, adequately reflect the profile generated in human liver microsomes. According to these results, rats and dogs are rodents and animals that are not rodents, respectively, suitable for pharmacological and Toxicological evaluations. In vitro studies show that Compound IV does not induce relevant isoforms of CYP450 (cytochrome P450-dependent monooxygenase) (CYP1A2, CYP2B6 or CYP3A4) and did not inhibit CYP1A2, CYP2C19, CYP2D6, or CYP3A4/5 at concentrations of < 30 μm. CYP2C9 is inhibited by Compound IV, but only at high concentrations (Ki=8 μm) and the possible pharmacokinetic drug-drug interactions are unlikely.

EXAMPLE 20

Biological activity of Compounds IV

Compound IV has a slight inhibitory effect or has no inhibitory effect in vitro (IC50≥ 300 µm) on hERG channel (product specific gene potassium channels of the human heart, from the English. human ether a-go-go-related gene). The compound in concentrations of 10 and 100 microns dozozawisimaya reduces APD 50and APD90(the duration of the action potential at 50% and 90% repolarization) in isolated Purkinje fibres dogs in vitro. However, Compound IV does not affect hemodynamic or cardiac function (blood pressure, heart rate, structure electrocardiogram or QT intervals (cardiac output)) when measured by telemetry in dogs at any dose (300 mg/kg). Observed no neuropharmacological or pulmonary effects. There has been no significant effects on renal function when using a single oral dose of Compound IV to 30 mg/kg. Watched only the excessive secretion of urine and the excretion in urine potassium ions and chlorine with the introduction of the highest tested dose (100 mg/kg). Oral administration of Compound IV in doses of 30-300 mg/kg in rats caused a significant increase peristalsis, and oral administration of Compound IV at a dose of 30 mg/kg in rats caused a significant increase in motility of the gastrointestinal tract and gastric acidity (most likely not due to effects on smooth muscles).

Compound IV at concentrations up to 200 μm inclusive, were not mutagenic and did not cause structural or numerical chromosomal aberrations in lymphocytes of peripheral blood in vitro. Compound IV x is well tolerated by rats and dogs after single and repeated oral administration (up to 28 days inclusive). Did not observe any pathological changes in the kidneys, liver, heart and other organs, were not targeted. There were no serious physical symptoms, effects on body weight, clinical pathological changes, ophthalmic, electrocardiographic or histopathological changes associated with orally administered Compounds IV males or females dogs for up to 28 days inclusive.

Along with the fact that this description is illustrated and described certain features of the invention, the experts in this field will continue to find numerous modifications, substitutions, changes and equivalents. Therefore, it should be understood that the invention is intended to include all such modifications and changes that fall under the notion of real essence of the invention.

1. A method for the treatment of advanced cancers of the prostate gland in the male subject, essentially consisting of introducing a therapeutically effective amount of the compounds of formula IV or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof:

2. The method according to p. 1, where said treatment common cancer of the prostate is carried out by lower levels of total testosterone in savoro the ke blood or free testosterone in the serum, and where the specified lower levels of total testosterone in serum or free testosterone in serum occurs by reducing the levels of luteinizing hormone in serum.

3. The method according to p. 1, where said treatment common cancer of the prostate is carried out by lower levels of total testosterone in serum or free testosterone in the serum, and where the specified lower levels of total testosterone in serum or free testosterone in the serum does not depend on reducing levels of luteinizing hormone in serum.

4. The method according to p. 3, where the specified lower levels of total testosterone in serum or free testosterone in serum is due to increasing levels of globulin that binds sex hormones (SHBG), inhibiting the production or secretion of testosterone by the Leydig cells in the testes or decrease steroidogeneza in the adrenal glands.

5. The method according to p. 4, where the total testosterone in serum contains free testosterone and bound testosterone, where the reduction of these levels of free testosterone, independent of a decrease in the levels of luteinizing hormone in serum, due to the increase of SHBG levels.

6. The method according to p. 2 or 3, where total is testosterone in serum or free testosterone in serum is reduced to less than about 100 ng/DL, 50 ng/DL or 25 ng/DL.

7. The method according to p. 1, where the introduction of this connection produces lower levels of total testosterone in serum or free testosterone in serum, without causing the side effects associated with antiandrogenna therapy (ADT).

8. The method according to p. 1, where the introduction of this connection produces lower levels of total testosterone in serum or free testosterone in serum, without causing hot flashes, gynecomastia, reduced bone mineral density or an increased tendency to fracture.

9. The method according to p. 8, where the specified lower levels of total testosterone in serum or free testosterone in serum occurs by reducing the levels of luteinizing hormone in serum.

10. The method according to p. 8, where the specified lower levels of total testosterone in serum or free testosterone in the serum does not depend on reducing levels of luteinizing hormone in serum.

11. The method according to p. 1, where this method also suppresses, reduces the incidence, reduces the severity or inhibits cell carcinoma of the prostate.

12. The method according to p. 1, where this method also provides palliative treatment of advanced cancers of the prostate.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of compounds presented by formula:

In the above formula, R1 represents S-Alk-R, wherein Alk represents methylene, C2-C6 polymethylene bond or C3-C6 alkenylene bond, R represents -N=C(NR3R4)(NR5R6) or -NR7[(NR3R4)C=NR5], or -N=C(R8)(NR9R10), wherein R3-R10 represents H, Alk, Ar or (CH2)nAr, wherein Ar represents an aryl group, and n represents an integer from 1 to 13, or R3 and R4, or R4 and R5, or R5 and R7, or R3 and R7, or R9 and R10, or R8 and R9 together can represent -(CH2)x-, wherein x represents an integer from 2 to 5, and R2 is specified in a group consisting of hydroxyl, alkyl having from 1 to 7 carbon atoms, and substituted by alkyl hydroxyl having from 1 to 7 carbon atoms.

EFFECT: preparing new cyclosporine derivatives.

5 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of (R)-5-[3-chloro-4-(2,3-dihydroxypropoxy)benz[2]ylidene]-2-([2]-propylimino)-3-ortho-tolylthiazolidin-4-one (compound 1) or its salt for obtaining a medication for prevention and/or treatment of a disease or disorder, associated with the immune system activation, where the medication represents a set of Compound 1 doses; with the dose inducing the heart desensitisation in an initial phase of treatment and being lower than the final dose; with the said initial phase of treatment the dose is introduced with a frequency ensuring support of the heart desensitisation until the next acute reduction of heart rate occurs, after which the dose is titrated with increase to the final dose of Compound 1; a corresponding method of treatment and the set of doses.

EFFECT: invention ensures reduction and minimisation of undesirable side effects of Compound 1 (acute reduction of heart rate, atrioventricular conduction, or fatigue and dizziness) aimed at increase of Compound 1 tolerance and safety, as well as minimises problems, associated with monitoring at the initial phase of treatment or after interruption of treatment in the period of repeated treatment.

22 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to a composition, possessing immunomodulating and anti-inflammatory properties. The dermatological composition, possessing immunomodulating and anti-inflammatory properties, as an active ingredient, contains an extract of the aboveground part/parts of oat, collected before ear formation. The cosmetic composition, possessing immunomodulating and anti-inflammatory properties. Application of the extract of the aboveground part/parts of oat, collected before ear formation, possessing immunomodulating and anti-inflammatory properties, as a medication.

EFFECT: composition and extract possess expressed immunomodulating and anti-inflammatory properties.

15 cl, 1 tbl, 3 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to molecular pharmacology and particularly to a peptide which is an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound. The invention shows that when bound with an alpha subunit of the receptor (IL-15Rα) the peptide inhibits T cell proliferation induced by IL-15, tumour necrosis factor α (TNFα) induction caused by IL-15, and expression of IL-8 and IL-6 caused by IL-15Rα. The invention also relates to use of the peptide in treating pathologies where anomalous expression of IL-15 or IL-15Rα is associated with the course of a disease such as rheumatoid arthritis (AR) and prostate cancer.

EFFECT: obtaining an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound.

18 cl, 6 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method relates to medicine, particularly to dermatology, and may be used in treating localised forms of psoriasis. That is ensured by administering 1% glutoxim 0.1 ml along the perimetre of a psoriasis patch at 1.0-1.5 cm once a day for 7-12 procedures.

EFFECT: effective treatment ensured by no side effects, and reduced length of treatment.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to dermatology. A method involves the ointment application and the ultrasound exposure. The ointment is methylprednisolone aceponate. The ultrasound exposure has an intensity of 0.7-1.0 Wt/cm2. The exposure length is 2-5 minutes per one field. The duration of a procedure is 12 minutes. The therapeutic course is 7 procedures.

EFFECT: method reduces the side effects and complications provides achieving the immediate clinical effect and prolongs the remission length.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, cosmetology, and may be used for treating or preventing light exposure on a human or an animal. That is ensured by a photoprotective composition, including in the form of a cosmetic preparation containing the carotenoid compound diadinoxantine or its pharmaceutically acceptable prodrug or salt. There are also offered a method for diadinoxantine recovery from algae, as well as a method for producing a photoprotective or photoprotected product involving application or impregnation of said product with photoprotective composition containing diadinoxantine.

EFFECT: composition is effective in protection against light of wave length 350 to 500 nm.

21 cl, 4 tbl, 3 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds with formula , where R, selected from H, SiR'3, SOR', SO2R', C(=O)R' or not necessarily substituted C1-C6alkyl; R' is selected from the C1-C6alkyl group; R" is selected from CH2OR, C1-C6alkyl, C1-C6halogenalkyl, C2-C6alkenyl or C1-C6alkylidene; substitutes are the alkoxigroup. The invention also relates to the compounds with the formula , , , , where R1, R2, R4 and R6 are selected from PMB, benzyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 2,6-dichlorbenzyl, 3,4-dichlorbenzyl, TBS, TES, TBDPS, TIPS and TMS; R5 is selected from OR', N(R')2, N(R')(C1-C4alkoxi); and -R' is selected from C1-C6alkyl and C7-C10aralkyl, L is the stereospecific leaving group. The method for synthesis of the compound with formula 5 is invented, which includes removal of the protective groups from the precursor's hydroxyl groups. The methods for producing the compounds with the formulas 14 and 26 are invented, which include the precursor's tailing by interacting with CH3C(O)R5, where R5 is the group selected from OR', N(R')2, N(R')(C1-C4alkoxi); and R' is C1-C6alkyl and C7-C10aralkyl. The method for producing the compounds with the formulas 19 and 30 , which include the precursor's tailing by interacting with ethylmagnesiumbromide. The pharmaceutical composition based on the compound with the formula I with the cytotoxic activity is invented.

EFFECT: production of pharmaceutical agent for tumor treatment is available.

47 cl, 1 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds with formula , where R, selected from H, SiR'3, SOR', SO2R', C(=O)R' or not necessarily substituted C1-C6alkyl; R' is selected from the C1-C6alkyl group; R" is selected from CH2OR, C1-C6alkyl, C1-C6halogenalkyl, C2-C6alkenyl or C1-C6alkylidene; substitutes are the alkoxigroup. The invention also relates to the compounds with the formula , , , , where R1, R2, R4 and R6 are selected from PMB, benzyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 2,6-dichlorbenzyl, 3,4-dichlorbenzyl, TBS, TES, TBDPS, TIPS and TMS; R5 is selected from OR', N(R')2, N(R')(C1-C4alkoxi); and -R' is selected from C1-C6alkyl and C7-C10aralkyl, L is the stereospecific leaving group. The method for synthesis of the compound with formula 5 is invented, which includes removal of the protective groups from the precursor's hydroxyl groups. The methods for producing the compounds with the formulas 14 and 26 are invented, which include the precursor's tailing by interacting with CH3C(O)R5, where R5 is the group selected from OR', N(R')2, N(R')(C1-C4alkoxi); and R' is C1-C6alkyl and C7-C10aralkyl. The method for producing the compounds with the formulas 19 and 30 , which include the precursor's tailing by interacting with ethylmagnesiumbromide. The pharmaceutical composition based on the compound with the formula I with the cytotoxic activity is invented.

EFFECT: production of pharmaceutical agent for tumor treatment is available.

47 cl, 1 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, cosmetology, and may be used for treating or preventing light exposure on a human or an animal. That is ensured by a photoprotective composition, including in the form of a cosmetic preparation containing the carotenoid compound diadinoxantine or its pharmaceutically acceptable prodrug or salt. There are also offered a method for diadinoxantine recovery from algae, as well as a method for producing a photoprotective or photoprotected product involving application or impregnation of said product with photoprotective composition containing diadinoxantine.

EFFECT: composition is effective in protection against light of wave length 350 to 500 nm.

21 cl, 4 tbl, 3 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely urology, and can be used for treating advanced prostate cancer in male individuals. That is ensured by administering a therapeutically effective amount of a compound of formula IV or its isomer, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate or any combination thereof.

EFFECT: method provides treating effectively, inhibiting, reducing an incidence, relieving a severity or inhibiting advanced prostate cancer, as well as conducting the palliative treatment of advanced prostate cancer.

12 cl, 21 ex, 20 tbl, 23 dwg

FIELD: medicine.

SUBSTANCE: invention concerns using 3-methyl-6-(1-methylethinyl)cyclohex-3-en-1,2-diol epoxides described by formulas 1-3 including their stereoisomers, optically active forms as well, as medicinal products for treating Parkinson disease, and anti-convulsants, and can be used in medicine.

EFFECT: medicinal products possess high activity and can be produced from an accessible herbal raw material.

2 cl, 2 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

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