Nonsteroid modulators of androgen receptor, method of production, pharmeceutical composition thereof and use

FIELD: chemistry.

SUBSTANCE: invention relates to novel nonsteroid synthetic derivatives with the following structures or their pharmaceutically acceptable salts:

, , ,

,

or

, which are capable of modulating the androgen receptor.

EFFECT: invention relates to pharmaceutical compositions containing said derivatives and use thereof to make nonsteroid medicinal agents for treating and/or preventing conditions or diseases such as prostate hyperplasia, prostate cancer, hirsutism, severe hormone-dependant alopecia or acne etc, resulting from antagonistic activity towards the androgen receptor.

6 cl, 5 dwg, 3 tbl,12 ex

 

The scope of the invention

The invention relates to the field of pharmaceutical chemistry and belongs to the nonsteroidal androgen receptor modulators, methods of their production, pharmaceutical compositions containing the non-steroidal androgen receptor modulators, and the use of nonsteroidal androgen receptor modulators for the preparation of drugs for the prevention and/or treatment of symptoms or diseases, such as prostatic hyperplasia, prostate cancer, hirsutism, severe androgen alopecia and acne, etc.

Background of the invention

Androgens are an important category gonadal steroid hormones in the human body. They stimulate cell differentiation and tissue growth by linking with the appropriate specific receptors, thereby taking part in many important physiological functions, such as the formation of the reproductive organs in male fetus (such as prostate, seminal vesicle, epididymis, and so on), the development and maintenance of secondary sexual characteristics and the formation of sperm. Men and women there is a certain proportion of androgens, such as Androsterone, androstenediol and adrenosterone etc. Androgens are important physiological effects by binding to androgen what ecapture (AR). Metabolic disorder and functional impairment of androgens or their receptors can induce various diseases or to intensify the disease, including prostate hyperplasia, prostate cancer, male infertility, hirsutism, severe androgen alopecia and acne (acne), etc. These diseases have a very strong influence on the physical and mental health of patients, and significantly reduce their quality of life.

Benign hyperplasia (adenoma) of the prostate is benign adenomatous hyperplasia of cells in the prostate around the urethra, but is not cancer. Adenoma grows slowly and will not spread to other parts of the body. Benign prostatic hyperplasia is one of the most common diseases surgery of the urinary tract and has become the "invisible killer", threatening the health of men. Clinical statistics showed that the incidence of benign hyperplasia of the prostate is approximately 50% among men aged 40-79 years and can reach up to 80% after the age of 80 years. Together with the increasing stress of modern lifestyle gradually increasing number of patients with benign prostatic hyperplasia, and age at onset of the disease has a tendency of becoming who I was younger. Benign prostatic hyperplasia disrupts daily life of patients, and it is likely to cause many kinds of hidden complications such as acute urinary retention, urinary tract infection, macroscopic hematuria, diverticulum (protrusion) bladder stones, hydronephrosis and renal failure, etc. Clinical studies in literature data indicate that the dihydrotestosterone in the body of the patient is the main stimulus of benign prostate hyperplasia.

Prostate cancer is a severe disease of older men, morbidity and mortality is very high in the West and occupies the first place among malignant tumors in men [Landis SH, Murray T, 1998. CA Cancer J. Glin. 48. 6-29]. Although the incidence of prostate cancer in China is lower than in the West, together with the increasing proportion of the aging population, changes in the traditional diet and the improvement of the diagnosis of this disease in recent years, the incidence increased significantly. Clinical studies have shown that the age of the patients committed to a younger, especially among the population, which required a lengthy stay in a sitting position, for example, among programmers, and taxi drivers, etc. the Study of ethyol is GIII methods for clinical treatment of prostate hyperplasia/prostate cancer has attracted wide attention in the pharmaceutical industry worldwide.

Protein AR is a member of the superfamily of nuclear receptors and functions as a ligand-activated transcription factor. As shown in figure 1, AR protein has three structural domains: N-terminal domain (NTD), a DNA binding domain (DBD) and the ligand-binding domain (LBD) [Not C. Kemppainen. JA. 1999, J. Bio). Chem. 274(52), 37219-25]. Androgen forms a complex with LBD endovenosa receptor (AR) and is associated with the element of response to androgen (ARE)localized in the promoter region of the target genes AR, to detect activation or inhibition of the expression of target genes, thereby regulating the physiological functions of the target tissue. The prostate gland is an important target organ for androgen. In the embryonic period, the androgen binds to the AR, distributed in the endoderm of the urogenital sinus, causing phenotypic differentiation of epidermal cells of the prostate gland and inducyruya the formation of specific proteins in the prostate. In Mature glandular organs androgen activates mitosis and proliferation of epidermal cells of the prostate gland to maintain the morphology and functions of the authority [Waller AS, Sharrard RM, 2000. J. Mol. Endocrinol. 24(3), 339-351]. In addition, androgen regulates the metabolic activity of the cells of the prostate gland, such as the biosynthesis of lipids, and controls the formation of some specific to the prostate is EleSy expressed proteins (such as prostatespecific antigen, PSA) and the like.

The mechanism of action of androgens and AR includes a system of complex and accurate transfer processes (translation, transduction) signal, and the specific binding of androgen plays an irreplaceable role. Many diseases associated with, AR, caused by imbalance in the interaction between the androgen and is due to abnormal hormone levels or dysfunction of the receptor. Individuals suffering from such diseases, medicines provide a therapeutic effect by enhancing or inhibiting the activity. Thus, in the presence of a target detection of chemical compounds with the activity of modulating functions of the androgen receptor (AR) has become the focus of global research. In accordance with the pharmacological properties of the AR modulators can be classified as AR agonists and antagonists of AR. The AR antagonist is an important tool for the treatment of benign prostatic hyperplasia/prostate cancer (especially for late stages), and it competitively binds to the AR in the field of malignant tumors, blocks the uptake of androgen cells and inhibits the effects of androgen in target organs, thus inhibiting the growth of cancer cells, reducing tumor volume and delaying the development of the disease [Leewansangtong S, 1998, Endocrine-rented Cancer 5, 325-339]. what about the comparison with other treatment modalities, any abscopal activity of androgen, e.g., orchiectomy, the introduction of analogs of luteinizing hormone releasing hormone inhibitors or testosterone synthetase (e.g., 5α-reductase), the AR antagonist can block the binding of androgen to the AR [Hong-Chiang. .Hiroshi M. 1999. Proc. Natl Acad. Sci. USA 96. 11173-11177] to overcome the shortcomings antiandrogenna therapy. In addition, the AR antagonist can also be used to treat some common diseases, such as hirsutism, severe androgen alopecia (baldness), acne, etc. are now widely used antagonists of the androgen can be divided into two groups: steroid and non-steroid. Steroid medicines include tsiproteronatsetat (CPA), and non-steroidal drugs include to be, nilutamide and bicalutamide (casodex) etc.

Nonsteroidal AR antagonists have a high selectivity for AR and do not cause hormone-like or antihormonal effects in relation to other steroid receptors, thus they are widely used in clinics. However, all commercially available antiandrogens have many problems that need to be addressed. First, after the introduction of anti-androgens patients may suffer from various side effects such as discomfort in the gastrointestinal tract, sickening the and, vomiting, insomnia, lack of exercise, headache, anxiety, blurred vision and hyposexuality, etc. secondly, when alone with antiandrogen for the treatment of benign prostatic hyperplasia/prostate cancer patients will develop a "syndrome" anti-androgens (AWS). Syndrome detects the rapid rise in the previously inhibited PSA levels and increased tumor volume over time after injection. Treatment should be terminated or should be used other antiandrogennoe preparty [Dicker AP, 2003, Lancet Oncol 4(1), 30-36; Laufer M, Sinibaldi VJ, 1999, Urology 54(4). 745]. The molecular mechanism AWS is still unknown, but in General it is considered that due to the mutation of the AR gene in the cells of the prostate drugs that initially have antagonistic activity against AR, can cause agonistic activity against AR. Thus, there is an unmet medical need for modulators of AR with new chemical structures.

Description of the invention

Using randomized high-throughput screening and the subsequent study of the dependence of activity on the structure of the inventors synthesized and optimized class of low molecular weight non-steroidal compounds that can be divided into three classes. The results of the experiment is s by competitive binding with the receptor indicate that the affinity of representative derivatives with AR are less than 0.2 μm, and in the experiment on the gene transfection AR together with the reporter gene luciferase derivatives exhibit antagonistic activity against AR activity indicating new androgen receptor modulators.

Thus, the aim of the present invention is the provision of a class of non-steroidal derivatives, regulators of androgen receptors, or their pharmaceutically acceptable salts, having the basic structure of the following General formula I.

Another aim of the invention is the provision of a method of preparation of these derivatives of the General formula I.

Another aim of the invention is to provide pharmaceutical compositions containing derivatives of General formula I, or their pharmaceutically acceptable salts.

An additional aim of the invention is the provision of the use of derivatives of General formula I or their pharmaceutically acceptable salts for the preparation of drugs for the prevention and/or treatment of symptoms or diseases associated with the androgen receptor, such as prostatic hyperplasia, prostate cancer, hirsutism, severe androgen alopecia or acne, etc.

Nonsteroidal androgen receptor modulators or FA is matemticas acceptable salt, presented in the invention have a structure of the following General formula I:

where X1represents N, CH, O or S; and when X1means O or S, R4does not exist;

X2represents O, NH or CHR, where R represents H, C1-6alkyl, CF3, aromatic ring or aromatic heterocyclic ring;

Each of R1and R2represents H, C1~6alkyl, benzyl, halogen, OR, SR, NR2, NO2CN, CF3, COOR, CONR2, CONHR or COR, where the definition of R means the same as above;

Each of R3and R4represents H, C1~6alkyl benzyl,3-7cycloalkyl arbitrarily substituted R7, R8and R9, aromatic ring optionally substituted by R7, R8and R9, an aromatic heterocyclic ring, optionally substituted by R7, R8and R9or (CHR)n, where n is an integer 1-3 and the definition of R is the same as above;

R5represents H, C1-18alkyl, benzyl, halogen, OR, SR, NR2, NO2CN, CF3With3-7cycloalkyl arbitrarily substituted R7, R8and R9, aromatic ring optionally substituted by R7, R8and R9or aromatic heterocyclic ring, optionally substituted by R7, R 8and R9where the definition of R is the same as above; or R5may form a ring, fused with R3;

R6represents H, C1-18 alkyl, benzyl, halogen, OR, SR, NR2, NO2CN, CF3, aromatic ring arbitrarily substituted R7, R8and R9or aromatic heterocyclic ring, optionally substituted by R7, R8and R9where the definition of R is the same as above;

where each of R7, R8and R9represents H, C1-18alkyl, benzyl, halogen, OR, SR, NR2, NO2CN, CF3, COOR. CONR2. CONHR or R, where the definition of R is the same as above; and

R10represents C=O, SNON or SN=.

In accordance with the definition of R10where X1is N, the derivatives of the invention are the following three rows:

In derivatives of General formula I, represented by the invention, preferably X1represents N, R10means C=O, R4means N, X2does not exist; the structural formula is derived as follows:

When the molecule chiral carbon derivatives represented by the General formula I of the invention are racemic or is automatically active derivatives.

If the existence of X1in the form of N derivatives of General formula I, represented by the invention, can be obtained in two ways, where:

Preparation method 1, which includes the following stages:

Derivatives of acetophenone, an aromatic aldehyde or butyric aldehyde and organic amine used as starting compounds for the reaction of manniche in the presence of a polar solvent (e.g. ethanol, methanol, isopropanol, etc.) and catalytic amount of concentrated hydrochloric acid to produce alkali hydrochloride, manniche, which was neutralized with a suitable amount of a base to obtain the Mannich bases (1); received pursuant manniche carbonyl group was reducible catalytic hydrogenation (for example, Ni/H2Raney) or chemical recovery (e.g., NaBH4, LiAlH4and so on) to obtain the derivative (2); derived (2) dehydrational by acid catalytic conditions (when catalyzed with sulfuric acid, para-toluensulfonate acid and so on; with benzene or toluene as solvent, the reaction on the counterflow principle) to obtain the derivative (3); and the course of the reaction is demonstrated as follows:

where the definition of X2, R1, R2, R3, R4, R5and R6are the same as above.

The method of preparation 2, which includes the following stages:

Derivatives of acetophenone, aromatic aldehyde aldehyde or oil, organic primary amine secondary amine used as starting substances in acidic or alkaline conditions (such as sulfuric acid, hydrochloric acid, para-toluensulfonate acid, an inorganic hydroxide, sodium alcoholate and so on), a derivative of acetophenone are condensed with an aromatic aldehyde or an oil aldehyde to obtain α,β-unsaturated carbonyl derivative, then under the action of catalytic amounts of alkali were subjected to the reaction of Michael, the accession of organic primary amine secondary amine to obtain the derivative (1); In the resulting reaction derivative (1) carbonyl group was reducible catalytic hydrogenation or chemical reduction to obtain the derivative (2); derived (2) dehydrational under catalytic conditions in an acidic medium to obtain the derivative (3)

Derivatives of General formula I of the invention can be subjected to interact with any suitable acid conventional salt-forming methods for obtaining chemical way of their pharmaceutically who priemlimyh salts. For example, the acid means an inorganic acid such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and so on; organic acid such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid and so on; alkylsulfonate acid, such as methylsulfonate acid, ethylsulfonyl acid, etc.; arylsulfonic acid, such as benzolsulfonat acid, para-toluensulfonate acid, etc.

The pharmaceutical composition represented by the invention, comprises one or more therapeutically effective doses of the derivatives of General formula I or their pharmaceutically suitable salts, and optionally may include one or more pharmaceutically suitable carriers or excipients.

The ideal ratio of pharmaceutical compositions presented by the invention is the ratio at which the derivatives of General formula I or their pharmaceutically acceptable salts as active components comprise 50%-99.5% of the total mass, the other ratio is not more than 50%.

Derivatives of General formula I or their pharmaceutically acceptable salts possess antagonistic activity is in relation to AR, can also be used to obtain non-steroidal drugs for the prevention and/or treatment of symptoms or diseases, such as prostatic hyperplasia, prostate cancer, hirsutism, severe androgen alopecia or acne, etc.

Description of the drawings

Figure 1 is a schematic depiction illustrating three structural domain of the AR protein.

Figure 2 shows the comparison of the activities derived MWW6032 and bicalutamide in cells MDA-MB-453, transfected with a reporter gene. Dihydrotestosterone (DHT) induces the expression of luciferase in the cells, so that increases the bill at check chemiluminescence and reduced chemiluminescence induced by DHT, indicates antagonistic effect derived on the androgen receptor.

Figure 3 shows the impact of derivative MWW6032 and bicalutamide on the proliferation of LNCaP cells induced by DHT. The results show that the derived MWW6032 has defined any abscopal action on the proliferation of LNCaP cells induced by DHT, the value of the IC50a derivative is 2.28 mm.

Figure 4 and figure 5 show respectively the effect of derivative MWW6032 and bicalutamide on wet weight and dry weight of the prostate tissues and seminal vesicles of castrated rats with the addition of androgen. Cazaux the TSA has significant inhibitory effects on the growth of the prostate and seminal vesicles, induced by exogenous testosterone and its derivative MWW6032 detects a certain inhibitory effect on the growth of the above tissues when stimulated by testosterone.

The best way inventions

The invention is describe in detail in the following parts, but it should not be limited.

Definition

Unless otherwise specified, the special and scientific terms used in the invention have the same values in accordance with generally accepted understanding in accordance with the scope of the invention. All patents, patent applications, laid patent applications and other publications and sequences of libraries of genes and other databases mentioned herein incorporated by reference. If the definitions are interpreted in this section are contrary or inconsistent with the definitions included in the patents or references, patent applications, laid patent applications and other publications and sequences of libraries of genes and other databases listed in the patent, then choose definitions covered in this section.

Used in this description of "a" or "one" include "at least one" or "one or more".

Used in the present description, the term "hyperplasia" refers to benign adenomatous hyperplasia of the prostate around the urethra, which can operate the AMB different levels obstructive diseases violating the outflow from the bladder, or symptoms, also called "benign prostatic hypertrophy".

Used in the present description, the term "prostate cancer" refers to a common malignant tumor of the genital organs in men, mainly adenocarcinoma.

Used in the present description, the term "hirsutism" refers to the symptoms of excessive body hair growth in women, resulting from disease, leading to increased secretion of androgen. That is, a lot of long, thick and dark hair breaks on parts of the body where hair should not grow, or hair spread across the male type, for example, the phenomenon of wide, thick and dark eyebrows, pubic hair growing on the belly or even reach the navel.

Used in the present description, the term "heavy androgen alopecia" refers to severe seborrheic baldness also known as alopecia, "male type".

Used in the present description, the term "acne" refers to chronic inflammation of the sebaceous glands, which often occurs on the face or chest-back and may occur in the form of lesions such as acne, pimple, pustule, tubercul and cyst etc., also called acne vulgaris.

"Effective dose" compounds for the treatment of specific diseases as use the form here refers to the dose that can be improved, or to some extent alleviate the symptoms that accompany this disease. This dose can be entered as a single dose, can also be introduced in accordance with the treatment regimen. This dose can cure diseases or typically introduced to improve symptoms. To improve symptoms may be a re-introduction.

Used in the present description, the term "pharmaceutically acceptable salts, esters or other derivatives" include any salts, esters or derivatives, which can be easily prepared by a person skilled in the art using known methods. Derivatives, received and made, therefore, can be used on animals and on humans without any toxic effects. Derivatives have activity of medicinal substance or are prodrugs.

Used in the present description, the term "treatment" means the improvement or other favorable change in the disease and symptoms in any method. "Treatment" also includes the use of derivatives of this invention in medicine.

Used in the present description, the term "improving" the symptoms of certain specific diseases by introducing some specific the th pharmaceutical composition refers to any relief, regardless permanent, temporary, chronic or temporary, may be connected or associated with the introduction of the composition.

Used in the present description, the term "substantially pure" means sufficient uniformity and impurity compounds can not be detected by standard analytical methods used by the experts in this field to assess purity. These standard analytical methods include, for example, thin-layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC). Or sufficient purity also means detected physico-chemical characteristics of the substance, such as enzymatic activity and biological activity, can not be changed even if further cleaning substance. Methods for cleaning compositions for the preparation of substantially chemically pure compositions are well known to specialists in this field. However significantly chemically pure derivative can be a mixture of stereoisomers, or isomers. In this case, further treatment may increase the specific activity of the derivatives.

Used in the present description, the term "prodrug" refers to a derivative, introduced in vivo, which can be metabolized or converted into biologically, the pharmaceutical is Eski or therapeutically active form. For the production of prodrugs pharmaceutically active derivative is modified so that as a result of metabolic processes have formed an active derivative. The prodrug can be constructed in the form of a precursor, which alter the metabolic stability or the properties of the transfer to protect against adverse effects or toxicity, to improve the taste of the medicine or change other properties. Once pharmaceutically active compound is known, the person skilled in the art can konstruirovanie the prodrug compounds based on knowledge of the pharmacokinetics and metabolism of drugs in vivo [See Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York. 1985, pages 388-392].

The term "substantially" equal or equivalent or similar may have some change in the context in accordance with the understanding of a specialist in this area the right way and generally has a similarity of at least 70%, preferably at least 80%, more preferably at least 90% and most preferably at least 95%.

The term "composition", as used here, refers to any mixture, which may be a solution, suspension, liquid, powder, ointment, aqueous, nonaqueous, or any combination thereof.

The term "combination"as used here, means any combination of d is Oh or more.

The term "subject"used herein includes humans and animals, such as dogs, cats, cattle, pigs, rodents and so on. A qualified technician must understand that the subject is suitable and would like to be treated and can be prevented from diseases or symptoms caused or accompanied by functional disorders of androgen and/or androgen receptor, such as hyperplasia, prostate cancer, hirsutism, severe androgen alopecia and acne, etc.

Reduce any protective groups, amino acids and other compounds used here are in accordance with generally accepted their well-known abbreviations or biochemical name, published by authority of the IUPAC-IUB (nep., IUPAC (IUPAC (international Union of pure and applied chemistry), IUB international biochemical Union), unless given a special definition.

Composition and dosage

In accordance with the invention, derivatives of the present invention may be applied in pure form or together with other drugs, carriers or fillers and can be prepared in the form of medication for any kind of suitable routes of administration such as intraoral introduction, subcutaneous injection, intravenous, intramuscular, transdermal entered the e, oral or local administration. This method can be applied injectable drug that can be introduced in the form of single dose vials or in the packaging of the drug for multiple reception with the addition of a buffer. The preparation may take the following forms, for example form of a suspension, solution or emulsion in oily or aqueous medium. The drug may contain a substance for preparation of compositions, for example suspendisse substance, stabilizing and/or dispersing agent. Additionally, the active ingredients in powder form can be medicinal form with the appropriate media, sterile pyrogen-free water or other solvents. Local introduction in accordance with this invention may take the form of a foam, gel, paste, ointment, transdermal patch or cream.

Pharmaceutical compositions and routes of administration used in the invention may relate, but are not limited to the compounds described in U.S. patent No. 5736154; 6197801; 5741511; 5886039; 5941868; 6258374 In and 5686102.

Dose for treatment or prevention may vary depending on the severity of the condition of the disease and the route of administration of the drug. And the dose and frequency of injection are different depending on age, body weight, health status and individual responses of patients.

It must be emphasized (the doctor should also know)that therapeutic dose should be limited, interrupted or reduced, depending on the toxicity and side effect. On the contrary, in the absence of obvious clinical response without toxicity and side effects) the physician shall appropriately adjust the treatment regimen by increasing the dose.

Any suitable route of administration may be adopted. Dosage forms include tablet, toffee, capsule-shaped pea, dispersion, suspension, solution, capsule, film and the like, etc.

In the practical application of the derivatives of the invention, in pure form or in combination with other drugs, can be accurately mixed with carriers of drugs or fillers, such as β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin, in accordance with generally accepted pharmaceutical blending technology. In accordance with the requirement of the introduction can be used in standard media or media for local or parenteral route. Similar native medicinal product, such as water, ethylene glycol. oil, buffer, sugar, preservative, liposome, etc. that are well known to specialists in this field can be used for the preparation of parenteral dosage forms, nab the emer compositions for intravenous injection or perfusion. Examples of such parenteral compositions include, but are not limited to, 5% (wt./about.) dextrose, normal saline or other solutions. The total dose derivative of the invention in pure form or in combination with other drugs can be injected by intravenous injection using ampoules of 1 ml to 2000 ml Level of dilution varies depending on the total dose, which is entered.

The invention also provides a kit for providing a treatment regimen. The set contains an effective dose of the derivative of the invention in pure form or in combination with other agents in pharmaceutically acceptable form in one or more containers. Preferred dosage forms is combined with sterile saline, dextrose, buffered solution, or other pharmaceutically acceptable sterile fluid. Alternatively, the composition can be lyophilized or dried. In this case, the set contains selectively one pharmaceutically acceptable solution, preferably sterile solution in a single container to form a composition, in order to recover the solution for the object injection. Typical pharmaceutically acceptable solutions are saline and the solution dextr the threat.

In another variant embodiment of the invention, the kit of the invention further comprises a needle or syringe, preferably packaged in sterile form, for injecting the composition and/or packaged alcoholic swab. The kit may arbitrarily contain a detailed description for doctors or patients.

The following, the invention is additionally explained in conjunction with specific examples, but they do not limit the invention.

Example 1

Synthesis of 3-phenyl-3-(4-Chloroaniline)-1-(4-were)-1-acetone

10.60 g (0.1 mol) of benzaldehyde, of 12.76 g (0.1 mol) of 4-Chloroaniline, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 10 minutes at room temperature the mixture was added 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was conducted for 20 hours under stirring at room temperature. After completion of the reaction, the reaction solution was cooled overnight, the separated solid precipitate was filtered and washed with absolute alcohol. Formed in the reaction, the solid is suspended in 150 ml of 95% ethanol and was stirred for 2 hours at room temperature. The resulting solution was neutralized with saturated NaHCO3to alkaline values of the Oia. Stirring was continued for 1 hour. The solution was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product was recrystallized from a mixed solvent of ethanol/water (volume ratio 1:1) to obtain 25,61 g of acicular crystals, and the output was 73.2 per cent.

mp (trans., melting point)152-154°C. 1H-NMR (DCl3) (Tr, 1H-NMR spectrum, NMR analysis by atomic hydrogen in the solvent CDCl3: 7,79 (2H, d, J=8,2 Hz, Ar-H), 7,12~7,42 (7H, m, Ar-H), 7,02 (2H, d, J=8,8 Hz, Ar-H), 6,50 (2H, d, J=8,8 Hz, Ar-H), to 4.92 (1H, dd, J=7,4 Hz, CH), of 3.45 (2H, t, J=7,4Hz, CH2), is 2.40 (3H, s, CH3); MS(FAB): 350(M+H) (TRANS., MS(FAB) - FAB-mass spectrometry, mass spectrometry with the bombardment of accelerated atoms.

Example 2

Synthesis of 3-phenyl-3-(4-bromaniline)-1-(4-were)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, 17,20 g (0.1 mol) 4-bromoaniline, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 10 minutes at room temperature the mixture was added 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 24 hours under stirring at room temperature. After completion of the reaction, the reaction solution was cooled overnight, the separated solid precipitate was filtered and washed with POM is using absolute alcohol. Formed in the reaction, the solid is suspended in 180 ml of 95% ethanol and was stirred for 1.5 hours at room temperature. The resulting solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product was recrystallized from a mixed solvent of ethanol/water (volume ratio 1:1) to obtain 28,04 g of acicular crystals, and the output was 71,1%.

mp (trans., melting point)147-149°C.; 1H-NMR (DCl3): 7,79 (2H, d, J=8,2 Hz, Ar-H), 7,12~7,42 (7H, m, Ar-H), 6,79 (2H, d, J=8,1 Hz, Ar-H), 6.42 per (2H, d, J=8,1 Hz, Ar-H), 4,91 (1H, dd, J=7,4 Hz, CH), 3,49 (1H, d, J=7,4 Hz, CH2), 3,42 (1H, d, J=7,4 Hz, CH2), is 2.40 (3H, s, CH3); MS(FAB): 395(M+H).

Example 3

Synthesis of 3-phenyl-3-(4-nitroaniline)-1-(4-were)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, 13,82 g (0.1 mol) 4-nitroaniline, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 10 minutes at room temperature the mixture was added 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 24 hours under stirring at 32°C. After completion of the reaction, the reaction solution was cooled overnight, the separated solid precipitate otherthrow the Wali and washed with absolute alcohol. Formed in the reaction, the solid is suspended in 160 ml of 95% ethanol and was stirred for 1.5 hours at room temperature. The resulting solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product was recrystallized from a mixed solvent of ethanol/water (volume ratio 1:1) to obtain 32,04 g of crystals, and the output stood at 88.9%.

mp (trans., melting point)157-159°C.; 1H-NMR (DCl3): 7,79 (2H, d, J=9,1 Hz, Ar-H), 7,78 (2H, d, J=8,4Hz, Ar-H), 7,22-7,40 (7H, m, Ar-H), 6,50 (2H, d, J=9,1 Hz, p-NO2C6H4NH-), to 5.58 (1H, brs, NH), 5,07 (1H, t, J=5,8 Hz, CH), 3,48 (2H, d, J=5,8 Hz, CH2), is 2.40 (3H, s, CH3); MS (FAB): 361 (M+H).

Example 4

Synthesis of 3-phenyl-3-(4-carboxyaniline)-1-(4-were)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, 13,72 g (0.1 mol) of 4-aminobenzoic acid, 140 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 5 minutes at room temperature the mixture was added 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was conducted for 20 hours under stirring at 32°C. After completion of the reaction, the reaction solution was cooled overnight, the separated solid wasp is OK was filtered and washed with absolute alcohol. Formed in the reaction, the solid is suspended in 170 ml of 95% ethanol and was stirred for 1.5 hours at room temperature. The resulting solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product is recrystallized from alcohol to obtain 30,59 g of crystals, and the output was 85.1%.

mp (TRANS., the melting temperature)208-210°C.; 1H-NMR (DMSO-d6): 7,86 (2H, d, J=8,2 Hz, Ar-H), 7,58 (2H, d, J=8,6 Hz. Ar-H), 6,98~7,46 (7H, m, Ar-H), 6,51 (2H, d, J=8,6 Hz, Ar-H), is 5.06 (1H, m, CH), 3.24-to 3.35 (2H, m, CHz), is 2.37 (3H, s, CH3); MS (FAB): 360(M+H).

Example 5

Synthesis of 3-(4-were)-3-aniline-1-(4-were)-1-acetone

12,02 g (0.1 mol) of 4-methylbenzaldehyde, 9,31 g (0.1 mol) of aniline, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 10 minutes at room temperature the mixture was added 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 21 hours under stirring at 32°C. After completion of the reaction, the reaction solution was cooled overnight, the separated solid precipitate was filtered and washed with absolute alcohol. The resulting reaction solid WM who was enduropale in 160 ml of 95% ethanol and was stirred for 2 hours at room temperature. The resulting solution was neutralized with saturated Panso3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product was recrystallized from a mixed solvent of ethanol/water (volume ratio 1:1) to obtain 24,05 g of crystals, and the output stood at 88.9%.

mp (TRANS., the melting temperature)131-132°C.; 1H-NMR (Dl3): 7,81 (2H, d, J=8,1Hz, Ar-H),? 7.04 baby mortality-7,34 (N, m, Ar-H), 6,55 (2H, d, J=7,8 Hz, Ar-H), of 4.95 (1H, dd, J=6,4 Hz to 8.0 Hz, CH), 3,43 (1H, d, J=6,4 Hz, CH2), to 3.41 (1H, d, J=8,0 Hz, CH2), is 2.40 (3H, s, CH3), is 2.30 (3H, s, CH3); MS(FAB): 330(M+H).

Example 6

Synthesis of 3-phenyl-3-(4-Chloroaniline)-1-{4-nitrophenyl)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, of 12.76 g (0.1 mol) of 4-Chloroaniline, 180 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture for 10 minutes at room temperature the mixture was added 16,52 g (0.1 mol) of 4-nitroacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 26 hours under stirring at room temperature. After completion of the reaction, the reaction solution was cooled overnight, the separated solid precipitate was filtered and washed with absolute alcohol. Formed in the reaction, the solid is suspended in 200 ml of 95% ethanol is stirred for 1 hour at room temperature. The resulting solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product was recrystallized from a mixed solvent of ethanol/water (volume ratio 1:1) to obtain 31,23 g of crystals, and the output was 82,0%.

1H-NMR (in CDCl3): compared to 8.26 (2H, d, J=8,6 Hz, Ar-H), to 7.99 (2H, d, J=8,6 Hz, Ar-H), 7.23 percent-7,52 (5H, m, Ar-H),? 7.04 baby mortality (2H, d, J=6,4 Hz, Ar-H), of 6.52 (2H, d, J=6,4 Hz, Ar-H), equal to 4.97 (1H, t, J=6,2 Hz, CH), 3,54 (2H, d, J=6,0 Hz, CH2); MS (FAB): 382(M+H).

Example 7

Synthesis of 3-phenyl-3-(4-chloroanilino)-1-(4-were)-1-propanol

6,98 g (0.02 mol) of 3-phenyl-3-(4-chloroanilino)-1-(4-were)-1-acetone and 120 ml of methanol was introduced into the reaction vessel. After stirring the mixture at room temperature until complete dissolution of the solids in the mixture were added a catalytic amount of Nickel catalyst Raney. The reaction vessel was three times purged with hydrogen, then the vessel is tightly closed, then there was some recovery within 12 hours of the introduction of hydrogen at 60-70°C. After completion of the reaction, the reaction solution was cooled to room temperature and was filtered, the filter cake washed with a small amount of methanol. The filtrate was subjected to distillation under reduced pressure to remove the solvent,the thus obtained solid substance in powder form. The resulting solid is recrystallized from a mixture of alcohol/water (volume ratio 1:1) to obtain 5,80 g of crystals. The output was 82.6%.

1H-NMR (in CDCl3): 7,81 (2H, d, J=8,4 Hz, Ar-H), 7,11-7,40 (7H, m, Ar-H), 7,03 (2H, d, J=8,2Hz, Ar-H), 6.49 (2H, d, J=8,2Hz, Ar-H). of 5.05 (1H, t, J=7,1 Hz, CHOH), 4,94 (1H, dd, J=7,4 Hz, CH), 3,51 (2H, m, CH2), is 2.41 (3H, s, CH3); MS (FAB): 351(M+).

Example 8

Synthesis of 3-phenyl-3-(4-chloroanilino)-1-(4-were)-1-propylene

3.51 g (0.01 mol) of 3-phenyl-3-(4-chloroanilino)-1-(4-were)-1-propanol, a catalytic amount of para-toluensulfonate acid and 80 ml of toluene was introduced into the reaction vessel. The reaction was conducted for 3 hours under reflux with stirring. After completion of the reaction, the reaction solution was cooled to room temperature. Toluene layer was washed with a saturated solution of NaHCO3and successively with a saturated solution of salt. The organic layer was dried over anhydrous Na2SO4and the solvent was removed by distillation under reduced pressure. The residue was recrystallized from absolute alcohol to obtain 2.50 g of a white solid. The output amounted to 75.1%.

1H-NMR (DCl3): of 7.82 (2H, d, J=8,4 Hz, Ar-H), 7,16-7.42 (7H, m, Ar-H), 7,01 (2H, d, J=8,2 Hz, Ar-H), 6,63 (1H, dd, J=16,2 Hz. 7,4 Hz, CH), 6,46 (2H, d, J=8,2 Hz, Ar-H), 6,32 (1H, d, J=of 16.2 Hz, CH), 4,94 (1H, d, J=7,4 Hz, CH), of 2.45 (3H, s, CH3); MS (FAB): 334(M+H).

Example 9

Synthesis of 3-phenyl-(1-piperidino)-1-(4-were)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, charged 8.52 g (0.1 mol) of piperidine, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture at room temperature for 10 minutes in the reaction vessel was made 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 18 hours while stirring at 45°C. After completion of the reaction, the reaction solution was cooled overnight, the separated precipitate was filtered and washed with absolute alcohol. The precipitate suspended in 150 ml of 95% ethanol and was stirred for 2 hours at room temperature. The solution was neutralized with saturated NaHCO3to alkaline values and continued the stirring for 1 hour. The solution was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product is recrystallized from absolute alcohol to obtain 23,37 g of the solid in powder form. The output was 76,0%.

1H-NMR (Dl3): 7,76 (2H, d, J=7,6 Hz, Ar-H), 7,12~7,42 (7H, m, Ar-H), to 4.92 (1H, dd, J=7,4Hz, CH), of 3.45 (2H, t, J=7,4 Hz, CH2), 2,78 (4H, m, CH2), of 1.55 (6H, m, CH2); MS (FAB): 307(M+).

Example 10

Synthesis of 3-phenyl-3-(1-piperidino)-1-(4-nitrophenyl)-1-acetone

or 10.60 g (0.1 mol) of benzaldehyde, charged 8.52 g (0 mol) of piperidine, 180 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture at room temperature for 10 minutes in the reaction vessel was made 16,52 g (0.1 mol) of 4-nitroacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 18 hours while stirring at 45°C. After completion of the reaction, the reaction solution was cooled overnight, the separated precipitate was filtered and washed with absolute alcohol. The precipitate suspended in 150 ml of 95% ethanol and was stirred for 2 hours at room temperature. The solution was neutralized with saturated Panso3to alkaline values and continued the stirring for 1 hour. The solution was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product is recrystallized from absolute alcohol to obtain 20,31 g of the solid in powder form. The output was 60,0%.

1H-NMR (DCl3): of 8.27 (2H, d, J=8,4 Hz, Ar-H), of 7.96 (2H, d, J=8,4 Hz, Ar-H), 7.18 in-7,49 (5H, m, Ar-H), 4,89 (1H, t, J=6,2 Hz, CH), 3,54 (2H, d, J=6,2 Hz, CH2), a 2.75 (4H, m, CH2), was 1.58 (6H, m, CH2); MS (FAB): 338(M+).

Example 11

Synthesis of 3-methyl-3-(4-chloroanilino)-1-(4-were)-1-acetone

4,84 g (0.11 mol) of acetaldehyde, of 12.76 g (0.1 mol) of 4-Chloroaniline, 150 ml of absolute alcohol was introduced in the reaction is Oud. After stirring the mixture at room temperature for 5 minutes in a reaction vessel made 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was carried out for 16 hours under stirring at room temperature. After completion of the reaction, the separated precipitate was filtered and washed with absolute alcohol. The resulting solid residue suspended in 120 ml of absolute ethanol and was stirred for 1 hour at room temperature. The solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product is recrystallized from absolute alcohol to obtain 22,45 g of the solid in powder form. The output was 78.0%.

1H-NMR (DCl3): 7,81 (2H, d, J=8,4 Hz, Ar-H), 7,30 (2H, d, J=8,4 Hz, Ar-H), 7,05 (2H, d, J=8,6 Hz, Ar-H), 6,47 (2H, d, J=8,6 Hz, Ar-H), and 4.75 (1H, m, CH), of 3.43 (2H, t, J=7,4 Hz, CH2), 2.40 (3H, s, CH3), and 2.26 (3H, d, J=6,4 Hz, CH3); MS (FAB): 288(M+H).

Example 12

Synthesis of 3-isopropyl-3-(4-chloroanilino)-1-(4-methylpent)-1-acetone

7.30 g (0.1 mol) of Isobutyraldehyde, of 12.76 g (0.1 mol) of 4-Chloroaniline, 150 ml of absolute alcohol was introduced into the reaction vessel. After stirring the mixture at room temperature for 5 minutes in reacts the vessel was made 13,42 g (0.1 mol) of 4-methylacetophenone and a catalytic amount of concentrated hydrochloric acid, then the reaction was conducted for 20 hours under stirring at room temperature. After completion of the reaction, the separated precipitate was filtered and washed with absolute alcohol. The resulting solid residue suspended in 150 ml of absolute ethanol and was stirred for 1 hour at room temperature. The solution was neutralized with saturated NaHCO3to alkaline values, was filtered and the filter cake washed with a small quantity of absolute alcohol. The crude product is recrystallized from absolute alcohol to obtain 22,11 g of the solid in powder form. The output was 70,0%.

1H-NMR (Dl3): of 7.82 (2H, d, J=8,4 Hz, Ar-H), 7,28 (2H, d, J=8,4 Hz, Ar-H), 7,02 (2H. d, J=8,8 Hz, Ar-H), 6,51 (2H, d, J=8,8 Hz, Ar-H), and 4.75 (1H, m, CH), 3,43 (2H, m, CH2), was 2.34 (3H, s, CH3), is 1.81 (1H, m, CH), and 0.98 (6N, d, J=6,4 Hz, 2CH3); MS (FAB): 316(M+H).

Testing the biological activity

1. Materials and equipment

1.1 Plasmid and cell line: a plasmid expressing the androgen receptor, and a plasmid expressing the reporter gene luciferase, was designed by the National center of China for screening drugs; cancer cell lines human breast MDA-MB-453 cell line prostate cancer human LNCaP acquired ATSS, USA (trans., ATCC - American type culture collection).

1.2 eagency: fetal bovine serum (FBS, GIBCO/BRL, USA); fetal bovine serum, treated with activated charcoal coated with dextran (CD-FBS. Hydone, USA): medium DMEM and RPMI1640 (GIBCO/BRL, USA); environment MEM (Bioresource, USA), set for luciferase reporter assay (Promega Corporation, USA); reagent Fugene6 (Rocheltd., USA); [3H]-dihydrotestosterone (DHT, Amersham, UK); scintillation fluid (SuperMix™, PerkinElmer, USA); protein-receptor androgen was a product of the expression of the androgen receptor gene of the person, expressed in the baculovirus expression system in insect cells.

1.3. Equipment: Multi-function reader Envision2101 Multilabel Reader, PerkinElmer, USA); CO2incubator (Forma, USA); multi-detector Wallac MicroBeta® TriLux 1450 (PerkinElmer, USA); reader for the microplate VERSAmaxMicroplate Reader (Molecular Devices, USA).

2. Experimental methods and results

2.1 Testing the receptor-binding activity

Solutions of dihydrotestosterone (DHT) and each derivative of the invention, are shown in table 1, was prepared with DMSO, and the concentration gradient DHT was consistently 0; 0,3; 1; 3; 10; 30; 100 nm, and the concentration gradient was derived 0: 0,128; 0,64; 3,2; 16; 80; 400; 2000 nm in serial order. Five μl of each dilution DHT derived and tested in various concentrations were made respectively in each well of tablets for micrometrology. Protein-receptor androgen is obavljale to the buffer for analysis (25 mm NaH 2PO4, 10% glycerol, 10 mm NaMoO4, 10 mm KF, pH 7.5) with protease inhibitor, such as 1 μg/μl Aprotinin and leupeptin, etc, [3N]D was added to obtain a final concentration of 5 nm. Then the mixture was made into tablets of 195 μl to each well immediately after thorough mixing and incubated over night at 4°C. After incubation 50 μl of a solution of hydroxyapatite (ON) (25%), mm Na3PO4pH 4) was added to each well of the calender, was stirred by the constant shaking and incubated for 10 minutes, during the period the mixture was shaken once every 3 minutes. Centrifugation was carried out at 2500 rpm for 3 minutes, the supernatant was aspirated and the precipitate was left. Two hundred μl of buffer for analysis were added to each well, the draught was given the opportunity shaking for as long as possible and again spent centrifugation for 3 minutes. The supernatant was aspirated and the precipitate was left. The centrifugation was repeated once again, the supernatant was aspirated and the precipitate was left. 300 μl of scintillation fluid was added to each well. The mixture was stirred permanent Strahovanie, was calculated using a Wallac MicroBeta® TriLux 1450. In the nine derivatives had similar affinity to the androgen receptor as a positive control DHT, and their values IC 50was below 10 nm (see Table 1).

Table 1
Testing the activity of binding to the androgen receptor
DerivedStructureBinding to the receptor (IC50nm)
DHT6,85
MWW60032,928
MWW60152,848
MWW60169.486
MWW60216.455
MWW60224,306
MWW60303,246
MWW6031 3,608
MWW60322,886
MWW60333.007

2.2 Testing the expression of the reporter gene

Cells MDA-MB-453 were cultured in the medium MEM containing 10% FBS and 2 mm L-glutamine. The above medium was replaced with medium MEM containing 5% CD-FBS (lane, CD-FBS - fetal bovine serum, treated with activated charcoal coated with dextran), the day before transfection, and the Fugene6 reagent was used for transfection. Vectors with reporter gene and Fugene6 uniformly mixed in the ratio 1:3 and added dropwise to the cells. Cells were cultured at 37°C in 5% CO2within 6 hours. After dissociation, cells were planted in 96-well plate at the composition of 20000 cells/µl/well and cultured at 37°C for 2 hours together with the environment MEM containing 5% CD-FBS. To the cells was added to the test derivative, the concentration of bicalutamide was 0; 0,256; 1,28; 6,4; 32: 160; 800; 4000 nm in serial order, and the concentration derived MWW6032 were 0, 2,56; 12.8; 64; 320; 1600; 8000; 40000 nm in serial dilution. After culturing cells for 24 hours used set for luciferase reporter assay for detection fermentative the activity, to evaluate the pharmacological activity of the derivatives with respect to the androgen receptor. The data show in figure 2, and the derived MWW6032 found reliable antagonistic activity against androgen receptor.

2.3 Testing the proliferation of prostate cancer cells

The LNCaP cells were cultured in RPMI1640 medium containing 10% FBS and 2 mm L-glutamine. The above medium was replaced with RPMI1640 medium containing 5% CD-FBS the day before the experiment. As soon as the cell growth reached confluently 90%, cells were made in a 96-well plate at the composition of 4000 cells/90 MCP/well after dissociation of the cells with trypsin and cultured at 37°C over night. The tested derivatives were added to the cells at 10 μl/cell after diluted to specific concentrations. Concentrations of bicalutamide was 0; 0,64; 3,2; 16; 80; 400; 2000 nm in serial sequence, and the concentration derived MWW6032 was 0; 5,12; 25,6; 128; 640; 3200; 16000 NIV serial sequence. DHT (5 nm final concentration) was added to the cells in the form of the agonist after incubation of cells for 30 minutes. Cells were cultured at 37°C for 6 days and the medium containing derivatives and DHT, changed once on the third day. The MTT solution (5 mg/ml) was added at 20 μl/well before completion of the cultivation. The values of absorbance of light at 560 nm change the Yali at reference wavelength of 690 nm. Experimental data show in figure 3. Derived had significant inhibitory effect on the proliferation of LNCaP cells stimulated by DHT, and the value of the IC50was 2.28 ám.

2.4. Detection of antagonistic activity derived in relation to the androgen receptor using rat

24 male SD rats (trans., rats breed Sprague, doli) 3-weeks of age were randomly divided into 6 groups, which were: control group (group 1), group testosterone (group 2), group testosterone (T) + bicalutamide (casodex) 25 (group 3), a group of testosterone (T) + bicalutamide (casodex) 50 (group 4), a group of testosterone (T) + MWW6032 (group 5), Sham group (trans., the control group with "false action") (group 6), respectively. Then rats were subjected accommodation for 1 week, the group conducted Sham false operation in the other five groups of rats was dissected testes (castrated). Eight weeks after surgery, rats of group C were testosteroneinjection subcutaneously with 0.25 mg/kg of testosterone propionate daily; group testosterone + Casodex 25 were injected with subcutaneous (s.c.) using 0.25 mg/kg of testosterone propionate and intragastric (r.o.) was administered 25 mg/kg Casodex daily; group testosterone + Casodex 50 were injected subcutaneously with 0.25 mg/kg of testosterone propionate (s.c.) and 50 mg/kg of Casodex nutriglow the part (r.o.) daily; the group testosterone+MWW6032 was subcutaneously injected with 0.25 mg/kg of testosterone propionate and was administered intraperitoneally injected with 250 mg/kg derived MWW6032 daily. Rats sequentially injected drugs within 10 days. Twenty-four hours after the last injection, rats were scarificial, took their prostate gland and seminal vesicles for measurement of wet weight and dry weight. Differences between different groups were compared after adjusting for body weight (BW). The results of the experiments result in table 2 and 3 4 and 5. Subcutaneously injected testosterone propionate (0.25 mg/kg) could produce visible agonistic activity in castrated rats 11 weeks of age; mg/kg Casodex could significantly to counteract the action of testosterone propionate, and all the weight of prostate glands (PW) and the weight of the seminal vesicles (SVW) rats in group derived MWW6032 were lower than in the group with testosterone propionate, pointing to its antagonistic activity against AR in vivo.

Table 2 Wet weight of the prostate and seminal vesicle in castrated rats after antiandrogenna therapy

No. of groups groupGroup nameMass prostate/body weight × 100 The weight of the seminal vesicle/body weight × 100
1Control0,14±0,030,06±0,03
2Testosterone1,49±0,280,97±0,54
3Testosterone + Casodex 250,30±0,040,11±0,03
4Testosterone + Casodex 500,22±0,030,07±0,04
5Testosterone + MWW60321,12±0,300,69±0,22
6Control group with "false action"3,03±0,562,52±0,34
Table 3
Dry weight of the prostate and seminal vesicle in castrated rats after antiandrogenna therapy
no groupGroup nameMass prostate/body weight × 1000 The weight of the seminal vesicle/ body weight × 1000
1Control0,0048±0,0260,016±0,006
2Testosterone0,307±0,0650,212±0,121
3Testosterone + Casodex 250,073±0,0090,022±0,005
4Testosterone + Casodex 500,055±0,0060,020±0,006
5Testosterone + MWW60320,217±0,055to 0.127±0,040
6Control group with "false action"0,717±0,1880,623±is 0.102

3. Conclusion experiments

(1) Derivative WMW6003, 6015, 6016, 6021, 6022, 6030, 6031, 6032, 6033 demonstrated high affinity binding to the androgen receptor with values IC50below 10 nm, similar to the values for DHT.

(2) the Above derivative (for example, MWW6003 and MWW6032) were found antagonistic activity against androgen cocktail recipes. is the values IC 50close to the values for the androgen receptor antagonist of bicalutamide.

(3) Derived MWW6032 was found inhibitory effects on androgen-dependent proliferation of cell lines prostate cancer LNCaP, and the value of the IC50was 2.28 μm, giving the opportunity to suggest its potential application in the treatment of prostate cancer.

(4) In model animals castrated rats derived MWW6032 showed inhibitory profile suppress growth of the prostate gland and seminal vesicles induced by the addition of exogenous testosterone propionate.

1. Class synthetic derivatives having the following structure or their pharmaceutically acceptable salts:
,,,
,
or

2. Derivatives or their pharmaceutically acceptable salts according to claim 1, characterized in that the pharmaceutically acceptable salts are salts derived from hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, alkylsulfonic acid or arylsulfonic acid.

3. Pharmaceutical composition having the ability of androgen receptor modulator containing one or more therapeutically effective amounts of derivatives or their pharmaceutically acceptable salts according to claim 1.

4. The pharmaceutical composition according to p. 3, characterized in that it further comprises one or more pharmaceutically acceptable carriers or excipients.

5. The pharmaceutical composition according to claim 3 or 4, characterized in that the derivatives or their pharmaceutically acceptable salts as the active component comprise 50-99 .5% of the total mass.

6. The application class derivatives having the following structure or their pharmaceutically acceptable salts for the preparation of drugs for modulation of non-steroidal androgen receptor, to prevent and/or treat symptoms or diseases, such as prostatic hyperplasia, prostate cancer, hirsutism, severe androgen alopecia or acne:
,,
,,,
,or.



 

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51 cl, 13 tbl, 91 ex

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< / BR>
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49 cl, 149 ex

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24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new thiazole derivative of the formula I, where R1denotes a group of formula (a), (b), (C), R2denotes a group of formula (d), where Het represents a five - or six-membered heterocyclic group which is substituted by9and in the loop which, in addition to the nitrogen atom, can optionally contain an oxygen atom, R3denotes hydrogen, alkyl, cycloalkyl, phenyl, R4denotes hydrogen, phenyl, R5- R8independently of one another denotes hydrogen, R9denotes a group of formula (e) and (f), R10denotes phenyl, a-i denotes 0 or a positive integer, i.e

FIELD: chemistry.

SUBSTANCE: invention concerns new photoinitiators, method of their obtainment, compositions hardening with irradiation, and application of those compositions in coating preparation. Invention claims photoinitiators of formulae I , where R1, R2, R3 and R4 are independently C1-C8alkyl or benzyl; or R1 and R2 together and/or R3 andR4 together are cyclohexyl; R5 is hydrogen; A is OH, Br, -O-C1-C12alkyl, -O-R7, where R7 is linear or forked C2-C21hydroxyalkyl carbon chain interrupted by 1 to 9 oxygen atoms; or -NR8R9, where R8 and R9 are independently C1-C21alkyl or C2-C4alkyl substituted by one or more OH groups; A' is -O-; X and Y are independently -OH or -N(CH3)2; n is 2; R6 is linear or forked divalent -CO-NH-(C2-C16alkylene)-(NH-CO)- radical or linear or forked -CO-NH-(C0-C9alkylene)-(NH-CO)- which can be interrupted by phenylene, or linear or forked divalent -C2-C50alkylene radical with carbon chain interrupted by 1 to 15 oxygen atoms.

EFFECT: efficient method of obtaining new organic photoinitiators.

11 cl, 20 cx

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