KR20150004221A - Novel 1,2-diphenylethane derivatives and regulatory effect on androgen receptor thereof - Google Patents

Abstract

The present invention relates to a 1,2-diphenylethan derivative compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; a method for manufacturing the 1,2-diphenylethan derivative compound comprising the step of reacting a benzyl compound in which an electron withdrawing group is substituted, and an unsaturated hydrocarbon compound in which an aryl group is substituted in basic condition; and a pharmaceutical composition including the 1,2-diphenylethan derivative compound or pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating diseases related to an androgen receptor. The novel 1,2-diphenylethan derivative compound of the present invention effectively inhibits activation of the androgen receptor, thereby being used for preventing or treating excessive spermatogenesis, Beck′s nervus, polycystic ovary syndrome, hypertrophy of the heart, coronary heart disease, coronary artery disease, cancer, and metabolic disorders demanded for inhibiting baldness, hirsutism, behavioral disorder, acne, and spermatogenesis caused by overexpression of the androgen receptor.

Description

The present invention relates to novel 1,2-diphenyl ethane derivatives and their effect on regulating androgen receptor,

The present invention relates to a 1,2-diphenylethane derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof; Reacting a benzyl compound substituted with an electron withdrawing group and an unsaturated hydrocarbon compound substituted with an aryl group under basic conditions to prepare a 1,2-diphenylethane derivative compound; And a pharmaceutical composition for preventing or treating an androgen receptor-related disease by inhibiting androgen receptor activity, which comprises the 1,2-diphenylethane derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Metabolic disorders are also referred to as metabolic syndrome, syndrome X or X syndrome. It is a complex metabolic syndrome syndrome with increased risk when combined with coronary heart disease, diabetes mellitus, dyslipidemia and certain cancers, and insulin resistance and derivative diseases have been found to be major risk factors for this syndrome. This metabolic disorder is a common disease that affects approximately 25% of US and UK adults, especially among adults over 60 years old, overweight or obese. In metabolic diseases, insulin resistance plays a key role in the body's ability to respond to insulin, leading to the inability to store glucose. Insulin resistance is caused by obesity, lipid abnormalities, lack of exercise, or genetic factors It is known that excessive androgen receptor activity also causes this.

Cancer is one of the major causes of death in Korea. There have been many studies to conquer cancer. However, it is an incurable disease that can not be regulated. In cancer, cells divide and grow uncontrollably to form malignant tumors and invade adjacent tissues of the body. It can migrate not only to the adjacent tissue but also to the farther site through the lymphatic system or bloodstream. Existing therapies for cancer include surgery, chemotherapy, and radiation therapy. However, despite the existence of these various therapies, the mortality rate due to cancer has not decreased, and the survival rate has increased. However, this was because of early detection by endoscopy or the like rather than by treatment.

Cancer is a disease in which cells do not regulate and keeps on growing. It can occur anywhere other than dead cell tissue that does not grow like hair or nails, although the incidence varies depending on the tissue. The causes of these cancers have not yet been elucidated. However, to date, it has been known that mutations occur in normal cell genes or cancer suppressor genes. However, the cause of all cancers is not limited to a few mutations in a particular gene. Among these cancer diseases, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer are caused by excessive expression of androgen receptor This has been reported.

Meanwhile, the androgen receptor known as a cause of the metabolic diseases and cancer diseases is a type of nuclear receptor that is activated by the binding of the androgenic hormone testosterone or dihydrotestosterone in the cytoplasm and moves into the nucleus. The androgen receptor is closely related to the progesterone receptor, and high doses of progestin can block the androgen receptor. The main function of the androgen receptor functions as a DNA-binding transcription factor that regulates gene expression, but the androgen receptor also has other functions. The genes regulated by androgen are important for the development and maintenance of the male phenotype. In this regard, excessive expression of androgen receptors can induce hyperglycaemia, becker birth, polycystic ovary syndrome, cardiac hypertrophy, coronary heart disease and coronary artery disease, which require baldness, hirsutism, behavioral disorders, .

Therefore, the inventors of the present invention have made extensive efforts to develop a small molecule capable of inhibiting the excessive activity of the androgen receptor, and as a result, they have synthesized novel 1,2-diphenylethane derivatives and can effectively inhibit the activity of the androgen receptor And completed the present invention.

One object of the present invention is to provide a 1,2-diphenylethane derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the 1,2-diphenyl ethane derivative compound, which comprises reacting an electron withdrawing group-substituted benzyl compound with an aryl group-substituted unsaturated hydrocarbon compound under basic conditions .

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating an androgen receptor-related disease by inhibiting androgen receptor activity, comprising the 1,2-diphenylethane derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient To provide a composition.

According to one aspect of the present invention, the present invention provides a 1,2-diphenylethane derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

R ₁ is a C1 to C4 hydroxy alkyl _{(- (CH 2) n1 -1} CH 2 OH) , or C1 to C4 alkanoyloxy alkyl _{(- (CH 2) n2 COO} (CH 2) n3-1 CH 3);

;R ₂ is C1 to C4 alkanoyl _{(-COO (CH 2) n 4-1} CH 3), cyano (-CN) or

;

R ₃ is nitro (-NO ₂ ), C 1 to C 4 alkanoyl (-COO (CH ₂ ) _n5-1 CH ₃ ) or cyano (-CN);

;A is an aromatic ring containing a hetero atom or

;

R ₄ to R ₈ in A each independently represent a hydrogen atom (-H), a halogen atom (-X, X = F, Cl, Br, I), nitro (-NO ₂ ), C 1 to C 4 alkoxy _{(CH 2) n6-1 CH 3)} , C1 to C4 alkyl _{(- (CH 2) n7-1 CH} 3) , and;

N ₁ to n ₇ are each independently an integer of 1 to 4;

일 때, R₄ 및 R₈은 각각 독립적으로 수소원자(-H), 할로겐원자(-X, X=F, Cl, Br, I), 니트로(-NO₂); R₅ 및 R₇은 각각 독립적으로 수소원자(-H), C1 내지 C4 알콕시(-O(CH₂)_n6'-1CH₃), 염소원자(-Cl); R₆은 수소원자(-H), C1 내지 C4 알킬(-(CH₂)_{n7' -1}CH₃), 할로겐원자(-X, X=F, Cl, Br, I), C1 내지 C4 알콕시(-O(CH₂)_n6''-1CH₃), 니트로(-NO₂)이며, 상기 n_6', n_6'' 및 n_7'은 각각 독립적으로 1 내지 4의 정수인 화합물일 수 있다.
Preferably, the 1,2-diphenylethane derivative compound of the present invention is a 1,2-

R ₄ and R ₈ are each independently a hydrogen atom (-H), a halogen atom (-X, X = F, Cl, Br, I), nitro (-NO ₂ ); R ₅ and R ₇ are each independently a hydrogen atom (-H), a C 1 to C 4 alkoxy (-O (CH ₂ ) _{n 6'-1} CH ₃ ), a chlorine atom (-Cl); R ₆ represents a hydrogen atom (-H), a C1 to C4 alkyl (- (CH ₂ ) _{n7 ' - 1} CH ₃ ), a halogen atom (-X, X = F, Cl, Br, I) _{-O (CH 2) n6 ''} - and ₁ CH _3), nitro (-NO _2), wherein n _{6 ',} n _6''7 and _n' may be an integer of 1 to 4 compounds, each independently.

; R₃은 니트로(-NO₂), 메타노일(-COOCH₃) 또는 시아노(-CN); A는 퓨라닐 또는

이며; 상기 A에서 R₄ 및 R₈은 각각 독립적으로 수소원자(-H), 염소원자(-Cl), 니트로(-NO₂); R₅ 및 R₇은 각각 독립적으로 수소원자(-H), 메톡시(-OCH₃), 염소원자(-Cl); R₆은 수소원자(-H), 메틸(-CH₃), 할로겐원자(-X, X=F, Cl, Br, I), 메톡시(-CH₃), 니트로(-NO₂)인 화합물일 수 있다.More preferably R ₁ is hydroxymethyl or ethanoyloxyethyl (- (CH ₂ ) ₂ COOCH ₂ CH ₃ ); R ₂ is selected from the group consisting of methanoyl (-COOCH ₃ ), cyano (-CN)

; R ₃ is nitro (-NO ₂ ), methanoyl (-COOCH ₃ ) or cyano (-CN); A is furanyl or

; In the above A, R ₄ and R ₈ are each independently a hydrogen atom (-H), a chlorine atom (-Cl), nitro (-NO ₂ ); R ₅ and R ₇ each independently represent a hydrogen atom (-H), methoxy (-OCH ₃ ), chlorine atom (-Cl); R ₆ is a hydrogen atom (-H), methyl (-CH _3), halogen atoms (-X, X = F, Cl , Br, I), methoxy (-CH _3), nitro (-NO ₂₎ Lt; / RTI >

At this time, it is preferable that R ₃ is positioned ortho or para to the main chain skeleton.

Preferably, the compound represented by the formula (1)

1) 5-hydroxy-2- (2-nitrophenyl) -3-phenylpentanenitrile,

2) methyl 2- (1-cyano-4-hydroxy-2-phenylbutyl) benzoate,

3) 4- (1-Cyano-4-hydroxy-2-phenylbutyl) benzonitrile,

4) 2- (1-Cyano-4-hydroxy-2-phenylbutyl) benzonitrile,

5) methyl 4- (1-cyano-4-hydroxy-2-phenylbutyl) benzoate,

6) (E) -1-Ethyl 7-methyl 6- (4-nitrophenyl) -5-phenyl-2-heptenedioate,

7) (E) -7-benzyl 1-ethyl 6- (4-nitrophenyl) -5-phenyl-2-heptenedioate,

8) (E) -1-ethyl 7-methyl 6- (4-nitrophenyl) -5- p -tolyl-2-heptenedioate,

9) (E) -1-Ethyl 7-methyl 5- (4-chlorophenyl) -6- (4-nitrophenyl) -2-

10) (E) -1-Ethyl 7-methyl 5- (2,3-dichlorophenyl) -6- (4-nitrophenyl)

11) (E) -1-Ethyl 7-methyl 5- (4-bromophenyl) -6- (4-nitrophenyl)

12) (E) -1-Ethyl 7-methyl 5- (4-fluorophenyl) -6- (4-nitrophenyl)

13) (E) -1-Ethyl 7-methyl 5- (3-methoxyphenyl) -6- (4-nitrophenyl)

14) (E) -1-Ethyl 7-methyl 5- (3,4-dimethoxyphenyl) -6- (4-nitrophenyl)

15) (E) -1-Ethyl 7-methyl 5- (2-nitrophenyl) -6- (4-nitrophenyl) -2-

16) (E) -1-ethyl 7-methyl 5,6-bis (4-nitrophenyl) -2-heptenedioate, or

17) (E) -1-Ethyl 7-methyl 5- (2-furanyl) -6- (4-nitrophenyl) -2-heptenedioate.

The compounds 1 to 17 according to the present invention each have the following chemical structural formula.

[Compound 1]

[Compound 2]

[Compound 3]

[Compound 4]

[Compound 5]

[Compound 6]

[Compound 7]

[Compound 8]

[Compound 9]

[Compound 10]

[Compound 11]

[Compound 12]

[Compound 13]

[Compound 14]

[Compound 15]

[Compound 16]

[Compound 17]

In the above chemical formula, Me is a methyl group, and Et is an ethyl group.

In another embodiment, the present invention provides a process for preparing the compound of formula (1), comprising reacting a benzyl compound substituted with an electron withdrawing group and an aryl-substituted unsaturated hydrocarbon compound under basic conditions.

The reaction between the electron-withdrawing group-substituted benzyl compound and the aryl group-substituted unsaturated hydrocarbon compound can be performed by a Michael reaction. The Michael reaction is also known as Michael addition, and is a nucleophilic addition of carbanion or other nucleophiles to α, β-unsaturated carbonyl compounds. This reaction belongs to a broader category of conjugate addition. It is one of the most useful methods for the mild formation of carbon-carbon bonds. The substituent bonded on the nucleophile, that is, the Michael donor, is preferably an electron attractant by reacting with a base.

An example of the method for producing the 1,2-diphenylethane derivative represented by the formula (1) according to the present invention is as follows.

[Reaction Scheme 1]

The preparation method according to the present invention can include a compound in which an anion is bonded to a carbon-carbon double bond as an intermediate, as shown in Reaction Scheme 2 below. For example, when R < _{1 >} is a compound containing a carbon-oxygen bond, the intermediate may be an enolate.

[Reaction Scheme 2]

In the above Reaction Schemes 1 and 2, B: means a base capable of binding with a proton.

Preferably, the electron withdrawing group may be an acyl group or a cyano group. However, the electron attracting group is not limited to this, and the electron attracts electrons from the substituted carbon to form a partial positively charged atmosphere on the carbon, thereby easily losing the proton in the base condition and converting it into a carbon anion, which is a nucleophile, Substituents which can be used are not limited.

The "acyl group" is a functional group which is derived by removing one or more hydroxy groups from oxoacid containing an inorganic acid. In organic chemistry, acyl groups are generally derived from carboxylic acids (IUPAC name: alkanoyl). Therefore, it is represented by the formula "RCO-" in which the C = O group is linked to the alkyl group (R) as a single bond by a carbon-carbon single bond. The term generally applied to organic compounds, but acyl groups can in principle be derived from other classes of acids such as sulfonic acids and phosphoric acids. In the most common arrangement, an acyl group binds to a larger molecular fragment and contains carbon and oxygen atoms linked by a double bond. Well-known acyl compounds include acyl chlorides such as acetyl chloride (CH ₃ COCl) and benzoyl chloride (C ₆ H ₅ COCl). These compounds, which are treated as acylium cation sources, are excellent reagents for binding acyl groups to a variety of substrates. Ketones (R (C = O) R ) , and aldehyde (R (C = O) H ) with, as an amide (R (C = O) NR 2) and esters (R (C = O) R ') addition to the acyl compound .

The "cyano group" is a functional group composed of carbon atoms bonded to a nitrogen atom by a triple bond. The carbon atoms may further be combined with other functional groups via a single bond. The cyano group bonds to a hydrogen atom to form a hydrogen cyanide. The cyano group is bonded to a metal to bind a metal cyanide to an alkyl group or an aryl group to form a nitrile compound. Further, two cyano groups directly bond to each other to form cyanogen (NCCN) molecules. Both cyano groups and hydrogen cyanide were found in the interstellar space.

↔

=

)에 걸친 이러한 전하의 비편재화에 의해 이놀레이트는 다소 안정화된다.The production process of the present invention can also form an enolate as an intermediate. The term " enolate "refers to a structure comprising an oxygen anion linked to a carbon-carbon double bond, wherein a compound comprising a carbon-oxygen double bond, such as an aldehyde or ketone, Enolate is relatively unstable and is mainly formed as an intermediate of the reaction and mediates additional reactions. When the hydrogen atom on the carbon immediately adjacent to the C = O bond is removed by the action of the base, the extra electron pair moves toward the electron-attracting oxygen to form a C = C double bond and the oxygen atom is anionized. Enolates are generally highly basic and can therefore be present quantitatively in Bronsted acid free conditions. The negative charge of enolate is intercalated across oxygen and carbon atoms. Three atoms (

↔

=

Lt; RTI ID = 0.0 > of < / RTI >

Examples of the base for forming the ynolate the hydroxide (HO ^-), methoxide, alkoxide (RO ^-), such as ethoxide, butoxide, sodium hydride and lithium diisopropylamide (lithium diisopropylamide; LDA) But are not limited thereto. In particular, LDA is one of the preferred bases because it is a strong base and does not cause a nucleophilic reaction due to steric hinderance caused by two isopropyl groups.

In another aspect, the present invention relates to a pharmaceutical composition for inhibiting androgen receptor-mediated diseases caused by inhibition of androgen receptor activity, comprising the 1,2-diphenylethane derivative compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention can be effectively used for the prevention or treatment of diseases caused by over-expression or over-activity of the androgen receptor.

The term " androgen receptor "of the present invention is a type of nuclear receptor that activates by binding of androgenic hormone testosterone or dihydrotestosterone in the cytoplasm and migrates into the nucleus. The androgen receptor is closely related to the progesterone receptor, and high doses of progestin can block the androgen receptor. The main function of the androgen receptor functions as a DNA-binding transcription factor that regulates gene expression, but the androgen receptor also has other functions. The genes regulated by androgen are important for the development and maintenance of the male phenotype.

In some cells, testosterone directly interacts with the androgen receptor, whereas in other cells testosterone is converted to dihydrotestosterone, a potential agonist for androgen receptor activation by 5-alpha-reductase. Testosterone is the primary androgen receptor hormone in the wolffian duct while dihydrotestosterone is the main androgenic hormone of the urogenital sinus, urogenital tubercle and hair follicles. Thus, while testosterone is primarily involved in the development of primary sexual characteristics, dihydrotestosterone is involved in male secondary sexual characteristics.

The androgen receptor has two isoforms (A and B). Type A (AR-A) refers to a form of N-terminal cleavage by in vitro proteolysis of 87 kDa, and type B (AR-B) refers to the structure of full length of 110 kDa.

In connection with the disease, it has been reported that the above androgen receptor can induce metabolic disease by inducing insulin resistance when over-expressed or over-active. In addition, it has been reported that the androgen receptor is overexpressed in various cancer diseases, and it has been reported that it can induce various diseases related to male hormone such as baldness, hirsutism, behavioral disorder, acne and Becker's nevus.

The 1,2-diphenylethane derivatives represented by Formula 1 of the present invention may exist in the form of pharmaceutically acceptable salts. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the compounds of formula (1) include, unless otherwise indicated, salts of acidic or basic groups which may be present in the compounds of formula (1). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

As the salt of the 1,2-diphenylethane derivative of the present invention, there can be used a pharmaceutically acceptable salt such as a salt of a 1,2-diphenylethane derivative which exhibits an androgen receptor inhibitory effect equivalent to a 1,2-diphenylethane derivative compound Anyone can use it without restrictions.

The term "prevention" of the present invention means all actions that inhibit or delay the occurrence, spread and recurrence of androgen receptor-related diseases upon administration of the composition of the present invention. Means any act that improves or alters the symptoms of

The androgen receptor-related diseases that can be prevented or treated by the composition of the present invention include, but are not limited to, excessive spermatogenesis, baldness, hirsutism, behavioral disorders, And coronary artery disease. In addition, the present invention also provides a method of treating a metabolic disease such as obesity, osteoarthritis, type 2 diabetes, hyperinsulinemia and dyslipidemia or skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, , Central nervous system cancer, liver cancer, and prostate cancer.

The composition of the present invention may be formulated into various forms such as powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups, aerosols, and injections of sterilized injection solutions according to conventional methods And can be administered via various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil,

Esters and the like can be used. The supplements of suppositories are etwesol, macrogol, tween 61. Cacao butter, laurin, glycerogelatin and the like can be used. On the other hand, injecting agents may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives and the like.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount " of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, The type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of release, the duration of the treatment, the factors including the drugs used concurrently or concurrently and other factors well known in the medical arts . The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex and body weight of the patient, and is generally 1 to 10 mg, preferably 1 to 5 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

The present invention also relates to a method of preventing or treating an androgen receptor-related disease in a subject, comprising administering the 1,2-diphenylethane derivative compound represented by the above-mentioned formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. Provides a method of treatment.

The term "individual" of the present invention means a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit or a guinea pig, , And the pharmaceutical composition of the present invention can be administered to an individual to effectively prevent or treat the disease. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

The term "administering" of the present invention means providing the patient with the desired substance in any suitable manner, and the administration route of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The term "therapeutically effective amount " used in combination with the active ingredient in the present invention means the amount of the 1,2-diphenylethane derivative compound, or a pharmaceutically acceptable salt thereof, effective in preventing or treating the subject disease.

The pharmaceutical composition of the present invention can be used for preventing or treating any known disease other than the 1,2-diphenylethane derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient, depending on the kind of disease to be prevented or treated And may further comprise known drugs used. For example, when it is used for the prophylactic or therapeutic treatment of cancer, it is possible to further include a known anticancer agent in addition to the 1,2-diphenylethane derivative compound or its pharmaceutically acceptable salt as an active ingredient, Can be used in combination with other treatments known to those skilled in the art. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.

Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphate, Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin cisplatin and carboplatin; The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, And iridotecan, but are not limited thereto.

In another aspect, the present invention provides a food composition for preventing or ameliorating an androgen receptor-related disease comprising the 1,2-diphenylethane derivative compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient do.

The composition may contain, in addition to the active ingredient, a pharmaceutically acceptable food-aid additive.

The term "food-aid additive " as used in the present invention means a component which can be added to foods in a supplementary manner, and it can be appropriately selected and used by those skilled in the art as added to produce health functional foods of each formulation. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated drink. However, the types of the food auxiliary additives of the present invention are not limited by these examples.

A health functional food may be included in the food composition of the present invention. The term "health functional food " as used in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, 'functional' refers to the structure and function of the human body to obtain nutritional effects and obtain useful effects for health use such as physiological action. The health functional food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients that are conventionally added in the art. In addition, the formulations of the above health functional foods may also be manufactured without limitations as long as they are acceptable as health functional foods. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Can be ingested as an adjuvant to promote the effects of anticancer drugs or metabolic disease drugs.

The novel 1,2-diphenylethane derivatives of the present invention can effectively inhibit the activity of the androgen receptor, and thus can prevent diseases caused by over-expression of androgen receptor such as baldness, hirsutism, behavioral disorders, acne and spermatogenesis May be used for the prevention or treatment of the required hypertrophic spermatogenesis, Becker's rebound, polycystic ovary syndrome, cardiac hypertrophy, coronary heart disease, coronary artery disease, cancer disease and metabolic disease.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example  1: 1,2- Diphenylethane  Synthesis of derivative compounds

1.1. 5-hydroxy-2- (2- Nitrophenyl ) -3- Of phenylpentanenitrile  synthesis

(E) - cinnamaldehyde ((E) -cinnamaldehyde; 33 mg , 0.25 mmol) diphenyl program Raleigh play TMS ether (diphenylprolinol TMS ether) catalyst was added (8 mg, 0.025 mmol), and methanol (0.8 ml) in a After the addition, 4-nitrobenzoic acid (4 mg, 0.025 mmol) was added dropwise. Subsequently, 2- (2-nitrophenyl) acetonitrile (49 mg, 0.30 mmol) was added and stirred for 24 hours, followed by silica gel chromatography with 30% ethyl acetate / hexanes to obtain the main product , Which was dissolved in ethanol (1 ml) and sodium borohydride (1.0 mmol) was added at 0 ° C. The mixture was stirred for 30 minutes and then water was added to terminate the reaction. The desired compound was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by 40% ethyl acetate / hexane silica gel column chromatography Purification yielded compound 1 (80% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.07 (d, J = 8.4 Hz, 2H), 7.38-7.55 (m, 2H), 7.00-7.31 (m, 5H), 5.22 (d, J = 5.6 Hz 1H), 3.82 (ddd, J = 2.8, 6.0, 8.8 Hz, 1H), 3.78-3.83 (m, 2H), 2.22-2.30 (m, 2H).

1.2. methyl  2- (1- Cyano -4-hydroxy-2- Phenylbutyl ) Benzoate (Compound 2)

Compound 2 was obtained in the same manner as in 1.1. (Yield 56%), except that methyl 2- (cyanomethyl) benzoate was used instead of 2- (2-nitrophenyl) acetonitrile as a reactant.

^{1 H NMR (400 MHz, CDCl} 3): δ 7.05-7.61 (m, 9H), 5.60 (d, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.74-3.87 (m, 3H), 2.24 -2.32 (m, 2 H).

1.3. 4- (1- Cyano -4-hydroxy-2- Phenylbutyl ) Benzonitrile (Compound 3)

Compound 3 was obtained in the same manner as in 1.1. (Yield 67%), except that 4- (cyanomethyl) benzonitrile was used instead of 2- (2-nitrophenyl) acetonitrile as a reactant.

^{1 H NMR (400 MHz, CDCl} 3): δ 7.56 (d, J = 8.4 Hz, 2H), 6.93-7.29 (m, 7H), 5.22 (d, J = 5.6 Hz, 1H), 3.65-3.63 (m , 2H), 3.30-3.37 (m, 2H), 2.30-2.37 (m, 2H).

1.4. 2- (1- Cyano -4-hydroxy-2- Phenylbutyl ) Benzonitrile (Compound 4)

Compound 4 was obtained in the same manner as in 1.1. (Yield 85%), except that 2- (cyanomethyl) benzonitrile was used instead of 2- (2-nitrophenyl) acetonitrile as a reactant.

^{1 H NMR (400 MHz, CDCl} 3): δ 7.06-7.44 (m, 9H), 4.71 (d, J = 8.0 Hz, 1H), 3.65-3.83 (m, 3H), 2.25-2.33 (m, 2H) .

1.5. methyl  4- (1- Cyano -4-hydroxy-2- Phenylbutyl ) Benzoate (Compound 5)

Compound 5 was obtained in the same manner as in 1.1. (Yield 77%), except that methyl 4- (cyanomethyl) benzoate was used instead of 2- (2-nitrophenyl) acetonitrile as a reactant.

^{1 H NMR (400 MHz, CDCl} 3): δ 7.94 (d, J = 8.4 Hz, 2H), 6.97-7.29 (m, 5H), 6.98 (d, J = 7.2 Hz, 2H), 4.13-4.43 (m 2H), 3.97 (s, 3H), 3.72-3.81 (m, 2H), 2.22-2.30 (m, 2H).

1.6. (E) -1-ethyl-7- methyl  6- (4- Nitrophenyl ) -5- Phenyl -2- Heptenedioate (Compound 6)  synthesis

(E) - addition of cinnamaldehyde diphenyl program Raleigh play TMS ether catalyst (8 mg, 0.025 mmol) in (33 mg, 0.25 mmol) and was added to methanol (0.8 ml), 4- nitrobenzoic acid (4 mg, 0.025 mmol) was added dropwise. Subsequently, methyl 2- (4-nitrophenyl) acetate (56 mg, 0.30 mmol) was added and stirred for 48 hours, followed by silica gel chromatography with 30% ethyl acetate / hexanes to obtain the main product , Which was dissolved in dichloromethane (1 ml), and ethyl (triphenylphosphoranylidene) acetate (0.50 mmol) was added. The mixture was stirred for 3 minutes and then water was added to terminate the reaction. The objective compound was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by 20% ethyl acetate / hexane silica gel column chromatography Purification yielded compound 6 (yield 75%).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.25 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.29-7.38 (m, 6H), 5.77 (d, J = 15.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H) 3.78-4.01 (m, 2H), 3.52 (s, 3H), 2.48-2.78 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H).

1.7. (E) -7-benzyl 1-ethyl 6- (4- Nitrophenyl ) -5- Phenyl -2- Heptenedioate (Compound 7)  synthesis

Compound 7 was obtained (yield 40%) in the same manner as in 1.6 above, except that benzyl 2- (4-nitrophenyl) acetate was used instead of methyl 2- (4-nitrophenyl) acetate as a reactant.

^{1 H NMR (400 MHz, CDCl} 3): δ 8.22 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.21-7.58 (m, 11H), 5.74 (d, J J = 7.6 Hz, 2H), 3.72-3.98 (m, 2H), 2.39-2.76 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H).

1.8. (E) -1-ethyl-7- methyl  6- (4- Nitrophenyl ) -5- p - Tolyl -2- Heptenedioate (compound Synthesis of water 8)

A reactant (E) -. Cinnamaldehyde and the place of compound 8 in the same manner as in 1.6 but using (E) -3-p- tolyl-art reel aldehyde was obtained in (82% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.12-7.34 (m, 5H), 5.78 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H) 3.76-4.02 (m, 2H), 3.50 (s, 3H), 2.48-2.78 (m, 2H), 2.35 (s, 3H), 1.24 (t, J = 7.2 Hz, 3 H).

1.9. (E) -1-ethyl-7- methyl  5- (4- Chlorophenyl ) -6- (4- Nitrophenyl )-2- Heptendioate ( Compound 9)  synthesis

A reactant (E) - instead of cinnamaldehyde (E) -3- (4- chlorophenyl), except for using the acrylic aldehyde to give a compound 9 in the same manner as 1.6 (89% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.24 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.19-7.32 (m, 5H), 5.78 (d, J = 15.6 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H) 3.75-4.00 (m, 2H), 3.53 (s, 3H), 2.52-2.66 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).

1.10. (E) -1-ethyl-7- methyl  5- (2,3- Dichlorophenyl ) -6- (4- Nitrophenyl )-2- Heptende Oeight Compound 10)  synthesis

A reactant (E) - instead of cinnamaldehyde (E) -3- (3,4- dichlorophenyl), except for using the acrylic aldehyde to give the compound 10 in the same manner as the 1.6 (yield: 87%. ).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.04 (d, J = 8.8 Hz, 2H), 7.18-7.45 (m, 6H), 5.74 (d, J = 15.2 Hz, 1H), 4.24 (q, J = 7.6 Hz, 2H) 3.75-4.00 (m, 2H), 3.50 (s, 3H), 2.50-2.65 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H).

1.11. (E) -1-ethyl-7- methyl  5- (4- Bromophenyl ) -6- (4- Nitrophenyl )-2- Heptenedio It Compound 11)  synthesis

A reactant (E) - (E) instead of cinnamaldehyde-3- (4-bromophenyl), except for using the acrylic aldehyde to give the compound 11 in the same manner as 1.6 (68% yield). .

^{1 H NMR (400 MHz, CDCl} 3): δ 8.24 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.17-7.30 (m, 5H), 5.75 (d, J = 15.2 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H) 3.74-4.05 (m, 2H), 3.51 (s, 3H), 2.52-2.69 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H).

1.12. (E) -1-ethyl-7- methyl  5- (4- Fluorophenyl ) -6- (4- Nitrophenyl )-2- Heptendio Eight Compound 12)  synthesis

A reactant (E) -, except instead of cinnamaldehyde (E) -3- (4-fluorophenyl) the use of an acrylic aldehyde to give a compound 12 in the same manner as the 1.6 (yield 52%). .

^{1 H NMR (400 MHz, CDCl} 3): δ 8.24 (d, J = 8.4 Hz, 2H), 6.94-7.28 (m, 7H), 5.80 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H) 3.68-3.98 (m, 2H), 3.47 (s, 3H), 2.52-2.69 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).

1.13. (E) -1-ethyl-7- methyl  5- (3- Methoxyphenyl ) -6- (4- Nitrophenyl )-2- Heptenedio It Compound 13)  synthesis

A reactant (E) - except the use of (E) -3- (3- methoxyphenyl) instead of cinnamaldehyde acrylic aldehyde to give the compound 13 in the same manner as the 1.6 (yield 76%). .

^{1 H NMR (400 MHz, CDCl} 3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.25 (s, 1H), 6.78-7.20 (m, 4H 2H), 5.74 (d, J = 14.8 Hz, 1H), 4.23 (q, J = 7.6 Hz, 2H) 1.24 (t, J = 7.6 Hz, 3 H).

1.14. (E) -1-ethyl-7- methyl  5- (3,4- Dimethoxyphenyl ) -6- (4- Nitrophenyl )-2- Heptenedioate (Compound 14)  synthesis

. A reactant (E) - and is the compound 14 in the same manner as above except 1.6 instead of cinnamaldehyde (E) -3- (3,4- dimethoxyphenyl) in the use of an acrylic aldehyde was obtained (yield: 79 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 6.77-7.22 (m, 2H), 6.45-7.54 (m 2H), 5.78 (d, J = 15.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H) ), 1.23 (t, J = 7.2 Hz, 3 H).

1.15. (E) -1-ethyl-7- methyl  5- (2- Nitrophenyl ) -6- (4- Nitrophenyl )-2- Heptenedio It Compound 15)  synthesis

A reactant (E) - (E) instead of cinnamaldehyde-3- (2-nitrophenyl), except for using the acrylic aldehyde to give a compound 15 in the same manner as 1.6 (79% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.03 (d, J = 8.8 Hz, 2H), 7.19-7.6 (m, 7H), 5.73 (d, J = 15.6 Hz, 1H), 4.22 (q, J = 7.6 Hz, 2H) 3.68-4.05 (m, 2H), 3.54 (s, 3H), 2.52-2.72 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H).

1.16. (E) -1-ethyl-7- methyl  5,6- Bis (4- Nitrophenyl )-2- Heptenedioate (Compound 16)  synthesis

A reactant (E) - instead of cinnamaldehyde (E) -3- (4- nitrophenyl), except for using the acrylic aldehyde to give the compound 16 in the same manner as 1.6 (89% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ 8.22 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.14-7.32 (m, 4H), 5.76 (d, J (M, 2H), 1.24 (t, J = 7.2 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H) Hz, 3H).

1.17. (E) -1-ethyl-7- methyl  5- (2- Furanyl ) -6- (4- Nitrophenyl ) -2-heptenedioate (Compound 17)

A reactant (E) - (E) instead of cinnamaldehyde-3- (furan-2-yl), except for using the acrylic aldehyde to give the compound 17 in the same manner as 1.6 (85% yield). .

^{1 H NMR (400 MHz, CDCl} 3): δ 8.08 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.14-7.30 (m, 2H), 5.75-6.08 (m , 3H), 4.25 (q, J = 7.2 Hz, 2H) 3.72-4.07 (m, 2H), 3.54 (s, 3H), 2.52-2.68 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H ).

Example  2: 1,2- Diphenylethane  Androgen receptor inhibitory activity of derivative compounds

Reporter analysis was carried out to confirm the effect of the 1,2-diphe- teethane derivative of the present invention prepared in Example 1 on androgen receptor modulation. For this purpose, cells prepared by infecting the androgen receptor luciferase reporter vector with LNCap cells, a prostate cancer cell, and a lentivirus system were used. The cells were cultured for 1 day at a density of 1 × 10 ⁴ cells per well of a 96-well plate, and the 17 compounds shown in the following Tables 1-1 and 1-2 were cultured in a concentration of 10 μM for 24 hours And a reporter activity assay was performed. Cells of each well were lysed using RIPA buffer, and the luciferase activity of the cell lysate was measured and shown in Tables 1-1 and 1-2. Activity (%) recorded relative activity values. Three independent reporter analyzes yielded the mean ± SD.

[Table 1-1]

[Table 1-2]

As a result, as shown in Tables 1-1 to 1-2, it was confirmed that all 17 compounds inhibited the androgenic activity. In particular, the compounds except Compound 4 had a luciferase activity lower than 70% , And further, the compounds 6 to 17 were lowered to less than 30%. Overall, these results indicate that the 17 novel compounds according to the present invention can inhibit the activity of the androgen receptor in LNCap cells, which are prostate cancer cells, and thus can be used for the treatment of diseases that can be induced by over- or over- Prevention or treatment of the disease.

Claims (13)

A 1,2-diphenylethane derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
R ₁ is a C1 to C4 hydroxy alkyl _{(- (CH 2) n1 -1} CH 2 OH) , or C1 to C4 alkanoyloxy alkyl _{(- (CH 2) n2 COO} (CH 2) n3-1 CH 3);
R ₂ is C1 to C4 alkanoyl _{(-COO (CH 2) n 4-1} CH 3), cyano (-CN) or

;
R ₃ is nitro (-NO ₂ ), C 1 to C 4 alkanoyl (-COO (CH ₂ ) _n5-1 CH ₃ ) or cyano (-CN);
A is an aromatic ring containing a hetero atom or

;
R ₄ to R ₈ in A each independently represent a hydrogen atom (-H), a halogen atom (-X, X = F, Cl, Br, I), nitro (-NO ₂ ), C 1 to C 4 alkoxy _{(CH 2) n6-1 CH 3)} , C1 to C4 alkyl _{(- (CH 2) n7-1 CH} 3) , and;
N ₁ to n ₇ are each independently an integer of 1 to 4;
The method according to claim 1,
When A

when,
R ₄ and R ₈ are each independently a hydrogen atom (-H), a halogen atom (-X, X = F, Cl, Br, I), nitro (-NO ₂ ); R ₅ and R ₇ are each independently a hydrogen atom (-H), a C 1 to C 4 alkoxy (-O (CH ₂ ) _{n 6'-1} CH ₃ ), a chlorine atom (-Cl); R ₆ represents a hydrogen atom (-H), a C1 to C4 alkyl (- (CH ₂ ) _{n7 ' - 1} CH ₃ ), a halogen atom (-X, X = F, Cl, Br, I) _{-O (CH 2) n6 ''} - 1 CH 3), nitro (-NO _2), and the n _{6 ',} n _6''7 and _n' is an integer of 1 to 4 compounds, each independently.
3. The method of claim 2,
R ₁ is hydroxymethyl or ethanoyloxyethyl (- (CH ₂ ) ₂ COOCH ₂ CH ₃ );
R ₂ is selected from the group consisting of methanoyl (-COOCH ₃ ), cyano (-CN)

;
R ₃ is nitro (-NO ₂ ), methanoyl (-COOCH ₃ ) or cyano (-CN);
A is furanyl or

;
In the above A, R ₄ and R ₈ are each independently a hydrogen atom (-H), a chlorine atom (-Cl), nitro (-NO ₂ ); R ₅ and R ₇ each independently represent a hydrogen atom (-H), methoxy (-OCH ₃ ), chlorine atom (-Cl); R ₆ is a hydrogen atom (-H), methyl (-CH _3), halogen atoms (-X, X = F, Cl , Br, I), methoxy (-CH _3), nitro (-NO ₂₎ .
The method of claim 3,
Wherein R < ₃ > is ortho or para to the backbone skeleton.
5. The method of claim 4,
1) 5-hydroxy-2- (2-nitrophenyl) -3-phenylpentanenitrile,
2) methyl 2- (1-cyano-4-hydroxy-2-phenylbutyl) benzoate,
3) 4- (1-Cyano-4-hydroxy-2-phenylbutyl) benzonitrile,
4) 2- (1-Cyano-4-hydroxy-2-phenylbutyl) benzonitrile,
5) methyl 4- (1-cyano-4-hydroxy-2-phenylbutyl) benzoate,
6) (E) -1-Ethyl 7-methyl 6- (4-nitrophenyl) -5-phenyl-2-heptenedioate,
7) (E) -7-benzyl 1-ethyl 6- (4-nitrophenyl) -5-phenyl-2-heptenedioate,
8) (E) -1-ethyl 7-methyl 6- (4-nitrophenyl) -5- p -tolyl-2-heptenedioate,
9) (E) -1-Ethyl 7-methyl 5- (4-chlorophenyl) -6- (4-nitrophenyl) -2-
10) (E) -1-Ethyl 7-methyl 5- (2,3-dichlorophenyl) -6- (4-nitrophenyl)
11) (E) -1-Ethyl 7-methyl 5- (4-bromophenyl) -6- (4-nitrophenyl)
12) (E) -1-Ethyl 7-methyl 5- (4-fluorophenyl) -6- (4-nitrophenyl)
13) (E) -1-Ethyl 7-methyl 5- (3-methoxyphenyl) -6- (4-nitrophenyl)
14) (E) -1-Ethyl 7-methyl 5- (3,4-dimethoxyphenyl) -6- (4-nitrophenyl)
15) (E) -1-Ethyl 7-methyl 5- (2-nitrophenyl) -6- (4-nitrophenyl) -2-
16) (E) -1-ethyl 7-methyl 5,6-bis (4-nitrophenyl) -2-heptenedioate, and
17) (E) -1-ethyl 7-methyl 5- (2-furanyl) -6- (4-nitrophenyl) -2-heptenedioate.
A process for producing a compound represented by formula (1) according to any one of claims 1 to 5, comprising reacting an electron-withdrawing group-substituted benzyl compound with an aryl-substituted unsaturated hydrocarbon compound under basic conditions.
The method according to claim 6,
Wherein the electron withdrawing group is an acyl group or a cyano group.
The method according to claim 6,
Wherein the enolate is formed as an intermediate.
A pharmaceutical composition comprising a 1,2-diphenylethane derivative represented by the general formula (1) as set forth in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof as an active ingredient, and androgen receptor A pharmaceutical composition for preventing or treating a receptor-related disease.
10. The method of claim 9,
Wherein said androgen receptor-related disease is a disease caused by over-expression or hyperactivity of the androgen receptor.
11. The method of claim 10,
The androgen receptor-related diseases are selected from the group consisting of hypertrophic dysplasia, Becker's disease, polycystic ovary syndrome, cardiac hypertrophy, coronary heart disease, and coronary artery disease requiring baldness, hirsutism, behavioral disorders, acne and spermatogenesis inhibition / RTI >
11. The method of claim 10,
Wherein said androgen receptor-related disease is a metabolic disease selected from the group consisting of obesity, osteoarthritis, type 2 diabetes, hyperinsulinemia and dyslipidemia.
11. The method of claim 10,
The androgen receptor-related diseases are selected from the group consisting of skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer ≪ / RTI >