WO2013128927A1 - Novel androgen receptor antagonist - Google Patents

Description

Novel androgen receptor antagonist

The present invention relates to an androgen receptor antagonist having a novel structure useful for prostate cancer treatment and the like.

Androgen receptor (AR), together with estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), is a steroid / thyroid hormone nuclear receptor. Belongs to the superfamily. AR is a receptor that is expressed in numerous tissues in the body, thereby expressing the physiological and pathophysiological effects of endogenous androgen ligands such as testosterone (T) and dihydrotestosterone (DHT).
Compounds that bind to AR and mimic the action of endogenous AR ligands are called AR agonists, and compounds that inhibit the action of endogenous AR ligands are called AR antagonists, collectively referred to as AR modulators. be called.
AR modulators play an important role in both male and female health. AR antagonists are useful, for example, for the treatment of prostate enlargement and prostate cancer. Androgen receptor agonists are useful for the treatment of hypogonadism and muscle wasting disease.
Conventionally known AR antagonists include not only those used clinically but also those described in the literature, for example, the following.
Flutamide, bicalutamide, phthalimide derivative, androstane derivative (Patent Document 1), quinoline derivative (Patent Documents 2, 3, 4), imidazolidine derivative (Patent Document 5),

The compound represented by (Patent Document 6),

(Patent Document 7), curcumin derivatives (Patent Document 7, Non-Patent Documents 1 and 2), carbonylbenzimidazole derivatives (Patent Document 8), urea and thiourea derivatives (Patent Document 9), benzyl Sulfonamide derivative (Patent Document 10),

(Patent Document 11), Hydantoin Derivatives (Patent Documents 12 and 13), Sulfamatobenzothiophene Derivatives (Patent Document 14), Albiflorin and Paeoniflorin Derivatives (Patent Document 15),

And a compound represented by (Patent Document 16).
Currently, most androgen receptor (AR) antagonists used clinically (mainly for prostate cancer treatment) are compounds having a nitrophenyl group or a cyanophenyl group, such as flutamide and bicalutamide. However, these AR antagonists are often reported to lose their medicinal effects due to mutations in AR in prostate cancer cells. Therefore, the creation of AR antagonists with new structural elements is important in prostate cancer treatment.

Table 2001-14406 No. 2002-22585 gazette Japanese translation of PCT publication No. 2003-508397 JP-T-2004-524317 Table 2004-111012 JP 2005-519111 Gazette JP 2005-534626 Gazette JP-T-2006-513159 JP 2006-517578 A Special table 2007-501853 gazette Special table 2008-501800 Special table 2008-540523 Special table 2009-531439 gazette JP 2010-511640 A JP 2002-298766 A JP 2011-57474 A

J. Med. Chem. 2002, 45, 5037-5042 J. Med. Chem. 2009, 52, 5546-5550

An object of the present invention is to provide a novel AR antagonist useful for prostate cancer treatment and the like.

As a result of intensive studies to solve the above problems, the present inventors have found that the compound represented by formula (I) has an effect as an AR antagonist useful for prostate cancer treatment and the like, and to complete the present invention. It came.

That is, the present invention provides (1) Formula (I)

[Where:
X is -X ₁ -CONH-X _2- ,
-X ₁ -NHCO-X _2- ,
—SO ₂ NH— or —NHSO ₂ —
(Wherein X ₁ and X ₂ each independently represents a single bond, a divalent alkylene group having 1 to 4 carbon atoms, a divalent alkenylene group having 2 to 4 carbon atoms, or —NH—, provided that -NH- represents only when bonded to -CO-)
Y represents —O— or —CO—.
A ₁ to A ₄ are each independently
-C (R ³ ) = or -N =
(Wherein R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms),
R ¹ and R ² are each independently
-OR ⁴ (wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms),
- in the alkyl radical -N ^(R _{5) 2} (Equation 1 to 6 carbon atoms, the two ^{R 5,} each independently, .2 one ^{R 5} represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms Together, they may form a nitrogen-containing heterocycle having 3 to 6 members),
A halogen atom,
-NO ₂ ,
—CN 2 or —COOR ⁶ (wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).
m and n each independently represents an integer of 0 to 3.
When m is 2 or more, R ¹ may be the same as or different from each other, and when n is 2 or more, R ² may be the same as or different from each other.
When R ¹ and R ² are each 2 or more, R ¹ and R ² may be combined to form a condensed ring having 3 to 6 carbon atoms. An androgen receptor antagonist comprising as an active ingredient a compound represented by the formula:
(2) The compound represented by the formula (I) is represented by the formula (II)

(Wherein A ₁ to A ₄ and R ⁴ are the same as defined in the above formula (I)).
R ⁷ represents —OR ⁴ or —N (R ⁵ ) ₂ , and R ⁴ and R ⁵ are the same as defined in the above formula (I).
m1 and n1 each independently represents an integer of 0 to 2)
Androgen receptor antagonist according to the above (1), which is a compound represented by:
(3) The compound represented by the formula (II) is represented by the formula (III)

(Wherein R ⁴ , R ⁷ , m1 and n1 are the same as defined in the above formula (II).
R ⁸ represents an alkyl group having 1 to 3 carbon atoms, and p represents an integer of 0 to 2, and the androgen receptor antagonist according to (2) above.
The present invention also provides:
(4) A pharmaceutical preparation containing the androgen receptor antagonist according to any one of (1) to (3) above, and (5) an androgen receptor antagonist according to any one of (1) to (3) above. The present invention relates to an agent for treating prostate cancer.
Furthermore, the present invention provides
(6) Formula (IV)

[Wherein, A ₁ to A ₄ , R ⁴ and R ⁷ are the same as defined in the above formula (II). m2 and n2 each independently represents an integer of 0 to 2.
However, when A ₁ to A ₄ are all —C (R ³ ) = (wherein R ³ is the same as defined in formula (I)), m 2 and n 2 each independently represent 1 or 2 ] It is related with the compound represented by this.

The compounds of the present invention act as AR antagonists, but in particular the compounds of formula (III), especially the compounds of formulas (III-1) to (III-3), proliferate in an androgen-dependent manner. It significantly suppresses DHT (dihydrotestosterone, an endogenous agonist of AR) -dependent cell growth of SC-3 cells, and further suppresses DHT-dependent cell growth of human prostate cancer-derived cell line LNCaP. Therefore, it is useful as a therapeutic agent for diseases such as prostate cancer, prostatic hypertrophy, androgenetic alopecia, premature sexual maturity, acne vulgaris and seborrhea, especially for prostate cancer.

It is a graph which shows the growth inhibitory activity of this invention compound with respect to the proliferation of the LNCaP cell induced | guided | derived by dihydrotestosterone.

The novel AR antagonist of the present invention is a group of compounds having a structure represented by the following formula (I) and pharmaceutically acceptable salts thereof.

Where
X is
-X ₁ -CONH-X _2- ,
-X ₁ -NHCO-X _2- ,
—SO ₂ NH— or —NHSO ₂ — is represented.
Here, X ₁ and X ₂ each independently represent a single bond, a divalent alkylene group having 1 to 4 carbon atoms, a divalent alkenylene group having 2 to 4 carbon atoms, or —NH—. However, —NH— is limited to the case where it is bonded to —CO—.
Y represents —O— or —CO—.
A ₁ to A ₄ are each independently
-C (R ³ ) = or -N =
Represents.
Here, R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
R ¹ and R ² are each independently
-OR ⁴ (wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms),
- in the alkyl radical -N ^(R _{5) 2} (Equation 1 to 6 carbon atoms, the two ^{R 5,} each independently, .2 one ^{R 5} represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms Together, they may form a nitrogen-containing heterocycle having 3 to 6 members),
A halogen atom,
-NO ₂ ,
—CN 2 or —COOR ⁶ (wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).
m and n each independently represents an integer of 0 to 3.
When m is 2 or more, R ¹ may be the same as or different from each other, and when n is 2 or more, R ² may be the same as or different from each other.
When R ¹ and R ² are each 2 or more, R ¹ and R ² may be combined to form a condensed ring having 3 to 6 carbon atoms.
In the formula (I) of the present invention, the “alkyl group having 1 to 6 carbon atoms” includes a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i- Examples thereof include a butyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group. Examples of the “alkyl group having 1 to 3 carbon atoms” include those similar to those having 1 to 3 carbon atoms in the above examples.
In the formula (I) of the present invention, the “divalent alkylene group having 1 to 4 carbon atoms” includes a methylene chain, an ethylene chain, a propylene chain, a methylethylene chain, a butylene chain, a 1,2-dimethylethylene chain and the like. Can be mentioned.
In the formula (I) of the present invention, examples of the “divalent alkenylene group having 2 to 4 carbon atoms” include vinylene group, propenylene group, butenylene group and the like. The configuration of the alkenylene group may be either cis or trans.
In the formula (I) of the present invention, “halogen atom” represents iodine, bromine, chlorine, fluorine or the like.

“Pharmaceutically acceptable salt” means either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt, depending on the structure of the compound represented by formula (I). means.
“Pharmaceutically acceptable acid addition salt” means an organic or inorganic acid addition salt of a compound of formula (I).
Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sodium orthohydrogen phosphate, potassium hydrogen sulfate, and the like.
Organic acids include mono, di, and tricarboxylic acids. For example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenyl Examples include acetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid and the like.
“Pharmaceutically acceptable base addition salt” means an organic or inorganic base addition salt of a compound of formula (I).
Examples of the inorganic base include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium, calcium, magnesium or barium; ammonia and the like.
Organic bases include aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
The compounds of the present invention also include stereoisomers; solvates with pharmaceutically acceptable solvents such as water, ethanol and the like; prodrugs and the like.
The said compound can be used individually by 1 type or in mixture of 2 or more types.

Hereinafter, the compounds of the present invention are exemplified, but the compounds of the present invention are not limited thereto.

Among the compounds represented by the formula (I) of the present invention, the formula (II)

Are preferably represented by the group of compounds represented by formula (III)

The compound group represented by these is more preferable.
In the above formula (II) and formula (III), A ₁ to A ₄ and R ⁴ are the same as defined in formula (I).
R ⁷ represents —OR ⁴ or —N (R ⁵ ) ₂ , and R ⁴ and R ⁵ are the same as defined in formula (I).
R ⁸ represents an alkyl group having 1 to 3 carbon atoms.
m1, n1 and p each independently represents an integer of 0 to 2.
Here, examples of the alkyl group having 1 to 6 carbon atoms and the alkyl group having 1 to 3 carbon atoms are the same as defined in the above formula (I).
Of the compounds represented by the formula (III), the following compounds (III-1) to (III-3) are particularly preferred.

In the present invention, at least the compound represented by the following formula (IV) is a novel compound.

In the formula, A ₁ to A ₄ , R ⁴ and R ⁷ are the same as defined in the above formula (II). m2 and n2 each independently represents an integer of 0 to 2.
However, when A ₁ to A ₄ are all —C (R ³ ) = (wherein R ³ is the same as defined in formula (I)), m 2 and n 2 each independently represent 1 or 2 .

(Production method)
The compound of this invention can be manufactured by a conventionally well-known method besides what is marketed.
When X in the formula (I) is —X ₁ —CONH—, —SO ₂ NH— or —X ₁ —NHCONH— and Y is —O—, for example, it can be produced by the following method.

In the above reaction formula, A ₁ to A ₄ , R ¹ , R ² , m and n are the same as defined in formula (I). Xa represents —X ₁ —CONH—, —SO ₂ NH— or —X ₁ —NHCONH— (wherein X ₁ is as defined in formula (I)), W represents a leaving group such as a halogen atom, Z represents -X ₁ -COW, -SO ₂ W, -X ₁ -NHCOW (wherein W represents a leaving group such as a halogen atom) or -X ₁ -NCO.

Step 1 In this step, the nitrobenzene derivative (a) and the phenol derivative (b) are reacted in a solvent in the presence of a base to obtain an ether compound (c).
The solvent is not particularly limited, and for example, tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. The base is not particularly limited. For example, lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium, metal potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, Potassium carbonate, cesium carbonate, 1,4-diazabicyclo [2.2.2] octene (DABCO), lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium Hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium and the like can be used. The reaction conditions vary depending on the raw materials used, but the desired product is generally obtained by reacting at 0 to 50 ° C. for 1 to 20 hours.

Second Step By reducing the ether compound (c) obtained in the first step in a solvent, the nitro group is changed to an amino group to produce an amine compound (d). This reduction method is performed by a catalytic hydrogenation reaction in which a nitro group is reduced using a hydrogen source and a catalyst in a suitable solvent. Examples of the solvent include methanol, ethanol, isopropanol, n-hexane, cyclohexane, dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, ethyl acetate, methyl acetate, N, N-dimethylformamide, water, acetic acid and the like alone or in combination. Can be used. As the hydrogen source, hydrogen, formic acid, ammonium formate, cyclohexadiene, or the like can be used. As the catalyst, for example, palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination. The hydrogen pressure in the catalytic hydrogenation reaction is usually normal pressure. The reaction conditions in the catalytic hydrogenation reaction are usually 30 to 24 hours at 0 to 50 ° C. In addition, this reaction may use metal reduction in which a nitro group is reduced using a mixture of a metal such as iron, zinc or tin and hydrochloric acid or sulfuric acid as a reducing agent in a suitable inert solvent.

Third Step The amine compound (d) obtained in the second step and the compound (e) are reacted in a solvent in the presence or absence of a base to obtain the target compound (f). Here, in the compound (e), when Z is —X ₁ —COW, —SO ₂ W, —X ₁ —NHCOW (wherein W represents a leaving group such as a halogen atom) or —X ₁ —NCO Any compound.
The solvent is not particularly limited, and for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile and the like can be used. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, Sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be used. The reaction temperature is −20 to 80 ° C., and the reaction time is 30 minutes to 48 hours.

Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers. For example, a racemic mixture is optically resolved by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. To the pure isomer. Further, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

(Androgen receptor antagonist)
The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is an androgen receptor antagonist.
As used herein, “androgen” means a sex hormone, a compound known to act by a mechanism similar to androgens, such as testosterone, dihydrotestosterone, and androstenedione, and androgen receptor agonists. However, it is not limited to these.
As used herein, “androgen receptor antagonist” means a compound that partially or completely suppresses the activity of an androgen receptor agonist.
A compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat or alleviate symptoms associated with inappropriate activation of the androgen receptor. Such cases include, but are not limited to, diseases such as prostate cancer, benign prostatic hyperplasia, androgenetic alopecia, sexual prematurity, acne vulgaris, seborrhea, and hirsutism.

(Formulation)
The pharmaceutical composition of the present invention comprises an effective amount of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a prodrug or a solvate thereof, and a pharmaceutically acceptable carrier. If so, it may contain other androgen receptor antagonists.

The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable carrier, excipient, binder, diluent, stabilizer, lubricant, corrigent, Disintegrating agent, coating agent, coloring agent, antioxidant, buffering agent, aqueous solvent, oily solvent, tonicity agent, dispersing agent, preservative, solubilizing agent, fluidizing agent, soothing agent, pH adjusting agent, antiseptic It can be administered orally or parenterally as a pharmaceutical composition containing together with additional components such as agents and bases. Examples of the above-mentioned pharmaceutical composition include oral preparations such as granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions and suspensions, and parenteral preparations include, for example, subcutaneous. Injections, intravenous injections, intramuscular injections, intraperitoneal injections and the like; transdermal administration agents such as ointments, creams, and lotions; rectal suppositories, vaginal suppositories, etc .; Examples include nasal preparations. These preparations can be produced by known methods usually used in the preparation process.

Examples of the excipient used in the pharmaceutical composition of the present invention include saccharides such as lactose, sucrose, glucose, D-mannitol, and sorbit; celluloses such as crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; Derivatives; starch and derivatives thereof such as corn starch, potato starch, α-starch, dextrin, β-cyclodextrin, sodium carboxymethyl starch, hydroxypropyl starch; synthetic aluminum silicate, magnesium aluminate silicate, calcium silicate, silica Silicates such as magnesium phosphate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; tartaric acid, potassium hydrogen tartrate, Examples thereof include magnesium hydroxide.

Examples of binders include agar, stearyl alcohol, gelatin, tragacanth, polyvinyl alcohol, polyvinyl pyrrolidone; cellulose such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and derivatives thereof; corn starch, potato starch, α-starch , Dextrin, β-cyclodextrin, carboxymethyl starch sodium, hydroxypropyl starch and other derivatives thereof; and sugars such as lactose, sucrose, glucose, D-mannitol and sorbit.

Examples of the stabilizer include hydrogenated oil, sesame oil, sodium chondroitin sulfate, dibutylhydroxytoluene, adipic acid, ascorbic acid, L-ascorbic acid stearate, sodium L-ascorbate, L-aspartic acid, L-aspartic acid. Sodium, acetyltryptophan sodium, acetanilide, aprotinin solution, aminoethylsulfonic acid, aminoacetic acid, DL-alanine, L-alanine; paraoxybenzoates such as methylparaben, propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol, etc. Alcohols; benzalkonium chloride; phenols such as phenol and cresol; sorbic acid; sulfites such as sodium hydrogen sulfite and sodium sulfite; Sodium door acid, such as edetate salts such as tetrasodium edetate, and the like.

Examples of lubricants include gum arabic powder, cacao butter, carmellose calcium, carmellose sodium, caropeptide, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, glycerin, light liquid paraffin, crystalline cellulose, Hardened oil, synthetic aluminum silicate, sesame oil, wheat starch, talc, macrogols, phosphoric acid; stearic acids such as stearic acid, calcium stearate, magnesium stearate; waxes such as honey beeswax and carnauba wax; sulfuric acid such as sodium sulfate Salts; silicic acids such as magnesium silicate and light anhydrous silicic acid; and lauryl sulfates such as sodium lauryl sulfate.

Examples of the corrigent include, for example, ascorbic acid, L-aspartic acid, sodium L-aspartate, magnesium L-aspartate, aspartame, armature, armature extract, armature powder, aminoethylsulfonic acid, aminoacetic acid, DL-alanine, saccharin sodium Dl-menthol, l-menthols; sugars such as lactose, sucrose, glucose, D-mannitol and the like.

Examples of the disintegrant include agar, gelatin, tragacanth, adipic acid, alginic acid, sodium alginate; cellulose such as crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and derivatives thereof; calcium carbonate, sodium bicarbonate, magnesium carbonate, etc. Carbonates such as corn starch, potato starch, α-starch, dextrin, β-cyclodextrin, sodium carboxymethyl starch, hydroxypropyl starch, and derivatives thereof.

Examples of the coating agent include shellac, polyvinyl pyrrolidones, polyethylene glycol, macrogol, methacrylic acid copolymers, liquid paraffin, Eudragit; cellulose such as cellulose acetate, hydroxypropyl cellulose, cellulose acetate phthalate, and hydroxypropyl methylcellulose. Derivatives and the like.

Examples of the colorant include indigo carmine, caramel, riboflavin and the like.

Examples of the buffer include aminoacetic acid, L-arginine, benzoic acid, sodium benzoate, ammonium chloride, potassium chloride, sodium chloride, dried sodium sulfite, dried sodium carbonate, diluted hydrochloric acid, citric acid, calcium citrate, sodium citrate. , Disodium citrate, calcium gluconate, L-glutamic acid, sodium L-glutamate, creatinine, chlorobutanol, crystalline sodium dihydrogen phosphate, disodium succinate, acetic acid, potassium acetate, sodium acetate, tartaric acid, sodium bicarbonate, Sodium carbonate, triethanolamine, lactic acid, sodium lactate solution, glacial acetic acid, boric acid, maleic acid, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium acetate, anhydrous sodium carbonate, anhydrous sodium monohydrogen phosphate, none Trisodium phosphate, anhydrous sodium dihydrogen phosphate, dl-malic acid, phosphoric acid, trisodium phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diphosphate Examples thereof include sodium hydrogen monohydrate.

Examples of the aqueous solvent include distilled water, physiological saline, Ringer's solution, and the like.

Examples of the oily solvent include propylene glycol; vegetable oils such as olive oil, sesame oil, cottonseed oil, and corn oil.

Examples of the isotonic agent include potassium chloride, sodium chloride, glycerin, sodium bromide, D-sorbitol, nicotinamide, glucose, boric acid and the like.

Examples of the dispersant include gum arabic, propylene glycol alginate, sorbitan sesquioleate, D-sorbitol, tragacanth, methylcellulose, aluminum monostearate, aminoalkyl methacrylate copolymer RS, lactose, concentrated glycerin, propylene glycol, and macrogols. And sodium lauryl sulfate; stearic acid such as zinc stearate and magnesium stearate and salts thereof.

Examples of preservatives include benzalkonium chloride, benzethonium chloride, dry sodium sulfite, dry sodium sulfate, cresol, chlorocresol, dibutylhydroxytoluene, potassium sorbate, sodium dehydroacetate, phenol, formalin, phosphoric acid, anthracite, thimerosal And thymol; alcohols such as chlorobutanol, phenethyl alcohol, propylene glycol, and benzyl alcohol; and paraoxybenzoic acid esters such as isobutyl paraoxybenzoate, ethyl paraoxybenzoate, and methyl paraoxybenzoate.

Examples of solubilizers include sodium benzoate, ethylenediamine, citric acid, sodium citrate, glycerin, sodium acetate, sodium salicylate, sorbitan sesquioleate, nicotinamide, glucose, benzyl alcohol, polyvinylpyrrolidones, acetone, ethanol , Isopropanol, D-sorbitol, sodium hydrogen carbonate, sodium carbonate, lactose, urea, sucrose and the like.

Examples of the fluidizing agent include hydrous silicon dioxide, talc, anhydrous ethanol, crystalline cellulose, synthetic aluminum silicate, calcium hydrogen phosphate; stearic acid such as calcium stearate and magnesium stearate and salts thereof.

Examples of soothing agents include benzalkonium chloride, procaine hydrochloride, meprilucaine hydrochloride, lidocaine hydrochloride, lidocaine and the like.

Examples of the pH adjuster include hydrochloric acid, citric acid, succinic acid, acetic acid, boric acid, maleic acid, sodium hydroxide and the like.

Examples of the preservative include benzoic acid, sodium benzoate, cetylpyridinium chloride, salicylic acid, sodium salicylate, sorbic acid, potassium sorbate, thymol, methyl paraoxybenzoate, and butyl paraoxybenzoate.

Examples of bases include glycerin, stearyl alcohol, polyethylene glycols, propylene glycol, cetanol, lard, white petrolatum, paraffin, bentonite, lanolin fatty acid isopropyl, petrolatum, polysorbates, macrogols, lauryl alcohol, sodium lauryl sulfate. , Ethyl linoleate, sodium hydrogen phosphate, rosin; vegetable oils such as olive oil, sesame oil and wheat germ oil.

The dosage of the pharmaceutical composition of the present invention can vary widely depending on the type of subject to be administered (such as warm-blooded animals including humans), severity of symptoms, age, sex, administration method, doctor's diagnosis, etc. Although possible, for example, the dose of the compound represented by the formula (I) to an adult is about 0.1 to 500 mg / kg per day for both oral and parenteral administration. The above dose is a value per unit weight of the administration subject. In the present invention, depending on the severity of symptoms, judgment of a doctor, etc., the above dose may be administered once a day to 1 month, or divided into several times or more. May be.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited thereto.

(1) Synthesis Example [Synthesis Example 1]
N- {4- (4-hydroxyphenoxy) phenyl} -3-methoxybenzamide (Compound 6)

(Process 1)
Synthesis of 4- (4-nitrophenoxy) phenol Under argon atmosphere, 8.75 mL of 5 mol / L sodium hydroxide aqueous solution was added to 25 mL of dimethyl sulfoxide and stirred for 10 minutes. Then, 2.34 g of hydroquinone was added and stirred at 50 ° C. for 15 minutes. did. After adding 2.50 g of 4-fluoronitrobenzene to the reaction solution and further stirring at 50 ° C. for 5 hours, the reaction solution was put into ice water and the precipitate was removed by filtration. The filtered aqueous phase was acidified with 2 mol / L hydrochloric acid, and the precipitated white crystals were collected by filtration and dried. The crystals were washed with hexane and purified by silica gel column chromatography (elution solvent hexane: ethyl acetate = 5: 1) to give the title compound (2.25 g, yield 56%).
The NMR measurement values of the title compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ): d 8.18 (d, 2H, J = 9.2 Hz), 6.98 (d, 2H, J = 8.9 Hz), 6.97 (d, 2H, J = 9.2 Hz), 6.89 (d, 2H, J = 9.0 Hz), 4.94 (s, 1H).

(Process 2)
Synthesis of 4- (4-aminophenoxy) phenol 2.25 g of 4- (4-nitrophenoxy) phenol synthesized in Step 1 was dissolved in 100 mL of methanol, 228 mg of 5% palladium on carbon was added, and 2 at room temperature under a hydrogen atmosphere. Stir for hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent hexane: ethyl acetate = 3: 1) to obtain 1.82 g of the title compound in a yield of 92%.
The NMR measurement values of the title compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ): d 6.84 (d, 2H, J = 9.2 Hz), 6.82 (d, 2H, J = 9.2 Hz), 6.75 (d, 2H, J = 9.0 Hz), 6.65 (d, 2H, J = 8.8 Hz), 4.71 (br s, 1H), 3.54 (br s, 2H).

(Process 3)
Synthesis of N- {4- (4-hydroxyphenoxy) phenyl} -3-methoxybenzamide 100 mg of 4- (4-aminophenoxy) phenol synthesized in Step 2 was dissolved in 15 mL of tetrahydrofuran, and 261 mg of 3-methoxybenzoyl chloride was dissolved. In addition, the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with dichloromethane to obtain 142 mg of the title compound in a yield of 84%.
The NMR measurement values of the title compound are shown below.
¹ H-NMR (400 MHz, CDCl ₃ ): d 6.84 (d, 2H, J = 9.2 Hz), 6.82 (d, 2H, J = 9.2 Hz), 6.75 (d, 2H, J = 9.0 Hz), 6.65 (d, 2H, J = 8.8 Hz), 4.71 (br s, 1H), 3.54 (br s, 2H).

Hereinafter, the compounds of Synthesis Examples 2 to 6 were synthesized in the same manner as in Synthesis Example 1.
[Synthesis Example 2]
N- {4- (4-hydroxyphenoxy) phenyl} benzamide (Compound 5)

¹ H-NMR (400 MHz, CDCl ₃ ): d 7.87 (d, 2H, J = 7.0 Hz), 7.73 (br s, 1H), 7.58-7.54 (m, 1H), 7.56 (d, 2H, J = 9.0 Hz), 7.50 (t, 2H, J = 6.9 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.93 (d, 2H, J = 9.0 Hz), 6.81 (d, 2H, J = 9.0 Hz) ), 4.70 (s, 1H).

[Synthesis Example 3]
N- {4- (4-hydroxyphenoxy) -3-methylphenyl} -3-methoxybenzamide (Compound 7)

¹H-NMR (400 MHz, DMSO-d₆) ：d 10.12 (s, 1H), 9.19 (s, 1H), 7.67 (d, 1H, J = 2.2 Hz), 7.54-7.51 (m, 1H), 7.53 (d, 1H, J = 6.3 Hz), 7.44 (dd, 1H, J = 8.0, 7.8 Hz), 7.44 (dd, 1H, J = 2.4, 1.6 Hz), 7.15 (ddd, 1H, J = 8.2, 2.6, 0.9 Hz), 6.77 (d,2H, J = 7.4 Hz), 6.75 (d, 1H, J = 5.5 Hz), 6.72 (d, 2H, J = 7.5 Hz), 3.84 (s, 3H), 2.30, (s, 3H).

¹ H-NMR (400 MHz, DMSO-d ₆ ): d 10.12 (s, 1H), 9.19 (s, 1H), 7.67 (d, 1H, J = 2.2 Hz), 7.54-7.51 (m, 1H), 7.53 (d, 1H, J = 6.3 Hz), 7.44 (dd, 1H, J = 8.0, 7.8 Hz), 7.44 (dd, 1H, J = 2.4, 1.6 Hz), 7.15 (ddd, 1H, J = 8.2, 2.6, 0.9 Hz), 6.77 (d, 2H, J = 7.4 Hz), 6.75 (d, 1H, J = 5.5 Hz), 6.72 (d, 2H, J = 7.5 Hz), 3.84 (s, 3H), 2.30 , (s, 3H).

[Synthesis Example 4]
N- {4- (4-hydroxyphenoxy) -3,5-dimethylphenyl} -3-methoxybenzamide (Compound 8)

¹ H-NMR (400 MHz, Acetone-d ₆ ): d 9.36 (brs, 1H), 7.92 (br s, 1H), 7.62 (s, 2H), 7.57 (d, 1H, J = 7.6 Hz), 7.54 (dd, 1H, J = 2.4, 1.6 Hz), 7.42 (dd, 1H, J = 7.9,7.9 Hz), 7.13 (ddd, 1H, J = 8.2, 2.6, 0.9 Hz), 6.76 (d, 2H, J = 9.1 Hz), 6.61 (d, 2H, J = 9.0 Hz), 3.88 (s, 3H), 2.11 (s, 6H).

[Synthesis Example 5]
N- {6- (4-hydroxyphenoxy) pyridin-3-yl} -3-methoxybenzamide (Compound 9)

¹ H-NMR (400 MHz, DMSO-d ₆ ): d 10.32 (s, 1H), 9.33 (s, 1H), 8.46 (d, 2H, J = 2.4 Hz), 8.14 (dd, 1H, J = 8.9 , 2.7 Hz), 7.54 (ddd, 1H, J = 7.9, 1.2, 1.2 Hz), 7.49 (t, 1H, J = 2.4 Hz), 7.45 (t, 1H, J = 8.0 Hz), 6.94 (d, 1H , J = 9.3 Hz), 6.93 (d, 2H, J = 8.9 Hz), 6.78 (d, 2H, J = 8.9 Hz), 3.84 (s, 3H).

[Synthesis Example 6]
N- {2- (4-hydroxyphenoxy) pyrimidin-5-yl} -3-methoxybenzamide (Compound 10)

¹ H-NMR (400 MHz, Acetone-d ₆ ): d 9.75 (brs, 1H), 8.95 (s, 2H), 8.23 (s, 1H), 7.58 (ddd, 1H, J = 7.9, 1.5, 1.0 Hz ), 7.55 (dd, 1H, J = 2.4, 2.0 Hz), 7.44 (dd, 1H, J = 8.1, 8.0 Hz), 7.30 (d, 2H, J = 9.0 Hz), 7.17 (ddd, 1H, J = 8.2, 2.7, 1.9 Hz), 6.88 (d, 2H, J = 9.0 Hz), 3.87 (s, 3H).

(2) Test example [Test example 1]
≪Evaluation of binding to human AR≫
E. coli HB101 incorporating GST-ARLBD (androgen receptor ligand binding domain, 627-919 amino acids) is cultured in 1 L of LB medium, 1 mM of IPTG (isopropyl-β-thiogalactopyranoside) is added, and cultured at 27 ° C. for 5 hours. Induced protein expression. 40 mL each of the cells collected and freeze-stocked are suspended in 1 mL of disruption buffer (10 mM Tris-HCl (pH = 7.4), 1 mM EDTA, 10% glycerol, 10 mM sodium molybdate, 10 mM dithiothreitol). After sonication and centrifugation, the supernatant was diluted with an assay buffer (20 mM Tris-HCl (pH = 8.0), 0.3 M KCl, 1 mM EDTA). Trimethyl-labeled dihydrotestosterone (manufactured by Perkin Elmer) and a dimethyl sulfoxide solution of an evaluation compound ^{(Note 1)} were added to 300 μL of the adjusted protein solution. The final concentration of tritium-labeled dihydrotestosterone was 4 nM, and the final concentration of dimethyl sulfoxide was 2%. The mixture is incubated at 4 ° C. for 18 hours, and 30 μL of an activated carbon suspension (10% Norit-A, 0.5% dextran 70, 0.5% γ-globulin assay buffer suspension) is added to each sample. The plate was placed at 4 ° C. for 10 minutes and centrifuged at 3000 G for 10 minutes. 200 μL of the supernatant was mixed with a liquid scintillation cocktail, and the radioactivity was measured with a liquid scintillation counter. As a control, non-specific binding was measured by competing with 800 nM of unlabeled dihydrotestosterone instead of the evaluation compound.
(Note 1) Compounds 5 to 8 synthesized in Synthesis Examples 1 to 4 and hydroxyflutamide (Compound 2) which is a known AR antagonist were used as evaluation compounds.
The results are shown in Table 1.

[Test Example 2]
≪Evaluation experiment using SC-3 cells≫
The mouse breast cancer-derived cell line SC-3 was subcultured in MEMα medium supplemented with 2% fetal calf serum and 1 nM dihydrotestosterone at 37 ° C. in a 5% CO ₂ atmosphere. The cells were detached by trypsin treatment, suspended in MEMα medium supplemented with activated charcoal-treated fetal bovine serum 2%, adjusted to 20,000 cells / mL, and then distributed to a 96-well plate at 100 μL / well. After 24 hours, 10 μL of the medium was removed from each well, and 10 μL of medium supplemented with dihydrotestosterone and a dimethyl sulfoxide solution of the evaluation compound was added. The final concentration of dihydrotestosterone was 1 nM, and the final concentration of dimethyl sulfoxide was 0.1%. After compound addition, the cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere for 72 hours. 10 μL of Cell Counting Kit-8 (manufactured by Dojindo Laboratories) was added to each well, and after culturing at 37 ° C. for 90 minutes, the absorbance at 450 nm of each well was measured to obtain the relative value of the number of cells. The growth inhibitory activity of the compound on the proliferation of SC-3 cells induced by dihydrotestosterone was calculated.
As a result, among the above compounds, particularly, Compounds 6, 7 and 8 remarkably suppressed DHT-dependent cell proliferation, and in particular, Compound 7 exhibited IC ₅₀ = 0.75 μM.

[Test Example 3]
≪Evaluation experiment using LNCaP cells≫
Human prostate cancer-derived cell line LNCaP cells were subcultured at 37 ° C. in a 5% CO ₂ atmosphere using RPMI 1640 medium supplemented with 10% fetal calf serum. The cells were detached by trypsin treatment, suspended in RPMI 1640 medium supplemented with 10% activated carbon-treated fetal bovine serum, adjusted to 20,000 cells / mL, and then distributed to a 96-well plate at 100 μL / well. After 24 hours, 10 μL of the medium was removed from each well, and 10 μL of medium supplemented with dihydrotestosterone and a dimethyl sulfoxide solution of the evaluation compound was added. The final concentration of dihydrotestosterone was 10 nM and the final concentration of dimethyl sulfoxide was 0.1%. After compound addition, the cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere. After 72 hours, 50 μL of the medium was removed from each well, and 45 μL of RPMI 1640 medium supplemented with 10% activated carbon fetal bovine serum and 5 μL of medium supplemented with dihydrotestosterone and a dimethyl sulfoxide solution of the evaluation compound were added. After further incubation for 48 hours, 10 μL of Cell Counting Kit-8 (manufactured by Dojindo Laboratories) was added to each well and incubated at 37 ° C. for 90 minutes. The growth inhibitory activity of the compound on the proliferation of LNCaP cells induced by dihydrotestosterone was calculated.
The results are shown in FIG.

[Test Example 4]
≪Reporter gene assay using MDAkb2 cells≫
MDAkb2 cells stably expressing AR reporter (Toxicological Sciences, 2002, 66, 69-81) were subcultured in Leibovitz L-15 medium supplemented with 10% fetal bovine serum at 37 ° C in 100% air atmosphere Cultured. The cells were detached by trypsin treatment, suspended in phenol red-free DMEM medium supplemented with activated charcoal-treated fetal bovine serum 8%, adjusted to about 200,000 cells / mL, and then distributed to a 96-well plate by 90 μL / well. . After 24 hours, 10 μL of a medium supplemented with dihydrotestosterone and a dimethyl sulfoxide solution of the evaluation compound was added to each well. The final concentration of dihydrotestosterone was 0.1 nM and the final concentration of dimethyl sulfoxide was 0.1%. After compound addition, the cells were cultured for 24 hours at 37 ° C. in a 5% CO ₂ atmosphere. Stedy-Glo (Promega) was added to each well in an amount of 100 μL, and after 5 minutes, chemiluminescence of each well was measured, and the growth inhibitory activity of the compound against the luciferase activity induced by dihydrotestosterone was calculated.
As a result, it was shown that particularly Compound 7 and Compound 8 significantly suppressed DHT-induced enhancement of luciferase activity and suppressed AR transcriptional activation by DHT.
The results are shown in Table 2.

[Test Example 5]
<< Evaluation experiment using 22Rv1 cells >>
Human prostate cancer-derived cell line 22Rv1 cells were subcultured at 37 ° C. in a 5% CO ₂ atmosphere using RPMI 1640 medium supplemented with 10% fetal calf serum. The cells were detached by trypsin treatment, suspended in RPMI 1640 medium supplemented with 10% activated carbon-treated fetal bovine serum, adjusted to 20,000 cells / mL, and then distributed to a 96-well plate at 100 μL / well. After 24 hours, 10 μL of the medium was removed from each well, and 10 μL of medium supplemented with dihydrotestosterone and a dimethyl sulfoxide solution of each evaluation compound was added. The final concentration of dihydrotestosterone was 10 nM and the final concentration of dimethyl sulfoxide was 0.1%. After compound addition, the cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere. After 72 hours, 10 μL of Cell Counting Kit-8 (Dojindo Laboratories) was added to each well, and after culturing at 37 ° C. for 90 minutes, the absorbance at 450 nm of each well was measured to obtain the relative number of cells. The growth inhibitory activity of the compound on the proliferation of 22Rv1 cells induced by dihydrotestosterone was calculated.
As a result, compounds 6 to 10 remarkably suppress DHT-dependent cell proliferation of human prostate cancer-derived cell line 22Rv1 cells having mutant AR (H874Y-AR), and are effective against various mutant ARs. It was found.
The results are shown in Table 2.

[Test Example 6]
≪Evaluation experiment using PC-3 cells≫
Human prostate cancer-derived cell line PC-3 cells were subcultured in Ham's F-12K medium supplemented with 10% fetal calf serum at 37 ° C. in a 5% CO ₂ atmosphere. The cells were detached by trypsin treatment, suspended in RPMI 1640 medium supplemented with 10% activated carbon-treated fetal bovine serum, adjusted to 20,000 cells / mL, and then distributed to a 96-well plate at 100 μL / well. After 24 hours, 10 μL of the medium was removed from each well, and 10 μL of medium supplemented with a dimethyl sulfoxide solution of each evaluation compound was added. The final concentration of dimethyl sulfoxide was 0.1%. After compound addition, the cells were cultured at 37 ° C. in a 5% CO ₂ atmosphere. After 72 hours, 10 μL of Cell Counting Kit-8 (Dojindo Laboratories) was added to each well, and after culturing at 37 ° C. for 90 minutes, the absorbance at 450 nm of each well was measured to obtain the relative number of cells. The growth inhibitory activity of the compound on the proliferation of PC-3 cells was calculated.
As a result, among the compounds described above, it was revealed that especially Compound 6 and Compound 7 inhibit the growth of androgen-independent human prostate cancer-derived cell line PC-3 cells, and these compounds are androgen-independent. It has been shown to be effective for various prostate cancers.
The results are shown in Table 2.

Claims (6)

Formula (I)

[Where:
X is -X ₁ -CONH-X _2- ,
-X ₁ -NHCO-X _2- ,
—SO ₂ NH— or —NHSO ₂ —
(Wherein X ₁ and X ₂ each independently represents a single bond, a divalent alkylene group having 1 to 4 carbon atoms, a divalent alkenylene group having 2 to 4 carbon atoms, or —NH—, provided that -NH- represents only when bonded to -CO-)
Y represents —O— or —CO—.
A ₁ to A ₄ are each independently
-C (R ³ ) = or -N =
(Wherein R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms),
R ¹ and R ² are each independently
-OR ⁴ (wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms),
- in the alkyl radical -N ^(R _{5) 2} (Equation 1 to 6 carbon atoms, the two ^{R 5,} each independently, .2 one ^{R 5} represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms Together, they may form a nitrogen-containing heterocycle having 3 to 6 members),
A halogen atom,
-NO ₂ ,
—CN 2 or —COOR ⁶ (wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).
m and n each independently represents an integer of 0 to 3.
When m is 2 or more, R ¹ may be the same as or different from each other, and when n is 2 or more, R ² may be the same as or different from each other.
When R ¹ and R ² are each 2 or more, R ¹ and R ² may be combined to form a condensed ring having 3 to 6 carbon atoms. ]
An androgen receptor antagonist comprising as an active ingredient a compound represented by the formula: or a pharmaceutically acceptable salt thereof. The compound represented by the formula (I) is represented by the formula (II)

(Wherein A ₁ to A ₄ and R ⁴ are the same as defined in the above formula (I)).
R ⁷ represents —OR ⁴ or —N (R ⁵ ) ₂ , and R ⁴ and R ⁵ are the same as defined in the above formula (I).
m1 and n1 each independently represents an integer of 0 to 2)
The androgen receptor antagonist of Claim 1 which is a compound represented by these. The compound represented by the formula (II) is represented by the formula (III)

(Wherein R ⁴ , R ⁷ , m1 and n1 are the same as defined in the above formula (II).
3. The androgen receptor antagonist according to claim 2, wherein R ⁸ represents an alkyl group having 1 to 3 carbon atoms, and p represents an integer of 0 to 2. A pharmaceutical preparation comprising the androgen receptor antagonist according to any one of claims 1 to 3. A therapeutic agent for prostate cancer comprising the androgen receptor antagonist according to any one of claims 1 to 3. Formula (IV)

[Wherein A ₁ to A ₄ , R ⁴ and R ⁷ are the same as defined in the above formula (II). m2 and n2 each independently represents an integer of 0 to 2.
However, when A ₁ to A ₄ are all —C (R ³ ) — (wherein R ³ is the same as defined in formula (I)), m2 and n2 each independently represent 1 or 2 ] The compound represented by this.

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