JP2003073374A - Bicyclic aromatic amine derivative - Google Patents

Abstract

(57) [Problem] To have a specific and strong AR binding affinity,
A novel nonsteroidal compound exhibiting an R agonist or antagonistic activity or a salt thereof, and a medicament containing these as an active ingredient are provided. SOLUTION: General formula (I) Or a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bicyclic aromatic amine derivative having a specific and strong androgen receptor-binding affinity and exhibiting androgen receptor agonist or antagonist action, or a pharmacologically acceptable derivative thereof. And salts containing them.

[0002]

BACKGROUND OF THE INVENTION Androgen is a general term for C19 steroids, and it is a sex hormone that is important for normal sexual differentiation and development in men, virilization in adolescence, activation of early spermatogenic function in testes and maintenance of male function. is there. About 90% of androgens are produced from testicular Leydig cells and the remaining 10% from the adrenal gland, mainly as testosterone, and secreted into the blood. Testosterone is taken up by target cells and is converted to dihydrotestosterone (DHT), which has strong biological activity, by 5α-reductase, and along with testosterone, secondary sex manifestations in men (proliferation of sebaceous glands, acne, hair growth, voice change, It plays an important role in the development of beards), the development of external genitals (penis, testicles), the development of accessory genitals (prostate, seminal vesicles), and the development of sexual drive and erection.

[0003] On the other hand, in addition to these main actions, there are actions other than the reproductive system such as anabolic action (increase of skeletal muscle and bone mass), gonadotropin secretion inhibitory action, erythropoiesis enhancing action, and androgen target cells In addition to being present in the external and accessory genital tissues, it is widely distributed in the brain, pituitary gland, muscular tissue, bone and kidney (N Engl J Med 334, 707-714, 1996).

[0004] In addition to these roles, androgens have been reported to exhibit anti-inflammatory action. By suppressing the proliferation of inflammatory cells and the production of cytokines such as IL-6, arthritis and autoimmune diseases are alleviated. Is being revealed today (Ann Rheum Dis 55, 811-815, 1996).

All androgen action is caused by the androgen receptor (Andr) having a molecular weight of about 100,000 existing in the nucleus of the target cell.
gen Receptor, hereinafter referred to as AR).
In 1988, the gene was cloned by Chang and Lubahn et al., And it was revealed that AR has a structure similar to that of estrogen, progesterone, mineralocorticoid and glucocorticoid receptors, and forms a family of nuclear steroid receptors. (Science 240, 324-32
6, 327-330, 1988). The androgen, which is highly lipophilic, passes through the target cell membrane by passive diffusion, binds to the hormone-binding region of AR with high specificity and forms a dimer, and the androgen-responsive DNA region existing upstream of the specific gene. (Androgen Response Element: ARE). Then, transcription of the target gene is initiated, mRNA expression occurs, and a functional protein that controls androgen action is produced and the action is expressed (Trend in Endocrinology and Metabolis
m 9,317-324, 1998). In this mechanism, a compound that binds to AR and expresses an action similar to that of a natural ligand such as testosterone is defined as an agonist, while a ligand that suppresses the action is called an antagonist.

[0006] As an AR agonist, an injectable testosterone ester (testoste) having improved durability after in vivo administration.
rone enanthate, testosterone propionate) or a methyl group at the 17α-position to protect the inactivation of the 17α-hydroxyl group due to oxidative oxidation and enhance its activity (methyltestosteron
e, fluoxymesterone) has been used for a long time. These androgenic steroid formulations are often given in relatively large amounts and for long periods of time for the disease of interest. Therefore, side effects such as liver dysfunction, virilization, vocal cord changes in women (male-like hoarseness), gastrointestinal disorders, euphoria, hirsutism of the body and baldness are observed. In particular, 17α
Androgens with a methyl group at the position have been reported to cause severe liver dysfunction (N Engl J Med 334, 7
07-714, 1996).

As AR antagonists, steroidal antiandrogens such as gestagen derivatives chlormadinone acetate and cyprotelol acetate have been used as therapeutic agents. However, it has been pointed out that these steroid preparations enhance the negative feedback mechanism of the hypothalamus-pituitary due to their progesterone action, resulting in a decrease in blood testosterone level and a decrease in sexual function and libido. (Drugs Aging 5,
59-80, 1994).

In recent years, in order to reduce such side effects of steroids, AR agonists and AR antagonists of non-steroidal synthetic compounds have been desired.

[0009]

The present invention has been made in view of the treatment and therapeutic research of such AR-mediated diseases, and the object of the present invention is to have a specific and strong AR binding affinity. However, the present invention provides a novel non-steroidal compound which exhibits an AR agonistic or antagonistic effect and has few side effects, and a salt thereof, and further provides a drug containing these compounds as an active ingredient.

[0010]

Means for Solving the Problems As a result of intensive studies to solve these problems, the present inventors have found that a bicyclic aromatic amine derivative has an AR-mediated physiological action and They have found that they have an excellent therapeutic effect on the disease that develops, and have completed the present invention.

That is, according to one aspect of the present invention, formula (I)

[0012]

[Chemical 4]

[Wherein R ¹ is a hydrogen atom, a halogen atom,
Or, it represents an alkyl group having 1 to 5 carbon atoms which may be substituted with a fluorine atom, and R ² represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a carbon atom having 7 carbon atoms.
~ 9 aralkyl group, R ³ is a hydrogen atom, a C 1-5 alkyl group optionally substituted with a fluorine atom, a C 7-9 aralkyl group, or aryl optionally substituted with R ^7. Represents a group (wherein R ⁷ represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom or a hydroxyl group), and R ⁴ is substituted with a hydrogen atom or a fluorine atom. Represents an alkyl group having 1 to 5 carbon atoms, Y
_{Is, -CH 2 -, - O -} , - OCO -, - NR 8 -, - N
^{R 8 CO -, - NR 8} SO 2 -, - NHCONH -, - N
HCSNH- or -NR ⁸ COO- (in the formula, R ⁸ independently represents the same meaning as the above R ² ), R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, R an optionally substituted aralkyl group having a carbon number of 7 to 9 with ⁹ (wherein R ⁹
Each independently has the same meaning as R ⁷ . ), Is an aryl group which may (wherein R ¹⁰ substituted by R ¹⁰ is independently as defined above R ^7.) Or R may be substituted with ¹¹ heteroaryl group (wherein R ¹¹ is , Independently representing the same meaning as R ⁷ above) (provided that when Y is other than —CH ₂ —, R ⁵ is not a halogen atom), R ⁶ is a hydrogen atom or Represents a halogen atom,
The dashed line represents a single bond or a double bond together with the solid line. ] The present invention relates to a bicyclic aromatic amine derivative or a pharmacologically acceptable salt thereof, a drug containing them as an active ingredient, and an androgen receptor modulator.

Here, the "androgen receptor modulator" refers to a drug that acts on the androgen receptor and regulates the action mediated by the androgen receptor. A compound that acts on AR and expresses an action similar to that of a natural ligand such as testosterone is called an agonist, while a ligand that suppresses the action is called an antagonist.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents in the above formula (I) will be described. Specific examples of the "alkyl group having 1 to 5 carbon atoms" include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-
Butyl group, sec-butyl group, n-pentyl group, ter
Examples thereof include linear or branched alkyl groups such as t-amyl group, 3-methylbutyl group and neopentyl group.

Specific examples of the "alkoxy group having 1 to 5 carbon atoms" include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group. Group, n-
Examples thereof include linear or branched alkoxy groups such as a pentyloxy group, a tert-amyloxy group, a 3-methylbutoxy group and a neopentyloxy group.

Specific examples of "halogen atom" include fluorine atom, chlorine atom, bromine atom and iodine atom. Specific examples of the "cycloalkyl group having 3 to 7 carbon atoms" include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group.

Specific examples of the "C7-C9 aralkyl group" include a benzyl group, a phenethyl group and a phenylpropyl group. Specific examples of the "aryl group" include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like.

Specific examples of the "heteroaryl group" include:
Examples thereof include a pyridyl group, a thienyl group and a furanyl group. Specific examples of the fluorine atom-substituted alkyl group of the "alkyl group having 1 to 5 carbon atoms which may be substituted with a fluorine atom" include trifluoromethyl group, trifluoroethyl group, tetrafluoroethyl group and the like.

In the compound of formula (I), preferred embodiments are as follows. Y is preferably O. The broken line is
Preferred is the case where together with the solid line represents a double bond. The preferable bonding position of the amide group represented by A above is the 6-position or the 7-position.

One example of the preferred compound of the general formula (I) is the compound of the following formula (II) or a pharmaceutically acceptable salt thereof.

[0022]

[Chemical 5]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁶ are
As defined in the general formula (I)) Another example of the preferable general formula (I) compound is a compound of the following formula (III) or a pharmaceutically acceptable salt thereof.

[0024]

[Chemical 6]

(In the formula, R^FiveIs R⁹Carbon that may be replaced by
Aralkyl groups of the formulas 7 to 9 (wherein R is⁹Is a carbon number of 1 to 5
Alkyl group, alkoxy group having 1 to 5 carbon atoms, halogen atom
Or represents a hydroxyl group. ), R^TenMay be replaced with
Ru group (R in the formula^TenAre independently R⁹Has the same meaning as
You ) Or R¹¹A heteroaryl group which may be substituted with
(R in the formula¹¹Are independently R⁹Means the same as. )
Represents R¹, R², R³, R ^FourAnd R⁶Is of the general formula (I)
As defined by Preferred embodiments of the compounds of formulas (I) to (III)
Is the following. R²Is preferably H. R³And R
^FourIs preferably either or both CH₃
Is. R^FiveR in the definition of⁷May be replaced with
For the radical, R⁷The preferred substitution position of is the p position
It R⁶Is preferably H.

Particularly preferred compounds of the compound of the present invention are as follows. N- (2-oxo-2H-chromen-6-yl) -2-
Phenoxypropionamide 2-hydroxy-2-methyl-N- (4-methyl-2-
Oxo-2H-chromen-7-yl) propionamide 2-hydroxy-2-methyl-N- (4-trifluoromethyl-2-oxo-2H-chromen-7-yl) propionamide represented by formula (I) When an asymmetric carbon atom is present in the compound of the present invention, any of its racemate, diastereomer and individual optical isomers and mixtures thereof are included in the present invention.

The pharmacologically acceptable salt of the compound of the present invention represented by formula (I) is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include fluorate and hydrochloric acid. Hydrohalides such as salts, hydrobromides and hydroiodes, inorganic salts such as nitrates, perchlorates, lead sulfates, phosphates and carbonates, methanesulfonates, trifluoro Lower alkyl sulfonate such as methane sulfonate, ethane sulfonate, benzene sulfonate, aryl sulfonate such as p-toluene sulfonate, acetate, fumarate, succinate, citrate, Tartrate,
Examples thereof include carboxylates such as oxalate and maleate, amino acid salts such as glycine salt, alanine salt, glutamate and aspartate, and alkali metal salts such as sodium salt and potassium salt. Examples of the solvate include solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether and the like.

The bicyclic aromatic amine derivative of the present invention can be produced by the following method. [Production method 1]

[0029]

[Chemical 7]

(In the formula, all symbols are the same as above.) The compound of the present invention represented by the formula (I) includes a compound represented by the formula (a) and a compound represented by the formula (b): Reacting in a solvent-free or inert solvent in the presence or absence of a base,
It can be produced by forming an amide bond. The compounds of formulas (a) and (b) are available as commercially available reagents or from them by easy derivation by conventional chemical reactions. The reaction of forming an amide bond from an acid and an amine is known, and examples thereof include a method via an acid halide and a method using a condensing agent.

Explaining these reactions concretely, the method via an acid halide is as follows. The compound represented by the formula (b) is acidified in a solvent with a halogenating reagent such as thionyl chloride, oxalyl chloride or thionyl bromide. It is converted to a halide, and then this acid halide and formula (a)
In the presence or absence of a base, the compound represented by is reacted in a solvent-free or inert solvent to amidate.

The amount of the halogenating reagent used is preferably 1 equivalent to a large excess amount with respect to the compound represented by the formula (b). The reaction solvent used in the process of obtaining the acid halide is not particularly limited as long as it does not significantly inhibit this reaction, and dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene and the like can be used. preferable. The reaction temperature is preferably 0 to 100 ° C., and the reaction time is preferably 1 to 12 hours.

The base used in the amidation process is preferably a tertiary amine, such as triethylamine and pyridine. The compound represented by the formula (b) is preferably used in an amount of 1 to 10 equivalents based on the acid halide. The base is preferably used in an amount of 1 to a large excess with respect to the acid halide. The reaction solvent is not particularly limited as long as it does not significantly inhibit this reaction, but dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene, pyridine and the like are preferable. The reaction temperature is preferably 0 to 80 ° C., and the reaction time is 30.
Minutes to 24 hours are preferred.

The method using a condensing agent is as follows. The compound represented by the formula (a) and the compound represented by the formula (b) are combined with 2-chloro-1,3-dimethylimidazolinium chloride, dicyclohexylcarbodiimide or 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide is a method of reacting in the presence or absence of a base in a solvent-free or inert solvent. The condensing agent is preferably used in 1 to 2 equivalents relative to the compound represented by the formula (b). The base is preferably a tertiary amine, and examples thereof include triethylamine and pyridine. The base is preferably used in 1 equivalent to a large excess amount based on the compound represented by the formula (b). The reaction solvent is not particularly limited as long as it does not significantly inhibit this reaction, but N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane and the like are preferable. The reaction temperature is preferably 0 to 150 ° C., and the reaction time is preferably 1 to 48 hours. [Production method 2]

[0035]

[Chemical 8]

(In the formula, Boc represents a tert-butoxycarbonyl group, and other symbols are the same as the above.) Among the compounds of the present invention, the compound represented by the formula (d) is represented by the formula (c). The compound can be prepared by treating the compound with an acid and deprotecting it.

Explaining this reaction concretely, the acid is preferably an organic acid or an inorganic acid, and examples thereof include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and sulfuric acid. The acid is 1 to the compound represented by the formula (c).
It is preferable to use 50 equivalents. The reaction solvent is not particularly limited as long as it is a solvent that does not significantly inhibit this reaction, but is not limited to dichloromethane, chloroform, 1,2-dichloroethane, hexane, benzene, toluene, dioxane,
Tetrahydrofuran, acetonitrile, methanol, ethanol, water, a mixed solvent thereof or the like is preferable.
The reaction temperature is preferably 0 to 100 ° C., and the reaction time is preferably 30 minutes to 24 hours. [Manufacturing method 3]

[0038]

[Chemical 9]

(In the formula, E represents a chlorosulfonyl group, a halogenated carbonyl group, an isocyanato group or an isothiocyanato group, and Y'is -NHCO-, -NHSO _2- ,
It represents -NHCONH- or -NHCSNH-, and other symbols are the same as defined above. ) Among the compounds of the present invention, the compound represented by the formula (I ′) includes a compound represented by the formula (d) and a compound represented by the formula (e) or (f).
The compound represented by can be produced by reacting in the presence or absence of a base in a solventless or inert solvent.

Specific examples of the "halogenated carbonyl group" include a chlorocarbonyl group and a bromocarbonyl group. Explaining this reaction concretely, the base is preferably a tertiary amine, and examples thereof include triethylamine and pyridine. The compound represented by the formula (e) or (f) is 1 to 1 with respect to the compound represented by the formula (d).
It is preferable to use 0 equivalent. The base is preferably used in an amount of 1 equivalent to a large excess amount based on the compound represented by the formula (e) or (f). The reaction solvent is not particularly limited as long as it is a solvent that does not significantly inhibit this reaction, but is not limited to dichloromethane, chloroform, 1,2-dichloroethane, 1,
1,2,2-Tetrachloroethane, toluene, dimethylformamide, tetrahydrofuran and the like are preferable. The reaction temperature is preferably 0 to 80 ° C, and the reaction time is 30 minutes to 1
2 hours is preferred. [Manufacturing method 4]

[0041]

[Chemical 10]

(In the formula, E represents a carbonyl halide group, Y ″ represents —OCO—, and other symbols are the same as the above.) Among the compounds of the present invention, the compound represented by the formula (I ″) ) Is a compound of formula (g) and a compound of formula (e) or (f)
The compound represented by can be produced by reacting in the presence or absence of a base in a solventless or inert solvent.

Specific examples of the "halogenated carbonyl group" include a chlorocarbonyl group and a bromocarbonyl group. Explaining this reaction concretely, the base is preferably a tertiary amine, and examples thereof include triethylamine and pyridine. The compound represented by the formula (e) or (f) is 1 to 1 with respect to the compound represented by the formula (g).
It is preferable to use 0 equivalent. The base is preferably used in an amount of 1 equivalent to a large excess amount based on the compound represented by the formula (e) or (f). The reaction solvent is not particularly limited as long as it is a solvent that does not significantly inhibit this reaction, but is not limited to dichloromethane, chloroform, 1,2-dichloroethane, 1,
1,2,2-Tetrachloroethane, toluene, dimethylformamide, tetrahydrofuran and the like are preferable. The reaction temperature is preferably 0 to 80 ° C, and the reaction time is 30 minutes to 1
2 hours is preferred.

The compound of the present invention produced by the above-mentioned production method is isolated and purified as a free compound, a salt thereof, various solvates such as hydrates or ethanol solvates, or polymorphic substances. The pharmaceutically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization and various fractionation chromatography. The optical isomer can be converted into a stereochemically pure isomer by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound.

The bicyclic aromatic amine derivative of the present invention or a salt thereof has an excellent AR-regulating action, and it can be used as a drug or an AR-regulating agent by using them as an active ingredient, and various ARs can be used. It can be widely applied to prevention and treatment of related diseases.

AR-related diseases include the following A or B
I can give you one. A. Diseases that can be cured by the physiological action of androgens: male hypogonadism, male dysfunction (impotence, male infertility due to spermatogenic dysfunction), dyssexual differentiation (male hermaphroditism), male delayed puberty Onset, male infertility, aplastic anemia, hemolytic anemia, sickle cell anemia,
Idiopathic thrombocytopenic purpura, myelofibrosis, renal anemia, wasting disease (post-operative, malignant tumor, trauma, chronic kidney disease, burn, AIDS infection), osteoporosis, pain relief for end-stage female genital cancer, inoperable Breast cancer, mastopathy, endometriosis and female sexual dysfunction.

B. Diseases where androgens are aggravating factors:
For example, prostate cancer, benign prostatic hyperplasia, virilization, acne,
Examples include seborrhea, hirsutism, baldness, precocious puberty and polycystic ovary syndrome.

For the above-mentioned diseases A, the compound having an AR agonistic action of the present invention can be used. For example, the compound of Example 1 shown below was suggested to be an AR agonist by the test examples described below.

For the above-mentioned diseases B, the compound having an AR antagonistic effect of the present invention can be used. For example, the compounds of Examples 22 and 23 shown below are
The test example described below suggested that it was an AR antagonist.

The pharmaceutical agent of the present invention can be widely applied to these AR-related diseases, and for the diseases not exemplified here, the functional regulation of AR is required now or in the future. In some cases, the medicine of the present invention can be applied.

The pharmaceutical of the present invention can be administered orally or parenterally, and may be systemic or local. The dosage form is also not particularly limited and can be appropriately selected depending on the administration route. For example, tablets,
Capsules, dragees, granules, fine granules, inhalants, suppositories,
Liquid, syrup, dry syrup, suspension, emulsion, lotion, ointment, patch, spray, gel, nasal drop,
Examples include eye drops and injections.

These preparations contain organic or inorganic solid or liquid excipients, auxiliary substances, stabilizers, wetting agents, emulsifiers, buffers, and other various pharmacologically acceptable additives, It can be manufactured.

The dose of the medicament of the present invention to humans depends on the purpose of treatment or prevention, sex of the patient, weight, age, health condition,
It is appropriately determined according to various conditions such as the type and degree of disease, dosage form, administration route, and administration period. The daily dose of the bicyclic aromatic amine derivative of the present invention is about 0.01 to
It is in the range of 100 mg / kg.

The medicine of the present invention can be used for domestic animals, pet animals,
It may be used for the treatment of androgen receptor mediated diseases in captive or warm-blooded animals such as wild animals. The dosage form and dose in this case can be determined with reference to the dosage form and dose for humans.

[0055]

EXAMPLES The compounds and production methods of the present invention are described in more detail below with reference to Examples, but the present invention should not be construed as being limited thereto.

The ¹ H-NMR spectrum was measured using JNM-EX with tetramethylsilane (TMS) as an internal standard.
It was measured with a 270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.), and the δ value was shown in ppm.

In the following structural formulas and tables, E
t is an ethyl group, Pr is a propyl group, Bu is a butyl group, P is
h represents a phenyl group, Bn represents a benzyl group, and Ac represents an acetyl group.

[Example 1] N- (2-oxo-2H-chromene-6-
Production of (yl) -2-phenoxypropionamide

[0059]

[Chemical 11]

6-aminocoumarin hydrochloride (100 mg,
0.51 mmol) to N, N-dimethylacetamide 5
After dissolving in ml, 2-phenoxypropionyl chloride (0.087 ml, 0.56 mmol) was added under ice cooling.
After stirring at room temperature for 105 minutes, the reaction solution was poured into ice water to stop the reaction. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (168 m)
g was obtained. The physical property values are shown below.

¹ H-NMR (CDCl ₃ ) δ: 1.68 (3H, d, J = 6.6H
z), 4.82 (1H, q, J = 6.6Hz), 6.45 (1H, d, J = 9.4H
z), 6.99 (1H, d, J = 9.4Hz), 7.48-7.03 (6H, m), 7.69
(1H, d, J = 9.6Hz), 8.02 (1H, d, J = 2.6Hz), 8.34 (1
H, s). In the same manner as in Example 1, the compounds shown in Examples 2 to 20 were produced. The physical properties of the obtained compound are shown in Tables 1 to 4.

[0062]

[Table 1]

[0063]

[Table 2]

[0064]

[Table 3]

[0065]

[Table 4]

[0066]

[Table 5]

Example 21 N- (2-oxo-2H-chromene-
Preparation of 6-yl) -2- (4-chlorophenoxy) -propionamide

[0068]

[Chemical 12]

2- (4-Chlorophenyl) propionic acid (203 mg, 1.01 mmol) was dissolved in 5 ml of N, N-dimethylacetamide, thionyl chloride (0.089 ml, 1.21 mmol) was added under ice cooling, and the mixture was stirred for 25 minutes. did. 6-Aminocoumarin hydrochloride under ice cooling (100m
(g, 0.51 mmol) and stirred at room temperature for 12 hours, and then the reaction solution was poured into ice water to stop the reaction. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (175 mg). The physical property values are shown below.

¹ H-NMR (CDCl ₃ ) δ: 1.67 (3H, d, J = 6.6H
z), 4.77 (1H, q, J = 6.6Hz), 6.45 (1H, d, J = 9.6H
z), 7.48-6.89 (6H, m), 7.69 (1H, d, J = 9.6Hz), 8.01
(1H, d, J = 2.6Hz), 8.26 (1H, s). In the same manner as in Example 21, the compounds shown in Examples 22 to 48 were produced. Physical properties of the obtained compound are shown in Tables 5 to 7.

[0071]

[Table 6]

[0072]

[Table 7]

[0073]

[Table 8]

[0074]

[Table 9]

[0075]

[Table 10]

[0076]

[Table 11]

Example 49 [1- (2-oxo-2H-chromene
-6-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester

[0078]

[Chemical 13]

6-aminocoumarin hydrochloride (1.0 g,
5.06 mmol), N-Boc-L-alanine (1.
05 g, 5.57 mmol) was dissolved in 10 ml of N, N-dimethylformamide, 4-methylmorpholine (0.67 ml, 6.07 mmol), 1-hydroxybenzotriazole hydrate (821 mg, 6.0).
mmol), 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (1.16 g, 6.0
mmol) and stirred at room temperature for 6 hours, and further 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.16 g, 6.07 mmol) was added, followed by stirring at 100 ° C for 16 hours. After allowing to cool, ice was added to the reaction solution to stop the reaction, extraction was performed with ethyl acetate, and the extract was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent hexane: ethyl acetate = 2: 3) to obtain 1.43 g of the title compound.
The physical property values are shown below.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 6.9H
z), 1.48 (9H, s), 4.38 (1H, m), 5.12 (1H, d, J = 7.3H
z), 6.40 (1H, d, J = 9.6Hz), 7.19 (1H, d, J = 8.9),
7.34 (1H, dd, J = 2.3, 8.9Hz), 7.58 (1H, d, J = 9.6H
z), 7.91 (1H, d, J = 2.3Hz), 9.01 (1H, s).

Example 50 2-Amino-N- (2-oxo-2H-
Preparation of chromen-6-yl) -propionamide hydrochloride

[0082]

[Chemical 14]

1.43 g of the compound of Example 3 was dissolved in 20 ml of chloroform and a 4N hydrochloric acid-ethyl acetate solution (12 m) was added.
1 was added. After stirring at room temperature for 5 hours and 30 minutes, the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.12 g). The physical property values are shown below. ¹ H-NMR (DMSO-d ₆ ) δ: 1.50 (3H, d, J = 6.9Hz), 4.14 (1H,
m), 6.51 (1H, d, J = 9.6Hz), 7.42 (1H, d, J = 8.9),
7.82 (1H, dd, J = 2.3, 8.9Hz), 8.06 (1H, d, J = 2.3H
z), 8.11 (1H, d, J = 9.6Hz), 8.42 (2H, s), 11.21 (1H,
s).

Example 51 2-Amino-N- (2-oxo-2H-
Preparation of chromen-6-yl) -3-phenyl-propionamide hydrochloride

[0085]

[Chemical 15]

The title compound was obtained in the same manner as in Example 50. The physical property values are shown below. ¹ H-NMR (DMSO-d ₆ ) δ: 3.11-3.27 (2H, m), 4.31 (1H, m),
6.50 (1H, d, J = 9.6 Hz), 7.29-7.89 (7H, m), 7.96 (1
H, s), 8.09 (1H, d, J = 9.6 Hz), 8.47 (3H, s), 11.11
(1H, s).

Example 52 N-Methyl-N- (2-oxo-2H-
Preparation of chromen-6-yl) -2-phenoxypropionamide

[0088]

[Chemical 16]

74 mg of the compound of Example 1 was dissolved in N, N-dimethylformamide (2 ml) to give potassium-ter.
t-Butoxide (30 mg, 0.26 mmol) and methyl iodide (0.022 ml, 0.36 mmol) were added,
Stir at room temperature for 48 hours. Ice was added to the reaction solution to stop the reaction, extraction was performed with ethyl acetate, the extract was washed with a saturated sodium hydrogen carbonate aqueous solution, a saturated ammonium chloride aqueous solution, and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was thin layer plate (20 cm x 2
(0 cm x 0.5 mm x 3 sheets), and the title compound 2
8 mg was obtained. The physical property values are shown below. ¹ H-NMR (CDCl ₃ ) δ: 1.68 (3H, d, J = 6.9 Hz), 4.82 (1H,
q, J = 6.9 Hz), 6.45 (1H, d, J = 9.6 Hz), 6.81-7.49
(6H, m), 7.69 (1H, d, J = 9.6 Hz), 8.02 (1H, d, J =
2.3 Hz), 8.25 (1H, s). Next, the usefulness of the compound of the present invention will be described by the following test examples.

[Test Example 1] Competitive binding test for rat androgen receptor (rat AR) Preparation of rat AR fraction: 11-week-old male SD rats were orchidectomed, and the prostate was removed on the 3rd day, followed by ice cooling. ET buffer solution (10 mM
Tris, 1 mM EDTA, 5 mM DTT, 10 mM sodium molybdate,
pH 7.4). The prostate was minced, ET buffer was added, and the mixture was homogenized using a homogenizer. The homogenate was subjected to ultracentrifugation at 100,000 xg for 60 minutes at 4 ° C, and the supernatant was used as a rat AR fraction (hereinafter referred to as ARF). Binding test: ET with ³ H-testosterone (hereinafter ³ HT)
Dihydrotestosterone (DHT) prepared by diluting with buffer
Is 400 times the maximum concentration of ³ HT (2.5 nM) (final concentration 1 μ
M) was prepared. ³ Add HT preparation, add DHT,
Add to a 1.5 ml tube with no additions and test compound, and then add 200 μg ARF to a final volume of 100 μl. All test compounds were prepared at 1000 times concentration of ³ HT (2500 nM). After incubating at 4 ° C. for 2 hours, 300 μl of 0.05% dextran T70-1.0% activated carbon solution was added, and the mixture was incubated in ice for another 15 minutes to remove unbound ³ HT by adsorption. After centrifugation at 2,500 rpm for 5 minutes at 4 ℃, the supernatant 27
5 μl was taken in a liquid scintillation vial, 2 ml of clear sol was added, and the mixture was stirred and allowed to stand, and then ³ H radioactivity was measured with a liquid scintillation counter. The binding inhibition rate (%) of the compound of the present invention was calculated from the following formula. Binding inhibition rate (%) = 100 × [1- (ac) / (bc)] a: Radioactivity of a sample added with the compound of the present invention ( ³ H-T + compound) b: Radioactivity of sample without addition of the compound of the present invention ( ³ HT only: total binding amount) c: radioactivity of DHT-added sample ( ³ H-T + DHT: non-specific binding amount) Table 8 shows the binding inhibition rate (%) of the compound of the present invention obtained from the above.
Shown in.

[0091]

[Table 12] The compound of the present invention showed strong binding inhibitory activity almost equal to that of hydroxyflutamide.

Test Example 2 1) Test Method for Evaluating AR Agonist Action Male compound rats are subcutaneously administered once a day for 1 week once 5 days after orchidectomy. On the day after the final administration day, the wet weight of the ventral prostate is measured, and the AR agonistic effect is evaluated by the effect of the compound of the present invention on the increase in the weight of the prostate. 2) Test method for evaluating AR antagonistic effect After orchidectomy of male rats, testosterone propionate and the compound of the present invention are simultaneously subcutaneously administered once a day for 1 week after 5 days. The day after the final administration, the wet weight of the ventral prostate was measured, and the compound A of the present invention was treated by its inhibitory effect on the increase in weight of the prostate caused by testosterone propionate.
Evaluate R-antagonism.

[0093]

INDUSTRIAL APPLICABILITY The bicyclic aromatic amine derivative of the present invention and the medicine containing it as an active ingredient are specific and potent AR.
Since it has a binding affinity and has an AR agonistic or antagonistic effect, the AR function can be specifically regulated, and various AR-mediated diseases can be prevented and treated.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 5/28 A61P 5/28 7/06 7/06 13/08 13/08 15/08 15/08 19/10 19 / 10 35/00 35/00 C07D 311/18 C07D 311/18 405/12 405/12 (72) Inventor Hiromasa Nejijima 14 Shinomiya Minamigawaracho, Yamashina-Ku, Kyoto City Kyoto Research Institute ( 72) Inventor Noriko Yamamoto 14 Shinomiya Minamikawara-cho, Yamashina-ku, Kyoto Prefecture F-Term (Reference) in Kaken Pharmaceutical Co., Ltd. ZA81 ZB26 ZC10

Claims (7)

[Claims] 1. Formula (I): (In the formula, R ¹ represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with a fluorine atom, R ² represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, Represents a cycloalkyl group having 3 to 7 carbon atoms or an aralkyl group having 7 to 9 carbon atoms, R ³ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may be substituted with a fluorine atom, or 7 to 9 carbon atoms; Or an aryl group which may be substituted with R ⁷ (in the formula, R ⁷ represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom or a hydroxyl group), R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms which may be substituted with a fluorine atom, and Y represents —CH.
_{2 -, - O -, -} OCO -, - NR 8 -, - NR 8 CO
_{^{-, - NR 8 SO 2 -}} , - NHCONH -, - NHCSN
H- or -NR ⁸ COO- (wherein R ⁸ is independently a R
Represents the same meaning as ² . ) Represents, R ⁵ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an optionally substituted aralkyl group having a carbon number of 7 to 9 with R ⁹ (wherein R ⁹ is the independently represents the same meaning as R ^7.), it may be substituted with R ¹⁰ aryl group (wherein R ¹⁰ is may be substituted with.) or R ¹¹ as defined above R ⁷ independently hetero Represents an aryl group (in the formula, R ¹¹ independently has the same meaning as R ⁷ ) (provided that when Y is other than —CH ₂ —, R ⁵ is not a halogen atom). , R ⁶ is
Represents a hydrogen atom or a halogen atom, and a broken line represents a single bond or a double bond together with a solid line. ) A bicyclic aromatic amine derivative represented by the formula) or a pharmaceutically acceptable salt thereof. 2. The general formula (I) is represented by the following formula: (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁶ are each represented by the general formula (I)
The dicyclic aromatic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, represented by: 3. The general formula (I) is represented by the following formula: [Chemical 3] (In the formula, R^FiveIs R⁹C7-C9 which may be substituted with
Ralkyl group (R in the formula⁹Is an alkyl group having 1 to 5 carbon atoms, charcoal
Alkoxy groups with a prime number of 1 to 5, halogen atoms or hydroxyl groups
Represent ), R^TenAn aryl group which may be substituted with (in the formula, R
^TenAre independently R⁹Means the same as. ) Or R
¹¹A heteroaryl group which may be substituted with¹¹Is
Independently R⁹Means the same as. ), R¹, R
², R³, R ^FourAnd R⁶Is as defined in general formula (I)
The bicyclic aromatic amide according to claim 1, represented by
A min derivative or a pharmacologically acceptable salt thereof. 4. A drug containing as an active ingredient the bicyclic aromatic amine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 5. An androgen receptor modulator, which is an agent.
The medicine according to. 6. The medicine according to claim 5, wherein the androgen receptor modulator is an androgen receptor agonist. 7. The medicine according to claim 5, wherein the androgen receptor modulator is an androgen receptor antagonist.