WO1998022432A1 - Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same - Google Patents

Abstract

Acylamino-substituted acylanilide derivatives represented by general formula (I) or salts thereof, and a pharmaceutical composition comprising the same. They have an antiandrogenic activity and are useful as a prophylactic or therapeutic agent for prostatic cancer, prostatic hypertrophy, defemination, hypertrichosis, bald head, acne, seborrhea and the like in which androgen is involved as an exacerbating factor.

Description

 Specification

 Novel acylamino-substituted acylylanilide derivatives or pharmaceutical compositions thereof

 The present invention relates to a novel acylamino-substituted acylylanilide derivative, a salt thereof, and a pharmaceutical composition useful as an antiandrogen drug.

Androgen, a steroid hormone, is secreted from the testis and adrenal cortex and causes male hormones. Androgen is taken up into target cells and binds to the androgen receptor in the nucleus, and the androgen-bound receptor forms a dimer. This dimer binds to the androgen-response element on the DNA. to promote the synthesis of m RNA, by inducing protein responsible for androgen action, to express various actions in vivo (Prostate Suppl.45-51 (1996)) _c androgens in disease to be增悪factor These include prostate cancer, benign prostatic hyperplasia, androgenesis, hirsutism, baldness, acne, seborrhea, etc. _c Antiandrogens suppress the activation of androgen transcription and block the action of androgens Therefore, it is useful as a therapeutic agent for diseases in which these androgens are exacerbating factors.

 Antiandrogens are classified into compounds having a steroid skeleton similar to a substrate (steroidal antiandrogens) and compounds having a nonsteroidal skeleton (nonsteroidal antiandrogens ij).

As a nonsteroidal anti-androgen, flucamide (Japanese Patent Laid-Open No. 49-81332), which is an acylanilide derivative, is known. _C- flutamide itself does not have an anti-androgenic effect. The carbon atom directly linked to the carbonyl group by metabolism ( _α carbon It is known that the substitution of a hydroxyl group with an atom results in the formation of hydroxyflutamide, which exerts its activity, and this hydroxyl group is considered to be indispensable for the expression of antiandrogen action (J. Med. Chem 31, 954-959 (1988)). In addition, bicalutamide (GB 8, 221 and 421) has already been described in various countries, and GB 8, 221 and 42] shows that the acyl portion of an acylanilide derivative has aryl (or heteroaryl) sulfonyl ( Or an acylanilide derivative, such as an alkanol substituted with a sulfinyl or thio) aryl (or heteroaryl) amino. However, the compounds substantially disclosed are, like hydroxyflutamide, all compounds having a hydroxyl group at the _α- carbon atom. On the other hand, carbaminoaminoacetanilide derivatives include US Pat. No. 4,532,251, and 2,6-dizino substituted with a bilazinyl carbonyl group or a substituted imidazolyl carbenyl group.

Ricinamide has been disclosed as a fungicide. However, these compounds are

It has been disclosed or suggested that it has an effect.

_Ile words, gynecomastia, which is attributed to the action of the drug in the central, mastalgia (Semm. Oncol. 18 (5 Suppl 6) 13-18 (1991), J. Med. Chem. 3 1 954-959 ( 1988)) and agonism I after long-term use, and the onset of action (J. Urol. 153 (3 part 2) 1070-1072 (1995)). Because of the need to block, the development of agonist action is a major therapeutic problem.

 An object of the present invention is to provide a novel acylamino-substituted acylylanilide derivative and a salt thereof, which have a strong antiandrogenic action and have less of these side effects, and further provide a drug containing the same. . Disclosure of the invention

 The present inventors have conducted intensive studies to solve these problems associated with existing antiandrogens, and surprisingly, an acylylamide derivative substituted with an acylamino group has been required for the expression of activity. The present invention has been found to be a compound having strong oral activity and antiandrogenic activity without having a hydroxyl group of α-carbon atom, further having few side effects, and having good oral activity. Was completed.

 That is, the present invention relates to an acylamino-substituted acylylanilide derivative represented by the following general formula (I) or a salt thereof.

 (The symbols in the formula have the following meanings.

R ¹ and R ² : same or different, halogen atom, cyano, halogeno lower alkyl, nitro, carboxyl, lower alkanoyl or lower alkoxycarbonyl group R ³ : hydrogen atom or lower alkyl group

11: 0 or 1

R ⁴ , R ⁵ , ^RG and R ⁷ : identical or different, hydrogen atoms, lower alkyls which may be substituted, or heteroatoms in which R ⁴ and R ⁵ are in the form of ^May form a cycloalkyl group, or when n is 1, R ⁵ and R ⁶ may form a cycloalkylene group, A and A ₂ : Same or different binding or low S

R ⁸ : a hydrogen atom, a hydroxyl group, a lower alkoxy, or a combination of R ⁸ and R ⁵ may form a nitrogen-containing cycloalkylene group;

And R ⁷ and R ⁸ may be combined to form a nitrogen-containing cycloalkylene group:

Z: acetyl group

 X ,: oxygen atom or sulfur atom

However, when Z is a heteroarylcarbonyl group, at least one of R ⁴ and R ⁵ represents a group other than a hydrogen atom. )

:, Z is Y—R ⁹ (The symbols in the formula have the following meanings.

 Y: represented by the formula: s1 — s— or — C—N—

X ₂ , ( ^{0) m} JR '.

R ⁹ : lower alkyl, cycloalkyl, or aryl which may have a substituent, aralkeninole, aralkyl, or aryloxy lower alkyl, or a heteroaryl group which may be condensed with a benzene ring

R ¹⁰ : hydrogen atom or lower alkyl group

X ₂ : oxygen atom or sulfur atom

m: 0 or 1, 2

However, when Y is a carbonyl group and R ⁹ is a heteroaryl group, at least one of R ⁴ and R ⁵ represents a group other than a hydrogen atom: :), or an acylamino-substituted acylylanilide derivative or a salt thereof; Consists of halogen atoms, hydroxyl groups, lower alkoxy, lower alkanoyloxy, halogeno lower alkyl groups having one or more substituents of the lower alkyl group or aralkyl group of R ⁴ or R ⁵ , R "and R ^T A substituent selected from the group consisting of R ⁹ : aryl, aralkenyl, aralkyl or aryloxy lower alkyl, or benzene The substituent of the heteroaryl group which may be condensed with a ring is one or more of the same or different halogen atoms, hydroxyl groups, halogeno lower alkyl, lower alkyl, lower alkoxy, halogeno lower alkoxy, cyano, nitro, A substituent selected from the group consisting of lower alkanoyloxy, phenyl, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl, lower alkanoylamino and oxo; An acylamino-substituted acylylanilide derivative or a salt thereof,

More preferably, n is 0 and R ⁴ or R ⁵ is the same or different and is a hydrogen atom, or one or more of the same or different substituents is a hydroxyl group, lower alkoxy, lower alkanoyloxy, halogeno lower alkyl group. An acylamino-substituted acylylanilide derivative or a salt thereof, which is a lower alkyl or aralkyl group which may have a substituent selected from the group consisting of:

 Most preferably, a compound selected from the group consisting of: or a salt thereof:

 N— (4-cyano 3-trifluoromethylphenyl) lvamoyl] -1-1-methylethyl

-4-Fluoro-benzamide;

 N—one [(3,4—dicyanophenoline) rubamoyl] — 1—methylethyl} —4

N— {1 — [(3-chloro-1-41-cyanophenyl) canolenoc-moyl ”—1-methyl / reethyl i—4-fluorobenzamide;

 N- {1-[(4-cyano 3-trifluoromethylphenyl) rubamoyl]-1-methylethyl}-1, 2, 4, 6-trifluorobenzamide;

 4-Chloro-N— {1-[(4-Cyanol 3-trifluoromethylphenyl) -lvamoyl] — 1-methylethyl} benzamide;

 Out;

 The present invention also relates to a pharmaceutical composition containing an acylamino-substituted acylylanilide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, in particular, a pharmaceutical composition which is an antiandrogen, especially for prostate cancer and prostatic hyperplasia. The present invention relates to a pharmaceutical composition which is an agent for preventing or treating masculosis, hirsutism, baldness, acne, and seborrhea.

 The compound represented by the general formula (I) will be further described as follows.

In the definition of the general formula in the present specification, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. An aryl group which may have a substituent, an aralkenyl group, an aralkyl group, a heteroaryl group which may be condensed with a benzene ring, or an aryloxy lower alkyl group has 1 to ³ substituents on the ring. It may have a halogen atom, a halogeno lower alkyl group, a lower alkyl group, a lower alkoxy group, a halogeno lower alkoxy group, a cyano group, a nitro group, a lower alkyl group, a hydroxyl group, a phenyl group, a monoalkyl group. Or a di-lower alkylamino group, a mono- or di-lower alkylamino group, a lower alkylamino group or an oxo group:

In R ⁴ , R ⁵ , R ⁶ and R ⁷ , the substituent of “substituted or substituted, lower alkyl group or aralkyl group” may be one or more identical or different substituents. The group is selected from the group consisting of hydroxyl, lower alkoxy, lower alkanoyloxy, and halogeno lower alkyl:

 “Lower alkyl group” means a straight or branched lower alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isoflurane, n-butyl, isobutyl, sec-butyl, ten-butyl. —Butyl, n-pentyl, n-hexyl, etc. ~ 3 lower alkyl groups are preferred \,

 The term "lower alkylene group" refers to a linear or branched lower alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, propylene, isobutylpyrene, butylene, pentamethylene, hexamethylene and the like. Preferred are lower alkylene groups having 1 to 3 carbon atoms, and more preferably methylene.

"Ariru group" is preferably an aromatic carbon hydrogen group having 6 to 12 carbon atoms, for example Fuyuniru, Hina Fuchiru, ₂ further including β- naphthyl is preferably from 6 to 1 carbon atoms () ₌

"Aralkyl group" means "aryl-1 lower alkylene-1".

 "Aralkyloxy group" means "aryl-1 lower alkylene-1-". .

"Ararukeniru group" means "Ariru one lower alkenylene one", preferably C ₆ - a ₁₀ Ariru one C. _ ₆ alkenyl group, phenylene Rueteniru, Fueniruburo Bae alkenyl, naphth / Reeteyuru, Nafuchirupuro Bae alkenyl such as Is mentioned.

 "Aryloxy lower alkyl group" means "aryl-O-lower alkylene-".

"Lower alkoxy" means "lower alkyl-o-":

 “Lower alkoxycarbonyl” means “lower alkyl—O—C (= o) —” :: “Lower alkanoyl” means “lower alkyl-C (= 〇) —” —

“Lower alkanoyloxy group” means “lower alkyl-1 c (= o) —o—”. "Lower alkanoyloxy Noi Rua amino group" of the "lower Arukiru - C (two O) - NR ^{1 1} -" means, R '' represents a water atom or a lower Arukiru _group: -:

 "Halogen atom" includes, for example, fluorine, chlorine, bromine or iodine atom

"Halogeno-lower alkyl group" of the lower Arukiru groups of the C, _"6 Arukiru group i this the Bruno nuclear ^ - is 3 or obtained by replacing, triflumizole Ruo b preferably methyl ::

 “Halogeno lower alkoxy group” means “halogeno lower alkyl mono-”

 "Acyl group" means a broadly defined acyl group, meaning carbonyl and sulfonyl derivatives:

 “Cycloalkyl group” means a 3- to 8-membered saturated hydrocarbon ring, preferably 3 to (member)

"Cycloalkylene group" is a bond of the above cycloalkyl

 “Mono or di-lower alkylamino group” means an amino group in which the lower alkyl group is substituted by 1 or 2 groups.

 “Mono or di-lower alkylaminocarbonyl group” means “mono or di-lower alkylamino C (= O) —”:

And forming a "R ⁴ and R ⁵ gar body and turned by cycloalkyl group which may contain a hetero atom", the cycloalkyl containing carbon atom bonded to R ⁴ and R ⁵ and them as ring atoms —

The ring contains one heteroatom selected from nitrogen, oxygen, and sulfur.

In addition, the hetero atom, for example, a sulfur atom is substituted with one or two oxo groups and

Atom Les substituted by a lower alkyl group, yo Re \ _be; heteroatom is preferably an oxygen atom, the concrete include Okisaniru.

"And n is a R ⁵ and R ⁶ gar body case 1, to form a cycloalkylene group" and includes a carbon atom bonded to R ⁵ and R ⁶ and its those as ring atoms It means forming the above cycloalkylene.

“Heteroaryl group optionally condensed with a benzene ring” means 5 or (containing a heteroaryl group or benzene containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur atoms. A heterocyclic aryl fused with a ring, and the heteroaryl includes bilol, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, thiophene, thiopyran, furan, pyran, dioxolan, thiazole, Isothiazole, thiadiazole, Examples include azine, oxazole, isoxazole, oxaziazole, furazane, dioxazole, oxazine, oxazineazine, dioxazine, and the like. Examples of nitrogen-containing heteroaryl fused to a benzene ring include indole, isoindole, quinoline, isoquinoline, benzothiophene, and benzothiazolone. And benzofuran, benzofurazan and the like:: preferably, pyridine, p ^: limidine, indole, quinoline, thiophene, furan and the like ::

“Heteroarylcarbonyl group” means “heteroaryl c (= o) —”, and heteroaryl means the above 5 or ⁽ membered heteroaryl):

"R ⁸ and R together form a nitrogen-containing cycloalkylene group" or "When n is 1, R ⁷ and R ⁸ together form a nitrogen-containing cycloalkylene group" are defined as ring atoms R ⁸ and the 5- to 7-membered nitrogen-containing cycloalkane, or a ring atoms containing a carbon atom to which nitrogen atom and R ⁵ being substituted is substituted is substituted with R ⁸ les, Ru nitrogen atom and R ⁷ There substituting means to form a 4 to 7-membered nitrogen-containing cycloalkane containing Les, Ru carbon atoms and a _2, specifically pyrrole, piperidine, Kisahidoro Azepin the like to 2, Pyrrole or Pyridine is preferred \:

 In the compound of the present invention, the compound having a tertiary amine may be oxidized with respect to the amine, and includes all oxidized derivatives thereof.

 The compound (I) of the present invention has a tautomer based on an amide bond .: Depending on the type of the substituent, the compound (I) may have one or more asymmetric carbon atoms. And isomers such as (S) isomers, racemic forms, diastereomers, etc. :: Also, depending on the type of substituent, there may be a double bond, (Z) form, (E) form The compound having a ring may have cis-trans. The present invention includes all separated or mixed forms of these isomers.

The compound of the present invention forms a salt. Specifically, the acid addition salts with inorganic or organic acids, there have is a salt with an inorganic or organic bases, Le Shi pharmaceutically acceptable salt is preferred _\: is a salt thereof , Specifically, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, or acidic amino acids such as aspartic acid or glutamic acid, sodium, Inorganic bases such as potassium, magnesium, calcium, aluminum, and lithium; organic bases such as methylamine, ethylamine, and ethanolamine; lysine; Examples thereof include salts with basic amino acids such as ditin. It can also be a quaternary ammonium salt. The quaternary ammonium salt is specifically an ammonium salt obtained by reacting with a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate or a benzyl halide, and preferably a salt with a methinoyl or benzyl chloride. Is

Further, the compound of the present invention can form a hydrate, a solvate with ethanol or the like, or a crystalline polymorph. The present invention includes all of these hydrates, solvates or crystalline polymorphs separated or mixed compounds _:

(Manufacturing method)

 The compound (I) of the present invention can be produced by applying various production methods: The typical production methods are described below.

 First manufacturing method

 (II) (l)

 (The symbols in the formula are the same as above.)

 This production method comprises the steps of amidating a substituted α-salt represented by the general formula (II) with a carboxylic acid or a reactive derivative or a thio-acid or a reactive derivative thereof represented by the general formula (in) to protect the compound. This is a method for producing the compound (I) of the present invention by removing the protecting group when having a group.

 Examples of the reactive derivative of the compound (III) include ordinary esters such as methyl ester, ethyl ester, isobutyl ester, and tert-butyl ester of carboxylic acid; acid chlorides such as acid chloride and acid bromide; acid azide; Active esters, symmetrical acid anhydrides, alkyl carbonate halides, etc., obtained by reacting with phenolic compounds such as 4-dinitrophenol and N-hydroxyamines such as I-hydroxysuccinimide and I-hydroxybenzotriazole Reaction with an organic acid-based mixed acid anhydride, diphenylphosphoryl chloride, N-methylmorpholine obtained by reacting with halocarbonic acid alkyl ester or bivaloyl halide, or triphenylphosphoric acid

) Obtained by combining an organic compound with an activator such as N-bromosuccinimide. Active esters of organic origin include:

 When reacting a carboxylic acid with a free acid, or when reacting without isolating the activity, dicyclohexylcarposimide, carbonyldiimidone, diphene / lephosphoryl / azide, getylphosphoryl cyanide, ] -Ethyl-3- (3-methylaminopropyl) carbo

: Hydrochloride, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride,

- Lou 1- Iruokishi Kisafuruorofu Osufue Bok to Bok squirrel (Jimechiruamino) Fosufoniumu, anhydride Torifuruoro acetic acid, acetic anhydride, ^Pi: Baroiruku port chloride, to use a condensing agent such as methanesulfonyl chloride Ya tosyl chloride are _preferred: in particular In the present invention, a method using an acid chloride or a mixed acid anhydride of phosphoric acid is advantageous:

 The reaction varies depending on the reactive derivative used and the condensing agent, but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, polyester, and the like. Inert organics such as ethers such as tetrahydrofuran, esters such as ethyl acetate, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide. The reaction is performed in a solvent, under cooling, under cooling to room temperature, or at room temperature to heating.

 In the reaction, an excess of substituted aniline (Π) may be used, or N-methylmorpho 11so 1, "amine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-pyridine, picoline, lutidine) It is sometimes advantageous to carry out the reaction in the presence of a base such as pyridine, etc. Pyridine etc. can be used as a solvent ::

 In this case, it may be desirable that oxygen, sulfur, nitrogen, etc. present in the molecule be bonded to a protecting group, and such a protecting group is described in Greene and Wuts, "Protective Groups in Organic." And the like. The protecting groups described in “Synthesis” 2nd edition can be used, and these can be used and divided appropriately according to the reaction conditions.

 Second manufacturing method

(The symbols in the formula are the same as above.) This production method comprises the steps of: (a) adding a substituted amine represented by the present compound (IV) or a salt thereof to a carboxylic acid or a reactive derivative thereof, a sulfonic acid or a reactive derivative thereof, thiocarboxylic acid or a reactive derivative thereof To produce the compound (1) of the present invention by using the same reaction conditions as in the first production method:

 Further, when synthesizing urea or thiourea derivatives, it is preferable to use a condensation reaction with an isocyanate ester or an isothiocyanate derivative in addition to the above.

 The reaction varies depending on the reactive derivative used and the condensing agent, but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene, xylene, ether, tetrahydrofuran, etc. In an organic solvent inert to the reaction of ethers such as ethers, esters such as ethyl acetate, and N, N-dimethylformamide N, N-dimethylacetamide, dimethyl sulfoxide, etc., under cooling, under cooling to room temperature, Or at room temperature or under heating:

 In the reaction, the compound (IV) of the present invention was used in excess, or N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, bicholine, The reaction in the presence of a base such as lutidine may be advantageous for the smooth progress of the reaction. :: Pyridine etc. can be used as a solvent.

 Third manufacturing method

 (la) (lb)

 (The symbols in the formula are the same as above.)

 In this production method, the amide group represented by the compound (la) of the present invention is converted to a thioamide group to produce the compound (lb) of the present invention.

 This reaction can be prepared by any of the known chemical methods for synthesizing thioamide derivatives from amide derivatives such as dipentapentasulfide and Lawesson's reagent:

The reaction is usually carried out with halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ether and tetrahydrofuran, esters such as ethyl acetate and pyridine. In an organic solvent inert to the reaction Rejected, performed under cooling to room temperature, or at room temperature to heating

 When there are multiple amide groups or ureas in the molecule, it is possible to convert any site or multiple amide groups to thioamide groups and urea to thiourea by adjusting the reaction conditions, etc .:

 In addition, hydrolysis, hydrogenation, ureidation, etc. are also carried out by ordinary methods.

 The compound of the present invention thus produced can be isolated and purified as a salt, a hydrate, a solvate, or a polymorphic substance of the compound of the present invention as it is free. Salt can also be produced by subjecting it to a conventional salt formation reaction.

 Although the starting compound of the above-mentioned production method may contain a novel substance, it may be produced by applying the production method described in Reference Example, a method analogous to the production method, or a modified method arbitrarily practicable by those skilled in the art. it can. Isolation and purification are performed by applying ordinary chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography:

By selecting appropriate starting compounds, various isomers can be separated by utilizing the difference in physicochemical properties between isomers. For example, by optical isomers selecting appropriate raw materials, or by racemic resolution method of racemic compounds, the availability of the _c industry that can be force S lead to stereochemically pure isomers

 The compound of the present invention has a strong anti-androgenic effect by suppressing the transcriptional activation by androgen, and is a compound having few side effects such as central action and agonist action.

 Therefore, the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which androgen is involved as an adverse factor, for example, prostate cancer, prostatic hypertrophy, virilization, hirsutism, baldness, acne, seborrhea and the like. is there. The usefulness of the compound of the present invention has been confirmed by the following test methods! RU

1. Transcriptional activation of human androgen receptor

Human androgen receptor expression gene, MMTV reporter gene stable transformant and

Obtaining SV40 reporter gene stable transformant

CHO cells were seeded on a 100-mm-diameter cell culture dish with 10 ⁶ IX cells, and 12 to 18 hours later, a human androgen receptor expression plasmid co-precipitated with calcium phosphate, MMTV-LTR The luciferase jelly boater plasmid (including the neomycin resistance gene) was added and transfection was performed. After 15 hours, the medium was removed, the cells were diluted in several steps, and replated, and the medium was fed with GENETICIN® (neomycin) to a final concentration of 500 μg / ml .: About 1 week later, the cells were selected by neomycin. The isolated cells were detached, and cells expressing the human androgen receptor expression gene, MMTV-luciferase revoter-gene, constitutively expressing and isolated by the limiting dilution method (CHO / MMTV stable transformant:

 An SV40 reporter gene stable transformant was obtained in the same manner as described above. However, the SV40 reporter plasmid and the neomycin resistance gene expression plasmid were simultaneously transfected (CHO / SV40 stable transformant; ^

a) Evaluation of transcriptional activation on human androgen receptor (agonist effect)

CHO / MMTV stable transformant cells and CHO / SV40 stable transformant cells were seeded at 1 × 10 ⁴ cells / well in a luminobure 1 for% well cell culture, and the compound of the present invention was added 6 to 8 hours later. 18 minutes after compound addition, add 20 μl of a solution containing 1% Triton-X and 10% glycerol to lyse the cells, add 100 μl of luciferase substrate solution containing 0.47 mM luciferin, and use a luminometer. The luminescence was measured and these were taken as the luciferase activities obtained by MMTV-LTR transcriptional activation by the human androgen receptor and non-specific SV40 flow motor transcriptional activation:

 The transcription activation effect of the compound of the present invention was calculated by the following formula as a ratio to the transcription activity induced by InM DHT.

 Induction ratio (%) = 100 (-8) / (1-8)

 I: (MMTV Luciferase activity) / (SV40 Luciferase activity) when InM DHT is added B: Untreated (MMTV Luciferase activity) / (SV40 Luciferase activity)

 X: (MMTV luciferase 'activity) / (SV40 luciferase' activity) when the compound of the present invention is added b) Evaluation of transcriptional activation inhibitory effect on human androgen receptor (antagonist effect)

CHO / MMTV stable transformant cells and CHO / SV40 stable transformant cells were seeded at 1 × 10 ⁴ cells each in a luminoblate for% well cell culture, and after 6 to 8 hours, simultaneously with DHT (final concentration 0.3 nM). The compound of the present invention was added. Eighteen hours after the addition of the compound, the cells were lysed by adding 20 μl of a solution containing 1% Triton-X and 10% glycerol, and 100 μl of a luciferase substrate solution containing 0.47 mM luciferin was added, followed by luminescence using a luminometer. Measure the amount Luciferase activity obtained by MMTV-LTR transcriptional activation by human androgen receptor and non-specific SV40 promoter transcriptional activation:

 The inhibitory effect on transcriptional activation by the compound of the present invention was calculated by the following formula as the inhibition rate against the transcriptional activity induced by 0.3 nM DHT.

 Inhibition rate (%) = 100 (1'-Χ ') / (Γ-Β)

 Γ: 0.3ηΜ When only DHT is added (MMTV luciferase “activity”) / (SV40 luciferase “activity”) B: Untreated (MMTV luciferase “activity” / (SV40 luciferase ”activity)

 X ': (MMTV luciferase' activity when simultaneously adding the compound of the present invention and 0.3 nM DHT

 Sex) / (SV40 Luciferase-active)

The IC ₅₀ was determined from the concentration of the compound of the present invention at which the inhibition rate calculated by the above method was 50%. The activity of the compound of the present invention determined by the above a) and b) is shown below:

 table 1

 2. Inhibitory effect on testosterone-induced increase in prostate weight in young castrated rats

 Three-week-old male Wistar rats were simultaneously administered testosterone propionate and the compound of the present invention once a day for 5 consecutive days from 72 hours after castration. Six hours after the final administration, the wet weight of the ventral prostate was measured, and the inhibitory effect of the compound of the present invention on the increase in prostate weight by testosterone propionate was examined.

Testosterone propionate was dissolved in cottonseed oil containing 5% ethanol and subcutaneously administered at a dose of 0.5 mg / kg body weight of the rat _{: the} compound of the present invention was orally administered in a 0.5% methylcellulose solution ::

The prostate weight increase inhibitory effect of the compound of the present invention was as follows: test group in which testosterone flobionate and the compound of the present invention were administered together, test group in which testosterone propionate alone was administered, and control group, and no testosterone propionate and the compound of the present invention. The group was set as an untreated group and calculated by the following formula. Suppression rate (%) = 100 (8 ^) / (8)

 A: Wet weight of ventral prostate in test group

 B: Wet weight of ventral prostate in control group

 C: Ventral prostate wet weight in the untreated group

 The activity of the compound of the present invention determined by the above test method is shown below.

Table 2

From these tests, it was confirmed that the compound of the present invention had a pure antiandrogen action and strongly inhibited the action of androgen. In addition, it was also confirmed that the compound had a low central nervous system, and that there were few side effects. , Androgen is a compound useful as a therapeutic agent for the prevention and treatment of diseases associated with exacerbation factors ₌

 Preparations containing one or more of the compound of the present invention or a salt thereof as an active ingredient are prepared using carriers, excipients and other additives that are usually used for preparation.

The drug can be administered orally in the form of tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous and intramuscular injections, and parenteral administrations such as suppositories and transdermals. _good:: dose symptoms, age of the administration subject, taking into account the sex and the like when an adult per day force through normal oral administration is appropriately determined on a case-by-case basis () 0 1~:. l OOOmg about 1 to 100 mg, preferably 0.1 to 100 mg per adult for parenteral administration per day (). 1 to 100 mg, preferably about 0.001 to 50 mg, divided into 1 dose or 2 to 4 doses Dosing _c

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances include at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with acid, magnesium aluminate: The composition is formulated according to the usual practice with additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as calcium cellulose dalcholate. Tablets or pills may contain sucrose, gelatin, hydroxypropylcellulose, hydroxypro as required, including stabilizers such as lactose and solubilizing agents such as glutamic acid or aspartic acid. -Sugar coatings or gastric-soluble coatings such as ト may be coated with a film of enteric substance:

 Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, tablets, elixirs and the like, and are generally inert diluents such as purified water. Contains: In addition to the inert diluent, this composition may contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, preservatives, :

Injections for parenteral administration include sterile aqueous or non-aqueous solutions ij, aqueous solutions including suspensions and emulsions, and suspensions include, for example, distilled water for injection and physiological saline. Contains saline. Non-aqueous solutions and suspensions, for example ^blanking: b propylene glycol, Boriechiren glycolate Ichiru, vegetable oils such as Oribu oil, alcohols such as ethanol, Borisorubeto 80. - Such compositions In addition, it may contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the production of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

 The following examples are provided to describe the present invention in more detail. The present invention is not limited to these examples. :: Production of the starting compounds used in the examples The method is explained as a reference example

Reference example:!

 Methyl 2- (4-fluorophenylsulfonylamino) butanoate

 Dissolve 1.54 g of methyl 2-aminobutanoate hydrochloride in 15 ml of chloroform and add dropwise 23.23 g of triethylamine and 1.95 g of p-fluorophenylsulfonyl chloride under ice-cooling. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with 35 ml of chloroform, washed with 50 ml of 1N hydrochloric acid and 5 () ml of saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diisopropyl ether was added to the residue. () ml was added, and the precipitated crystals were recrystallized from ethyl acetate to give 2.73 g of the title compound as colorless crystals.

The following Reference Example was synthesized in the same manner as Reference Example 11-11. Reference example Compound name

Reference Example 1 2 Li (4-Funore “Iku-Nozylamino”) 2 Methyl methyl propanoate

Reference Example 1-3-2 (2-Methoxyziramino) methyl 2-methylpropanoate

Reference Example 1-42- (4-cyano ^ non "ylamino) 2-methylpropanoate

Reference Example 1 52 2- (4-Trifluoromethylbenzoylamino) 2-methylpropanoate Methyl Reference Example 1-62 2- (4-Funolei Lof :: Nylsulfonylamino 2-Methylpropanoate Reference Example 1-72 2- (4-Nitrophenylsulfonylamino) methyl 2-methylpropanoate Reference Example 1-82--(4-Methoxyphenylsulfonylamino) 2-methylpropanoate Reference Example 1-93 -(4-Funolelov: Nylsulfonylamino) methyl methyl lobanoate

Reference Example 1-10 Methyl 3- (4-fluoro-: nylsulfonylamino) butanoate

REFERENCE EXAMPLE 1-1 1 1 1 (4-FURULOF: Nisulfonylamino) cyclo 'Methyl propylcarboxylate' ■ REFERENCE 1-1 Methyl

REFERENCE EXAMPLE 1 13: 1 Methyl (4-fluorophenylsulfonylamino) cyclopentylcarboxylate Reference Example 1-14-1 (4-Fluorobe: zylamino) methyl pentylcarboxylate

REFERENCE EXAMPLE 1 15 1 (4-FUNORESHILOF ;: Nylsulfonylamino) cyclo 'methyl hexylcarboxylate Reference Example 1-16 1- (4-Fluorobe, zolylamino) cyclohexylcarboxy

Reference Example 1-17 4- (4-Funoleolo ^: Zyrylamino) tetrahydro πpyran-4 Methyl carboxylate Reference Example 1-18 3- (4-Fluoro-nozylamino) -2.2,3 Ethyl trimethylbutanoate Reference Example twenty one

 2— (4—Funoleolopheninolesulfonyla:

Dissolve 2.73 g of methyl 2- (4-fluorophenylsulfonylamino) butanoate in 4 () ml of methanol, add 2 () ml of 1N aqueous sodium hydroxide solution under ice-cooling, and stir at room temperature for 8 hours. After the methanol was distilled off under reduced pressure, 2 () ml of 1N hydrochloric acid was added dropwise under ice cooling to pH2, and the organic layer _c extracted four times with 50 ml of ethyl acetate was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 20 ml of diisopropyl ether was added to the residue, and the precipitated crystals were recrystallized from ethyl acetate to obtain 1.5: 3 _g of the title compound as colorless crystals ::

 The following Reference Example was synthesized in the same manner as Reference Example 2-1.

 Reference example Compound name

Reference Example 2—2 2 — [(4-Fluorophenylsulfonyl) methinoleamino] propanoic acid

Reference Example 2—3 2— (4-Fluorobenzoylamino) -2-methylpropanoic acid

Reference Example 2—42- (2-Methoxybenzoylamino) -1-methylpropanoic acid

Reference Example 2—5 2— (4-cyanobenzoylamino) 2 methylpropanoic acid

Reference Example 2—62— (4-Trifluoromethylbenzoylamino) -2-methylbutyric acid

Reference Example 2— 7 2— (4-Fluorophenylsulfonylamino) 2--methylp'banic acid

Reference Example 2—8 2— (4-Nitrophenylsulfonylamino) 2-methylpyrrole ¾

Reference Example 2-92- (4-methoxyphenylsulfonylamino) 2-methylpropanoic acid

Reference Example 2—10 2— (N--Ninoleoxy 4-Fluoro-Kunsamide) One 2-Methyl / Ref. Lono, acid Reference Example 2-1 13- (4-Fluorophenylsulfonylamino) propanoic acid

Reference Example 2—12 3- (4-Fluorophenylsulfonylamino) butanoic acid

Reference Example 2-13 1- (4-Fluorophenylsulfonylamino) cyclopropylfuronic acid Reference Example 2—14— (4-1: boric acid Reference Example 2—15 1— (4-fluorophenylsulfonylamino) cyclopentylcarboxylic acid Reference Example 2—16 1— (4-funo π- Reference Example 2—17 (4-Fluorophenylsulfonylamino) cyclohexylcarboxylic acid g Reference Example 2-18 (4: no) cyclohexylcarboxylic acid

Reference Example 2—194- (4 full 4-carboxylic acid

Reference Example 2—20 3 -— (4-2.2.3-trimethylbutanoic acid Reference Example 3

2 — [(4-Fluoroferylsulfonyl) methylamino] f ^: methyl rovanate

After dissolving 500 mg of methyl 2- (4-fluorophenylsulfonylamino) pitanate in 5 ml of N, N-dimethylformamide, 320 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 10 minutes. of methyl iodide was added 330 m _g, under an argon atmosphere, the reaction solution was stirred at room temperature for 12 hours then diluted with acetic acid Echiru 5 () ml, washed with distilled water 50 ml, ₌ vacuo was drying over anhydrous magnesium sulfate After evaporating the solvent, the obtained crude crystals were recrystallized from ethyl acetate to obtain 470 mg of the title compound as colorless crystals.

Reference Example 41

 2— ^ benzyloxycarbonylamino-N— (4-cyano-13-trifluoromethylphenyl) prononamide

2 base Nji Ruo alkoxycarbonyl § amino Pro vans acid 6. and N, N-a Jimechiruase Bok amide 70 ml mixture, after cooling to 20 3, ₌ argon Kiri囲gas under dropwise Chionirukurorido 3. 93 _g, same After stirring at the temperature for 1 hour, 5.58 g of ^4- amino- ² -trifluoromethylbenzonitrile was added little by little, and the mixture was further stirred for 3 hours. The reaction solution was diluted with 2 () () ml of ethyl acetate, washed with 200 ml of saturated aqueous sodium bicarbonate, twice with 20 () ml of distilled water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain crude crystals from a fraction eluted with ethyl acetate ( ₇ : 3) :: These crude crystals were recrystallized from ethyl acetate. 8.17 g of the title compound was obtained as colorless crystals. The following Reference Example was synthesized in the same manner as Reference Example 411.

 Reference example Compound name

Reference example 4 2 2 N-dioxy carbonylamino-N (4-cyano 3- -trifluoromethylphenyl) methylpropananilide

Reference Example ₄ 3 2-benzyl O butoxycarbonylamino over ^N: - (4-Shiano 3 triflate Ruo B methyl phenyl) 3-methoxy propanamide Reference Example 4 4 3 base Nji Ruo alkoxycarbonylamino over N-(4-Shiano 3 triflate Ruo Russia methyl phenylene Honoré) 2, 2-Jimechinorefurono, ⁰ N'amido

Reference Example 4 52 2-Aryloxycarbonylamino-N— (3,4-dicyanophenyl) -1-methyl Reference Example 4 61 Benzyloxycarbonylamino-N— (4-cyano 3- Trifluoromethylphenyl) cyclobutylcarboxamide Reference Example 5

 2- (N-benzyloxycarbonylamino) -2-rononic acid

 To a 1 N aqueous sodium hydroxide solution 56 m], under ice-cooling, add 5-79 g of 2-methylpropanoic acid, followed by benzyloxycarbonyl chloride. The mixture was added dropwise and left at room temperature for 3 hours. After washing with the reaction solution three times, IN hydrochloric acid was added until the pH reached 2, and the mixture was extracted three times with 3 () () ml of ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give 6.95 g of the title compound as colorless crystals. Reference Example 6

 4'-cyano 3'-trifluoromethyl trifluoroacetanilide

 5.0 () g of 4-amino-2 trifluoromethylbenzonitrile was dissolved in 20 ml of chloroform, and 5.3 ml of anhydrous trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. After washing with chloroform, 3.93 g of the title compound was obtained:

Reference Example 7

 4-Monomethylamino-2-trifluoromethylbenzonitrile

Suspension of sodium hydride 0. 22 g N, N- dimethylformamide 10 ml, the 4 '- Shiano one 3' - stirred triflate Ruo b methyltriflate Ruo B acetonate § oxanilide 1 41 _g was added under ice-cooling for 30 minutes. :: after stirring at reaction solution methyl iodide 0. 62 ml was added 4 hours 60 ^e C, water cooling under a saturated aqueous solution of potassium carbonate 10ml was added and stirred for 1 hour at the same temperature to the reaction solution. The reaction mixture was diluted with 50 ml of ethyl acetate, washed twice with 50 ml of distilled water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 0.63 g of the title compound from a fraction eluted with ethyl acetate (3: 7).

Reference Example 8

2- (benzyloxyamino) -1-ethyl methyl propanoate 1-95 g of a-bromoisobutyrate ethyl acetate and 1.6 g of Ο-benzylhydroxy / reamine hydrochloride in 2 () ml of N, N-dimethylformamide solution, calorie 3.3 g of anhydrous potassium carbonate. The mixture was stirred under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with (). 5N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, and the title compound 0.3 was obtained as an oil from the hexane monoethyl acetate (1 (): 1) eluted portion, Reference Example 9

2- (N-benzyloxy-4-fluorobenzamide) -2-ethyl ethyl propylate 2- (benzyloxyamino) -1-ethyl ethyl ethyl methyl bromide 0.85 g pyridine solution 10 m 2 4-fluorobenzoyl chloride 0.68 g was added, the :: reaction solution was heated to reflux for 10 hours under reduced pressure Shimono reduced, the iN hydrochloric acid was added to the residue, and extracted with acetic acid _Echiru:: the organic layer was washed with water and dried over anhydrous sulfate magnesium © beam . The solvent was distilled off under reduced pressure, and the obtained crystals were washed with petroleum ether to obtain 0.95 g of the title compound.

Reference Example 10-1

 2-amino-N- (4-cyano-3-lomethylphenyl) furovanamide

Reference Example 4 2-Nilamino-N- (4-cyano-3-tritinolerefle) synthesized in 1-11: 5 mU of, 2-dichloroethane, dissolved in water, under cooling with water, 79 () mg of dimethylsulfide, trifluoride boron Jefferies chill ether complex 6 () () mg forward; under an argon atmosphere, was stirred at room temperature for 13 hours, the mixture was stirred for 30 minutes at _c further at room temperature was added a saturated chloride Anmoniumu solution 10 ml, under ice-cooling, pH IO the 1 N aqueous sodium hydroxide until added, extracted three times with acetic Echiru 50 ml, the solvent was distilled off ₌ vacuo was dried over anhydrous magnesium sulfate and the organic layer, the residue methanol was added to the precipitated crystals Was recrystallized from methanol to obtain 189 mg of the title compound as colorless crystals.

 (Alternative)

277 nig of 2-amino-2-methylpropionic acid was suspended in 3 ml of N, N-dimethylacetamide, 0.26 ml of thionyl chloride was added at -10 C, and the mixture was stirred at the same temperature for 1 hour. Then, 4-amino-1-2-trifluoromethylbenznitrile was added, and the mixture was stirred for 2 hours while gradually warming to room temperature. Water was added to the reaction solution, washed with ethyl acetate, and then washed with a 1N aqueous sodium hydroxide solution. It was made alkaline. The released oil was extracted with butyl acetate, and the solvent dried over anhydrous sodium sulfate was reduced. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and 4 () () mg of the title compound was obtained as a colorless oil from a fraction eluted with chloroform-methanol (97: 3). row recrystallized from hexane Chiru to give the title _compound:: physical properties of this compound were in complete agreement with the compound obtained et the above:

 The following Reference Example was synthesized as in Reference Example 10-1.

Reference Example 10-2

 2-amino-N- (4-cyano 3-trifluoromethylphenyl) -1-methylbrovanamide Reference Example 10-3

 N- (4-cyano 3-trifluoromethylphenyl) -1-methylfurolinamide hydrochloride Reference Example 1 1 1 1

 2-amino-1 N- (13,4-dicyanophenyl) -1-2-methylfurovanamide

(1) A mixture of 30 g of 2-benzyloxycarbonylamino-2-methylpropanoic acid and 130 ml of N, N-dimethylacetamide was cooled to 12 () C, and 2 ml of thionino rechloride K) was added dropwise. After stirring for 1 hour at the same temperature in an argon atmosphere, a mixed solution of 18.2 g of 4-aminophthalonitrile and 70 ml of N, N-dimethylacetoamide was added dropwise at the same temperature for 7 hours. was stirred for 18 h at _0¾:: after diluting the reaction solution with acetic acid Echiru and lavage with a saturated sodium bicarbonate solution: in addition, 1N hydrochloric acid, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude crystal.

(2) The obtained crude crystals were dissolved in 100 ml of dichloromethane, 25 ml of dimethyl sulfide and 15 ml of boron trifluoride-ethylester complex were sequentially added under ice cooling, and the mixture was stirred at room temperature for 3 days. 25 ml, boron trifluoride GETS chill etherate 15ml was added, 1N hydrochloric acid was added to the ₌ reaction was 1 day stirred at room temperature, and separated after stirring, the aqueous layer was washed with black port Holm. After addition of 1N sodium hydroxide until the aqueous layer strength) H10, and extracted with acetic acid Echiru ₌ the solvent was distilled off under reduced pressure and the resulting crude crystals were recrystallized from a mixed solvent of hexane and acetic acid Echiru 4.7 g of the title compound were obtained ₌

 Reference Example 1 The following Reference Example was synthesized in the same manner as 1-1.

Reference Example 11 1 2

2-amino-2- (3,4-dicyanophenylcarbamoyl) ethyl acetate -Dissolve Og in 30 ml of acetonitrile, add 1.4 ml of trimethylsilane iodide under ice-cooling, and add 1 ml of the same temperature at the same temperature for 1 hour. The stirred reaction solution was weighed sequentially with 1 ml of methanol and 30 ml of water, and washed with getyl ether. After adding saturated aqueous sodium bicarbonate until the aqueous layer reached pH 9, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystal was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound]., () G: similar to Reference Example 12-1 The following reference examples were synthesized. .

Reference Example 12-2

 1—Amino N— (4—Siano 3—Trifluolo 'mouth

Reference Example 12-3

 3—Amino N— (4—Cyano 3—Trifluoro-2,2-amide

Reference Example 13

 2-Amino (3,4-dicyanophenyl) -3--3-Synthesis of 2-aryloxycarbonylamino-N- (3,4--3-methylbutanamide 1.88 g in Example 10 and 530 mg of formic acid in tetrahydrofuran

After adding 1.66 _g of phenylphosphine palladium and heating and refluxing for 10 hours in an argon stream, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 1N hydrochloric acid and ethyl acetate, and the aqueous layer was separated. The aqueous layer was basified with 1 N sodium hydroxide solution and extracted the liberated oil in acetic E Ji Le, a ₌ the solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting residue The residue was purified by silica gel column chromatography, and 435 mg of the title compound was obtained as a colorless oil from a fraction eluted with chloroform-methanol (95: 5, V / V).

Reference Example 14

 1-Benzyloxycarbonyl N- (4-cyano 3-trifluoromethylphenyl) -2-methylprolinamide

(1) Dissolve 3.2 g of 1-benzyloxycarbonyl-2-methyl-1-proline in 10 ml of 1,2-dichloroethane, add 470 mg of oxalyl chloride dropwise under ice-cooling, and add a catalytic amount of N, N dimethylformate. Muamide was added, and the mixture was stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure, 1,2-dichloroethane (20 ml) was added and the residue was distilled off again: The resulting residue was dissolved in N, N dimethylacetamide (5 ml), and the mixture was dissolved in ice and cooled with ice to give 4-amino-12-trifluoro. After adding 3 and 2 g of o-methylbenzonitrile in small portions, the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with 50 ml of dimethyl acetate, and washed with 50 ml of 1N hydrochloric acid, 50 ml of saturated sodium bicarbonate solution and 50 ml of distilled water. , And dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-hexane to obtain 5.64 g of the title compound.

Reference Example 15-1- [4- (4-fluorobenzoyl) amido] cyclohexylcarboxylic acid

 4 1.43 g of aminocyclohexyl carboxylic acid (mixture of cis and Lmn.s) was dissolved in l () ml of 1N aqueous sodium hydroxide solution, and triethylamine 1. () lg was added:: then 4 A solution of 1.59 g of tetrafluorofuran (5 ml) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, washed with ether, acidified with conc. Extracted with ethyl, dried and concentrated to obtain 2.41 g of the title compound.

 The following Reference Example was synthesized as in Reference Example 15-1:

Reference example 15-2

 1- (4-fluorobenzoyl) azetidine-1: 3-carboxylic acid

 The physical properties of these Reference Examples are shown in the table.

 The symbols in the table have the following meanings:

 Ref.Ex .: Reference example number AcOEt: Ethyl acetate

 DATA: Physical and chemical properties Hex: Hexane

 NMR: nuclear magnetic resonance spectrum EtOH: ethanol

(Unless otherwise _{stated, DMSO-d 6, (Et} ) 2 0: Jefferies chill ether

 L, 2-diCl-Et: l, 2-dichloroe mp: 測定

Table 3

 Ref.Ex DATA

1 -1 NMR: ό: 0.77 (3H, t, J = 7.3 Hz), 1.40-1.66 (2H, m), 3.40-3.64 (1 H, m), 3.68 (3H, s), 7.28 -7.47

 (2H, m), 7.77-7.92 (2H, m), 8.15 (1H, d, J = 8.8Hz)

1 -2 NMR (CDCI ₃ , TMS internal standard)

 5: 1.68 (6H, s), 3.79 (3H, s), 6.77 (1H, br), 7.00-7.19 (2H, m), 7.71 -7.87 (2H, m)

1 -3 NMR (CDCI _3> TMS internal standard)

tLlP0/L6d£/lDd Z - b: 1.65 (6H, s), 3.62 (3H, s), 4.00 (3H, s), 6.95-7.45 (3H, m), 8.20-8.49 (2H, m)

tLlP0 / L6d £ / lDd Z-

実施例 1 PLlP0 / L6d £ / lDd OAV

Example 1

N- (4- -L) -1-2-((methylsulfonyl) amino] mouth Reference Example 1 2-amino-1-N- (4-cyano-3-3-trifluoromethylphenyl synthesized in () -11 ) Puroban'amido 25 () was dissolved mg to black port Holm 5 ml under ice-cooling, Toryechiruamin 1 10 m _g, methanesulfonyl chloride 12 () mg was added, under argon, ₌ reaction click was stirred for 3 hours at room temperature After diluting with 50 ml of roloform, washing with 50 ml of 1N hydrochloric acid and 5 () ml of saturated saline, and drying with anhydrous magnesium sulfate: The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate. This gave 114 mg of the title compound as a colorless product _c:

It was synthesized in Example 2 16 in the same manner as in Example _1:

 Example 17

 N- (4-cyano 3-trifluoromethylphenyl) -1-2-[[(4-fluorophenizole) sulfonyl] amino] butyramide

Dissolve 500 mg of 2- (4-fluorophenylsulfonylamino) butanoic acid in 5 ml of tetrahydrofuran, add 470 mg of oxalyl chloride dropwise under ice cooling, and add a catalytic amount of N, N-dimethylformamide. The mixture was stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure, tetrahydrofuran (20 ml) was added and distilled off again. The obtained residue was dissolved in 5 ml of N, N-dimethylformamide, and 580 mg of 4-amino-2-trifluoromethylbenzonitrile was added little by little under ice-cooling, followed by stirring at room temperature for 6 hours. The reaction solution was diluted with 50 ml of ethyl acetate, washed with 5 () ml of 1N hydrochloric acid, 50 ml of saturated aqueous sodium hydrogen carbonate and 50 ml of distilled water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and dissolved in ethyl acetate-hexane (17: 3). A crude crystal was obtained from the outlet. The crude crystals were recrystallized from ethyl acetate, and Example] 8-21 was synthesized in the same manner as in Example 3 of the title compound as colorless crystals.

Example 22

 N- (4-cyano 3-trifluoromethylphenyl) 1-2- (4-fluorophenyl) amino] propanthioamide

 Dissolve 600 mg of N- (4-cyano 3-trifluoromethylphenyl) -1-{[(4-fluorophene: -norre] amino} propanamide in l () ml of toluene and add 29 () mg of Lawesson's reagent. After heating under reflux in an argon atmosphere for 3 days, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl ethyl acetate. (4: 1) Crude crystals were obtained from the eluted portion, and the crude crystals were recrystallized from ethyl acetate to give 339 mg of the title compound as colorless crystals.

 Examples 23 and 24 were synthesized in the same manner as in Example 1.

Example 25

 N— {1 — [(4-cyano 3-trifluoromethylphenyl) -rubamoyl] -1—methylethyl} 1-41-fluorobenzamide

 Dissolve 500 mg of 2- (4-fluorobenzoylamino) -1-methylpropanoic acid in 30 ml of dichloromethane, add 933 mg of triphenylinolephosphine and 633 mg of N-bromosuccinimide in small portions under ice-cooling, and then add argon. The mixture was stirred at the same temperature for 2 hours .: Further, 872-nig of 4-amino-2-trifluoromethylbenzonitrile was added little by little, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to obtain crude crystals from a fraction eluted with ethyl acetate (17: 3). The crude crystals were recrystallized from ethyl acetate to give 156 mg of the title compound as colorless crystals.

 Examples 26 to 33 were synthesized in the same manner as in Example 25-Examples 34 to 64 were synthesized in the same manner as Example 1.

Example 65

 N— {1-([4-cyano 3-trifluoromethylphenyl) -lvamoyl] 1-1-methylethyl} 1-2-cyanobenzamide

(1) Phthanolamide 5. Dissolve Og in dichloromethane. Then, 6.37 ml of ethyl and chloroformate were added, and the mixture was stirred for 1 hour and further stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, a mixed solvent of benzene and hexane was added, and the precipitated crystals were separated by filtration. Was distilled off to give 2-cyanobenzoic anhydride (58 mg).

(2) Reference Example 10-2 2-amino-N- (4-cyano-13-trifluoromethylphenyl) -2-methylfrovanamide 2 () 0 mg dichloromethane solution in 1 Oml 323 _mg of 2-cyanobenzoic anhydride was added, and the mixture was stirred at room temperature for 9 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain crude crystals from a fraction eluted with ethyl acetate / hexane (1: 1). the crude crystals were recrystallization with methanol monoacetate Echiru mixed solvent, to give the title compound ₁₉ () m _g Ω

Example 66

 Ν— (4-cyano 3-trifluoromethylphenyl) 1-2- [2- (4-fluorophenyl) a cetylamino] -2-methylpropanamide

(1) To 5 ml of a dichloromethane solution of 2 mg of 4-fluorophenylacetic acid l ⁽⁾ , add 0.057 ml of oxalyl chloride and a catalytic amount of N, N-dimethylformamide under ice-cooling, stir at room temperature for 2 hours, and reduce the pressure. The solvent is concentrated to dryness, and 4-fluorophenylacetylchloro '

 (2) 2-amino-N- (4-cyano 3-) synthesized in Reference Example 10-2

B) Add 2 ml of bi'lysine to 5 ml of a dichloromethane solution of 150 mg of 1-methylmethylarovanamide, add 5 ml of the above-mentioned dichloromethane solution of 4-fluorophenylacetyl chloride under ice-cooling, and incubate at the same temperature for 1.5 hours. After stirring, the mixture was stirred at room temperature for 1.5 hours. :: Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The solvent was distilled off to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to give 98 mg of the title compound.

Example 67

 N— {1 — [(4-Cyanol 3-trifluoromethylphenyl) potamyl] -1-1-methylethyl} -1-hydroxybenzamide

Dissolve 150 mg of 2-((U — [( ⁴ -cyano-3-trifluoromethylphenyl) carbamoyl] -111-methylethyl) potassium phenylacetate synthesized in Example 44 in 1 ml of methanol. After adding 3 ml of 1N aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 2 hours. Methano under reduced pressure After distilling off the solvent, 1N hydrochloric acid was added to obtain crude crystals :: The crude crystals were recrystallized with a mixed solvent of ethyl acetate and hexane to obtain 2 mg of the title compound l ().

Example 68

 N—U — [(4-cyan-1-3-trifluoromethylphenyl) rubamoyl]

1} 8-quinolinecarboxamide

 (1) To 5 ml of 8-quinoline azo solution, add oxalyl chloride (). 114 ml and a catalytic amount of N, N-formamide under ice-cooling, stir under ice-cooling for 30 minutes, and concentrate the solvent under reduced pressure to dryness. This gave 8-quinolinecarboyl chloride hydrochloride:

(2) Reference Example 10-2 2-amino-N- (4-cyano-13-trifluoromethylphenyl) -1-methylpropanamide 30 () mg 30 mL dichloromethane solution in 5 ml under ice-cooling added dichloromethane 5 ml and Bok Ryechiruamin 0. 364 ml of 8-halfhearted down force Rubonirukurorido hydrochloride, acetate Echiru added to the stirred ₌ reaction solution at room temperature for 2 hours, which saturated aqueous sodium bicarbonate solution, followed by After washing with water, the organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 1) elution part A crude crystal was obtained. The crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 155 mg of the title compound.

 Examples 69-78 were synthesized in the same manner as in Example 68.

Example 79

 N— {1-[[4- (1-cyano-13-trifluoromethylpheninole) rubamoyl] — 1-methylethyl-4-viridinecarboxamide

To a mixture of 0.15 g of nicotinic acid and 10 ml of dichloromethane was added 0.18 g of N-hydroxybenzotriazole and 0.25 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride under ice-cooling. sequentially added and ₌ at the same temperature, 2 more hours after stirring, 2-Amino one N-(4 one Shiano - 3- Torifuruo Romechirufueniru) one 2-methylpropanamide 0. 30 g of Karoe, 6 hours at room temperature, further tetrahydro furan 5ml was added a saturated aqueous sodium hydrogen carbonate was added to the ₌ reaction was stirred 65 hours at the same temperature, out extraction with acetic Echiru, washed with saturated aqueous sodium chloride solution, the solvent ₌ vacuo drying over anhydrous magnesium sulfate The crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.26 g of the title compound.

Examples 80 to 87 were synthesized in the same manner as in Example 79. Example 88

 2 — [(4-Cyanol 3-Trifluoromethylphenol) Lubamoyl] —2— (2-Fluorobenzoamide) ethyl acetate

(1) 3.9 g of 3-acetoxy-2-benzyloxycarbonylaminopropanoic acid was dissolved in N, N-dimethylacetoamide 3 Oml (this was dissolved and cooled to -2 () ^; C, then thionyl chloride 1.1 ml) After stirring under an argon atmosphere for 1 hour, 2.6 _g of 4-amino-3-trifluoromethylbenzonitrile was added little by little, and the mixture was stirred at the same temperature for 2 hours. Was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, further washed with 0.1N hydrochloric acid and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Got ::

 (2) The obtained crude crystals were dissolved in dichloromethane (100 ml), dimethylsulfide (10 ml) and boron trifluoride diethyl ether complex (8 ml) were sequentially added under water cooling, and the mixture was stirred at room temperature for 4 hours. , Extracted with ethyl acetate, and washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude crystal.

(3) The obtained crude crystals were dissolved in 5 ml of dichloromethane, and 0.56 ml of 2-fluorobenzoyl chloride and 06 ml of triethylamine (). (06 ml) were sequentially added under cooling with water, followed by stirring at room temperature for 2 hours. to the reaction solution, saturated aqueous sodium bicarbonate was added, followed by extraction with acetic acid Echiru, 0. iN hydrochloric acid, dried with _c anhydrous magnesium sulfate was washed with saturated aqueous sodium chloride solution, the solvent was distilled off under reduced pressure, the crude crystals The obtained crude crystal was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.25 g of the title compound.

 Ν— {1— [(4-cyano 3-trifluoromethylphenyl) -lubamoyl] -1-2-hydroxyethyl} -1-2-fluorobenzamide

2— [(4-Cyan-3-trifluoromethylphenyl) potassium] Dissolve 0.50 g of 2- (2-fluorobenzoamide) ethyl acetate in 5 ml of methanol, and saturate under ice-cooling. added aqueous potassium carbonate 2 ml, 1 hour at the same temperature further and PH2 adding iN hydrochloric acid _c reaction solution was stirred for 1 hour at room temperature, the precipitated crystals were _Iorito:; the resulting crude crystals were washed with water After that, recrystallization from dimethyl acetate-hexane gave 26 g of the title compound ::

Example 90

Ν- {1-[(4-cyano 3-trifluoromethylphenyl) rubamoyl] — 1-methylethyl} 1-4-methoxybenzamide Dissolve 43 () mg of 2-amino-N- (4-cyano: 3-trifluoromethylphenyl) -1-methylfuro ^: rohanamide in 5 ml of tetrahydrofuran, and cool with ice-cooling, triethylamine 26 () μI. 310 mg of 4,4-methoxybenzoyl chloride were sequentially added, and the mixture was stirred for 40 minutes under ice-cooling, and then ice was added. partitioned between Echiru 30ml and iN aqueous hydrochloric acid, the organic layer with saturated aqueous sodium bicarbonate solution 15 ml, / l 5 ml X, washed with brine 15 ml, the solvent was distilled off under _c vacuum drying over sodium sulfate, The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and the resulting oil was crystallized from diisobutylpyruether monoethyl acetate, and the obtained crystals were recrystallized from ethyl acetate. Crystallized and colorless crystal of the title compound 326 _mg Got ::

 Examples 9] and 92 were synthesized as in Example 90:

Example 93

 4-Bromo-2-chloro-N— {1-([4-Cyanol 3-trifluoromethylphenyl) potassium] — 1-Methylethylbenzoylamide

Dissolve 52 () mg of 4-bromo-2-monobenzoic acid in 1 ⁽ ) ml of tetrahydrofuran, add 230μl of oxazinololechloride under ice-cooling and add 1 drop of ザ, Ν, Ν-dimethylformamide sequentially, and stir at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and 1,2-dichloroethane was added to the residue, followed by distillation again. The residue was dissolved in 4 ml of tetrahydrofuran, and 540 mg of 2-amino-N- (4-cyano: 3-trifluoromethylenolephenyl) -l-methylprono, amide and 10 μl of triethylamine were added under ice-cooling. ) The mixture was stirred for minutes. Ice was added to the reaction mixture, and the mixture was stirred for 2 hours and 30 minutes. The solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate 5 (3 ml and 1N aqueous hydrochloric acid 30 ml), and the organic layer was diluted with saturated aqueous sodium hydrogen carbonate solution. 30 ml, washed with brine 30 ml X 2, and dried over sodium _sulfate:; after distilling off the solvent under reduced pressure, the residue was recrystallized from acetic E Chiru ether to give the title compound 572M _g of colorless crystals ₌

 Example 94 was synthesized in the same manner as in Example 93.

Example 95

 N-ΙΊ-[[(4-cyano-13-trifluoromethylphenyl) -l-bamoyl] -1-1-methylethyl '}-1-hydroxybenzamide

N— {11-[(4-Cyan-13-trifluoromethylpheninole) rubamoyl] —340 mg of 1-methyleth-4-methoxybenzamide is dissolved in 10 ml of methylene chloride, and the mixture is dissolved at 78 ^C C with 1 M 3.5 ml of a boron methylene chloride solution was added, and the mixture was stirred at room temperature for 40 hours. The reaction solution was ice-cooled, 1 Oml of water was added, the mixture was stirred for 5 minutes, and extracted with 6 Oml of chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution (3 Oml), water (3 Oml), saturated aqueous citric acid solution (3) ml × 2, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The crystals were recrystallized from diisopropyl ether-ethyl acetate, and recrystallized from acetic acid acetate / lehi-fu / ro-lo'sole-hexane, to give 1 mg of the title compound as colorless crystals.

Example 96

 N-benzyloxy N- {1-i [(4-■ 3

 De '

2- (4-N-fluoro-N-zincsiloxy-: de) -2- -acid). Add 7 ml of dichloromethane and 20 ml of dichloromethane, and stir the mixture with 0.15 to 1 ^: 1.

 After stirring at 10 C for 1 hour, 0.59 g of 4-amino-2-trifluoromethyl 'small lyl was added at the same temperature, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with chloroform and washed with water. , And dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography 1. The crystals obtained from the elution with hexane monoethyl acetate (2: 1) were washed with diisofurvir ether to give the title compound 0. (U got lg.

Example 97

 N— {1— [(4-cyano 3-trifluoromethylphenyl) rubamoyl] — 1-methylethyl} -1 4-fluoro-N-hydroxybenzamide

N-benzyloxy N— {1-[(4-cyano-3-trifluoromethylphenyl) carbamoyl] -1-methylethyl) -14-fluorobenzamide 0.3 g and ammonium formate 0.15 g ethanol 10 ml L () in the suspension solution. / o a palladium Karoe carbon 0. 05G, after filtering off the _c Barajiumu carbon was stirred at room temperature for 30 minutes, water was added and extracted with acetic acid Echiru. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography ₌ hexane-ethyl acetate (1: 1). Recrystallization from a mixed solvent of ethyl and hexane gave the title compound 0,] _ 8 g.

Example 98

 N- (4-Icyan-3-trifluoromethylphenyl) -2-methyl-2- (3-phenyl,

'Mid To a 10 ml dichloromethane solution of 300 mg of 2-amino-N- (4-cyano-3 trifluoromethylphenyl) -2methylbrovanamide synthesized in Reference Example 10-2, was added 659 mg of phenylisocyanate under ice-cooling. The mixture was stirred at room temperature for 4.5 hours. To the reaction solution, saturated aqueous sodium bicarbonate solution, followed by addition of IN hydrochloric acid, collected by filtration was _c crude crystals were recrystallized from acetic Yuchiru the precipitated crude crystals, to give the title compound 205 mg ₂

Example 99

N- (4-cyano 3 trifluoromethylphenyl) 2-methyl 2- (thiobenzamide) 400 mg of 2 amino-N- (4-cyano 3--2-methyl bronamide synthesized in Reference Example 10-2 in 5 ml of pyridine After dissolving, 344 mg of (thiobenzoylthio) acetic acid and 226 mg of triethylamine were added, and the mixture was stirred at room temperature for 110 hours .: The reaction solution was poured into a 2N aqueous solution of sulfuric acid, and extracted with ethyl acetate. after washing, the solvent was distilled off under reduced pressure and then dried over anhydrous magnesium sulfate, the residue was subjected to silica gel column chromatography, acetic Echiru - hexane:. 1) was obtained from the eluate crude _crystals: the crude The crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 6 () mg of the title compound.

 Example 1 (X) —1 () 4 was synthesized in the same manner as in Example 25.

 Example 1 () 5-107 was synthesized in the same manner as in Example 1.

 Example 108 was synthesized in the same manner as in Example 25.

 Example K) 9-11 11 was synthesized in the same manner as in Example 1.

Example 1 12-122 was synthesized in the same manner as in Example 25 ₌

 Examples 123 to 129 were synthesized in the same manner as in Example 1.

Example 130

 N- (4-cyano 3-trifluoromethylbenzoyl) [4 4 fluorobenzoyl) amide [4- (4-fluorobenzoyl) amido] cyclohexylcarboxy synthesized in Reference Example 15-1 The reaction and post-treatment were carried out in the same manner as in Reference Example 14 using an acid. The obtained crude extract was purified by silica gel column chromatography, and a single compound (A) was obtained from a portion eluted with ethyl ethyl oxane (1: 1). Elution was continued to obtain another isomer (B).

Example 131 was synthesized in the same manner as in Example 130. : The structures and physical properties of these examples are shown in the table.

R ⁴ R ⁵ R ⁶ R ⁷

 , And A in the table corresponds to the part in the general formula (I) ::

: なお，表中の記号は参考例の表と同様の意味を有し，それ以外の記号にっレ' 意味を有する。

: The symbols in the table have the same meanings as in the table of the reference example, and the other symbols have the same meanings.

 Ex .: Example number MS: Mass spectrometry value

Me: methyl (i- p _{r) 2} 0: Jiisofuropirue

Et: ethyl MeOH: methanol

 Ac: acetyl i-PrOH: isoflavanol

Benzyl -CH- Table 4

7ί

7ί

VL \ VQIL6i £ llDA zzm OAX

9 Halla

PLlPQ / L6dr / lDd z zz OAX

8ε

厶 0/ム 6dfAl;Dd ra/86 OAV 6ε-

0 / m 6dfAl; Dd ra / 86 OAV 6ε-

^ 0 / m 6U7i:) d zera / 86 OAV

Z/86 OAV

Z / 86 OAV

6 Halla

ra / 86 OAV

 ON

 H 〇

 \ People z v n

 H

L L Halla

o

PLlP0 / L6dT / Dd Tehi z OAV

表 1 3

Table 13

前記の実施例以外に以下に本発明の別の化合物を表に示す- これらの化合物は，上記の製造法及び実施例中に記載した合成経路と方法，及び通常 の当業者にとって公知であるそれらの変法を用いて合成することができ，特別の実験を必 要とするものではない。

In addition to the above examples, other compounds of the invention are shown in the table below-these compounds may be prepared according to the above-mentioned preparation methods and the synthetic routes and methods described in the examples and those known to the person skilled in the art. It can be synthesized using the modified method described above, and does not require special experiments.

Here, the symbols in the table have the following meanings _c

Com .: Compound number Table 14

Claims

The scope of the claims 1. Shown by the following general formula (I).

 (The symbols in the formula have the following meanings. R ¹ and R ^{2 are the} same or different and are a halogen atom; R ³ : hydrogen atom or lower alkyl group η: 0 or 1 R ⁴ , R ⁵ , R ⁶ and R ⁷ : the same or different, a hydrogen atom, a lower alkyl which may have a substituent, or a hetero-atom in which R ⁴ and R ⁵ are in the form of A good cycloalkyl group may be formed, or, in the case of η21, R “'and R” may be in the form of a cycloalkylene group; and Α ₂ : same or different bond Or lower alkylene group R ⁸ : hydrogen atom, hydroxyl group, lower alkoxy, lower alkyl, aralkyl or lower aralkyloxy group Alternatively, R ⁸ and R ⁵ may be in the form of a nitrogen-containing cycloalkylene group, or when η is 1, R ⁷ and R ^s may be in the form of a nitrogen-containing cycloalkylene group. May form: Z: acetyl group  X :: oxygen atom or sulfur atom However, when Z is a heteroarylcarbonyl group, at least one of R ⁴ and R ⁵ represents a group other than a hydrogen atom. )  2. An acylamino-substituted acylylanilide derivative represented by the following general formula (1) or a salt thereof

(The symbols in the formula have the following meanings R ¹ and R ² : same or different, halogen atom, cyano, halogeno lower alkynole, -i, mouth, carboxyl, lower alkanol or lower alkoxycarbonyl group  0 or 1 R ⁴ , R ⁵ , R ^H and R ⁷ : same or different and may have a hydrogen atom or a substituent  Or aralkyl group Alternatively, R ⁴ and R ⁵ may be in the form of a cycloalkyl group containing a heteroatom, or may include a hetero atom, or when n is 1, R ⁵ and R ⁶ may be in the form of Good to form a cycloalkylene group and A ₂ : same or different R ^8: a hydrogen atom, a hydroxyl group, lower alkoxy, lower or may become R ⁸ and R ⁵ gar body to form a nitrogen-containing cycloalkylene group, or η7]; 1 Noto-out R ⁷ and R ^s is May form a nitrogen-containing cycloalkylene group: Z: Y— R ⁹  Υ: represented by the formula -S- or -C-N-;  (0) ι  X. R R ⁹ : lower alkyl, cycloalkyl, or optionally substituted aryl, aralkenyl, aralkyl, or aryloxy lower alkyl, or a heteroaryl group which may be condensed with a benzene ring R ³ and R ^1Q : hydrogen atom or lower alkyl group X ₁ and X _2: oxygen atom or sulfur atom : 11: 0 or 1, 2 However, when Y is a carbonyl group and R ⁹ is a heteroaryl group, at least one of R ⁴ and R ⁵ represents a group other than a hydrogen atom. )  3. An acylamino substituted acylylanilide derivative represented by the following general formula (I) or a salt thereof

(The symbols in the formula have the following meanings. R ¹ and R ² : same or different, halogen atom, cyano, halogeno lower alkyl, nitro, carboxyl, lower alkanoyl or lower alkoxycarbonyl group A and A ₂ : the same or different bonds or lower alkylene groups n: () or 1 R ⁴ or R ⁵ , ^RG and R ⁷ : identical or different, consisting of a hydrogen atom, or one or more identical or different halogen atoms, hydroxyl groups, lower alkoxy, lower alkanoyloxy, halogeno lower alkyl groups R ⁴ and R ⁵ may have a substituent selected from the group, or may form a heteroalkyl including a hetero atom to form a cycloalkyl group, or When n is 1, R ⁵ and R ⁶ may be combined to form a cycloalkylene group. R ⁸ : hydrogen atom, hydroxyl group, lower alkoxy, lower alkyl, aralkyl or lower aralkyloxy group Alternatively, R ⁸ and R ⁵ may be in the form of a nitrogen-containing cycloalkylene group, or when n is 1, R ⁷ and R ⁸ may be in the form of a nitrogen-containing cycloalkylene group. Is also good. Z: YR ⁹  Y: represented by the formula S—S— or —C—N—; x ₂ ' ^{(0) m} x ₂ R' ° R ⁹ : lower alkyl, cycloalkyl, one or more same or different, halogen atom, hydroxyl group, halogeno lower alkyl, lower alkyl, lower alkoxy, halogeno lower alkoxy, cyano, nitro, lower alkanoyloxy, phenyl Aryl or aralkenyl optionally having a substituent selected from the group consisting of, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl, lower alkanoylamino and oxo group , Aralkyl, or aryloxy lower alkyl, or a heteroaryl group which may be condensed with a benzene ring R ³ and R ^1Q : hydrogen atom or lower alkyl group X and X ₂ : oxygen atom or sulfur atom  1 1: 0 or 1, 2 However, when Y is a carbonyl group and R ⁹ is a heteroaryl group, at least one of R ⁴ and R ⁵ represents a group other than a hydrogen atom. ) 4. n is 0 and R ⁴ or R ⁵ is the same or different and is a hydrogen atom, or one or more of the same or different substituents is selected from hydroxyl, lower alkoxy, lower alkanoyloxy, halogeno lower alkyl; 7. The acylamino diacyl anilide derivative or a salt thereof according to claim 6, which is a lower alkyl or aralkyl group which may have a substituent selected from the group consisting of:  5. The compound according to claim 1, wherein the compound is selected from the group consisting of: or a salt thereof: N— {1 -— ((4-cyano-13-trifluoromethylphenyl) potassium) -l-methylethyl } -4-Fluorobenzamide;  N— {1 -— [(3,4-dicyanophenyl) potassium] -1-methylethyl} -1-4-fluorobenzamide;  N— {11-([3-1-41-Cyanophene]) L-bamoyl] 1-1-Methylethyl I 4-Fluo-benzamide;  N— {11-[(4-cyano-13-trifluoromethylphenyl) -lubamoyl] -1-1-methylethyl} -2,4,6-trifluorobenzamide;  4-chloro-N— (4-cyano 3-trifluoromethylphenyl) -rubamoyl] —11-methylethyl / benzamide  6. A pharmaceutical composition comprising, as an active ingredient, the acylamino-substituted acylylanilide derivative or the pharmaceutically acceptable salt thereof according to claim 1.  7. The pharmaceutical composition according to claim 6, which is an anti-androgenic agent.  8. The pharmaceutical composition according to claim 7, which is an agent for preventing or treating prostate cancer, prostatic hypertrophy, virilization, hirsutism, baldness, acne, and seborrhea.