JPH10182457A - Antiandrogen agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an antiandrogen agent, capable of acting as an androgen antagonist and useful for treating and preventing prostatic hypertrophy or prostatic cancer by making the agent include a specific compound therein. SOLUTION: This antiandrogen agent comprises a compound represented by the formula A is C-R<4> or N; T<1> to R<4> are each H, F or nitro; Q is [C(R<5> )(R<6> )] (R<5> and R<6> are each H or a 1-4C alkyl) or a single bond; Y is a (substituted)isoxazolyl, a (substituted)pyrazolyl, a (substituted)phenyl, etc.}, e.g. 2-(3,5-dimethylisoxazol-4-ylmethyl)-4,5,6,7-tetrafluoro-1H-isoxazole-1 ,3-dione. The compound is obtained by reacting, e.g. tetrafluorophthalic anhydride with 3,5- dimethyl-4-aminomethylisoxazole, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anti-androgen used as a medicament for treating and / or preventing prostatic hypertrophy and prostate cancer.

[0002]

2. Description of the Related Art Steroids such as "Chlormadinone" and non-steroidal anti-androgens such as "Flutamide" are used as antiandrogens in the treatment of benign prostatic hyperplasia and prostate cancer. Of these antiandrogens, "flutamide"
Is considered to exert a cell growth inhibitory effect and an antitumor effect by inhibiting the binding of androgen to the androgen receptor of prostate cancer tissue. Therefore, compounds that act as androgen antagonists are expected to be useful as antiandrogen agents for the treatment and prevention of benign prostatic hyperplasia and prostate cancer. In addition, DIMP [N- (3,5-dimethyl-4-is
ooxazolylmethyl) phthalimide] has been reported to have androgen antagonistic activity (Boris,
A., et al., ACTA ENDOCRINOLOGIA, 72, pp.604-614, 19
73).

[0003]

DISCLOSURE OF THE INVENTION The present inventors have been diligently focused on the biological action of phthalimide compounds and have been working to produce various new phthalimide compounds. Found that these compounds have an effect on regulating tumor necrosis factor production
(Miyachi, H., et al., Bioorganic & Medicinal Chemi
stry Letters, 6 (19), pp.2293-2298, 1996; Japanese Patent Application 8-1
No. 74108, Japanese Patent Application No. 8-184129, Japanese Patent Application No. 8-184
No. 130, Japanese Patent Application No. 8-234672, and 1996
Patent application filed on February 17, for example, refer to the title of the invention such as "phthalimide derivatives or salts thereof, methods for producing them and pharmaceutical compositions containing them"). The present inventor has continued research to find further biological effects of these compounds and their analogs, and as a result, the compounds represented by the following formulas can act as androgen antagonists, It has been found to be useful as an androgenic agent. The present invention has been completed based on these findings.

That is, the present invention provides the following general formula (I):

Embedded image [Wherein A represents CR ⁴ or a nitrogen atom; R ¹ , R ² , R ³ ,
And R ⁴ each independently represent a hydrogen atom, a fluorine atom, or a nitro group; Q is a group represented by-[C (R ⁵ ) (R ⁶ )]-(wherein R ⁵ and R ⁶ are each Independently represents a hydrogen atom or a C _1-4 alkyl group) or a single bond; Y represents a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted group An indanyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted cyclohexyl group, or -CH (COR ⁷ ) (CO
R ⁸ ) (wherein R ⁷ and R ⁸ are each independently C
_{1-4 represents} an alkyl group), provided that A is CR ⁴
R ¹ , R ² , R ³ , and R ⁴ are hydrogen atoms; Q is -C
H ₂ and Y ₂ is a substituted or unsubstituted isoxazolyl group except when it is a substituted or unsubstituted isoxazolyl group].

According to another aspect of the present invention, there is provided a compound represented by the following general formula (II):

Embedded image (Wherein R ¹¹ and R ¹² each independently represent a C _1-4 alkyl group), and a medicament containing the compound, preferably an antiandrogen. According to still another aspect of the present invention, the above general formula (I) or (II)
Use of the compound represented by the above general formula (I) or (II) for the manufacture of a pharmaceutical composition comprising a compound represented by the formula (I) or (II); and a method for treating benign prostatic hyperplasia or prostate cancer, There is provided a method comprising the step of administering to a patient an effective amount of a compound represented by the general formula (I) or (II).

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), A is C
—R ⁴ or a nitrogen atom, and R ¹ , R ² , R ³ , and R ⁴ each independently represent a hydrogen atom, a fluorine atom, or a nitro group.
Preferred compounds are compounds in which R ¹ , R ² , R ³ , and R ⁴ are all hydrogen atoms; compounds in which R ¹ , R ² , R ³ , and R ⁴ are all fluorine atoms; R ¹ , R ² and R ³ are hydrogen atoms and A is a nitrogen atom; R ¹ , R ² and R ³ are hydrogen atoms and R ⁴ is a fluorine atom; R ¹ , R ² ,
Compounds in which R ⁴ is a hydrogen atom and R ³ is a fluorine atom; and compounds in which R ¹ , R ² , and R ⁴ are hydrogen atoms and R ³ is a nitro group.

In the above general formula (I), Q is-[C (R ⁵ )
(R ⁶ )]-, and R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl group. R ⁵ and R ⁶ may be the same or different. As the C _1-4 alkyl group, any of a straight chain or a branched chain may be used, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, or the like is used. be able to. Preferred groups include, for example, a group in which R ⁵ and R ⁶ are both hydrogen atoms; a group in which R ⁵ is a methyl group and R ⁶ is a hydrogen atom; and a group in which both R ⁵ and R ⁶ are a methyl group Groups. When Q is a single bond, the above formula
The compound represented by (I) corresponds to a compound in which the group represented by Y is directly substituted on the nitrogen atom of the phthalimide group.

In the general formula (I), Y is a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted indanyl group, a substituted or unsubstituted group. A naphthyl group, a substituted or unsubstituted biphenyl group, or a substituted or unsubstituted cyclohexyl group. When these cyclic groups have a substituent, the number of substituents on the ring is not particularly limited, and may have, for example, one or more substituents. Examples of such a substituent on the ring include a linear or branched C _1-4 such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a tert-butyl group. An alkyl group; or a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom can be used. For example, these cyclic groups may have one or two methyl groups or chlorine atoms on the ring.

[0009] The bond between these cyclic groups and Q or the bond between these cyclic groups and the nitrogen atom of the phthalimide group is not particularly limited, and these cyclic groups may be Q or phthalimide at any position on the ring. It can be attached to the nitrogen atom of the group. Examples of the cyclic group having a preferred substitution position include, for example, isoxazol-4-yl group, pyrazol-4-yl group, indan-1-yl group, indan-2-yl group, 1-naphthyl group, biphenyl-2 -An yl group. Further, preferred examples when these groups have a substituent on the ring include, for example, 3,5-dimethyl-isoxazol-4-yl group, 3,5-dimethyl-pyrazol-4-yl group, 2 , 6-dichlorophenyl group and the like. A phenyl group, a cyclohexyl group, a naphthyl group, a biphenyl group, or an indanyl group can also be suitably used as an unsubstituted cyclic group.

In addition to the above cyclic groups, Y is --CH (COR ⁷ ) (CO
It may be a group represented by R ⁸ ). R ⁷ and R ⁸ each independently represent a C _1-4 alkyl group, but R ⁷ and R ⁸ may be the same or different. As the C _1-4 alkyl group, a linear or branched alkyl group can be used, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and the like. Can be used. Preferably, R ⁷ and R ⁸ are both methyl groups.

In the compound represented by the above general formula (I), Q is
- [C (R ⁵⁾ (R ^6)] - a case where R ⁵ and R ⁶ are different (e.g., R ⁵ is a methyl group, R ⁶ is a hydrogen atom) in the, R ⁵ and The carbon atom to which R ⁶ is attached is an asymmetric carbon. Further, depending on the type of R ⁵ , R ⁶ , R ⁷ , and / or R ⁸ , there may be one or more asymmetric carbons. Any such optical isomer based on one or more asymmetric carbons or any mixture thereof, any diastereoisomer based on two or more asymmetric carbons or any mixture thereof, or Racemates and the like may be used as the active ingredient of the medicament of the present invention. In particular, when R ⁵ and R ⁶ are different, it has been found that the respective optical isomers may have different degrees of action. Therefore, it is important to select an appropriate optical isomer. In addition, any hydrate or solvate of the above compounds may be used as an active ingredient of the medicament of the present invention.

The compounds suitable for the medicament of the present invention include:
For example, (a) in the compound of the above formula (I), when A is a nitrogen atom, R ¹ , R ² and R ³ are all hydrogen atoms, and A is C
When -R ⁴ , R ¹ , R ² , R ³ , and R ⁴ are both hydrogen atoms or both fluorine atoms, or R ¹ , R ² , and R ³ are hydrogen atoms and R ⁴ is A compound in which R ¹ , R ² and R ⁴ are a hydrogen atom and R ³ is a fluorine atom or a nitro group; or (b) a compound of the general formula (I) or In the compound of a), Y is a substituted or unsubstituted isoxazol-4-yl group, a substituted or unsubstituted pyrazol-4-yl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted indane.
-1-yl group, substituted or unsubstituted indan-2-yl group,
Substituted or unsubstituted 1-naphthyl group, substituted or unsubstituted
2-biphenyl group, substituted or unsubstituted cyclohexyl group, or a group represented by -CH (COR ⁷ ) (COR ⁸ ) (wherein R ⁷ and
R ⁸ each independently represents a C _1-4 alkyl group);

(C) In the compound of the formula (I) or the compound of the above (a), Y is a substituted isoxazol-4-yl group,
Unsubstituted pyrazol-4-yl group, substituted or unsubstituted phenyl group, unsubstituted indan-1-yl group, unsubstituted indan-2
-An yl group, an unsubstituted 1-naphthyl group, an unsubstituted 2-biphenyl group, an unsubstituted cyclohexyl group, or a group represented by -CH (COR ⁷ ) (COR ⁸ ), wherein R ⁷ and R ⁸ are each (D independently represents a C _1-4 alkyl group); (d) a compound of the general formula (I) or the compound of the above (a), wherein Y is 3,5-diC _1-4 alkyl-substituted isoxazole- Four-
Yl group, 3,5-di C _1-4 alkyl-substituted pyrazol-4-yl group, 2,6-dihalogen-substituted phenyl group, unsubstituted phenyl group, unsubstituted indan-1-yl group, unsubstituted indan-2- An unsubstituted 1-naphthyl group, an unsubstituted 2-biphenyl group, an unsubstituted cyclohexyl group, or a group represented by —CH (COR ⁷ ) (COR ⁸ ) (wherein R ⁷ and R ⁸ are each independently _{Represents a} C _1-4 alkyl group).

(E) In the compound of any of the above (b), (c), or (d), Y is a pyrazolyl group, a phenyl group, a naphthyl group, a cyclohexyl group, or -CH (COR ⁷ ) (COR ⁸ (Wherein R ⁷ and R ⁸ each independently represent a C _1-4 alkyl group) when Q is-[C (R ⁵ ) (R ⁶ )]- Wherein, R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl group), and when Y is an indanyl group or a biphenyl group, Q is a single bond; In the compound of (e), Y is a pyrazolyl group or a group represented by —CH (COR ⁷ ) (COR ⁸ ) (wherein, R ⁷ and R ⁸ each independently represent a C _1-4 alkyl group) Q if
Is -CH _2- ; or (g) in the compound of the above (e), when Y is a phenyl group, a naphthyl group, or a cyclohexyl group, Q is -C
A compound which is H (CH ₃ ) −;

In the general formula (I), A is CR
It is ^{4; R 1, R 2,} R 3, and R ⁴ are both a hydrogen atom;
Q is be -CH _2; and, Y is a substituted or unsubstituted isoxazolyl group, particularly a substituted isoxazolyl group, for example, 3,5-dimethyl - compounds which are 4-yl group, antiandrogens of the invention It is not included in the scope of the agent. The following Table 1 shows compounds that are particularly preferably used in the medicament of the present invention, but the active ingredients of the medicament of the present invention are not limited to the following compounds (in the table, Q is represented by "-"). Indicates that Q is a single bond.
When (R) -CH (CH ₃ )-or-(S) -CH (CH ₃ )-is displayed, the configuration of the asymmetric carbon in Q is
(R) or (S) configuration).

[0016]

[Table 1] ────────────────────────────────── Compound No. AR ¹ R ² R ³ QY ── _{──────────────────────────────── HM-2 CF FFF -CH 2} - 3,5-dimethyl-isoxazol-4 -yl HM-3 CH HHH - indan -2-yl HM-4 CH HHH -CH 2 - 3,5-dimethyl-pyrazol-4-yl HM-5 CH HHH - indan-1-yl HM-6 CH HHH - _{CH 2 - CH (COCH 3)} 2 HM-8 CH HHH -C (CH 3) 2 phenyl HM-13 CH HHH -CH 2 - 2,6-dichlorophenyl HM-14 CF FFF - indan-2-yl HM-15 CF FFF-indan-1-yl HM-18 CF FFF-(R) -CH (CH ₃ ) -phenyl HM-19 CF FFF-(S) -CH (CH ₃ ) -phenyl HM-20 CF FFF-(R ) -CH (CH ₃ )-1-naphthyl HM-21 CF FFF-(S) -CH (CH ₃ )-1-naphthyl HM-24 CH HH NO _2- (R) -CH (CH ₃ ) -phenyl HM _{-25 CH HH NO 2 - (S} ) -CH (CH 3) - phenyl HM-26 NHHH -CH 2 - 3,5-dimethyl-isoxazol-4-yl HM-27 CF HHH -CH 2 - 3,5- dimethyl-isoxazol-4-yl HM -28 CH HHF -CH 2 - 3,5-dimethyl-isoxazol-4-yl HM-29 CH HH NO 2 -CH 2 - 3,5-dimethyl-isoxazol-4-yl HM -30 CF FFF-(R) -CH (CH ₃ )-cyclohexyl HM-31 CF FFF-(S) -CH (CH ₃ )-cyclohexyl HM-32 CH HHH-3,5-dimethyl-isoxazol-4-yl HM-33 CF FFF-3,5-dimethyl-isoxazol -4-yl HM-34 CH HHH - biphenyl-2-yl HM-35 CF FFF - biphenyl-2-yl HM-36 CF FFF -CH 2 - 2,6-dichlorophenyl ────────── ────────────────────────

The compound represented by the above general formula (I) is known per se or can be easily produced by a method described in the literature. For example, HM-18, HM-19, HM-20, HM-2 in the above table
1, HM-30 and HM-31 are described in Miyachi, H., et a.
l., Bioorganic & Medicinal Chemistry Letters, 6 (1
9), pp. 2293-2298, 1996, and references cited therein, and can be easily produced.Other compounds are also described in Japanese Patent Application Nos. 8-174108 and 8-184129. Issue specification,
It is described in Japanese Patent Application No. 8-184130 and Japanese Patent Application No. 8-234672. Also, regarding the manufacturing methods of some of the new substances and their physicochemical properties, see the specification of the patent application filed before the filing of the present patent application (the specification attached to the patent application filed on December 17, 1996). , Applicant: Ishihara Sangyo Co., Ltd.,
Hashimoto Yuichi; Applicant's reference number: P9605801; Name of invention "phthalimide derivative or salt thereof, production method thereof and pharmaceutical composition containing them"), and described in Examples of the present specification It can also be manufactured by the method described.

A general formula provided by another aspect of the invention
In the compound of (II), R ¹¹ and R ¹² are each independently
It represents a C _1-4 alkyl group. As the C _1-4 alkyl group, a linear or branched alkyl group can be used, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
A butyl group, a tert-butyl group and the like can be used.
The compound represented by the general formula (II) may have R ¹¹ and / or R
^{Some of the 12} types may further have one or more asymmetric carbons. Any such optical isomer based on one or more asymmetric carbons or any mixture thereof, any diastereoisomer based on two or more asymmetric carbons or any mixture thereof, or Racemic forms and the like are all included in the scope of the present invention. In addition, any hydrate or solvate of the above compound is also included in the scope of the present invention.

Among the compounds of the general formula (II), preferred are compounds wherein R ¹¹ and R ¹² are simultaneously a methyl group.
(HM-16), and the compound (HM-17) in which R ¹¹ and R ¹² are simultaneously an isopropyl group, but the compound of the present invention is not limited thereto. Further, the active ingredient of the medicament of the present invention is not limited to these compounds. In the examples of the present specification, since the production methods of the above compounds and their physicochemical properties are specifically disclosed, those skilled in the art can easily produce the compounds encompassed by the above formula (II). Will be understood.

Since the compounds represented by the above formulas (I) and (II) have androgen antagonist activity,
The medicament of the present invention containing the above compound as an active ingredient is useful as an anti-androgen agent for the prevention and / or treatment of benign prostatic hyperplasia and prostate cancer. However, the types of diseases to which the medicament of the present invention is to be applied are not limited to these specific diseases, and in general, diseases for which antiandrogen agents have been proven to be effective for their prevention and / or treatment, or It is needless to say that the present invention can be applied to diseases in which the therapeutic and / or prophylactic utility of the antiandrogen agent is suggested. In addition, the anti-androgenic activity of the compounds included in the general formulas (I) and (II) is, for example, the assay method described in the Examples of the present specification, or by adding appropriate modifications and alterations thereto. It can be easily confirmed by the method.

The administration form of the medicament of the present invention is not particularly limited, and it can be administered orally or parenterally. As the medicament of the present invention, the above-mentioned formula (I) or (II) which is an active ingredient
May be used, but one or more of the compounds as active ingredients and one or more of pharmacologically and pharmaceutically acceptable additives for pharmaceutical preparations may be used. Is preferably administered in the form of a pharmaceutical composition comprising Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, solubilizers and the like. Dissolution aids, tonicity agents, pH adjusters, stabilizers, propellants, adhesives and the like can be used. Examples of preparations suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups. Examples of preparations suitable for parenteral administration include injection. Preparations, drops, suppositories, inhalants, transdermal absorbents, transmucosal absorbents, patches, and the like. In addition, by applying various drug delivery systems available to those skilled in the art, the medicament of the present invention can be selectively transferred into the prostate, or the active ingredient can be continuously released into the blood. The effect of the medicament of the present invention can be enhanced.

The dose of the medicament of the present invention is not particularly limited.
The appropriate dose can be selected according to various conditions such as the type of the compound as the active ingredient, the purpose of treatment or prevention, the type of disease, the age and symptoms of the patient, and the administration route.
Generally, about 1 mg per adult daily for oral administration
About 1,000 mg, preferably about 50 mg to 500 mg, can be administered. The daily dose may be divided and administered in about 2 to 3 times per day, or the unit dose may be administered intermittently once every 2 to 7 days.

[0023]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. In the examples, compound numbers such as "HM-2" correspond to the compound numbers mentioned in the above [Table 1] and [Embodiments of the invention].

Example 1: Production of an active ingredient of the medicament of the present invention (Reference Example) HM-2 [2- (3,5-Dimethylisoxazole-4-ylmethyl) -4,5,6,7
-tetrafluoro-1H-isoxazole-1,3-dione] A mixture of tetrafluorophthalic anhydride (2.0 g) and 3,5-dimethyl-4-aminomethylisoxazole (1.90 g) at 190-200 ° C The mixture was heated and stirred for 1.5 hours. After cooling, the reaction mixture was dissolved in chloroform, and purified by silica gel chromatography (methylene chloride: methanol = 20: 1, v / v). The obtained crystals were recrystallized from a mixed solvent of n-hexane-ethyl acetate to give 1.29 g of the desired product as pale yellow needles. Yield 43% mp 144-146 ° C MS (FAB +) m / z: 329 (M + H ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.33 (3H, s), 2.53 (3
H, s), 4.56 (2H, s) Anal calcd. For Cl ₄ H ₈ F ₄ N ₂ O ₃ : C, 51.23; H, 2.46; N,
8.53, Found: C, 51.24; H, 2.26; N, 8.64.

Similarly, the following compounds were prepared. HM15: mp 157 to 158.5 ° C MS (EI +) m / z: 335 (M ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.38 to 2.44 (1H, m), 2.
45 ~ 2.61 (1H, m), 2.97 ~ 3.05 (1H, m), 3.35 ~ 3.43
(1H, m), 5.85 (1H, dd, J = 9.27 Hz, 5.86 Hz), 7.09
~ 7.11 (1H, m), 7.15 ~ 7.19 (1H, m), 7.25 ~ 7.31 (2
H, m) Anal calcd. For C ₁₇ H ₉ F ₄ NO ₂ : C, 60.90; Hm 2.71; N,
4.18, Found: C, 60.98; H, 2.63; N, 4.28.

HM26: mp 38-140 ° C. MS (EI +) m / z: 257 (M ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.54 (3
H, s), 4.61 (2H, s), 7.75 (1H, d, J = 4.88 Hz), 9.09
(1H, d, J = 4.88 Hz), 9.16 (1H, s) Anal calcd. For C ₁₃ H ₁₁ N ₃ O ₃ : C, 60.70; H, 4.31; N,
16.33, Found: C, 60.63; H, 4.25; N, 16.11.

HM27: mp 156 ° -157 ° C. MS (EI +) m / z: 274 (M ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34 (3H, s), 2.54 (3
H, s), 4.57 (2H, s), 7.40 (1H, dt, J = 8.30 Hz, 2.44
Hz), 7.52 (1H, dd, J = 7.07 Hz, 2.44 Hz), 7.85 (1H,
(dd, J = 8.30 Hz, 4.40 Hz) Anal calcd. for C ₁₄ H ₁₁ FN ₂ O ₃ : C, 61.31; H, 4.04; N,
10.21, Found: C, 61.18; H, 3.98; N, 10.18.

HM28: mp 128.5-129.5 ° C. MS (EI +) m / z: 274 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.54 (3
H, s), 4.57 (2H, s), 7.39 (1H, t, J = 8.55 Hz), 7.67
(1H, d, J = 7.33 Hz), 7.71 to 7.74 (1H, m) Anal calcd. For C ₁₄ H ₁₁ FN ₂ O ₃ : C, 61.31; H, 4.04; N,
10.21, Found: C, 61.56; H, 4.00; N, 10.27.

HM29: mp 166 to 167.5 ° C. MS (EI +) m / z: 301 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.34 (3H, s), 2.54 (3
H, s), 4.62 (2H, s), 7.93 (1H, d, J = 7.63 Hz), 8.15
(1H, s) Anal calcd. For C ₁₄ H ₁₁ N ₃ O ₅ : C, 55.82; H, 3.68; N,
13.95, Found: C, 55.60; H, 3.57; N, 13.74.

HM32: mp 168-169.5 ° C. MS (EI +) m / z: 242 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.21 (3H, sI, 2.36 (3
H, s), 7.83 (2H, dd, J = 5.50 Hz, 3.05 Hz), 7.95 (2
(H, dd, J = 5.50 Hz, 3.05 Hz) Anal calcd. For C ₁₃ H ₁₀ N ₂ O ₃ : C, 64.46; H, 4.16; N,
11.56, Found: C, 64.62; H, 4.18; N, 11.37.

HM33: mp 180.5-181.5 ° C. MS (EI +) m / z: 314 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.19 (3H, s), 2.35 (3
H, s) Anal calcd. For C ₁₃ H ₆ F ₄ N ₂ O ₃ : C, 49.70; H, 1.92; N,
8.92, Found: C, 49.40; H, 2.07; N, 9.22.

HM34: mp 163-164 ° C. MS (EI +) m / z: 299 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 7.20-7.34 (5H, m), 7.
50 to 7.54 (4H, m), 7.70 (2H, dd, J = 5.50 Hz, 3.05 H
z), 7.81 (2H, dd, J = 5.50 Hz, 3.05 Hz) Anal calcd. for C ₂₀ H ₁₃ NO ₂ : C, 80.25; H, 4.38; N,
4.68, Found: C, 80.32; H, 4.58; N, 4.63.

HM35: mp 189-191 ° C. MS (EI +) m / z: 371 (M ⁺ ) ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 7.23-7.32 (6H, m), 7.
48 to 7.53 (2H, m), 7.56 to 7.59 (1H, m) Anal calcd. For C ₂₀ H ₉ F ₄ NO ₂ : C, 64.70; H, 2.44; N,
3.77, Found: C, 64.63; H, 2.61; N, 3.97.

Example 2: Preparation of the compound of the present invention HM-16 [N- (2,6-Dimethylphenyl) -2,3,4,5,6-pentafluor
obenzanilide] 2,6-dimethylaniline (480 mg), triethylamine (24
A mixture of 2 mg) and chloroform (5 ml) was stirred under ice cooling, and a solution of pentafluorobenzoyl chloride (202 mg) in chloroform (5 ml) was added dropwise. After the reaction solution was stirred for 1 hour under ice cooling, stirring was further continued at room temperature overnight. After diluting the reaction solution with methylene chloride, the reaction solution was sequentially washed with dilute hydrochloric acid, dilute aqueous sodium hydroxide solution, and saturated saline. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (methylene chloride: methanol = 30: 1, V / V), and the obtained crude crystals were separated into n-hexane-acetic acid. Recrystallization from a mixed solvent of ethyl gave 520 mg of the desired product as colorless needles. Yield 83
% mp 170-171 ° C MS (EI +) m / z: 315 (M + H ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34 (6H, sI, 7.16-7.
18 (4H, m) Anal calcd. For C ₁₅ H ₁₀ F ₅ NO: C, 57.15; H, 3.20; N,
4.44, Found: C, 57.42, H, 2.98; N, 4.48.

The following compounds were prepared in the same manner. HM17 [N- (2,6-Diisopropylphenyl) -2,3,4,5,6-pentaflu
orobenzanilide] mp 265-267 ° C MS (EI +) m / z: 371 (M ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (12H, d, J = 6.84 H
z), 3.19 (2H, hept, J = 6.84 Hz), 7.10 (1H, brsI, 7.
24 (2H, s), 7.38 (1H, t, J = 7.81 Hz) Anal calcd. For C ₁₉ H ₁₈ F ₅ NO: C, 61.45; H, 4.89; N,
3.77, Found: C, 61.65, H, 4.60; N, 3.88.

Example 3: Action of the drug of the present invention (CAT assay) The anti-androgenic action of the drug of the present invention was evaluated by a transient expression assay (CAT assay: Sasaki, et al., Biochemistry, 3).
4, pp. 370-377, 1995). A CAT reporter plasmid containing an androgen receptor expression vector and a consensus androgen response element (ARE) was prepared, and this DNA was used to prepare Dulbecco's modified Eagle's medium (phenol-free, dextran-coated activated carbon-treated 5% fetal bovine serum Added)
HeLa cells cultured in the cells were transfected by the calcium phosphate method. For transfection, cells cultured in 9 cm Petri dishes (40-50% confluent)
Using μg of DNA, 500 ng of the androgen receptor expression vector was used for 2 μg of the CAT reporter plasmid. In order to standardize the variation in transfection efficiency, the assay was performed in the presence of a β-galactosidase expression vector (pCH110, manufactured by Pharmacia, 3 μg) as an internal standard, and Bluescribe M1 was used as a vector.
The total amount of DNA was adjusted using 3+ (Stratagene).

One hour after transfection and when the medium was changed, testosterone (1 × 10 ⁻⁸ M) was added to the medium.
After culturing was continued for 20 hours together with the DNA precipitated with calcium phosphate, the cells were washed with fresh medium, and the culturing was continued for another 20 to 24 hours. Prepare cell extract by freeze-thaw method,
Chloramphenicol acetyltransferase activity was measured after normalization with β-galactosidase activity. The assay measures the radiation dose of radioactive acetylchloramphenicol expressed in the absence of the test compound,
The extent to which expression was suppressed when 10 ⁻⁶ M test compound was co-present was measured as a decrease in radiation count, and used as an index of antiandrogen action. As positive controls for antiandrogen action, non-steroidal androgen antagonists flutamide and DIMP
(N- (3,5-dimethyl-4-isooxazolylmethyl) phthalimide;
Boris, A., et al., ACTA ENDOCRINOLOGIA, 72, pp.604
-614, 1973). The results are shown in Table 2 below. The active ingredient of the medicament of the present invention had stronger androgen antagonism than flutamide and DIMP.

[0038]

[Table 2] ──────────────────── Test compound (10 ^-6 M) Radiation count number ^a ──────────────下 In the absence of ^b 327.90 Flutamide 241.80 DIMP 103.10 HM-17 58.70 HM-18 44.53 HM-19 54.59 HM-20 55.68 HM-21 28.65 HM-24 80.28 HM-25 57.01 HM-26 69.48 HM-30 62.92 HM-31 72.50 ──────────────────── ^a Background: 31.14 counts ^b Testosterone only (10 ^-8 M)

Example 4: Action of the medicament of the present invention (cell proliferation test using androgen-dependent cells) Androgen-dependent cells SC-3 (Kasayama, S) in MEM medium (with 2% FBS and antibiotic mycostatin) ., et a
l., Journal of Cellular Physiology, 154, pp.254-26
1, 1993) 1 × 10 ⁵ / ml testosterone (1 ×
When cultured in the presence of (10 ⁻⁸ M), the number of cells rapidly increases from day 4 and reaches about 5.5 × 10 ⁵ / ml after 6 days (the medium is replaced on day 3). . On the other hand, when the same number of cells were cultured without the addition of testosterone, no rapid cell growth was observed, and the number of cells was about doubled on the sixth day. The above cells (1 × 10 ⁵ / ml) were cultured in the presence of testosterone (1 × 10 ⁻⁸ M) and the drug of the present invention, and the cell growth inhibitory effect was measured to determine the anti-androgen activity of the drug of the present invention. Activity was evaluated. On the third day of the culture, the medium containing the test compound was completely replaced, and on the sixth day, the number of cells was counted. Flutamide was used as a positive control for antiandrogen action.
Independent tests were performed twice, and the results shown in Table 3 were obtained. In the table, the proliferation rate is a value obtained by expressing the number of cells in the case of culturing in the presence of a test compound as a percentage, with the number of control cells being 100%. As is clear from these results, the medicament of the present invention suppressed the growth of SC-3 cells, and had the same or higher inhibitory effect as flutamide.

[0040]

[Table 3] ───────────────── Test compound concentration (M) Proliferation rate (%) ───────────────── Control ^a -100 Flutamide 1 × 10 ^-6 66 HM-16 1 × 10 ^-6 21 HM-17 1 × 10 ^-6 50 HM-18 1 × 10 ^-6 28 HM-19 1 × 10 ^-6 3 HM-20 1 × 10 ^-6 9 HM-21 1 × 10 ^-6 21 HM-25 1 × 10 ^-6 23 HM-30 1 × 10 ^-6 2 HM-31 1 × 10 ^-6 5 ───────── ──────── cultured in ^a testosterone alone (10 ^-8 M) (cell count: 434 × 10 ³ / ml)

[0041]

The compound of the formula (II) provided by the present invention has an androgen antagonistic effect and is useful as an active ingredient of a drug such as an antiandrogen. Further, the medicament of the present invention containing the compound of the formula (I) or the formula (II) as an active ingredient is useful as an antiandrogen agent for the prevention and / or treatment of diseases such as benign prostatic hyperplasia and prostate cancer.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C233 / 65 C07C233 / 65 C07D403 / 06209 C07D403 / 06209 413/06209 413/06209 // C07D209 / 48 471/04 104Z 471/04 104 209 / 48Z

Claims (6)

[Claims] 1. The following general formula (I): [Wherein A represents CR ⁴ or a nitrogen atom; R ¹ , R ² , R ³ ,
And R ⁴ each independently represent a hydrogen atom, a fluorine atom, or a nitro group; Q is a group represented by-[C (R ⁵ ) (R ⁶ )]-(wherein R ⁵ and R ⁶ are each Independently represents a hydrogen atom or a C _1-4 alkyl group) or a single bond; Y represents a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted group An indanyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted cyclohexyl group, or -CH (COR ⁷ ) (CO
R ⁸ ) (wherein R ⁷ and R ⁸ are each independently C
R represents a _1-4 alkyl group), wherein A is CR ⁴ ;
¹ , R ² , R ³ , and R ⁴ are all hydrogen atoms; and Q is -CH ₂
Excluding the case where Y is a substituted or unsubstituted isoxazolyl group]. 2. The following general formula (II): (Wherein, R ¹¹ and R ¹² each independently represent a C _1-4 alkyl group). 3. A medicament comprising a compound represented by the above general formula (II) (R ¹¹ and R ¹² are as defined above). 4. An antiandrogen comprising a compound represented by the above general formula (II) (R ¹¹ and R ¹² are as defined above). 5. The antiandrogen according to claim 1 or 4, which is in the form of a pharmaceutical composition comprising the compound as an active ingredient and an additive for pharmaceutical preparation. 6. The antiandrogen according to claim 1, which is applied to benign prostatic hyperplasia or prostate cancer.