JP2009079039A - Coumarin compound and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound capable of inhibiting 3-type 17β-hydroxysteroid dehydrogenase, thereby useful in treating or preventing androgen-dependent diseases. <P>SOLUTION: A 3-type 17β-hydroxysteroid dehydrogenase inhibitory composition is provided, being characterized by comprising a coumarin compound represented by formula (A) or the like and an inert carrier. Use or the like of the coumarin compound contained, as an active ingredient for inhibiting 3-type 17β-hydroxysteroid dehydrogenase, in the above composition is also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a coumarin compound and its use.

  Androgen-dependent diseases such as prostate cancer, benign prostatic hypertrophy, acne, seborrhea, hirsutism, androgenetic alopecia, sexual prematurity, adrenal hypertrophy and polycystic ovary syndrome are Promoted by androgenic activity.

  Type 3 17β-hydroxysteroid dehydrogenase is an enzyme that catalyzes the conversion of androstenedione, a low activity male hormone, to testosterone, a high activity male hormone. For example, in cancerous prostate tissue, it has been observed that the expression level of type 3 17β-hydroxysteroid dehydrogenase gene is higher than the expression level in normal tissue (for example, Non-Patent Document 1).

The Prostate, 53, 154-159, (2002)

  The object of the present invention is to provide compounds that can inhibit type 3 17β-hydroxysteroid dehydrogenase and are therefore useful in the treatment or prevention of male hormone-dependent diseases.

［式中、
Ｘ_Ａは、C1-C4アルキルカルボニル基、ハロゲン原子、C1-C4アルキル基、トリフルオロメチル基、ニトロ基、C1-C4アルキルチオ基、シクロプロピルメチルチオ基又はａ_Ｉ−ＣＨ_２Ｓ−基（ａ_Ｉは、単数のハロゲン原子で置換されてもよいフェニル基、同一又は相異なる複数のハロゲン原子で置換されたフェニル基又はトリフルオロメチル基で置換されたフェニル基を表す。）で示される置換基群から選ばれる、単数の基で置換されてもよい、又は、同一又は相異なる複数の基で置換された、ベンゼン環、ピリジン環、ピリミジン環、チオフェン環、イミダゾール環、１，２，４−トリアゾール環、テトラゾール環、チアゾール環、４，５−ジヒドロチアゾール環、１，２，４−チアジアゾール環、１，３，４−チアジアゾール環、ベンゾキサゾール環又はベンゾチアゾール環を表し、
Ｙ_Ａは、水素原子又はハロゲン原子を表し、
Ｚ_Ａは、水素原子、ハロゲン原子又は水酸基を表し、
Ｚ_Ａ'は、水素原子又はハロゲン原子を表し、
Ｗ_Ａは、−Ｏ−基、−Ｓ−基、−ＳＯ−基、−ＮＨ−基又はメチレン基を表し、
Ｒ_Ａは、水素原子、−ＳｉＲ_１Ｒ_２Ｒ_３基（Ｒ_１、Ｒ_２及びＲ_３は、同一又は相異なり、C1-C6アルキル基を表す。）、C1-C4アルキルカルボニル基又はC1-C4アルコキシカルボニル基を表す。］
で示されるクマリン化合物と不活性担体とを含有することを特徴とする３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物；
２．式（B）

［式中、
Ｘ_Ｂは、アセチル基、メチル基、トリフルオロメチル基又はニトロ基で置換されてもよい、２−ピリジル基、１，３，４−チアジアゾール−２−イル基、２−イミダゾリル基、４，５−ジヒドロチアゾール−２−イル基又はチアゾール−２−イル基を表し、
Ｙ_Ｂは、水素原子又はハロゲン原子を表し、
Ｚ_Ｂ及びＺ_Ｂ'は、同一又は相異なり、水素原子又はハロゲン原子を表し、
Ｗ_Ｂは、−Ｓ−基又はメチレン基を表し、
Ｒ_Ｂは、水素原子、−ＳｉＲ_１Ｒ_２Ｒ_３基（Ｒ_１、Ｒ_２及びＲ_３は、同一又は相異なり、C1-C6アルキル基を表す。）、C1-C4アルキルカルボニル基又はC1-C4アルコキシカルボニル基を表す。
ただし、Ｘ_Ｂが置換基を有さない２−ピリジル基であってＷ_Ｂが−Ｓ−基のとき、Ｙ_ＢＺ_Ｂ、Ｚ_Ｂ'及びＲ_Ｂが同時に水素原子となることはない。］
で示されるクマリン化合物；
３．式（I）

［式中、
X_Ｉは、ハロゲン原子、C1-C4アルキル基、トリフルオロメチル基、ニトロ基、C1-C4アルキルチオ基、シクロプロピルメチルチオ基又はａ_Ｉ−ＣＨ_２Ｓ−基（ａ_Ｉは、単数のハロゲン原子で置換されてもよいフェニル基、同一又は相異なる複数のハロゲン原子で置換されたフェニル基又はトリフルオロメチル基で置換されたフェニル基を表す。）で示される置換基群から選ばれる、単数の基で置換されてもよい、又は、同一又は相異なる複数の基で置換された、ベンゼン環、ピリジン環、ピリミジン環、チオフェン環、イミダゾール環、１，２，４−トリアゾール環、テトラゾール環、チアゾール環、４，５−ジヒドロチアゾール環、１，２，４−チアジアゾール環、１，３，４−チアジアゾール環、ベンゾキサゾール環又はベンゾチアゾール環を表し、
Ｙ_Ｉは、水素原子又はハロゲン原子を表し、
Ｚ_Ｉは、水素原子又は水酸基を表し、
Ｗ_Ｉは、−Ｓ−基、−ＳＯ−基、−ＮＨ−基又はメチレン基を表し、
Ｒ_Ｉは、水素原子、C1-C4アルキルカルボニル基又はC1-C4アルコキシカルボニル基を表す。］
で示されるクマリン化合物と不活性担体とを含有することを特徴とする３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物；
４．式（II）

［式中、
X_ＩＩは、メチル基、トリフルオロメチル基又はニトロ基で置換されてもよい、２−ピリジル基、１，３，４−チアジアゾール−２−イル基、２−イミダゾリル基、４，５−ジヒドロチアゾール−２−イル基又はチアゾール−２−イル基を表し、
Ｙ_ＩＩは、水素原子又はハロゲン原子を表し、
Ｒ_ＩＩは、水素原子、Ｃ１−Ｃ４アルキルカルボニル基又はC1-C4アルコキシカルボニル基を表す。
ただし、X_ＩＩが置換基を有さない２−ピリジル基であるとき、Ｙ_ＩＩ及びＲ_ＩＩが同時に水素原子となることはない。］
で示されるクマリン化合物；
５．式（III）で示されるクマリン化合物；

６．式（IV）で示されるクマリン化合物；

７．式（V）で示されるクマリン化合物；

８．式（VI）で示されるクマリン化合物；

９．式（VII）で示されるクマリン化合；

１０．式（VIII）で示されるクマリン化合物；

１１．式（IX）で示されるクマリン化合物；

１２．式（X）で示されるクマリン化合物；

１３．式（XI）で示されるクマリン化合物；

１４．式（XII）で示されるクマリン化合物；

１５．式（XIII）で示されるクマリン化合物；

１６．式（XIV）で示されるクマリン化合物；

１７．式（XV）で示されるクマリン化合物；

１８．式（XVI）で示されるクマリン化合物；

１９．式（XVII）で示されるクマリン化合物；

２０．式（XVIII）で示されるクマリン化合物；

２１．式（XIX）で示されるクマリン化合物；

２２．式（XX）で示されるクマリン化合物；

２３．式（XXI）で示されるクマリン化合物；

２４．式（XXII）で示されるクマリン化合物；

２５．前項２又は４に記載のクマリン化合物と不活性担体とを含有する３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物；
２６．前項５〜２４のいずれか一項に記載のクマリン化合物と不活性担体とを含有する３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物；
２７．前項１又は３に記載の３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物に有効成分として含有されるクマリン化合物の３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための使用；
２８．３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための前項２又は４に記載のクマリン化合物の使用；
２９．３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための前項５〜２４のいずれか一項に記載のクマリン化合物の使用；
３０．３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害する方法であって、治療的に有効な量の前項１又は３に記載の３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物に有効成分として含有されるクマリン化合物を該阻害を必要とする患者に投与することを特徴とする方法；
３１．男性ホルモン依存性疾患を処置又は予防する方法であって、治療的に有効な量の前項１又は３に記載の３型１７β−ヒドロキシステロイドデヒドロゲナーゼ阻害組成物に有効成分として含有されるクマリン化合物を該処置又は予防を必要とする患者に投与することを特徴とする方法；
３２．男性ホルモン依存性疾患が、前立腺癌、良性前立腺肥大、前立腺上皮内新生物形成、多毛症、アクネ、脂漏症、男性ホルモン性脱毛症、性的早熟、副腎性肥大又は多嚢胞性卵巣症候群である、前項３１に記載の方法；
等を提供するものである。 As a result of intensive studies under these circumstances, the present inventors have found that the compounds represented by the following formulas (A), (B), (I) to (XXIV) (hereinafter collectively referred to as the present compound). Has been found to have the ability to inhibit type 3 17β-hydroxysteroid dehydrogenase, leading to the present invention.
That is, the present invention
1. Formula (A)

[Where:
X _A is, C1-C4 alkylcarbonyl group, a halogen atom, C1-C4 alkyl group, a trifluoromethyl group, a nitro group, C1-C4 alkylthio group, a cyclopropylmethyl thio group or a _I -CH 2 _S- group (a _I Represents a phenyl group which may be substituted with a single halogen atom, a phenyl group substituted with a plurality of the same or different halogen atoms, or a phenyl group substituted with a trifluoromethyl group). Benzene ring, pyridine ring, pyrimidine ring, thiophene ring, imidazole ring, 1,2,4-triazole, which may be substituted with a single group selected from the above, or substituted with a plurality of the same or different groups Ring, tetrazole ring, thiazole ring, 4,5-dihydrothiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, benzoxa Over represents Le ring or benzothiazole ring,
Y _A represents a hydrogen atom or a halogen atom,
Z _A represents a hydrogen atom, a halogen atom or a hydroxyl group,
Z _A ′ represents a hydrogen atom or a halogen atom,
W _A is, -O- group, -S- group, an -SO- group, -NH- group or methylene group,
R _A represents a hydrogen atom, a —SiR ₁ R ₂ R ₃ group (R ₁ , R ₂ and R ₃ are the same or different and represent a C1-C6 alkyl group), a C1-C4 alkylcarbonyl group, or a C1- Represents a C4 alkoxycarbonyl group. ]
A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising a coumarin compound represented by formula (II) and an inert carrier;
2. Formula (B)

[Where:
X _B is acetyl group, it may be substituted with a methyl group, a trifluoromethyl group or a nitro group, a 2-pyridyl group, 1,3,4-thiadiazol-2-yl group, 2-imidazolyl group, 4,5 -Represents a dihydrothiazol-2-yl group or a thiazol-2-yl group,
Y _B represents a hydrogen atom or a halogen atom,
Z _B and Z _B ′ are the same or different and each represents a hydrogen atom or a halogen atom,
W _B represents an —S— group or a methylene group,
R _B represents a hydrogen atom, a —SiR ₁ R ₂ R ₃ group (R ₁ , R ₂ and R ₃ are the same or different and represent a C1-C6 alkyl group), a C1-C4 alkylcarbonyl group, or a C1- Represents a C4 alkoxycarbonyl group.
However, when the _{W B} is -S- group a 2-pyridyl group is _{X B} having no substituent _{group, Y B Z B, Z B} ' and _{R B} are not a hydrogen atom at the same time. ]
A coumarin compound represented by:
3. Formula (I)

[Where:
X _I is a halogen atom, C1-C4 alkyl group, a trifluoromethyl group, a nitro group, C1-C4 alkylthio group, the cyclopropylmethyl thio group or a _I -CH 2 _S- group (a _I, a halogen atom singular A phenyl group which may be substituted, a phenyl group substituted with the same or different plural halogen atoms, or a phenyl group substituted with a trifluoromethyl group). Benzene ring, pyridine ring, pyrimidine ring, thiophene ring, imidazole ring, 1,2,4-triazole ring, tetrazole ring, thiazole ring, which may be substituted with the same or different groups 4,5-dihydrothiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, benzoxazole ring or benzothiazole It represents a ring,
Y _I represents a hydrogen atom or a halogen atom,
Z _I represents a hydrogen atom or a hydroxyl group,
W _I represents a —S— group, a —SO— group, a —NH— group or a methylene group;
R _I represents a hydrogen atom, a C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group. ]
A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising a coumarin compound represented by formula (II) and an inert carrier;
4). Formula (II)

[Where:
X _II is a methyl group, may be substituted with a trifluoromethyl group or a nitro group, a 2-pyridyl group, 1,3,4-thiadiazol-2-yl group, 2-imidazolyl group, 4,5-dihydro-thiazole Represents a 2-yl group or a thiazol-2-yl group,
Y _II represents a hydrogen atom or a halogen atom,
R _II represents a hydrogen atom, a C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group.
However, when X _II is a 2-pyridyl group having no substituent, Y _II and R _II are not simultaneously hydrogen atoms. ]
A coumarin compound represented by:
5). A coumarin compound represented by formula (III);

6). A coumarin compound represented by formula (IV);

7). A coumarin compound represented by formula (V);

8). A coumarin compound represented by formula (VI);

9. A coumarin compound represented by formula (VII);

10. A coumarin compound represented by formula (VIII);

11. A coumarin compound represented by formula (IX);

12 A coumarin compound represented by formula (X);

13. A coumarin compound represented by formula (XI);

14 A coumarin compound represented by the formula (XII);

15. A coumarin compound represented by the formula (XIII);

16. A coumarin compound represented by the formula (XIV);

17. A coumarin compound represented by the formula (XV);

18. A coumarin compound represented by the formula (XVI);

19. A coumarin compound represented by the formula (XVII);

20. A coumarin compound represented by the formula (XVIII);

21. A coumarin compound represented by the formula (XIX);

22. A coumarin compound represented by the formula (XX);

23. A coumarin compound represented by the formula (XXI);

24. A coumarin compound represented by the formula (XXII);

25. A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising the coumarin compound according to item 2 or 4 and an inert carrier;
26. 25. Type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising the coumarin compound according to any one of 5 to 24 above and an inert carrier;
27. Use of the coumarin compound contained as an active ingredient in the type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to item 1 or 3 for inhibiting type 3 17β-hydroxysteroid dehydrogenase;
Use of a coumarin compound according to item 2 or 4 for inhibiting 28.3 type 17β-hydroxysteroid dehydrogenase;
Use of a coumarin compound according to any one of 5 to 24 above for inhibiting 29.3 type 17β-hydroxysteroid dehydrogenase;
A method for inhibiting type 30.3 17β-hydroxysteroid dehydrogenase, which is a coumarin compound contained as an active ingredient in a therapeutically effective amount of the type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to item 1 or 3 above Administering to a patient in need of said inhibition;
31. A method for treating or preventing a male hormone-dependent disease, comprising a coumarin compound contained as an active ingredient in a therapeutically effective amount of the type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to 1 or 3 above. Administering to a patient in need of treatment or prevention;
32. Male hormone-dependent diseases include prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, seborrhea, androgenetic alopecia, premature sexual maturity, adrenal hypertrophy or polycystic ovary syndrome 32. The method according to item 31 above;
Etc. are provided.

  According to the present invention, development and provision of a composition or the like for treating or preventing male hormone-dependent diseases by inhibiting the activity of type 3 17β-hydroxysteroid dehydrogenase and suppressing the enhancement of male hormone activity in tissues. It becomes possible.

Hereinafter, the present invention will be described in detail.
In the present invention, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present invention, examples of the C1-C4 alkyl group include a methyl group, an ethyl group, an isopropyl group, and a t-butyl group, examples of the C5 alkyl group include an isopentyl group, and examples of the C6 alkyl group include texyl. Examples of the C1-C4 alkylthio group include a methylthio group, an ethylthio group, and a propylthio group. Examples of the C1-C4 alkylcarbonyl group include an acetyl group and a propionyl group. Examples of the C1-C4 alkoxycarbonyl group include a methoxycarbonyl group and a t-butoxycarbonyl group.

  In this compound, when it has a pyridine ring, the N-oxide is also included.

  The compounds also represent their pharmacologically acceptable salts. The pharmacologically acceptable salt represents a salt of the present compound with an inorganic acid, a salt with an organic acid, a salt with an inorganic base or a salt with an organic base. Examples of the salt with an inorganic acid include hydrochloride and hydrobromide. Examples of the salt with an organic acid include acetate and benzoate. Examples include potassium salts and sodium salts, and examples of salts with organic bases include pyridine salts and morpholine salts.

  Below, it describes about the manufacturing method (1)-(4) of this compound.

該反応において、反応温度の範囲は、通常、室温〜溶媒還流温度であり、反応時間の範囲は、通常、瞬時〜約２４時間である。該反応は、通常、塩基の存在下で行うが、用いられる塩基としては、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジメチルアニリン、トリブチルアミン、Ｎ−メチルモルホリン等の有機塩基、水素化ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基等があげられる。該反応に供せられる試剤の量は、化合物（1’）１モルに対して、化合物（1’’）は通常１〜２モル、塩基は通常１〜７モルである。上記反応において、溶媒は必ずしも必要ではないが、通常は溶媒の存在下に行われる。該反応に使用しうる溶媒としては、ヘキサン、石油エーテル等の脂肪族炭化水素類、ベンゼン、トルエン等の芳香族炭化水素類、クロロホルム、ジクロロエタン等のハロゲン化炭化水素類、ジエチルエーテル、ジオキサン、テトラヒドロフラン等のエーテル類、アセトン、メチルエチルケトン等のケトン類、酢酸エチル、炭酸ジエチル等のエステル類、メタノール、エタノール、イソプロパノール等のアルコール類、アセトニトリル、イソブチルニトリル等のニトリル類、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド等のアミド類、ジメチルスルホキシド等の硫黄化合物類等又はそれらの混合物があげられる。反応終了後の反応液は、有機溶媒抽出、水洗後、有機層を減圧濃縮する等の通常の後処理を行い、必要に応じ、クロマトグラフィー、再結晶等の操作によって精製することにより、化合物（1）を得ることができる。
化合物（1’）は、例えば、文献Ｊ．Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍ．（２００４），４７（２７），６７９２に記載されている。 Production method (1):
Among these compounds, the compound represented by the formula (1) (wherein X _B , Y _B , Z _B , Z _B ′ and R _B represent the same meaning as described above) includes, for example, the formula (1 ') (Wherein V represents a chlorine atom or a bromine atom, and Y _B , Z _B , Z _B ' and R _B represent the same meaning as described above), and a compound represented by the formula (1 '') (Wherein X _B represents the same meaning as described above).

In the reaction, the reaction temperature is usually from room temperature to the solvent reflux temperature, and the reaction time is usually from instantaneous to about 24 hours. The reaction is usually carried out in the presence of a base. Examples of the base used include organic bases such as pyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine, sodium hydride, sodium hydroxide. And inorganic bases such as potassium hydroxide and potassium carbonate. The amount of the reagent used for the reaction is usually 1 to 2 mol for the compound (1 ″) and 1 to 7 mol for the base, relative to 1 mol of the compound (1 ′). In the above reaction, a solvent is not always necessary, but it is usually performed in the presence of a solvent. Solvents usable in the reaction include aliphatic hydrocarbons such as hexane and petroleum ether, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloroethane, diethyl ether, dioxane, and tetrahydrofuran. Ethers such as acetone, methyl ethyl ketone, esters such as ethyl acetate and diethyl carbonate, alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile and isobutylnitrile, formamide, N, N-dimethylformamide Amides such as dimethylsulfoxide, sulfur compounds such as dimethyl sulfoxide, and mixtures thereof. The reaction solution after completion of the reaction is subjected to usual post-treatment such as extraction with an organic solvent, washing with water, and concentration of the organic layer under reduced pressure. If necessary, the reaction mixture is purified by operations such as chromatography, recrystallization, etc. 1) can be obtained.
Compound (1 ′) is described, for example, in J. Org. Medicinal Chem. (2004), 47 (27), 6792.

該反応において、反応温度の範囲は、通常、溶媒還流温度を上限として０℃〜１２０℃であり、反応時間の範囲は、通常、瞬時〜約５０時間である。該反応は、通常、酸性溶媒中で行われる。酸性溶媒としては、例えば、濃硫酸、７０％硫酸、トリフルオロ酢酸、メタンスルホン酸、オキシ塩化リン、ポリリン酸等があげられる。該反応に供せられる試剤の量は、化合物（2’）１モルに対して、化合物（2’’）は通常０．８〜２モルである。反応終了後は、製造法（１）と同様にして、化合物（2）を得ることができる。
化合物（2’’）は、例えば、文献Ｊ．Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍ．（１９９８），４１（１７），３２６１に記載の方法で、製造することができる。 Production method (2):
Among the compounds, the compound represented by the formula (2) (wherein X _B , Z _B and Z _B ′ represent the same meaning as described above) is, for example, the formula (2 ′) (wherein Z _B and Z _B ′ represent the same meaning as described above.) And a compound represented by formula (2 ″) (wherein X _B represents the same meaning as described above, and R ′ represents C1 It represents a -C4 alkyl group.) And can be produced by reacting with a compound represented by

In the reaction, the reaction temperature range is usually from 0 ° C. to 120 ° C. up to the solvent reflux temperature, and the reaction time range is usually from instantaneous to about 50 hours. The reaction is usually performed in an acidic solvent. Examples of the acidic solvent include concentrated sulfuric acid, 70% sulfuric acid, trifluoroacetic acid, methanesulfonic acid, phosphorus oxychloride, polyphosphoric acid and the like. The amount of the reagent used for the reaction is usually 0.8 to 2 mol of the compound (2 ″) with respect to 1 mol of the compound (2 ′). After completion of the reaction, compound (2) can be obtained in the same manner as in production method (1).
Compound (2 ″) is described, for example, in literature J. Medicinal Chem. (1998), 41 (17), 3261.

該反応において、反応温度の範囲は、通常、室温〜溶媒還流温度であり、反応時間の範囲は、通常、瞬時〜約２４時間である。該反応は、通常、塩基の存在下で行うが、用いられる塩基としては、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジメチルアニリン、トリブチルアミン、Ｎ−メチルモルホリン、イミダゾール等の有機塩基、水素化ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基等があげられる。該反応に供せられる試剤の量は、化合物（3’）１モルに対して、酸ハライド、酸無水物、炭酸ジエステル、クロロ炭酸エステル又はトリアルキルシリルハライドは通常１〜２モル、塩基は通常触媒量〜７モルである。上記反応において、溶媒は必ずしも必要ではないが、通常は溶媒の存在下に行われ、例えば、製造法（１）にあげられた溶媒が該反応に使用しうる。酸ハライドとしては、塩化アセチル、塩化プロピオニル等があげられ、酸無水物としては、無水酢酸等があげられ、炭酸ジエステルとしては、二炭酸ジ−ｔ−ブチル等があげられ、クロロ炭酸エステルとしては、クロロ炭酸エチル等があげられ、トリアルキルシリルハライドとしては、ブロモトリメチルシラン、クロロ（ジメチル）テキシルシラン、トリイソプロピルシリルクロリド等があげられる。反応終了後は、製造法（１）と同様にして、化合物（3）を得ることができる。 Production method (3):
Among the compounds of formula (3) _(wherein, X _B, Y _B, 'is and _{W B,} represents the same meaning as _{above, R B' Z B, Z} B is, -SiR ₁ R ₂ R ₃ A compound represented by a group (R ₁ , R ₂ and R ₃ represent the same meaning as described above), a C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group) is represented by, for example, the formula (3 ') _{(wherein, X B, Y B, Z} B, Z B' is and _{W B,} the compound shown by the representative.) the same meaning as above, acid halides, acid anhydrides, carbonic acid diester, chlorocarbonate It can be produced by reacting with an ester or trialkylsilyl halide.

In the reaction, the reaction temperature is usually from room temperature to the solvent reflux temperature, and the reaction time is usually from instantaneous to about 24 hours. The reaction is usually carried out in the presence of a base. Examples of the base used include pyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine, imidazole and other organic bases, sodium hydride, water Examples thereof include inorganic bases such as sodium oxide, potassium hydroxide and potassium carbonate. The amount of the reagent used for the reaction is usually 1 to 2 moles for acid halide, acid anhydride, carbonic acid diester, chlorocarbonate or trialkylsilyl halide, and usually base for 1 mole of compound (3 ′). The amount of catalyst is 7 mol. In the above reaction, a solvent is not necessarily required, but the reaction is usually carried out in the presence of a solvent. For example, the solvents mentioned in the production method (1) can be used for the reaction. Examples of the acid halide include acetyl chloride and propionyl chloride. Examples of the acid anhydride include acetic anhydride. Examples of the carbonic acid diester include di-t-butyl dicarbonate. Examples of the chlorocarbonate include Examples of the trialkylsilyl halide include bromotrimethylsilane, chloro (dimethyl) texylsilane, and triisopropylsilyl chloride. After completion of the reaction, compound (3) can be obtained in the same manner as in production method (1).

該反応において、反応温度の範囲は、通常、室温〜溶媒還流温度であり、反応時間の範囲は、通常、瞬時〜約２４時間である。該反応は、通常、塩基の存在下で行うが、用いられる塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基等があげられる。該反応に供せられる塩基の量は、化合物（4’）１モルに対して、塩基は通常１〜７モルである。上記反応において、通常は溶媒の存在下に行われ、使用しうる溶媒としては、ジエチルエーテル、ジオキサン、テトラヒドロフラン等のエーテル類、アセトン、メチルエチルケトン等のケトン類、メタノール、エタノール、イソプロパノール等のアルコール類、アセトニトリル、イソブチルニトリル等のニトリル類、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド等のアミド類、ジメチルスルホキシド等の硫黄化合物類、水又はそれらの混合物があげられる。反応終了後は、製造法（１）と同様にして、化合物（4）を得ることができる。 Production method (4):
Among the compounds of formula (4) _{(wherein, X B, Y B, Z} B, Z B ' and _{W B} represent. The same meanings as the above), a compound represented by, for example, the formula (4 ) _{(wherein, X B, Y B, Z} B, Z B ' and _{W B} represent the same meaning as above, _{R B'} a 'is C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group It can be produced by hydrolyzing the compound represented by.

In the reaction, the reaction temperature is usually from room temperature to the solvent reflux temperature, and the reaction time is usually from instantaneous to about 24 hours. The reaction is usually carried out in the presence of a base, and examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate. The amount of the base used for the reaction is usually 1 to 7 moles with respect to 1 mole of the compound (4 ′). In the above reaction, it is usually carried out in the presence of a solvent, and usable solvents include ethers such as diethyl ether, dioxane and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and isopropanol, Nitriles such as acetonitrile and isobutyl nitrile, amides such as formamide and N, N-dimethylformamide, sulfur compounds such as dimethyl sulfoxide, water, or a mixture thereof. After completion of the reaction, the compound (4) can be obtained in the same manner as in the production method (1).

  Among these compounds, compounds (a) represented by compound numbers (1) to (38) are exemplified in Tables 1 to 4.

本化合物のうち、化合物番号（３９）〜（４４）で表される化合物（ｂ）を、表５に例示する。

Among the present compounds, compounds (b) represented by compound numbers (39) to (44) are exemplified in Table 5.

本化合物のうち、化合物番号（４５）〜（４８）で表される化合物（ｂ）を、表６に例示する。

Table 6 illustrates compounds (b) represented by compound numbers (45) to (48) among the present compounds.

This compound has the ability to inhibit the activity of type 3 17β-hydroxysteroid dehydrogenase. This ability is important to prevent the onset and progression of male hormone-dependent diseases by suppressing the production of testosterone, a highly active male hormone, leading to a decrease in male hormone activity in tissues. Therefore, the present compound inhibits the activity of type 3 17β-hydroxysteroid dehydrogenase and suppresses the enhancement of androgen activity in tissues, thereby treating or preventing androgen-dependent diseases (pharmaceuticals, cosmetics, It can be used as an active ingredient of food additives and the like.
For example, the compound comprises a method of inhibiting type 3 17β-hydroxysteroid dehydrogenase comprising administering a therapeutically effective amount of at least one compound to a patient in need of such inhibition. Can be used to
Also for example, the compound is a method of treating or preventing androgen-dependent diseases, comprising the step of administering a therapeutically effective amount of at least one compound to a patient in need of the treatment or prevention. It can be used for the method of inclusion.

This compound is useful for the prevention or treatment of androgen-dependent diseases whose onset or progression is promoted by the activity of androgen.
Applicable androgen-dependent diseases of the present compounds include, for example, prostate cancer and other androgen-dependent neoplasms, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, androgenetic alopecia (ie, male patients and Pattern baldness in both female patients), hirsutism, polycystic ovary syndrome, premature sexual maturity, adrenal hypertrophy, seborrhea and acne. For example, a method for treating or preventing prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, seborrhea, androgenetic alopecia, sexual prematurity, adrenal hypertrophy or polycystic ovary syndrome It can be used in a method comprising the step of administering a therapeutically effective amount of at least one compound to a patient in need of such treatment or prevention.

  A preferred dosage (effective amount) is about 0.001 to 500 mg of the compound per kg body weight per day. A more preferred dosage is about 0.01 to 25 mg of the compound per kg body weight per day, or a pharmaceutically acceptable salt of the compound or a solvate of the compound.

  The compound is usually administered in the form of a composition comprising at least one compound, or a pharmacologically acceptable salt of the compound or a solvate of the compound, and at least one inert carrier. The present compound contained in these compositions is usually from 0.01% to 99.99% by weight, and the inert carrier is usually from 99.99% to 0.01% by weight. The inert carrier is a pharmaceutically acceptable carrier or excipient. The composition of the present invention may further contain pharmaceutical additives, cosmetic additives, food additives and the like.

  The pharmaceutically acceptable carrier, excipient, pharmaceutical additive, food additive, cosmetic additive, etc. used to prepare the composition containing the present compound depend on the specific use of the composition. Can be selected as appropriate. Moreover, the form of this composition can also be made into various solids, liquids, etc. according to a specific use, for example.

  Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Examples of the solid carrier include magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions are described in A.C. Gennaro (eds.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing Co. , Easton, Pennsylvania.

  Liquid form preparations include solutions, suspensions, emulsions and the like. For example, water or water-propylene glycol solution for parenteral injection can be mentioned. Sweetening agents and opacifiers may be added to oral solutions, suspensions and emulsions. Examples of liquid form preparations may include solutions for intranasal administration.

  It may also be an aerosol formulation suitable for inhalation, in which case it may include solids in solution and powder form. Such solution or powder form solids may be formulated in combination with a pharmaceutically acceptable carrier such as an inert compressed gas (eg, nitrogen).

  Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compound may be administered transdermally. The transdermal composition can be in the form of a cream, lotion, aerosol and / or emulsion, and for this purpose, as usual in the art, in a matrix type transdermal patch or reservoir type It may be contained in a transdermal patch.
The compound may also be delivered subcutaneously. More preferably, the compound may be administered orally.

  The composition can also be in unit dosage form. In such form, the composition is subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.

  The amount of active compound in a unit dose of the composition may be adjusted to be from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. .

  The actual dosage used may vary depending on the patient's weight and the severity of the disease being treated. If needed for convenience, the total daily dosage may be divided into several doses.

  The dose and frequency of administration of this compound and / or pharmacologically acceptable salt of this compound are determined according to the judgment of the attending physician in consideration of the age, condition and physique of the patient and the severity of the disease to be treated. Adjusted. A typical recommended daily dosage regimen for oral administration can range from about 1 mg to about 500 mg per day, preferably from about 1 mg to about 200 mg per day, It can be administered in 4 divided doses.

  The invention includes a therapeutically effective amount of at least one compound, or a pharmacologically acceptable salt of the compound, or a solvate of the compound, and a pharmaceutically acceptable carrier, excipient or diluent. A kit comprising the agent is also provided. Such kits may include the above components in one or more containers within the kit.

When the compound is used by adding it to cosmetics, specific examples of cosmetics to which the compound is added include liquid, milky, cream, lotion, ointment, gel, aerosol, mousse and the like. it can. Lotions can be produced according to conventional methods using cosmetic additives such as suspending agents, emulsifying agents, preservatives and the like.
The dosage of the cosmetic product varies depending on the age, sex, weight, degree of disease, type of composition of the present invention, dosage form, etc. of the patient to be administered, but is usually about 0.01 mg as an active ingredient amount in a human adult. ˜about 50 mg may be administered. These doses can be administered in several divided doses.

When this compound is used as a food additive, specific examples of the food to which the additive is added include, for example, powders, tablets, beverages, ingestible gels or mixed liquids with syrup, such as seasonings. , Japanese confectionery, Western confectionery, ice confectionery, beverages, spreads, pastes, pickles, canned bottles, processed meat products, processed fish / fishery products, processed milk / egg products, processed vegetables products, processed fruit products, processed cereal products, etc. Food and drinks and favorite foods can be listed. Further, it can be added to feed and feed for domestic animals such as domestic animals, poultry, bees, cormorants and fish.
The dose varies depending on the age, sex, body weight, degree of disease, type of composition of the present invention, dosage form, etc. of the patient to be administered, but is usually about 0.1 mg to about 500 mg as an active ingredient amount in a human adult. May be administered. In addition, the above-mentioned daily dose can be administered once or divided into several times.

Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 The synthesis of this compound is described in Examples 1-1 to 1-26.

Example 1-1 Synthesis of the present compound [Compound No. (10)] 4-chloromethyl-7-hydroxy-2H-chromen-2-one 0.20 g, 4-mercaptopyridine 0.13 g and triethylamine 0.12 g in DMF 5 ml The solution was stirred at room temperature for 4 hours. Crystals precipitated by adding water were collected by filtration, washed successively with water, hexane, toluene and hexane and dried to obtain 0.18 g of a pale yellow crystal of the coumarin compound of Compound No. (10).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.59 (s, 2H), 6.31 (s, 1H), 6.73 (d, 1H, J = 1.1 Hz), 6.82 (d, 1H, J = 8.6 Hz), 7.32 (d, 2H, J = 4.9 Hz), 7.78 (d, 1H, J = 8.6 Hz), 8.39 (d , 2H, J = 4.9 Hz), 10.64 (broad s, 1H)

Example 1-2 Synthesis of this compound [Compound No. (11)] The same procedure as in Example 1-1 was performed except that 0.13 g of 2-mercapto-1,3,4-thiadiazole was used instead of 4-mercaptopyridine. Thus, 0.29 g of a white powder of the coumarin compound of Compound No. (11) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.77 (s, 2H), 6.29 (s, 1H), 6.74 (d, 1H, J = 2.4 Hz), 6.84 (dd, 1H, J = 2.2 Hz, 8.6 Hz), 7.80 (d, 1H, J = 8.6 Hz), 9.56 (s, 1H), 10.64 (broad s, 1H)

Example 1-3 Synthesis of the present compound [Compound No. (12)] Example 1 except that 0.19 g of 2-mercapto-4-methylthio-1,3,5-thiadiazole was used instead of 4-mercaptopyridine. In the same manner as in Example 1, 0.19 g of a white powder of the coumarin compound of Compound No. (12) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.61 (s, 3H), 4.77 (s, 2H), 6.38 (s, 1H), 6.74 (d, 1H, J = 1.6 Hz), 6.83 (d, 1H, J = 8.1 Hz), 7.79 (d, 1H, J = 8.6 Hz), 10.65 (broad, 1H)

Example 1-4 Synthesis of the present compound [Compound No. (13)] The compound was prepared in the same manner as in Example 1-1 except that 0.12 g of 1-methyl-2-mercaptoimidazole was used instead of 4-mercaptopyridine. 0.21 g of white crystals of the coumarin compound of number (13) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.45 (s, 3H), 4.29 (s, 2H), 5.88 (s, 1H), 6.72 (d, 1H, J = 2.4 Hz), 6.80 (dd, 1H, J = 2.2 Hz, 8.4 Hz), 6.97 (d, 1H, J = 1.4 Hz), 7.26 (d, 1H , J = 1.1 Hz), 7.68 (d, 1H, J = 8.6 Hz), 10.60 (broad, 1H)

Example 1-5 Synthesis of Compound [Compound No. (14)] To a solution of 2-mercaptopyridine-N-oxide (2.00 g) in ethanol (93 ml), potassium hydroxide (0.88 g) in ethanol (11 ml) was added dropwise at room temperature. The mixture was then stirred for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain a potassium salt of 2-mercaptopyridine-N-oxide. 4-Chloromethyl-7-hydroxy-2H-chromen-2-one 0.30 g, 2-mercaptopyridine-N-oxide potassium salt 0.24 g and potassium iodide 0.02 g in 7 ml of DMF was stirred at room temperature for 4 hours. did. Crystals deposited by adding water were collected by filtration, washed successively with water, hexane and ethanol, and dried to obtain 0.27 g of a coumarin compound of Compound No. (14).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.49 (s, 2H), 6.34 (s, 1H), 6.75 (d, 1H, J = 2.4 Hz), 6.85 (dd, 1H, J = 2.4 Hz, 8.6 Hz), 7.26 (t, 1H, J = 6.5 Hz), 7.38 (t, 1H, J = 6.2 Hz), 7 .50 (d, 1H, J = 7.8 Hz), 7.82 (dd, 1H, J = 2.4 Hz, 8.9 Hz), 8.33 (d, 1H, J = 5.7 Hz), 10. 65 (broad, 1H)

Example 1-6 Synthesis of this compound [Compound No. (16)] Compound No. (No. 16) was prepared in the same manner as in Example 1-1 except that 0.15 g of 2-mercaptobenzoxazole was used instead of 4-mercaptopyridine. 0.10 g of white crystals of the coumarin compound of 16) were obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.80 (s, 2H), 6.42 (s, 1H), 6.75 (d, 1H, J = 2.2 Hz), 6.85 (dd, 1H, J = 2.2 Hz, 8.9 Hz), 7.33 to 7.37 (m, 2H), 7.66 to 7.69 (m, 2H), 7.84 (d , 1H, J = 8.6 Hz), 10.66 (broad s, 1H)

Example 1-7 Synthesis of this compound [Compound No. (17)] Compound No. (17) was prepared in the same manner as in Example 1-1 except that 0.12 g of 2-mercaptothiazoline was used instead of 4-mercaptopyridine. 0.08 g of a white powder of the coumarin compound was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.49 (t, 1 H, J = 7.8 Hz), 4.17 (t, 1 H, J = 8.4 Hz), 4.54 (S, 2H), 6.28 (s, 1H), 6.74 (d, 1H, J = 2.2 Hz), 6.81 (dd, 1H, J = 2.7 Hz, 8.9 Hz), 7 .68 (d, 1H, J = 8.6 Hz), 10.62 (s, 1H)

Example 1-8 Synthesis of this compound [Compound No. (18)] Compound No. (18) was prepared in the same manner as in Example 1-1 except that 0.17 g of 2-mercaptobenzothiazole was used instead of 4-mercaptopyridine. ) 0.23 g of a white powder of coumarin compound.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.84 (s, 2H), 6.40 (s, 1H), 6.75 (d, 1H, J = 2.2 Hz), 6.84 (d, 1H, J = 8.6 Hz), 7.39 (t, 1H, J = 7.8 Hz), 7.49 (t, 1H, J = 7.8 Hz), 7.83 (d , 1H, J = 8.6 Hz), 7.89 (d, 1H, J = 7.8 Hz), 8.03 (d, 1H, J = 7.8 Hz), 10.65 (broad, 1H)

Example 1-9 Synthesis of this compound [Compound No. (19)] In the same manner as in Example 1-1 except that 0.12 g of 2-mercapto-1-methyltetrazole was used instead of 4-mercaptopyridine. 0.20 g of a white powder of the coumarin compound of number (19) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.91 (s, 3H), 4.66 (s, 2H), 6.23 (s, 1H), 6.74 (d, 1H, J = 2.4 Hz), 6.84 (dd, 1H, J = 2.2 Hz, 8.6 Hz), 7.81 (d, 1H, J = 9.2 Hz), 10.65 (s, 1H) )

Example 1-10 Synthesis of the present compound [Compound No. (20)] In the same manner as in Example 1-1 except that 0.16 g of 2-mercapto-5-nitropyridine was used instead of 4-mercaptopyridine. 0.18 g of a yellow crystal of the coumarin compound of number (20) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.73 (s, 2H), 6.35 (s, 1H), 6.74 (d, 1H, J = 2.2 Hz), 6.83 (dd, 1H, J = 2.4 Hz, 8.9 Hz), 7.66 (dd, 1H, J = 0.5 Hz, 9.5 Hz), 7.78 (d, 1H, J = 8. 9 Hz), 8.41 (dd, 1 H, J = 2.7 Hz, 8.9 Hz), 9.27 (dd, 1 H, J = 0.5 Hz, 2.7 Hz), 10.64 (broad, 1 H)

Example 1-11 Synthesis of the present compound [Compound No. (21)] The compound was prepared in the same manner as in Example 1-1 except that 0.13 g of 2-mercapto-6-methylpyridine was used instead of 4-mercaptopyridine. 0.04 g of white crystals of the coumarin compound of number (21) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.44 (s, 3H), 4.58 (s, 2H), 6.31 (s, 1H), 6.72 (d, 1H, J = 1.9 Hz), 6.81 (dd, 1H, J = 1.9 Hz, 8.6 Hz), 7.02 (d, 1H, J = 7.0 Hz), 7.13 (d, 1H) , J = 7.8 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 8.9 Hz), 10.59 (broad, 1H)

Example 1-12 Synthesis of this compound [Compound No. (22)] The same procedure as in Example 1-1 except that 0.18 g of 2-mercapto-5-trifluoromethylpyridine was used instead of 4-mercaptopyridine. 0.28 g of a pale yellow crystal of the coumarin compound of Compound No. (22) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.68 (s, 2H), 6.33 (s, 1H), 6.74 (d, 1H, J = 2.2 Hz), 6.83 (dd, 1H, J = 2.2 Hz, 8.6 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 8.6 Hz), 8 .05 (d, 1H, J = 8.4 Hz), 8.86 (s, 1H), 10.63 (broad, 1H)

Example 1-13 Synthesis of the present compound [Compound No. (23)] 4-chloromethyl-7-hydroxy-2H-chromen-2-one 0.20 g, 2-mercaptopyrimidine 0.13 g and potassium carbonate 0.16 g The DMF 5 ml solution was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to obtain 0.22 g of a pale red crystal of the coumarin compound of Compound No. (23). .
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.59 (s, 2H), 6.35 (s, 1H), 6.74 (d, 1H, J = 2.2 Hz), 6.83 (dd, 1H, J = 2.2 Hz, 8.6 Hz), 7.28 (t, 1H, J = 4.9 Hz), 7.77 (d, 1H, J = 8.6 Hz), 8 .68 (d, 2H, J = 4.9 Hz), 10.62 (broad, 1H)

Example 1-14 Synthesis of this compound [Compound No. (24)] 4-chloromethyl-7,8-dihydroxy-2H-chromene-in place of 4-chloromethyl-7-hydroxy-2H-chromen-2-one 0.05 g of white crystals of the coumarin compound of Compound No. (24) was obtained in the same manner as in Example 1-1 except that 0.19 g of 2-one was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.59 (s, 2H), 6.27 (s, 1H), 6.81 (d, 1H, J = 9.2 Hz), 7.16 (dd, 1H, J = 4.9 Hz, 7.3 Hz), 7.24 (d, 1H, J = 8.9 Hz), 7.36 (dd, 1H, J = 0.8 Hz, 8. 1 Hz), 7.68 (dt, 1 H, J = 1.1 Hz, 7.3 Hz), 8.49 (dd, 1 H, J = 1.1 Hz, 4.9 Hz)

Example 1-15 Synthesis of Compound [Compound No. (25)] 1.00 g of 7-hydroxy-4-[(2-pyridylthio) methyl] -2H-chromen-2-one was dissolved in a mixture of DMF and methylene chloride. Then, 1.15 g of di-tert-butyl carbonate and 0.4 ml of pyridine were added and stirred at room temperature for 4 hours. The reaction solution was subjected to column chromatography using alumina (eluent: hexane / ethyl acetate = 3/2) to obtain 0.98 g of an orange oil of the coumarin compound of Compound No. (25).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 1.47 (s, 9H), 4.69 (s, 2H), 6.45 (s, 1H), 7.19 (ddd, 1H, J = 0.8 Hz, 4.3 Hz, 7.3 Hz), 7.28 (dd, 1 H, J = 2.2 Hz, 7.8 Hz), 7.38 (dt, 1 H, J = 1.1 Hz, 5.1 Hz), 7.39 (d, 1 H, J = 2.2 Hz), 7.69 (dt, 1 H, J = 1.6 Hz, 6.8 Hz), 8.01 (d, 1 H, J = 7) .8 Hz), 8.49 (dq, 1H, J = 0.8 Hz, 4.6 Hz)

Example 1-16 Synthesis of the present compound [Compound No. (26)] 7-tert-Butoxycarbonyloxy-4-[(2-pyridylthio) methyl] -2H-chromen-2-one 0.44 g in 7 ml of methylene chloride To the mixture, 0.25 g of 3-chloroperbenzoic acid was added and stirred under ice cooling. The reaction solution was subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 3/1) to obtain 0.33 g of a yellow oily product of the coumarin compound of Compound No. (26).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 1.51 (s, 9H), 4.49 (d, 1H, J = 13.0 Hz), 4.82 (d, 1H, J = 12.7 Hz), 6.02 (s, 1 H), 7.15 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 7.32 (d, 1 H, J = 2.4 Hz), 7 .50 (ddd, 1H, J = 1.4 Hz, 4.9 Hz, 12.4 Hz), 7.68 (d, 1H, J = 8.9 Hz), 7.72 (d, 1H, J = 8.9 Hz) ), 7.9 (dt, 1H, J = 1.9 Hz, 7.8 Hz), 8.69 (dq, 1H, J = 0.8 Hz, 4.6 Hz)

Example 1-17 Synthesis of Compound [Compound No. (27)] 7-Hydroxy-4-[(2-pyridylthio) methyl] -2H-chromen-2-one 0.15 g and acetic anhydride 3 ml were refluxed. And stirred for 2 hours and 50 minutes. The reaction solution was subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 1/1) to obtain 0.14 g of a white crystal of the coumarin compound of Compound No. (27).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.31 (s, 3H), 4.69 (s, 2H), 6.52 (s, 1H), 7.15-7. 25 (2H), 7.30 (d, 1H, J = 2.2 Hz), 7.39 (d, 1H, J = 8.1 Hz), 7.65 to 7.85 (1H), 8.01 ( d, 1H, J = 8.6 Hz), 8.49 (1H, J = 5.1 Hz)

Example 1-18 Synthesis of Compound [Compound No. (28)] 7-tert-Butoxycarbonyloxy-4-[(2-pyridylsulfinyl) methyl] -2H-chromen-2-one 0.30 g, 3 ml of water, A mixture of 3 ml of trifluoroacetic acid and 6 ml of chloroform was stirred at room temperature for 2 hours and 20 minutes, and further 3 ml of trifluoroacetic acid was added and stirred at room temperature. The reaction solution was washed with an aqueous sodium bicarbonate solution, and the organic layer was washed with a saturated saline solution and then concentrated to obtain 0.29 g of a yellow crystal of the coumarin compound of Compound No. (28).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.38 (d, 1 H, J = 13.0 Hz), 4.70 (d, 1 H, J = 13.0 Hz), 5.84 (S, 1H), 6.66 (d, 1H, J = 1.9 Hz), 6.69 (dd, 1H, J = 2.7 Hz, 8.6 Hz), 7.48 (d, 1H, J = 8.6 Hz), 7.50 to 7.55 (1 H), 7.70 (d, 1 H, J = 7.8 Hz), 8.00 (dt, 1 H, J = 1.6 Hz, 7.8 Hz), 8.69 (d, 1H, J = 4.1 Hz), 10.61 (broad, 1H)

Example 1-19 Synthesis of this compound [Compound No. (29)] Compound No. (29) was prepared in the same manner as in Example 1-1 except that 0.12 g of 2-mercaptothiazole was used instead of 4-mercaptopyridine. 0.11 g of the coumarin compound was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.63 (s, 2H), 6.17 (s, 1H), 6.73 (d, 1H, J = 1.9 Hz), 6.82 (dd, 1H, J = 2.4 Hz, 8.6 Hz), 7.72 (d, 1H, J = 3.5 Hz), 7.76 (d, 1H, J = 8.6 Hz), 7 .80 (d, 1H, J = 3.2 Hz), 10.62 (s, 1H)

Example 1-20 Synthesis of this compound [Compound No. (31)] Compound No. (31) was prepared in the same manner as in Example 1-1 except that 0.06 g of 2-mercaptothiophene was used instead of 4-mercaptopyridine. 0.06 g of white crystals of the coumarin compound was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.16 (s, 2H), 5.70 (s, 1H), 6.72 (d, 1H, J = 2.4 Hz), 6.80 (dd, 1H, J = 2.4 Hz, 8.9 Hz), 7.03 (dd, 1H, J = 3.8 Hz, 5.7 Hz), 7.08 to 7.13 (1H), 7 .62-7.68 (1H), 7.72 (d, 1H, J = 8.6 Hz)

Example 1-21 Synthesis of the present compound [Compound No. (32)] A solution of 4-chloromethyl-7-hydroxy-2H-chromen-2-one 2.70 g and aniline 0.90 g in 30 ml of pyridine was stirred overnight at room temperature. did. Hexane was added and the precipitated crystals were collected by filtration, washed with ethyl acetate and dried to obtain 0.15 g of white crystals of the coumarin compound of Compound No. (32).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 5.62 (s, 1H), 6.22 (s, 2H), 6.85 (d, 1H, J = 2.4 Hz), 6.92 (dd, 1H, J = 2.2 Hz, 8.6 Hz), 7.67 (d, 1H, J = 8.6 Hz), 8.27 (t, 1H, J = 7.6 Hz), 8 .74 (t, 1H, J = 7.8 Hz), 9.21 (d, 2H, J = 5.4 Hz), 10.97 (s, 1H)

Example 1-22 Synthesis of the present compound [Compound No. (34)] (1) A 97.74 g acetic anhydride solution of 5.85 g 3-fluoro-7-hydroxy-4-methyl-2H-chromen-2-one The mixture was stirred at 120 ° C. for 2 hours. After cooling to room temperature, the precipitated crystals are collected by filtration, washed successively with ethanol, water and hexane and dried to give white crystals of 7-acetoxy-3-fluoro-4-methyl-2H-chromen-2-one. 5.28 g was obtained.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 2.35 (s, 3H), 2.41 (d, 3H, J = 3.0 Hz), 7.13 (s, 1H), 7. 15 (d, 1H, J = 1.9 Hz), 7.59 (d, 1H, J = 9.2 Hz)
(2) 7.90 g of N-bromosuccinimide and 0.10 g of benzoyl peroxide were added to a solution of 2.50 g of 7-acetoxy-3-fluoro-4-methyl-2H-chromen-2-one in 40 ml of carbon tetrachloride. The mixture was added and stirred under reflux for 5 hours. Furthermore, 0.05 g of benzoyl peroxide was added, and the mixture was heated and stirred for 8 hours under reflux. After cooling to room temperature, the insoluble material was collected by filtration, washed successively with a solution of 0.5 g of sodium thiosulfate in 150 ml of water, water and hexane and dried to give 7-acetoxy-4-bromomethyl-3-fluoro-2H. -2.95 g of a slightly red powder of chromen-2-one was obtained.
(3) 0.15 g of sodium hydride (60% oily) was suspended in 25 ml of DMF, and 0.44 g of 2-mercaptopyridine was added thereto at room temperature, followed by stirring at room temperature for 30 minutes. 1.60 g of 7-acetoxy-4-bromomethyl-3-fluoro-2H-chromen-2-one obtained in the previous section was added under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water, and the precipitate was collected by filtration, washed successively with water, hexane, toluene and hexane and dried to obtain 0.99 g of a white powder of the coumarin compound of Compound No. (34). It was.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 2.33 (s, 3H), 4.72 (d, 2H, J = 2.4 Hz), 7.05 to 7.15 (2H), 7.15 (d, 1H, J = 2.2 Hz), 7.19 (d, 1H, J = 8.1 Hz), 7.54 (t, 1H, J = 7.3 Hz), 7.82 (d , 1H, J = 8.9 Hz), 8.53 (d, 1H, J = 4.1 Hz)

Example 1-23 Synthesis of this compound [Compound No. (35)] 7-acetoxy-3-fluoro-4-[(2-pyridylthio) methyl] -2H-chromen-2-one in a methanol 40 ml solution At 0 ° C., a solution of 0.33 g of sodium hydroxide in 50 ml of methanol was added. After stirring at 0 ° C. for 1 hour, the reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and 5% aqueous potassium carbonate solution, the precipitate was collected by filtration, washed successively with water and hexane and dried to give compound number (35). 0.43 g of a white powder of the coumarin compound was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.68 (S, 2H), 6.79 (d, 1H, J = 2.2 Hz), 6.87 (d, 1H, J = 8.9 Hz), 7.15-7.25 (1H), 7.37 (d, 1H, J = 7.8 Hz), 7.65-7.80 (2H), 8.53 (1H), 10.58 (s, 1H)

Example 1-24 Synthesis of the Compound [Compound No. (36)] (1) 7-acetoxy-3-chloro-4-methyl-2H-chromen-2-one -0.73 g of bromosuccinimide and 20 mg of benzoyl peroxide were added, and the mixture was heated and stirred for 3 hours 30 minutes under reflux. After cooling to room temperature, the insoluble material was filtered off, the filtrate was concentrated and subjected to column chromatography using silica gel (eluent: chloroform), 7-acetoxy-4-bromomethyl-3-chloro-2H-chromene-2- 0.83 g of on-white crystals were obtained.
(2) 80 mg of sodium hydride (60% oily) was suspended in 15 ml of DMF, and 0.23 g of 2-mercaptopyridine was added thereto under ice cooling, followed by stirring at room temperature for 30 minutes. 0.67 g of 7-acetoxy-4-bromomethyl-3-chloro-2H-chromen-2-one obtained in the previous section was added at room temperature and stirred at room temperature for 2 hours 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, concentrated and subjected to column chromatography using silica gel (eluent: hexane / acetone = 1/1). By recrystallization from a mixed solvent of ethanol and chloroform, 0.20 g of a white solid of the coumarin compound of Compound No. (36) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.31 (s, 3H), 4.85 (s, 2H), 7.20 to 7.28 (2H), 7.35 to 7.45 (2H), 7.68-7.78 (1H), 8.00 (d, 1H, J = 10.8 Hz), 8.55-8.65 (1H)

Example 1-25 Synthesis of this compound [Compound No. (37)] 7-acetoxy-3-chloro-4-[(2-pyridylthio) methyl] -2H-chromen-2-one 0.14 g in a 10 ml methanol solution At room temperature, a solution of 0.05 g of sodium hydroxide in 10 ml of methanol was added. After stirring at room temperature for 1 hour, the reaction solution was adjusted to pH 7 with 10% hydrochloric acid and 5% aqueous potassium carbonate solution, and the precipitate was collected by filtration, washed with water and dried to give a pale yellow color of the coumarin compound of Compound No. (37). 0.11 g of solid was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.79 (S, 2H), 6.78 (d, 1H, J = 1.9 Hz), 6.84 (dd, 1H, J = 1.6 Hz, 8.6 Hz), 7.23 (dd, 1 H, J = 5.1 Hz, 7.3 Hz), 7.38 (d, 1 H, J = 7.3 Hz), 7.65-7. 75 (1H), 7.77 (d, 1H, J = 8.9 Hz), 8.57 (d, 1H, J = 4.1 Hz), 10.77 (broads, 1H)

Example 1-26 Synthesis of this compound [Compound No. (38)] 7-acetoxy-4-chloromethyl-2H-chromene instead of 7-acetoxy-4-bromomethyl-3-fluoro-2H-chromen-2-one Except that 0.50 g of -2-one was used, 0.48 g of white crystals of the coumarin compound of Compound No. (38) was obtained in the same manner as Example 1-22 (3).
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 2.43 (s, 3H), 2.51 (s, 3H), 4.57 (s, 2H), 6.57 (s, 1H) 6.89 (d, 1H, J = 7.6 Hz), 6.98 (d, 1H, J = 7.8 Hz), 7.08 (dd, 1H, J = 2.4 Hz, 8.9 Hz), 7.12 (d, 1H, J = 1.9 Hz), 7.40 (t, 1H, J = 7.6 Hz), 7.80 (d, 1H, J = 8.4 Hz)

Example 1-27 Synthesis of the present compound [Compound No. (39)] (1) 2.20 g of sodium hydride (60% oily) was suspended in 25 ml of THF, and a solution of 6.50 g of ethyl acetate in 25 ml of THF at 0 ° C. The mixture was added dropwise over 20 minutes and stirred at 0 ° C. for 10 minutes, and then 35 ml of n-butyllithium hexane solution (1.6N) was added dropwise at −5 to −10 ° C. over 20 minutes. After stirring at 0 ° C. for 20 minutes, a solution of 8.49 g of 2-chloromethyl-6-methylpyridine in 15 ml of THF was added dropwise at 0 to 5 ° C. over 15 minutes, followed by stirring at room temperature for 1 hour. The reaction solution was adjusted to pH 7-8 by adding 10% hydrochloric acid under ice-cooling, and concentrated under reduced pressure. The residue was extracted with 300 ml of ethyl acetate, and the organic layer was washed with saturated brine, concentrated and subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 1/2). 5- (6 4.20 g of a brown oily substance of ethyl -methylpyridin-2-yl) -3-oxopentanoate was obtained.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 1.28 (t, 3H, J = 4.6 Hz), 2.50 (s, 3H), 2.98 to 3.10 (m, 4H) ), 3.51 (s, 2H), 4.18 (q, 2H, J = 4.9 Hz), 6.90 to 7.00 (m, 1H), 7.15 to 7.30 (m, 1H) ), 7.46 (t, 1H, J = 7.3 Hz)
(2) 1.97 g of resorcinol, 4.20 g of ethyl 5- (6-methylpyridin-2-yl) -3-oxopentanoate and 44.8 ml of trifluoroacetic acid were mixed and heated and stirred under reflux for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, 40 ml of water was added to adjust the pH to 7-8 with saturated aqueous sodium hydrogen carbonate, ethyl acetate was added, and the precipitate was filtered off. This was washed with hexane and ethanol and dried to obtain 0.93 g of a pale yellow solid of the coumarin compound of Compound No. (39).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.45 (s, 3H), 3.03 (t, 2H, J = 6.2 Hz), 3.15 (t, 2H, J = 6.2 Hz), 6.08 (s, 1 H), 6.71 (d, 1 H, J = 2.4 Hz), 6.81 (dd, 1 H, J = 0.8 Hz, 8.6 Hz), 7 .08 (d, 1H, J = 8.1 Hz), 7.11 (d, 1H, J = 8.1 Hz), 7.59 (t, 1H, J = 7.6 Hz), 7.70 (d, 1H, J = 9.1Hz)

Example 1-28 Synthesis of Compound [Compound No. (40)] (1) After heating 1.0 g of 2-acetyl-6-bromopyridine, 10 ml of 2N hydrochloric acid and 5 ml of EtOH to 100 ° C. to obtain a homogeneous solution , Cooled. To this, 0.57 g of thiourea was added and refluxed for 4 hours. After cooling, the reaction solution was neutralized with a saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated and subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 2 / 1) 0.13 g of 6-acetyl-2-mercaptopyridine was obtained as a yellow powder.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 2.58 (s, 3H), 7.20 (dd, 1H), 7.35 (dd, 1H), 7.64 (dd, 1H) , 11.06 (brs, 1H)
(2) To 4 ml of DMF solution of 78 mg of 6-acetyl-2-mercaptopyridine and 52 mg of triethylamine, 0.5 ml of DMF solution of 90 mg of 4-chloromethyl-7-hydroxy-2H-chromen-2-one was added under cooling, Stir for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated. 1 ml of ethanol was added to 0.12 g of the concentrated residue, followed by re-washing to obtain 0.13 g of a yellow solid of the coumarin compound of Compound No. (40).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.52 (s, 3H), 4.70 (s, 2H), 6.34 (s, 1H), 6.74 (d, 1H, J = 2.4 Hz), 6.83 (dd, 1H, J = 2.4 Hz, 8.7 Hz), 7.63-7.70 (m, 2H), 7.81-7.90 (m , 2H), 10.62 (brs, 1H)

Example 1-29 Synthesis of the present compound [Compound No. (41)] To a solution of 0.50 g of the coumarin compound of Compound No. (39) obtained in Example 1-27 in 0.25 mg of DMF was added to 254 mg of imidazole, and at room temperature for 5 minutes. Stir. A solution of 411 mg of triisopropylsilyl chloride in 1 ml of DMF was added thereto, and the mixture was stirred at room temperature for 1 hour, further 127 mg of triisopropylsilyl chloride was added, and the mixture was stirred at room temperature for 2 hours and 20 minutes. 50 ml of water and 40 ml of ethyl acetate are added to the reaction solution, and the mixture is separated. The organic layer is washed with a saturated saline solution, concentrated and subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 1/1). ), 0.76 g of a pale yellow oily substance of the coumarin compound of Compound No. (41) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 1.05 (d, 18H, J = 7.3 Hz), 1.26 (sept, 3H, J = 6.8 Hz), 2.42 (S, 3H), 3.00 to 3.20 (m, 4H), 6.17 (s, 1H), 6.79 (d, 1H, J = 4.3 Hz), 6.87 (dd, 1H) , J = 2.4 Hz, 8.6 Hz), 7.05 (d, 1H, J = 7.6 Hz), 7.09 (d, 1H, J = 7.8 Hz), 7.56 (t, 1H, J = 7.6 Hz), 7.74 (d, 1H, J = 8.9 Hz)

Example 1-30 Synthesis of Compound [Compound No. (42)] 0.69 g of the coumarin compound of Compound No. (41) obtained in Example 1-29 was dissolved in a hydrogen chloride ethanol solution (0.2 mol / l). And stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was washed with 5 ml of tetrahydrofuran and dried to obtain 503 mg of white crystals of the coumarin compound of Compound No. (42).
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 1.06 (d, 18H, J = 7.3 Hz), 1.30 (sept, 3H, J = 7.8 Hz), 2.73 (S, 3H), 3.15-3.25 (m, 4H), 6.27 (s, 1H), 6.82 (d, 1H, J = 2.2 Hz), 6.86 (dd, 1H) , J = 2.4 Hz, 8.6 Hz), 7.69 (d, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.6 Hz), 7.88 (d, 1H, J = 8.6 Hz), 8.31 (t, 1H, J = 7.8 Hz)

Example 1-31 Synthesis of this compound [Compound No. (43)] To a solution of 0.50 g of the coumarin compound of Compound No. (39) obtained in Example 1-27 in 5 ml of DMF was added to 254 mg of imidazole, and 10 minutes at room temperature. Stir. To this, a solution of 381 mg of chloro (dimethyl) texylsilane in 1 ml of DMF was added and stirred at room temperature for 2 hours and 10 minutes. Further, 130 mg of chloro (dimethyl) texylsilane was added and stirred at room temperature for 1 hour and 10 minutes. 50 ml of water and 40 ml of ethyl acetate are added to the reaction solution, and the mixture is separated. The organic layer is washed with saturated brine, concentrated and subjected to column chromatography using silica gel (eluent: hexane / ethyl acetate = 2/1). ), 0.87 g of a pale yellow oily matter of the coumarin compound of Compound No. (43) was obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 0.28 (s, 6H), 0.92 (d, 6H, J = 6.8 Hz), 1.70 (sept, 1H, J = 7.0 Hz), 2.44 (s, 3H), 3.05 (t, 2H, J = 6.2 Hz), 3.18 (t, 2H, J = 5.9 Hz), 6.18 (s) , 1H), 6.82 (d, 1H, J = 2.2 Hz), 6.87 (dd, 1H, J = 2.4 Hz, 8.6 Hz), 7.08 (d, 1H, J = 7. 8 Hz), 7.12 (d, 1 H, J = 7.6 Hz), 7.59 (t, 1 H, J = 7.8 Hz), 7.76 (d, 1 H, J = 8.6 Hz)

Example 1-32 Synthesis of Compound [Compound No. (44)] Instead of the coumarin compound of Compound No. (41), 0.75 g of the Coumarin Compound of Compound No. (43) obtained in Example 1-31 was used. In the same manner as in Example 1-30, 578 mg of white crystals of the coumarin compound of Compound No. (44) were obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 0.28 (s, 6H), 0.92 (d, 6H, J = 7.0 Hz), 1.70 (sept, 1H, J = 6.8 Hz), 2.74 (s, 3H), 3.20 to 3.40 (m, 4H), 6.27 (s, 1H), 6.85 (s, 1H), 6.85. 6.95 (1H), 7.72 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.6 Hz), 7.88 (d, 1H, J = 8.6 Hz) ), 8.25-8.45 (1H)

Example 1-33 Synthesis of Compound [Compound No. (45)] 61.4 mg of 4-chlororesorcinol, 100 mg of ethyl 5- (6-methylpyridin-2-yl) -3-oxopentanoate and 5 ml of methanesulfonic acid Mix and stir overnight at room temperature. 30 ml of ice water was added to the reaction solution, and the pH was adjusted to 7-8 using 2N aqueous sodium hydroxide solution. The precipitate was separated by filtration, dissolved in ethanol, added with activated carbon, filtered, the filtrate was concentrated, the residue was recrystallized using ethanol and water, and 36 mg of white crystals of the coumarin compound of Compound No. (45). Got.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.45 (s, 3H), 3.03 (t, 2H, J = 7.0 Hz), 3.16 (t, 2H, J = 7.3 Hz), 6.15 (s, 1 H), 6.89 (s, 1 H), 7.08 (d, 1 H, J = 7.3 Hz), 7.10 (d, 1 H, J = 5) .7 Hz), 7.57 (t, 1 H, J = 7.6 Hz), 7.82 (s, 1 H), 11.35 (broad, 1 H)

Example 1-34 Synthesis of this compound [Compound No. (46)] Coumarin of Compound No. (46) was prepared in the same manner as Example 1-33 except that 430 mg of 2-chlororesorcinol was used instead of 4-chlororesorcinol. 82 mg of brown crystals of the compound were obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.44 (s, 3H), 3.04 (t, 2H, J = 6.5 Hz), 3.17 (t, 2H, J = 6.8 Hz), 6.17 (s, 1 H), 6.90 (d, 1 H, J = 8.9 Hz), 7.08 (d, 1 H, J = 7.8 Hz), 7.11 (d , 1H, J = 7.8 Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.69 (d, 1H, J = 8.9 Hz)

Example 1-35 Synthesis of this compound [Compound No. (47)] 1) 20 mL of concentrated sulfuric acid was added dropwise to a mixture of 3.13 g of resorcinol and 5.09 g of 5-chloro-3-oxopentanoic acid under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was poured into 200 mL of ice water. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to obtain 3.4 g of 7-hydroxy-4- (chloroethyl) coumarin as a tan solid. This was added to a mixture of 20 mL of acetic anhydride and 1 mL of pyridine and heated at around 120 ° C. for 1 hour. After cooling, the reaction solution was poured into 150 mL of diluted hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and 4.39 g of a brown viscous product was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1) 0.71 g of 7-acetoxy-4- (chloroethyl) coumarin was obtained as pale yellow crystals.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 2.32 (s, 3H), 3.30 (t, 2H), 4.00 (t, 2H), 6.46 (s, 1H), 7.19 (d, 1H), 7.30 (m, 1H), 7.92 (d, 1H)
(2) In a nitrogen atmosphere, 33 mg of sodium hydride (60% oily) was dissolved in 10 mL of DMF, and a solution of 2-hydroxypyridine 78 mg of DMF in 0.8 mL was added dropwise and stirred for 1 hour. 7-acetoxy-4- (chloroethyl) coumarin was added to 200 mg of DMF in 2 mL and heated at 50 ° C. for 1.5 hours. After cooling, the mixture was poured into 20 mL of water, extracted with ethyl acetate, washed with water, dried and concentrated to obtain 0.21 g of pale yellow crystals. This was added to 1 mL of ethanol, 1.2 mL of 1N NaOH was added dropwise, and the mixture was stirred at room temperature for 30 minutes, and then neutralized with 1N HCl. The precipitated crystals were collected by filtration, washed with water, dried and then washed with ethanol to give 118 mg of a coumarin compound of Compound No. (47) as a pale yellow solid.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.09 (t, 2H, J =
7.2 Hz), 4.15 (t, 2 H, J = 7.2 Hz), 6.09 (s, 1 H), 6.20 (m, 1 H), 6.40 (d, 1 H, J = 8. 7 Hz), 6.72 (d, 1 H, J = 2.4 Hz), 6.80 (dd, 1 H, J = 2.4 Hz, 8.7 Hz), 7.42 (m, 1 H), 7.64 ( dd, 1H, J = 1.8 Hz, 6.6 Hz), 7.84 (d, 1H, J = 8.7 Hz), 10.59 (brs, 1H)

Example 1-36 Synthesis of this compound [Compound No. (48)] The compound was prepared in the same manner as in Example 1-35 (2) except that 2-hydroxy-6-methylpyridine was used instead of 2-hydroxypyridine. 17 mg of white crystals of the coumarin compound of number (48) were obtained.
¹ H-NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.09 (t, 2H, J =
7.2 Hz), 4.15 (t, 2 H, J = 7.2 Hz), 6.13 (d, 1 H, J = 6.3 Hz), 6.20 (s, 1 H), 6.30 (d, 1H, J = 9.0 Hz), 6.66-6.74 (m, 2H), 6.82 (dd, 1H, J = 2.1 Hz, 8.7 Hz), 7.31 (t, 1H, J = 8.7 Hz), 7.96 (d, 1 H, J = 8.7 Hz), 10.59 (brs, 1 H)

Example 2 Measurement of the ability of this compound to inhibit type 3 17β-hydroxysteroid dehydrogenase (2-1) Preparation of plasmid for human type 17β-hydroxysteroid dehydrogenase expression Human testis cDNA (MTC Multiple Tissue cDNA Panels / Human II, Clontech) The cDNA of the human type 3 17β-hydroxysteroid dehydrogenase gene was cloned by PCR. A primer consisting of the base sequence shown in SEQ ID NO: 1 and a primer consisting of the base sequence shown in SEQ ID NO: 2 are added to a final concentration of 0.4 μM, respectively, and a heat-resistant DNA polymerase (TaKaRa LA Taq, Takara Bio) is used. The PCR reaction was performed with a thermal cycler (GeneAmp PCR System 9700, Applied Biosystem). The reaction conditions were 95 ° C for 5 minutes, 95 ° C for 30 seconds, 59 ° C for 1 minute, 72 ° C for 45 seconds, 30 cycles, and 72 ° C for 7 minutes. . The obtained PCR product was subjected to agarose gel electrophoresis, and about 1.1 kb of DNA was recovered.
The expression vector pcDNA3.1 / Hyg (Invitrogen) was digested with restriction enzyme HindIII (Takara Bio) and then treated with T4 DNA Polymerase (DNA Blunting Kit, Takara Bio) to smooth the ends.
The about 1.1-kb DNA obtained above and a linearized expression vector are mixed and ligated using T4 DNA Ligase (DNA Ligation Kit Ver.2.1, Takara Bio), and then competent for Escherichia coli DH5. The cell (Takara Bio) was introduced. From the obtained transformant, a plasmid for human 3 type 17β-hydroxysteroid dehydrogenase expression was obtained. The base sequence of the DNA cloned into the plasmid coincided with the corresponding base sequence of the human type 3 17β-hydroxysteroid dehydrogenase gene disclosed in GenBank, a public database, under the registration number U05659.
(2-2) Preparation of transiently expressing cells of human type 3 17β-hydroxysteroid dehydrogenase
10 mL of the cell suspension obtained by suspending 1.6 × 10 ⁶ HeLa cells in D-MEM medium containing 10% FCS was spread on a cell culture dish having a diameter of 10 cm, and allowed to stand in a CO ₂ incubator for 20 to 24 hours. 2 μg of the human 3 type 17β-hydroxysteroid dehydrogenase expression plasmid obtained in (2-1) was added to 300 μl of FCS-free D-MEM medium, and gently pipetted twice to mix gently. 50 μl of transfection reagent (PolyFect Transfection Reagent, Qiagen) was added to the obtained DNA solution, mixed by pipetting 5 times, and allowed to stand at room temperature for 10 minutes. To this DNA solution, 1 mL of 10% FCS-containing D-MEM medium was added and pipetting was performed twice to mix the DNA solution. The medium of the cells after standing for 20 to 24 hours was replaced with 8 mL of fresh medium, and the DNA solution was added. After leaving still in a CO ₂ incubator for 20 to 24 hours, the cells were detached with trypsin, spread on a 96-well plate, and used for enzyme activity measurement.
(2-3) Measurement of enzyme activity It was evaluated by a method in which androstenedione was added to HeLa cells in which human type 3 17β-hydroxysteroid dehydrogenase was transiently expressed, and the concentration of testosterone produced by conversion was measured. . The HeLa cells introduced with the human type 3 17β-hydroxysteroid dehydrogenase expression plasmid prepared in (2-2) were suspended in D-MEM medium containing 10% FCS. The obtained cell suspension was added to a 96-well plate at 1 × 10 ⁴ cells (100 μL) per well and allowed to stand in a CO ₂ incubator for 20 to 24 hours. After standing, the medium was extracted, and 80 μL of FCS-free medium was newly added. 10 μL of a compound solution diluted with a 1% DMSO-containing FCS-free medium was added, and the mixture was allowed to stand for 30 minutes in a CO ₂ incubator. Thereto was added 10 μL of an androstenedione solution diluted to 500 nM with a FCS-free medium, and left in a CO ₂ incubator for 20 minutes. Thereafter, using a time-resolved fluorescence reagent (DELFIA Testosterone Reagents, Perkin Elmer), the concentration of testosterone in the medium was measured according to the procedure attached to the reagent. The measurement used a multi-functional plate reader (manufactured by Tecan, Ultra). Measurement wavelength is excitation 340nm, fluorescence is 612nm. Lag time is 400μsec. Integration time is 400μsec. As a control value for 0% inhibition, 10 μL each of 1% DMSO-containing FCS-free medium and 500 nM androstenedione solution were added to the cells left to stand for 20 to 24 hours, and then the testosterone concentration was measured in the same manner. Further, as a control value for 100% inhibition, 10 μL each of 1% DMSO-containing FCS-free medium and FCS-free medium were added to the cells left to stand for 20-24 hours, and then the testosterone concentration was measured in the same manner. From the measured values thus obtained, the inhibition rate of 17β-hydroxysteroid dehydrogenase activity by each compound at each concentration was calculated.
This compound represented by any one of compound numbers (1) to (32) and (34) to (38) had an enzyme inhibition rate of 80% or more of human type 3 17β-hydroxysteroid dehydrogenase at a concentration of 10 μM. . In addition, this compound represented by compound numbers (33), (39), (40), (42), (44) to (46) has an enzyme inhibition rate of human 3 type 17β-hydroxysteroid dehydrogenase at a concentration of 1 μM. Was over 70%.

  INDUSTRIAL APPLICABILITY According to the present invention, development and provision of a composition and the like for treating or preventing male hormone-dependent diseases by inhibiting the activity of type 3 17β-hydroxysteroid dehydrogenase and suppressing the enhancement of male hormone activity in tissues. be able to.

SEQ ID NO: 1
Oligonucleotide primer designed for PCR SEQ ID NO: 2
Oligonucleotide primers designed for PCR

Claims (32)

Formula (A)

[Where:
X _A is, C1-C4 alkylcarbonyl group, a halogen atom, C1-C4 alkyl group, a trifluoromethyl group, a nitro group, C1-C4 alkylthio group, a cyclopropylmethyl thio group or a _I -CH 2 _S- group (a _I Represents a phenyl group which may be substituted with a single halogen atom, a phenyl group substituted with a plurality of the same or different halogen atoms, or a phenyl group substituted with a trifluoromethyl group). Benzene ring, pyridine ring, pyrimidine ring, thiophene ring, imidazole ring, 1,2,4-triazole, which may be substituted with a single group selected from the above, or substituted with a plurality of the same or different groups Ring, tetrazole ring, thiazole ring, 4,5-dihydrothiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, benzoxa Over represents Le ring or benzothiazole ring,
Y _A represents a hydrogen atom or a halogen atom,
Z _A represents a hydrogen atom, a halogen atom or a hydroxyl group,
Z _A ′ represents a hydrogen atom or a halogen atom,
W _A is, -O- group, -S- group, an -SO- group, -NH- group or methylene group,
R _A represents a hydrogen atom, a —SiR ₁ R ₂ R ₃ group (R ₁ , R ₂ and R ₃ are the same or different and represent a C1-C6 alkyl group), a C1-C4 alkylcarbonyl group, or a C1- Represents a C4 alkoxycarbonyl group. ]
A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising a coumarin compound represented by formula (II) and an inert carrier. Formula (B)

[Where:
X _B is acetyl group, it may be substituted with a methyl group, a trifluoromethyl group or a nitro group, a 2-pyridyl group, 1,3,4-thiadiazol-2-yl group, 2-imidazolyl group, 4,5 -Represents a dihydrothiazol-2-yl group or a thiazol-2-yl group,
Y _B represents a hydrogen atom or a halogen atom,
Z _B and Z _B ′ are the same or different and each represents a hydrogen atom or a halogen atom,
W _B represents an —S— group or a methylene group,
R _B represents a hydrogen atom, a —SiR ₁ R ₂ R ₃ group (R ₁ , R ₂ and R ₃ are the same or different and represent a C1-C6 alkyl group), a C1-C4 alkylcarbonyl group, or a C1- Represents a C4 alkoxycarbonyl group.
However, when the _{W B} is -S- group a 2-pyridyl group is _{X B} having no substituent _{group, Y B Z B, Z B} ' and _{R B} are not a hydrogen atom at the same time. ]
A coumarin compound represented by Formula (I)

[Where:
X _I is a halogen atom, C1-C4 alkyl group, a trifluoromethyl group, a nitro group, C1-C4 alkylthio group, the cyclopropylmethyl thio group or a _I -CH 2 _S- group (a _I, a halogen atom singular A phenyl group which may be substituted, a phenyl group substituted with the same or different plural halogen atoms, or a phenyl group substituted with a trifluoromethyl group). Benzene ring, pyridine ring, pyrimidine ring, thiophene ring, imidazole ring, 1,2,4-triazole ring, tetrazole ring, thiazole ring, which may be substituted with the same or different groups 4,5-dihydrothiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, benzoxazole ring or benzothiazole It represents a ring,
Y _I represents a hydrogen atom or a halogen atom,
Z _I represents a hydrogen atom or a hydroxyl group,
W _I represents a —S— group, a —SO— group, a —NH— group or a methylene group;
R _I represents a hydrogen atom, a C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group. ]
A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising a coumarin compound represented by formula (II) and an inert carrier. Formula (II)

[Where:
X _II is a methyl group, may be substituted with a trifluoromethyl group or a nitro group, a 2-pyridyl group, 1,3,4-thiadiazol-2-yl group, 2-imidazolyl group, 4,5-dihydro-thiazole Represents a 2-yl group or a thiazol-2-yl group,
Y _II represents a hydrogen atom or a halogen atom,
R _II represents a hydrogen atom, a C1-C4 alkylcarbonyl group or a C1-C4 alkoxycarbonyl group.
However, when X _II is a 2-pyridyl group having no substituent, Y _II and R _II are not simultaneously hydrogen atoms. ]
A coumarin compound represented by A coumarin compound represented by the formula (III).

A coumarin compound represented by the formula (IV).

A coumarin compound represented by the formula (V).

A coumarin compound represented by the formula (VI).

A coumarin compound represented by the formula (VII).

A coumarin compound represented by the formula (VIII).

A coumarin compound represented by the formula (IX).

A coumarin compound represented by the formula (X).

A coumarin compound represented by the formula (XI).

A coumarin compound represented by the formula (XII).

A coumarin compound represented by the formula (XIII).

A coumarin compound represented by the formula (XIV).

A coumarin compound represented by the formula (XV).

A coumarin compound represented by the formula (XVI).

A coumarin compound represented by the formula (XVII).

A coumarin compound represented by the formula (XVIII).

A coumarin compound represented by the formula (XIX).

A coumarin compound represented by the formula (XX).

A coumarin compound represented by the formula (XXI).

A coumarin compound represented by the formula (XXII).

  A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising the coumarin compound according to claim 2 or 4 and an inert carrier.   A type 3 17β-hydroxysteroid dehydrogenase inhibitor composition comprising the coumarin compound according to any one of claims 5 to 24 and an inert carrier.   Use of the coumarin compound contained as an active ingredient in the type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to claim 1 or 3 for inhibiting type 3 17β-hydroxysteroid dehydrogenase.   Use of a coumarin compound according to claim 2 or 4 for inhibiting type 3 17β-hydroxysteroid dehydrogenase.   Use of a coumarin compound according to any one of claims 5 to 24 for inhibiting type 3 17β-hydroxysteroid dehydrogenase. A method of inhibiting type 3 17β-hydroxysteroid dehydrogenase comprising:
A coumarin compound contained as an active ingredient in a type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to claim 1 or 3 in a therapeutically effective amount is administered to a patient in need of the inhibition. Method. A method of treating or preventing a male hormone dependent disease comprising:
A coumarin compound contained as an active ingredient in a type 3 17β-hydroxysteroid dehydrogenase inhibitor composition according to claim 1 or 3 in a therapeutically effective amount is administered to a patient in need of the treatment or prevention. And how to.   Male hormone-dependent diseases include prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, seborrhea, androgenetic alopecia, premature sexual maturity, adrenal hypertrophy or polycystic ovary syndrome 32. The method of claim 31, wherein: