JP2008007404A - Novel pyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pyridine derivative useful as a drug, particularly a C17-20 lyase inhibitor. <P>SOLUTION: The pyridine derivative is represented by formula (1) or its pharmacologically acceptable salt and is used as a drug. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  Diseases that are known to cause onset or exacerbation due to excess of sex hormone include diseases caused by excess of male hormones such as prostate cancer, benign prostatic hyperplasia, hirsutism, and male signs, breast cancer, ovarian cancer, uterus Diseases caused by excess female hormones such as cancer, mastopathy, endometriosis, uterine fibroids are known. Therapies for these diseases include luteinizing hormone-releasing hormone (LHRH) antagonists or agonists, sex steroid biosynthesis inhibitors (5α-reductase, aromatase inhibitors, etc.), or sex steroid reception Body antagonists and the like are currently used (see Non-Patent Documents 1 and 2).

  C17-20 lyase is one of the sex hormone biosynthetic enzymes. It exists in the testis, ovary, and adrenal cortex and produces dehydroepiandrosterone and androstenedione using 17-hydroxyprognenolone and 17-hydroxyprogesterone as substrates. Since the product of this enzyme is used only for the biosynthesis of sex hormones, drugs that inhibit this enzyme can become new endocrine therapeutic agents that inhibit the biosynthesis of sex hormones and can be provided to the medical field as therapeutic or preventive drugs Is expected (see Non-Patent Document 3).

  As C17-20 lyase inhibitors, steroidal inhibitors and nonsteroidal inhibitors have been reported. As the former, for example, compounds described in Patent Documents 1 and 2 have been reported (see Patent Documents 1 and 2). As the latter, for example, compounds having an imidazole ring as in Patent Documents 3, 4, and 5 and compounds having a pyridine ring as in Patent Documents 6, 7, and 8 and Non-Patent Documents 4 and 5 have been reported. . However, there is no compound marketed as a C17-20 lyase inhibitor until now, and the development of a lyase inhibitor has been eagerly desired from the clinical field (see Non-Patent Document 6).

JP-A-7-505377 US Pat. No. 5,994,335 JP 2001-187784 A JP 2002-80458 A International Publication No. 01/87875 Japanese Patent Application Laid-Open No. 2002-234843 International Publication No. 92/16507 International Publication No. 93/23375

Japan Clinical, Volume 58 (Special Issue, Diagnosis and Treatment of Breast Cancer), 311-333 (2000) Japan Clinical, Volume 58 (Special Issue, Diagnosis and Treatment of Prostate Cancer), 176-182 (2000) Japan Clinical, Vol. 58 (Special Issue, Diagnosis and Treatment of Prostate Cancer), 317-319 (2000) J. et al. Med. Chem. 39, 834-841 (1996) J. et al. Enzyme Inhibition, Vol. 8, 113-122 (1994) Japan Clinical, Volume 58 (Special Issue, Diagnosis and Treatment of Prostate Cancer), 312-316 (2000)

  The present invention provides a C17-20 lyase inhibitor useful as a medicament.

  As a result of extensive research, the present inventor has found that a novel pyridine derivative or a pharmacologically acceptable salt thereof inhibits C17-20 lyase, thereby completing the present invention.

That is, the present invention relates to the following (1) to (16).
(1) The following general formula (1)

［式中、Ａは下記一般式（２）

[Wherein A represents the following general formula (2)

或いは下記一般式（３）

Or the following general formula (3)

を示し、Ｘは酸素原子またはＮ−ＯＲ₁₁を示し、Ｒ₁、Ｒ₂はそれぞれ独立に同一か又は異なってもよく、水素原子及び低級アルキル基から成る群より任意に選択される基を示し、Ｒ₃、Ｒ₄はそれぞれ独立に同一か又は異なってもよく、水素原子及び低級アルキル基から成る群より任意に選択される基を示し（但し、Ｒ₃、Ｒ₄が共に水素原子である場合を除く）、Ｒ₅、Ｒ₆、Ｒ₇はそれぞれ独立に同一か又は異なってもよく、水素原子、水酸基、ハロゲン原子、置換基を有していてもよい低級アルキル基、置換基を有していてもよい低級アルコキシ基、アシル基、アシルオキシ基、置換基を有していてもよいアミノ基からなる群より任意に選択される基を示すか、又は更に、Ｒ₈、Ｒ₉、Ｒ₁₀のいずれか２つの基がメチレンジオキシ基またはエチレンジオキシ基を形成することを示し、Ｒ₈、Ｒ₉、Ｒ₁₀はそれぞれ独立に同一か又は異なってもよく、水素原子、水酸基、ハロゲン原子、置換基を有していてもよい低級アルキル基、置換基を有していてもよい低級アルコキシ基、アシル基、アシルオキシ基、置換基を有していてもよいアミノ基からなる群より任意に選択される基を示すか、又は更に、Ｒ₅、Ｒ₆、Ｒ₇のいずれか２つの基がメチレンジオキシ基またはエチレンジオキシ基を形成することを示し、Ｒ₁₁は水素原子、低級アルキル基、またはカルボキシアルキル基を示す（但し、置換基を有する場合、低級アルキル基及び低級アルコキシ基の置換基はアリール基又はハロゲン原子であり、アミノ基の置換基は低級アシル基、アリール基又はハロゲン原子で置換されいていてもよい低級アルキル基、アリール基、ベンジルオキシカルボニル基、又はtert-ブチルオキシカルボニル基である。）。］で表されるピリジン誘導体またはその薬理学的に許容される塩、
（２）
一般式（１）において、Ａが一般式（２）である（１）記載のピリジン誘導体またはその薬理学的に許容される塩、
（３）
一般式（１）において、Ｒ₁、Ｒ₂が共に水素原子である（２）記載のピリジン誘導体またはその薬理学的に許容される塩、
（４）
一般式（１）において、Ｒ₃、Ｒ₄のいずれかが低級アルキル基で、もう一方が水素原子である（３）記載のピリジン誘導体またはその薬理学的に許容される塩、
（５）
一般式（１）において、Ｒ₅、Ｒ₆、Ｒ₇が水素原子、ハロゲン原子、低級アルキル基、水酸基、低級アルコキシ基からなる群より任意に選択される基を示すか、又は更に、Ｒ₅、Ｒ₆、Ｒ₇のいずれか２つの基がメチレンジオキシ基またはエチレンジオキシ基を形成することを示す、（４）記載のピリジン誘導体またはその薬理学的に許容される塩、
（６）
一般式（１）において、Ｒ₅、Ｒ₆、Ｒ₇が水酸基、メチル基、エチル基、塩素原子、フッ素原子、メトキシキ基、エトキシ基、イソプロポキシ基からなる群より任意に選択される基を示すか、又は更に、Ｒ₅、Ｒ₆、Ｒ₇のいずれか２つの基がメチレンジオキシ基またはエチレンジオキシ基を形成することを示し、、Ｘが酸素原子である（５）記載のピリジン誘導体またはその薬理学的に許容される塩、
（７）
一般式（１）において、Ａが一般式（３）である（１）記載のピリジン誘導体またはその薬理学的に許容される塩、
（８）
一般式（１）において、Ｒ₁、Ｒ₂が共に水素原子である（７）記載のピリジン誘導体またはその薬理学的に許容される塩、
（９）
一般式（１）において、Ｒ₃、Ｒ₄のいずれかが低級アルキル基で、もう一方が水素原子である（８）記載のピリジン誘導体またはその薬理学的に許容される塩、
（１０）
一般式（１）において、Ｒ₈、Ｒ₉、Ｒ₁₀が水素原子、ハロゲン原子、低級アルキル基、水酸基、低級アルコキシ基からなる群より任意に選択される基を示すか、又は更に、Ｒ₈、Ｒ₉、Ｒ₁₀のいずれか２つの基がメチレンジオキシ基またはエチレンジオキシ基を形成することを示し、（９）記載のピリジン誘導体またはその薬理学的に許容される塩、
（１１）
一般式（１）において、Ｒ₈、Ｒ₉、Ｒ₁₀が水酸基、メチル基、フッ素原子、メトキシキ基、エトキシ基またはイソプロポキシ基から成る群より任意に選ばれ、Ｘが酸素原子である（１０）記載のピリジン誘導体またはその薬理学的に許容される塩、
（１２）
（１）乃至（１１）のいずれか一項に記載のピリジン誘導体またはその薬理学的に許容される塩を有効成分とする医薬、
（１３）
（１）乃至（１１）のいずれか一項に記載のピリジン誘導体またはその薬理学的に許容される塩を有効成分とする抗腫瘍剤、
（１４）
（１）乃至（１１）のいずれか一項に記載のピリジン誘導体またはその薬理学的に許容される塩を有効成分とする前立腺癌または乳癌の予防または治療剤、
（１５）
（１）乃至（１１）のいずれか一項に記載のピリジン誘導体またはその薬理学的に許容される塩を有効成分とする性ホルモン過剰症の予防または治療剤、
（１６）
（１）乃至（１１）のいずれか一項に記載のピリジン誘導体またはその薬理学的に許容される塩を有効成分とするＣ１７−２０リアーゼ阻害剤、
に関する。

X represents an oxygen atom or N-OR ₁₁ , and R ₁ and R ₂ may be the same or different and each represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group. , R ₃ and R ₄ may be the same or different and each represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group (provided that both R ₃ and R ₄ are hydrogen atoms) R ₅ , R ₆ and R ₇ may be the same or different from each other, and each may have a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted lower alkyl group or a substituent. Or a group selected from the group consisting of an optionally substituted lower alkoxy group, acyl group, acyloxy group, and optionally substituted amino group, or R ₈ , R ₉ , R any two groups are methylenedioxy groups of ₁₀ or Indicates that to form a ethylenedioxy _{group, R 8, R 9, R} 10 may be the same or different each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a lower be substituted An alkyl group, a lower alkoxy group which may have a substituent, an acyl group, an acyloxy group, a group arbitrarily selected from the group consisting of an amino group which may have a substituent, or Any two groups of R ₅ , R ₆ and R ₇ form a methylenedioxy group or an ethylenedioxy group, and R ₁₁ represents a hydrogen atom, a lower alkyl group or a carboxyalkyl group (provided that When it has a substituent, the substituent of the lower alkyl group and the lower alkoxy group is an aryl group or a halogen atom, and the substituent of the amino group is substituted with a lower acyl group, an aryl group or a halogen atom. Which may be a lower alkyl group, an aryl group, benzyloxycarbonyl group, or a tert- butyloxycarbonyl group.). Or a pharmacologically acceptable salt thereof,
(2)
In the general formula (1), A is a pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof, wherein A is the general formula (2),
(3)
In the general formula (1), R ₁ and R ₂ are both hydrogen atoms, the pyridine derivative according to (2) or a pharmaceutically acceptable salt thereof,
(4)
In the general formula (1), any one of R ₃ and R ₄ is a lower alkyl group, and the other is a hydrogen atom, or a pyridine derivative or a pharmaceutically acceptable salt thereof according to (3),
(5)
In the general formula (1), R ₅ , R ₆ and R ₇ each represents a group arbitrarily selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, or further R ₅ , A pyridine derivative or a pharmaceutically acceptable salt thereof according to (4), which shows that any two groups of R ₆ and R ₇ form a methylenedioxy group or an ethylenedioxy group,
(6)
In general formula (1), R ₅ , R ₆ and R ₇ are groups arbitrarily selected from the group consisting of a hydroxyl group, a methyl group, an ethyl group, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group and an isopropoxy group. Or further indicates that any two groups of R ₅ , R ₆ and R ₇ form a methylenedioxy group or an ethylenedioxy group, and X is an oxygen atom. A derivative or a pharmaceutically acceptable salt thereof,
(7)
In the general formula (1), A is a pyridine derivative or a pharmaceutically acceptable salt thereof according to (1), wherein A is the general formula (3),
(8)
In the general formula (1), R ₁ and R ₂ are both hydrogen atoms, the pyridine derivative according to (7) or a pharmaceutically acceptable salt thereof,
(9)
A pyridine derivative or a pharmaceutically acceptable salt thereof according to (8), wherein in general formula (1), either R ₃ or R ₄ is a lower alkyl group and the other is a hydrogen atom;
(10)
In the general formula (1), R ₈ , R ₉ and R ₁₀ each represents a group arbitrarily selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, or further R ₈ , R ₉ , or R ₁₀ forms a methylenedioxy group or an ethylenedioxy group, the pyridine derivative according to (9) or a pharmaceutically acceptable salt thereof,
(11)
In the general formula (1), R ₈ , R ₉ and R ₁₀ are arbitrarily selected from the group consisting of a hydroxyl group, a methyl group, a fluorine atom, a methoxy group, an ethoxy group or an isopropoxy group, and X is an oxygen atom (10 ) Pyridine derivatives or pharmacologically acceptable salts thereof,
(12)
(1) thru | or the pharmaceutical which uses the pyridine derivative as described in any one of (11), or its pharmacologically acceptable salt as an active ingredient,
(13)
An antitumor agent comprising the pyridine derivative according to any one of (1) to (11) or a pharmacologically acceptable salt thereof as an active ingredient,
(14)
(1) A preventive or therapeutic agent for prostate cancer or breast cancer comprising the pyridine derivative according to any one of (11) or a pharmacologically acceptable salt thereof as an active ingredient,
(15)
(1) A preventive or therapeutic agent for sex hormone hyperplasia comprising the pyridine derivative according to any one of (11) or a pharmacologically acceptable salt thereof as an active ingredient,
(16)
A C17-20 lyase inhibitor comprising the pyridine derivative according to any one of (1) to (11) or a pharmacologically acceptable salt thereof as an active ingredient,
About.

  The compounds described in the present invention showed excellent C17-20 lyase inhibitory activity. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is a medicament, particularly a prophylactic or therapeutic agent for prostate cancer or breast cancer, or a prophylactic or therapeutic agent for sex hormone excess. Useful as.

Details of the present invention will be described below.
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, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group. Tert-butyl group, n-pentyl group, amyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropylene Group, 1,2,2-trimethyl propyl group, 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. Of these, preferred groups include a methyl group and an ethyl group.

  In the present invention, the lower alkoxy group refers to an oxy group to which the above-mentioned lower alkyl group is bonded. For example, a methoxy group, an ethoxy group, an n-propyl group, an isopropoxy group, an n-butoxy group, an isobutoxy group, or a t-butoxy group. And so on. Among these, preferred groups include methoxy group, ethoxy group, n-propoxy group, and isopropoxy group.

  In the present invention, the substituent in the lower alkyl group or lower alkoxy group represents an aryl group or a halogen atom. Here, the aryl group represents an aromatic hydrocarbon group, and examples thereof include a phenyl group, an o-toluyl group, an m-toluyl group, a p-toluyl group, and a naphthyl group. The halogen atom is as described above. Preferred groups include a phenyl group and a fluorine atom.

  In the present invention, the acyl group means a carbonyl group to which the aforementioned lower alkyl group or the aforementioned aryl group is bonded, and examples thereof include an acetyl group, a propionyl group, and a benzoyl group.

  In the present invention, the acyloxy group refers to an oxy group to which the aforementioned acyl group is bonded, and examples thereof include an acetoxy group, a propionyloxy group, and a benzoyloxy group.

  In the present invention, the amino group which may have a substituent is an unsubstituted amino group, the above-mentioned lower acyl group, the above-mentioned lower alkyl group which may have a substituent, or the above-mentioned aryl group. , An amino group substituted with a benzyloxycarbonyl group or a tert-butyloxycarbonyl group, for example, formylamino group, propionylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-di A propylamino group, an N, N-diisopropylamino group, an N, N-di-n-butylamino group and the like can be mentioned.

  In the present invention, the alkyl group of the carboxyalkyl group represents the aforementioned lower alkyl group, and preferred groups include a methyl group and an ethyl group.

  The pyridine derivative in this invention may form a salt with an acid, and this invention also contains the salt of a compound (1). Examples of the salt with acid include inorganic acid salts such as hydrochloride, hydrobromide and sulfate, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid and benzoic acid. Examples thereof include salts with acids, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and other organic acids. These salts can be produced by a conventional method.

  Further, when these pyridine derivatives or salts thereof have hydrates and optical isomerism, all of hydrates, racemates and optical isomers are included.

  Examples of the compound represented by the general formula (1) include the following compounds.

When A is represented by the general formula (2)

When A is represented by the general formula (3)

Next, a method for producing the compound of the present invention will be described.
Of the pyridine derivatives represented by the general formula (1) of the present invention, a derivative in which X is an oxygen atom can be produced, for example, as shown in the reaction formula (1).

Here, A, R ₁ and R ₂ in the reaction formula (1) are the same as those in the general formula (1), B represents an atom or substituent which forms an enolate, and R ₁₂ represents R ₃ or R _4. Indicates. The compound represented by the general formula [B] or the general formula [D] is commercially available or can be easily synthesized.

  The compound represented by the general formula [B] is converted into the enolate represented by the general formula [C], and the compound represented by the general formula [C] present in the isolated or reaction system is converted into the compound represented by the general formula [D]. By reacting the represented compound, the compound of the general formula [E] can be derived. This reaction is already widely known as the aldol reaction. Examples of the enolate represented by the general formula [C] include lithium enolate, boron enolate, titanium enolate, tin enolate, zirconium enolate, and silyl enolate. The conversion reaction to enolate can be performed by a conventional method. Taking lithium enolate as an example, the desired enolate can be produced by applying a strong base such as lithium diiopropylamide at a low temperature. Taking silyl enolate as an example, other enolates represented by the general formula [C] are reacted with a silylating agent such as trimethylsilyl chloride, or represented by the general formula [B] in the presence of a base such as triethylamine. It can be produced by reacting a compound with a silylating agent such as trimethylsilyl chloride.

  The compound represented by the general formula [E] can be produced by reacting the compound represented by the general formula [C] with the compound represented by the general formula [D]. A highly reactive enolate, such as lithium enolate, can be produced by adding a compound represented by the general formula [D] to the reaction system. In the case of an enolate having low reactivity, such as silyl enolate, the compound represented by the general formula [D] and a Lewis acid such as titanium tetrachloride, boron trifluoride, trimethylsilyl triflate, etc. Can be produced.

  The solvent used in the production of the compound represented by the general formula [E] from the compound represented by the general formula [B] is preferably a solvent that dissolves the raw materials and does not easily react with them. , Tetrahydrofuran, dioxane, benzene, ether, methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, xylene, or a mixed solvent of two or more selected from these can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds, but the reaction can usually be carried out within a range from −80 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 minute to 120 hours, but is arbitrarily selected depending on the type of the raw material compound, the solvent, the reaction temperature, and the like.

  The compound represented by the general formula [E] can be led to the compound represented by the general formula [F] by a dehydration reaction. The dehydration reaction proceeds by an acid, a dehydrating agent, a halogenating agent, a sulfonating agent, an acid anhydride, an esterifying agent, an acidic ion exchange resin, an alkali, heating (in dimethyl sulfoxide or hexamethylphosphorotriamide), and the like. As the acid, inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid and oxalic acid can be used. As a dehydrating agent, dicyclohexylcarbodiimide-cupric chloride and the like, as a halogenating agent, thionyl chloride, phosphonyl chloride, phosphorus tribromide, iodine and the like, as a sulfonating agent, methanesulfonyl chloride, toluenesulfonyl chloride and the like, Moreover, acetyl bromide etc. can be used as an esterifying agent.

  The solvent used in the production of the compound represented by the general formula [F] from the compound represented by the general formula [E] is preferably a solvent that dissolves the raw materials and does not easily react with them. , Tetrahydrofuran, dioxane, benzene, ether, methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, xylene, or a mixed solvent of two or more selected from these can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds, but the reaction can usually be carried out within a range from −80 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 minute to 120 hours, but is arbitrarily selected depending on the type of the raw material compound, the solvent, the reaction temperature, and the like.

  The compound represented by the general formula (F) can be led to a compound represented by the general formula [G] by a reduction reaction. As the reducing agent, palladium-based reducing agents such as palladium / carbon, platinum-based reducing agents such as platinum oxide, metal-hydrogen complex compounds such as sodium borohydride, metals such as tin and zinc, nickel-based reducing agents such as Raney nickel, etc. Can be used. The solvent used for the reduction reaction is preferably a solvent that dissolves the raw materials and does not easily react with them. For example, when a palladium reducing agent is taken as an example, the reaction solvent is ethanol, methanol, acetic acid, dioxane, water, Tetrahydrofuran, ethyl acetate, dimethylformamide and the like can be used. Usually, the reaction can be carried out in the range of 0 ° C. to 100 ° C., preferably near room temperature, under normal pressure.

  Among the pyridine derivatives represented by the general formula (1) of the present invention, a derivative in which X is an oxygen atom can also be produced, for example, as shown in the reaction formula (2).

Here, A, R ₁ and R ₂ in the reaction formula (2) are the same as those in the general formula (1), and R ₁₂ represents R ₃ or R ₄ . The compound represented by the general formula [B] or the general formula [D] is commercially available or can be easily synthesized.

  The compound represented by the general formula (I) can be produced by subjecting the compound represented by the general formula [B] and the compound represented by the general formula [H] to a condensation reaction in the presence of an acid or a base. it can. This reaction is already widely known as an aldol reaction. Acids include inorganic acids such as hydrochloric acid, sulfuric acid, titanium tetrachloride and boron trifluoride, organic acids such as p-toluenesulfonic acid, acidic ion exchange resins, and sodium hydroxide, potassium hydroxide and hydrogenated bases. An inorganic base such as sodium or an organic base such as sodium methoxide or potassium tert-butoxide can be used.

  The solvent used in the production of the compound represented by the general formula [I] is preferably a solvent that dissolves the raw materials and does not easily react with them. For example, methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine , Tetrahydrofuran, dioxane, benzene, ether, methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, xylene, or a mixed solvent of two or more selected from these can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds, but the reaction can usually be carried out within a range from −80 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 minute to 120 hours, but is arbitrarily selected depending on the type of the raw material compound, the solvent, the reaction temperature, and the like.

  Moreover, it can also manufacture via the enolate represented by compound [C] as shown in Reaction Formula (1). Furthermore, when the condensation reaction is carried out, the compound (I) may proceed to the dehydration reaction all at once, in which case the compound represented by the general formula [J] is obtained.

  The compound represented by the general formula [J] can be led to a compound represented by the general formula [J] by a dehydration reaction. The conditions for the dehydration reaction are the same as in the production of the general formula [F] in the reaction formula (1).

  The compound of general formula [G] can be manufactured by carrying out a 1, 4- addition reaction with respect to the compound represented by general formula [J]. This reaction is already widely known as the Michael addition reaction. As the reactant, an organic copper ate complex such as lithium dimethyl cue plate can be used. The reagent used here, for example, lithium dimethyl cue plate, can be easily produced by the reaction of methyl lithium and cuprous chloride.

  The solvent used when producing the compound represented by the general formula [G] from the compound represented by the general formula [J] is preferably a solvent which dissolves the raw material and does not easily react with these, for example, tetrahydrofuran. , Dioxane, benzene, ether, toluene, xylene, or a mixed solvent of two or more selected from these can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds, but the reaction can usually be carried out within a range from −80 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 hour to 120 hours, but is arbitrarily selected depending on the type of raw material compound, solvent, reaction temperature, and the like.

Among the pyridine derivatives represented by the general formula (1) of the present invention, a compound in which X is N-OR ₁₁ is, for example, a compound having the general formula (1) where X is an oxygen atom, hydroxylamine hydrochloride, or Manufactured by using alkoxyamine hydrochloride such as methoxyamine hydrochloride, ethoxyamine hydrochloride, carbomethoxyamine 1/2 hydrochloride, etc. and using an inorganic base such as sodium acetate-acetic acid buffer or sodium carbonate as the reactant. can do. The solvent used in this reaction is preferably a solvent that dissolves the raw materials and does not easily react with them. For example, water, methanol, ethanol, tetrahydrofuran, dioxane, benzene, ether, toluene, xylene, or these are selected. Two or more kinds of mixed solvents can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds. Usually, the reaction can be carried out within the range of 0 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 hour to 240 hours, but is arbitrarily selected depending on the type of raw material compound, solvent, reaction temperature and the like.

Among the pyridine derivatives represented by the general formula (1) of the present invention, a compound in which X is represented by N-OR ₁₁ is obtained by alkylating a compound in which X is represented by N—OH synthesized by the above method. , X can be led to a compound represented by N-OR ₁₁ . In this case, the alkylation method can be produced by reacting R ₁₁ -L (L represents a halogen atom, lower alkyl, arylsulfonyloxy group, alkoxy group or the like) according to a conventional method. Here, the halogen atom, the lower alkyl group in the lower alkylsulfonyloxy group, and the aryl group in the arylsulfonyloxy group are as described above. The solvent used in this reaction is preferably a solvent that dissolves the raw materials and does not easily react with them. For example, water, methanol, ethanol, tetrahydrofuran, dioxane, benzene, ether, toluene, xylene, or these are selected. Two or more kinds of mixed solvents can be used. The solvents used are not limited to those listed here. The reaction temperature is not particularly limited as long as the reaction proceeds. Usually, the reaction can be carried out within the range of 0 ° C. to the reflux temperature of the solvent. The reaction time is usually 1 hour to 240 hours, but is arbitrarily selected depending on the type of raw material compound, solvent, reaction temperature and the like.

  When the pyridine derivative represented by the general formula (1) or a pharmaceutically acceptable salt is used as a medicine, it is used alone or as a carrier, excipient, disintegrant, binder, lubricant, fluidizing agent, coating agent. , Powders, granules, tablets, capsules mixed with pharmaceutically acceptable additives such as suspending agents, emulsifiers, stabilizers, preservatives, flavoring agents, flavoring agents, diluents, solubilizers, etc. And can be safely administered orally or parenterally (systemic administration, local administration, etc.) in the form of capsules, injections, suppositories, ointments and the like. The content of the compound of the present invention or pharmaceutically acceptable salt in the preparation varies depending on the preparation, but it is usually preferably 0.1 to 100% by weight. The dose varies depending on the route of administration, the age of the patient, and the actual symptoms to be prevented or treated, but when administered orally to an adult, for example, 0.01 mg to 2000 mg per day as an active ingredient, preferably 0.1 mg -1000 mg, and can be administered in 1 to several doses per day.

  The pyridine derivative represented by the general formula (1) or a pharmaceutically acceptable salt has a C17-20 lyase inhibitory action and is a drug, particularly a prophylactic or therapeutic agent for prostate cancer or breast cancer, or prevention of sex hormone excess. Or it is useful as a therapeutic agent.

The production examples of the compounds of the present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. In order to show the effectiveness of the compound of the present invention, the pharmacological test results of the representative compound of the present invention are shown in Test Examples. In the examples, ¹ H-NMR is a value measured using BARIAN GEMA200, and MS (ESI) is a value measured using SHIMADZU LCMS-QP8000α.

Example 1
Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) butan-1-one
(I) Production of 2′-ethoxy-4′-methoxyacetophenone 2′-hydroxy-4′-methoxyacetophenone (5.00 g, 30.1 mmol), potassium carbonate (4.16 g, 30) under argon atmosphere 0.5 mmol) was dissolved in N, N-dimethylformamide (20 ml), iodoethane (4.69 g, 30.1 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate (200 ml) and water (150 ml) were added for liquid separation. The organic layer was washed 4 times with 5% aqueous potassium carbonate solution (150 ml), once with water (150 ml), once with saturated brine (150 ml), and dried over sodium sulfate. After the solvent was distilled off, the concentrated residue was purified by silica gel column chromatography (eluted with methylene chloride) to obtain the title compound (3.73 g, yield 64%).

¹ H-NMR (CDCl ₃ ) ppm: 1.49 (3H, t, J = 6.7 Hz), 2.60 (3H, s), 3.85 (3H, s), 4.11 (2H, q , J = 7.0 Hz), 6.43 (1H, d, J = 2.3 Hz), 6.56 (1H, dd, J = 2.4, 8.8 Hz), 7.85 (1H, d, J = 8.7 Hz).
MS (ESI, POS) m / z: 195 [M + H] ⁺

(Ii) Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one Diisopropylamine (873 mg, 18.63 mmol) was added under an argon atmosphere. Tetrahydrofuran (75 ml) was added and cooled to -72 ° C. n-Butyllithium (1.58 M n-hexane solution) was added and the temperature was raised to 0 ° C. After stirring for 30 minutes, the mixture was again cooled to -72 ° C. A tetrahydrofuran solution (40 ml) of 2′-ethoxy-4′-methoxyacetophenone (3.62 g, 18.63 mmol) was added dropwise. After stirring at the same temperature for 1 hour, a tetrahydrofuran solution (18 ml) of 4-acetylpyridine (2.26 g, 18.63 mmol) was added dropwise, and the mixture was further stirred for 6 hours. Saturated aqueous ammonium chloride solution (300 ml) was added to stop the reaction, and 300 ml of ethyl acetate was added. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine (300 ml) and dried over sodium sulfate. After the solvent was distilled off, the concentrated residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 100/1) to obtain the title compound (4.46 g, yield 76%).

¹ H-NMR (CDCl ₃ ) ppm: 1.52 (3H, s), 1.53 (3H, t, J = 7.0 Hz), 3.41 (1H, d, J = 18.2 Hz), 3 .85 (1H, d, J = 18.2 Hz), 3.85 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 5.16 (1H, s), 6.43 (1H, d, J = 2.2 Hz), 6.49 (1H, dd, J = 2.4, 8.8 Hz), 7.38 (2H, m), 7.67 (1H, d, J = 8.7 Hz), 8.52 (2H, m).
MS (ESI, POS) m / z: 316 [M + H] ⁺

(Iii) Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl) -3-hydroxy- 3- (4-Pyridyl) butan-1-one (300 mg, 0.95 mmol) and p-toluenesulfonic acid (217 mg, 1.14 mmol) were suspended in toluene (6 ml) at 100 ° C. Stir for 6 hours. After cooling to room temperature, ethyl acetate (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) were added to separate the layers. The organic layer was further washed three times with saturated aqueous sodium hydrogen carbonate (20 ml) and once with saturated brine (20 ml), and dried over sodium sulfate. After the solvent was distilled off, the concentrated residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 100/1) to obtain the title compound (230 mg, 0.78 mmol, yield 82%).

¹ H-NMR (CDCl ₃ ) ppm: 1.37 (3H, t, J = 7.0 Hz), 1.49 (3H, t, J = 7.0 Hz), 2.50 (3H, d, J = 1.3 Hz), 3.86 (3H, s), 4.09 (2H, q, J = 7.0 Hz), 6.45 (1H, q, J = 2.3 Hz), 6.57 (1H, dd, J = 2.3, 8.8 Hz), 7.30 (1H, m), 7.43 (2H, m), 7.83 (1H, d, J = 8.7 Hz), 8.63 ( 2H, m).
MS (ESI, POS) m / z: 298 [M + H] ⁺

(Iv) Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) Ethanol (8.4 ml) was added to 2-buten-1-one (223 mg, 0.75 mmol) and a palladium-carbon catalyst (10% by weight), and the system was replaced with hydrogen. After stirring at room temperature for 5 hours and 30 minutes, the system was replaced with argon. The reaction solution was filtered through celite, and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 100/1) to obtain the title compound (168 mg, 0.56 mmol, yield 75%).

¹ H-NMR (CDCl ₃ ) ppm: 1.28 (3H, d, J = 6.8 Hz), 1.45 (3H, t, J = 7.0 Hz), 3.28 (2H, m), 3 .84 (3H, s), 4.11 (2H, q, J = 7.0 Hz), 6.43 (1H, d, J = 2.3 Hz), 6.50 (1H, dd, J = 2. 4, 8.8 Hz), 7.16 (2H, m), 7.73 (1H, d, J = 8.7 Hz), 8.49 (2H, m).
MS (ESI, POS) m / z: 300 [M + H] ⁺

Example 2
Production of 1- (2,4-diethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) Production of 2 ′, 4′-diethoxyacetophenone 2′- in Example 1 (i) A similar reaction was carried out using 2 ′, 4′-dihydroxyacetophenone (5 g, 32.86 mmol) instead of hydroxy-4′-methoxyacetophenone, and the title compound (4.75 g, 22.80 mmol) was collected. Yield 69%).

¹ H-NMR (CDCl ₃ ) ppm: 1.43 (3H, t, J = 7.0 Hz), 1.49 (3H, t, J = 7.0 Hz), 2.60 (3H, s), 4 .08 (2H, q, J = 7.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 6.43 (1H, d, J = 2.3 Hz), 6.50 (1H, dd, J = 2.8, 8.7 Hz), 7.83 (1H, d, J = 8.8 Hz).
MS (ESI, POS) m / z: 209 [M + H] ⁺

(Ii) Preparation of 1- (2,4-diethoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii) The same reaction was carried out using 2 ′, 4′-diethoxyacetophenone (1 g, 4.80 mmol) instead of 1 to obtain the title compound (1.14 g, 3.46 mmol, yield 72%). It was.
MS (ESI, POS) m / z: 330 [M + H] ⁺

(Iii) Preparation of 1- (2,4-diethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl in Example 1 (iii) ) -3-Hydroxy-3- (4-pyridyl) butan-1-one instead of 1- (2,4-diethoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one ( 329 mg, 1.0 mmol) was used for the same reaction to obtain the title compound (273 mg, 0.88 mmol, yield 88%).

¹ H-NMR (CDCl ₃ ) ppm: 1.37 (3H, t, J = 7.1 Hz), 1.44 (3H, t, J = 7.0 Hz), 2.49 (3H, d, J = 1.3 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.09 (2H, q, J = 7.1 Hz), 6.44 (1H, d, J = 2.3 Hz), 6.55 (1H, dd, J = 2.2, 8.8 Hz), 7.30 (1H, d, J = 1.4 Hz), 7.43 (2H, m), 7.82 (1H, d , J = 8.7 Hz), 8.63 (2H, m).
MS (ESI, POS) m / z: 312 [M + H] ⁺

(Iv) Production of 1- (2,4-diethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3 in Example 1 (iv) Instead of-(4-pyridyl) -2-buten-1-one 1- (2,4-diethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (262 mg, 0. 84 mmol) was used to carry out a similar reaction to obtain the title compound (234 mg, 0.75 mmol, yield 89%).

¹ H-NMR (CDCl ₃ ) ppm: 1.28 (3H, d, J = 6.8 Hz), 1.42 (3H, t, J = 7.0 Hz), 1.45 (3H, t, J = 7.0 Hz), 3.18 (2 H, m), 3.44 (1 H, m), 4.09 (4 H, m), 6.42 (1 H, d, J = 2.2 Hz), 6.44 (1H, dd, J = 2.2, 8.8 Hz), 7.16 (2H, m), 7.72 (1H, d, J = 8.7 Hz), 8.48 (2H, m).
MS (ESI, POS) m / z: 314 [M + H] ⁺

Example 3
Preparation of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 3-hydroxy-1- (2-hydroxy-4,6-dimethoxyphenyl) Preparation of -3- (4-pyridyl) butan-1-one In place of 2'-ethoxy-4'-methoxyacetophenone in Example 1 (ii), 2'-hydroxy-4 ', 6'-dimethoxyacetophenone (4 .90 g, 4.80 mmol) was used to carry out a similar reaction to obtain the title compound (5.18 g, 16.32 mmol, yield 65%).

¹ H-NMR (CDCl ₃ ) ppm: 1.52 (3H, s), 3.41 (1H, d, J = 18.4 Hz), 3.82 (3H, s), 3.88 (1H, d , J = 18.4 Hz), 3.90 (3H, s), 4.72 (1H, s), 5.94 (1H, d, J = 2.94 Hz), 6.03 (1H, d, J = 2.4 Hz), 7.37 (2H, m), 8.54 (2H, m), 13.28 (1H, s).
MS (ESI, POS) m / z: 318 [M + H] ⁺

(Ii) Preparation of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4 in Example 1 (iii) 3-methoxy-1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) instead of -methoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one The same reaction was performed using butan-1-one (317 mg, 1.0 mmol) to obtain the title compound (124 mg, 0.41 mmol, yield 41%).

¹ H-NMR (CDCl ₃ ) ppm: 2.42 (3H, d, J = 1.3 Hz), 3.85 (3H, s), 3.87 (3H, s), 5.95 (1H, d , J = 2.4 Hz), 6.12 (1H, d, J = 2.4 Hz), 7.31 (1H, dd, J = 1.2, 2.6 Hz), 7.41 (2H, m) 8.65 (2H, m), 13.98 (1H, s).
MS (ESI, POS) m / z: 300 [M + H] ⁺

(Iii) Preparation of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl in Example 1 (iv) ) -3- (4-Pyridyl) -2-buten-1-one instead of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one The same reaction was performed using (89 mg, 0.30 mmol) to obtain the title compound (73 mg, 0.24 mmol, yield 81%).
¹ H-NMR (CDCl ₃ ) ppm: 1.31 (3H, d, J = 6.8 Hz), 3.21 (1H, m), 3.33-3.48 (2H, m), 3.84 (3H, s), 5.93 (1H, d, J = 2.4 Hz), 6.07 (1H, d, J = 2.4 Hz), 7.18 (2H, m), 8.51 (2H M), 13.98 (1H, s).
MS (ESI, POS) m / z: 302 [M + H] ⁺

Example 4
Preparation of 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) -2-butene Preparation of -1-one Lithium diisopropylamine (1.58 M heptane-tetrahydrofuran-ethylbenzene solution, 0.67 ml, 1.2 mmol) was added to tetrahydrofuran (2 ml) at −72 ° C. under an argon atmosphere.
After stirring for 30 minutes, a tetrahydrofuran solution (1 ml) of 2 ′, 5′-dimethoxyacetophenone (180 mg, 1 mmol) was added dropwise. After stirring at the same temperature for 1 hour, a tetrahydrofuran solution (1 ml) of 4-acetylpyridine (121 mg, 1 mmol) was added dropwise, and the mixture was further stirred for 2 hours. Saturated aqueous ammonium chloride solution (10 ml) was added to stop the reaction, and 10 ml of ethyl acetate was added. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine (10 ml) and then dried over sodium sulfate. After the solvent was distilled off, the residue was vacuum dried to obtain a crude product (273 mg).
Subsequently, p-toluenesulfonic acid (205 mg, 1.08 mmol) and toluene (5.6 ml) were added, and the mixture was stirred at 100 ° C. for 2 hours. After cooling to room temperature, ethyl acetate (15 ml) and 1M hydrochloric acid (15 ml) were added to separate the layers. The aqueous layer was made basic by adding 6M aqueous sodium hydroxide solution, and extracted by adding ethyl acetate (15 ml). The organic layer was further washed twice with saturated aqueous sodium hydrogen carbonate (10 ml) and once with saturated brine (10 ml), and dried over sodium sulfate. After evaporation of the solvent, the concentrated residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 100/1) to give the title compound (123 mg, 0.44 mmol, yield 44% over 2 steps). Obtained.
MS (ESI, POS) m / z: 284 [M + H] ⁺

(Ii) Preparation of 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- in Example 1 (iv) 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (123 mg, 0.44 mmol) instead of (4-pyridyl) -2-buten-1-one ) To give the title compound (98 mg, 0.34 mmol, yield 79%).
MS (ESI, POS) m / z: 286 [M + H] ⁺

Example 5
Preparation of 1- (2-hydroxy-4-methoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (2-hydroxy-4-methoxyphenyl) -3- (4-pyridyl) Preparation of 2-buten-1-one Using 2′-hydroxy-4′-methoxyacetophenone (166 mg, 1.0 mmol) instead of 2 ′, 5′-dimethoxyacetophenone in Example 4 (i) The same reaction was carried out to obtain the title compound (169 mg, 0.63 mmol, yield of 63% over 2 steps).

¹ H-NMR (CDCl ₃ ) ppm: 2.50 (3H, d, J = 1.2 Hz), 3.86 (3H, s), 6.46 (1H, dd, J = 2.5, 8. 7 Hz), 6.48 (1 H, d, J = 1.6 Hz), 7.17 (1 H, dd, J = 1.3, 2.7 Hz), 7.47 (2 H, m), 7.68 ( 1H, dd, J = 1.5, 7.7 Hz), 8.69 (2H, m), 13.04 (1H, s).
MS (ESI, POS) m / z: 270 [M + H] ⁺

(Ii) Preparation of 1- (2-hydroxy-4-methoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl)-in Example 1 (iv) 1- (2-hydroxy-4-methoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (169 mg, instead of 3- (4-pyridyl) -2-buten-1-one, The same reaction was carried out using 0.63 mmol) to obtain the title compound (30 mg, 0.11 mmol, yield 18%).
MS (ESI, POS) m / z: 272 [M + H] ⁺

Example 6
Preparation of 1- (2-hydroxy-5-methylphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (2-hydroxy-5-methylphenyl) -3- (4-pyridyl) Preparation of 2-buten-1-one Using 2′-hydroxy-5′-methylacetophenone (150 mg, 1.0 mmol) instead of 2 ′, 5′-dimethoxyacetophenone in Example 4 (i) The same reaction was performed to obtain the title compound (165 mg, 0.65 mmol, yield of 65% over two steps).
MS (ESI, POS) m / z: 254 [M + H] ⁺

(Ii) Preparation of 1- (2-hydroxy-5-methylphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl)-in Example 1 (iv) Instead of 3- (4-pyridyl) -2-buten-1-one, 1- (2-hydroxy-5-methylphenyl) -3- (4-pyridyl) -2-buten-1-one (164 mg, The same reaction was performed using 0.65 mmol) to obtain the title compound (39 mg, 0.15 mmol, yield 24%).
MS (ESI, POS) m / z: 256 [M + H] ⁺

Example 7
Preparation of 1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) Preparation of 3 ′, 5′-dimethoxyacetophenone 2′-hydroxy- in Example 1 (i) The same reaction was carried out using 3 ′, 5′-dihydroxyacetophenone (1.52 g, 10 mmol) instead of 4′-methoxyacetophenone, and the title compound (1.47 g, 8.16 mmol, yield 82). %).
MS (ESI, POS) m / z: 181 [M + H] ⁺

(Ii) Preparation of 3-hydroxy-1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii) Instead, the same reaction was performed using 3 ′, 5′-dimethoxyacetophenone (180.2 mg, 1.0 mmol) to obtain the title compound (194 mg, 0.64 mmol, yield 64%).
MS (ESI, POS) m / z: 302 [M + H] ⁺

(Iii) Preparation of 1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl) in Example 1 (iii) 3-Hydroxy-1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (194 mg) instead of -3-hydroxy-3- (4-pyridyl) butan-1-one , 0.64 mmol) was used to obtain the title compound (130 mg, 0.46 mmol, yield 71%).
MS (ESI, POS) m / z: 284 [M + H] ⁺

(Iv) Preparation of 1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- in Example 1 (iv) 1- (3,5-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (130 mg, 0.46 mmol) instead of (4-pyridyl) -2-buten-1-one ) To give the title compound (107 mg, 0.37 mmol, yield 82%).
MS (ESI, POS) m / z: 286 [M + H] ⁺

Example 8
Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) pentan-1-one (i) 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) Preparation of Pentan-1-one Instead of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii), 2 ′, 4′-dimethoxyacetophenone (150.2 mg, 1.0 mmol) was replaced with 4- The same reaction was carried out using 4- (1-propionyl) pyridine (135.2 mg, 1.0 mmol) instead of acetylpyridine to give the title compound (275 mg, 0.87 mmol, yield 87%). Obtained.
MS (ESI, POS) m / z: 316 [M + H] ⁺

(Ii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -2-penten-1-one 1- (2-ethoxy-4-methoxyphenyl) in Example 1 (iii) 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) pentan-1-one (275) instead of 3-hydroxy-3- (4-pyridyl) -butan-1-one mg, 0.87 mmol) was used for the same reaction to obtain the title compound (83 mg, 0.28 mmol, yield 32%).
MS (ESI, POS) m / z: 298 [M + H] ⁺

(Iii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) pentan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- in Example 1 (iv) 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -2-penten-1-one (41 mg, 0.14 mmol) instead of (4-pyridyl) -2-buten-1-one ) To give the title compound (26 mg, 0.28 mmol, 62% yield).
MS (ESI, POS) m / z: 300 [M + H] ⁺

Example 9
Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) pentan-1-one (i) 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) Preparation of 2-penten-1-one 2′-ethoxy-4′-methoxyacetophenone (100 mg, 0.51 mmol) was replaced by 4-acetyl instead of 2 ′, 5′-dimethoxyacetophenone in Example 4 (i). The same reaction was carried out using 4- (1-propionyl) pyridine (70 mg, 0.51 mmol) instead of pyridine, and the title compound (83 mg, 0.27 mmol, 54% yield over 2 steps) was obtained. Obtained.
MS (ESI, POS) m / z: 312 [M + H] ⁺

(Ii) Preparation of 1- (2-ethoxy-4-methoxyphenyl) -3- (4-pyridyl) pentan-1-one 1- (2-ethoxy-4-methoxyphenyl)-in Example 1 (iv) 1- (2-Ethoxy-4-methoxyphenyl) -3- (4-pyridyl) -2-penten-1-one (41 mg, 0 instead of 3- (4-pyridyl) -2-buten-1-one .13 mmol) was used to obtain the title compound (29 mg, 0.09 mmol, yield 69%).
MS (ESI, POS) m / z: 314 [M + H] ⁺

Example 10
Preparation of 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) pentan-1-one (i) 1- (2,5-dimethoxyphenyl-3- (4-pyridyl) -2-pentene- Preparation of 1-one The same reaction was carried out using 4- (1-propionyl) pyridine (135 mg, 1 mmol) instead of 4-acetylpyridine in Example 4 (i), and the title compound (141 mg, 0 .47 mmol, yield 47% over two steps).
MS (ESI, POS) m / z: 298 [M + H] ⁺

(Ii) Preparation of 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) pentan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- in Example 1 (iv) Instead of (4-pyridyl) -2-buten-1-one, 1- (2,5-dimethoxyphenyl) -3- (4-pyridyl) -2-penten-1-one (17 mg, 0.057 mmol) was used. Were used for the same reaction to obtain the title compound (11 mg, 0.037 mmol, yield 65%).
MS (ESI, POS) m / z: 300 [M + H] ⁺

Example 11
Preparation of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) -pentan-1-one (i) 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- Production of (4-pyridyl) -2-penten-1-one Instead of 2 ′, 5′-dimethoxyacetophenone in Example 4 (i), 2′-hydroxy-4 ′, 6′-dimethoxyacetophenone (294 mg, 1.5 mmol) was subjected to a similar reaction using 4- (1-propionyl) pyridine (135 mg, 1.5 mmol) instead of 4-acetylpyridine, and the title compound (160 mg, 0.51 mmol) was obtained. The yield was 34% in two steps).
MS (ESI, POS) m / z: 314 [M + H] ⁺

(Ii) Preparation of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3- (4-pyridyl) pentan-1-one 1- (2-ethoxy-4-methoxyphenyl in Example 1 (iv) ) -3-Pyridin-4-yl-2-buten-1-one instead of 1- (2-hydroxy-4,6-dimethoxyphenyl) -3-pyridin-4-yl-2-penten-1-one The same reaction was performed using (86 mg, 0.27 mmol) to obtain the title compound (74 mg, 0.23 mmol, yield 86%).
MS (ESI, POS) m / z: 316 [M + H] ⁺

Example 12
Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) Production of butan-1-one A similar reaction was carried out using 2 ′, 4′-dimethoxyacetophenone (180 mg, 1 mmol) instead of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii). The title compound (213 mg, 0.71 mmol, 71% yield) was obtained.

¹ H-NMR (CDCl ₃ ) ppm: 1.52 (3H, s), 3.33 (1H, d, J = 18.0 Hz), 3.81 (1H, d, J = 17.5 Hz), 3 .85 (3H, s), 3.93 (3H, s), 5.16 (1H, brs), 6.45 (1H, d, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 10.9 Hz), 7.38 (2H, m), 7.66 (1 H, d, J = 8.4 Hz), 8.52 (2H, m).
MS (ESI, POS) m / z: 302 [M + H] ⁺

(Ii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl) in Example 1 (iii) Instead of -3-hydroxy-3- (4-pyridyl) butan-1-one, 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one (519. The same reaction was performed using 5 mg, 1.9 mmol) to obtain the title compound (180.6 mg, 0.71 mmol, yield 37%).

MS (ESI, POS) m / z: 284 [M + H] ⁺

(Iii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3-in Example 1 (iv) Instead of (4-pyridyl) -2-buten-1-one, 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (20.0 g, 70. 6 mmol) was used to carry out a similar reaction to obtain the title compound (20.3 g, 63.1 mmol, yield 89%).

¹ H-NMR (DMSO-d ₆ ) ppm: 1.20 (3H, d, J = 6.4 Hz), 3.08-3.3 (3H, m), 3.83 (3H, s), 3 .89 (3H, s), 6.59 (1H, dd, J = 2.3, 8.7 Hz), 6.65 (1H, d, J = 2.2 Hz), 7.26 (2H, m) 7.56 (1H, d, J = 8.7 Hz), 8.44 (2H, m).
MS (ESI, POS) m / z: 286 [M + H] ⁺

Example 13
Preparation of 1- (3-methoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (3-methoxyphenyl) -3-hydroxy-3- (4-pyridyl) butane-1- Production of ON The same reaction was carried out using 3′-methoxyacetophenone (300.4 mg, 2.0 mmol) instead of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii), and the title compound (519.5 mg, 1.91 mmol, yield 96%) was obtained.

MS (ESI, POS) m / z: 272 [M + H] ⁺

(Ii) Preparation of 1- (3-methoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl) -3 in Example 1 (iii) 1- (3-methoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one (519.5 mg, 1 instead of -hydroxy-3- (4-pyridyl) butan-1-one .9 mmol) to give the title compound (180.6 mg, 0.71 mmol, 37% yield).

MS (ESI, POS) m / z: 254 [M + H] ⁺

(Iv) Preparation of 1- (3-methoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- (4 in Example 1 (iv) 1- (3-methoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (80 mg, 0.32 mmol) instead of -pyridyl) -2-buten-1-one The same reaction was performed to obtain the title compound (36.5 mg, 0.14 mmol, yield 44%).

¹ H-NMR (CDCl ₃ ) ppm: 1.35 (3H, d, J = 6.8 Hz), 3.26 (2H, t, J = 6.7 Hz), 3.53 (1H, tq, J = 6.7 Hz), 3.85 (3 H, s), 7.11 (1 H, ddd, J = 8.0, 2.3, 1.2 Hz), 7.24 (2 H, dd, J = 4.6) 1.5Hz), 7.37 (1H, t, J = 5.2Hz), 7.44 (1H, dd, J = 4.0, 2.6, Hz), 7.51 (1H, dt, 8.0, 1.1 Hz), 8.52 (2H, 5.5 Hz).
MS (ESI, POS) m / z: 256 [M + H] ⁺

Example 14
Preparation of 1- (2,3-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one (i) 1- (2,3-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) Production of butan-1-one The same procedure was performed using 2 ′, 3′-dimethoxyacetophenone (180.2 mg, 1.0 mmol) instead of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii). The title compound (268.2 mg) was obtained.

MS (ESI, POS) m / z: 272 [M + H] ⁺

(Ii) Preparation of 1- (2,3-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one 1- (2-ethoxy-4-methoxyphenyl) in Example 1 (iii) Instead of -3-hydroxy-3- (4-pyridyl) butan-1-one, 1- (2,3-dimethoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one (268. 2 mg) to give the title compound (93.2 mg, 0.37 mmol, 37% yield (2 steps)).

MS (ESI, POS) m / z: 254 [M + H] ⁺

(Iii) Preparation of 1- (2,3-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one 1- (2-ethoxy-4-methoxyphenyl) -3- in Example 1 (iv) 1- (2,3-dimethoxyphenyl) -3- (4-pyridyl) -2-buten-1-one (45 mg, 0.16 mmol) instead of (4-pyridyl) -2-buten-1-one ) To give the title compound (31.3 mg, 0.10 mmol, 69% yield).

¹ H-NMR (CDCl ₃ ) ppm: 1.31 (3H, d, J = 7.3, Hz), 3.28 (2H, dd, J = 12.0, 6.7 Hz), 3.46 ( 1H, m), 3.83 (3H, s), 3.89 (3H, s), 6.95-7.1 (3H, m), 7.22 (2H, dd, J = 1.5, 4.6 Hz), 8.51 (2H, d, J = 5.5 Hz).
MS (ESI, POS) m / z: 256 [M + H] ⁺

Example 15
Preparation of 1- (2,4-dimethoxyphenyl) -3- (4- (3-methylpyridyl)) butan-1-one (i) 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- Preparation of (4- (3-methylpyridyl)) butan-1-one 2 ′, 4′-dimethoxyacetophenone (720.5 mg instead of 2′-ethoxy-4′-methoxyacetophenone in Example 1 (ii) 4.0 mmol) was replaced with 4-acetyl-3-methylpyridine (138.3 mg, 1.02 mmol) of literature known (J. Heterocyclic Chem., 27, 1751 (1990)) instead of acetylpyridine. ) To give the title compound (204.1 mg, 0.65 mmol, 64% yield (based on 4-acetyl-3-methylpyridine)) )

MS (ESI, POS) m / z: 316 [M + H] ⁺

(Ii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4- (3-methylpyridyl))-2-buten-1-one 1- (2-ethoxy- in Example 1 (iii) 1- (2,4-dimethoxyphenyl) -3-hydroxy-3- (4- (3-methylpyridyl) instead of 4-methoxyphenyl) -3-hydroxy-3- (4-pyridyl) butan-1-one )) Butan-1-one (204.1 mg, 0.65 mmol) was used to carry out a similar reaction to obtain the title compound (168.0 mg).

MS (ESI, POS) m / z: 298 [M + H] ⁺

(Iii) Preparation of 1- (2,4-dimethoxyphenyl) -3- (4- (3-methylpyridyl)) butan-1-one 1- (2-ethoxy-4-methoxy in Example 1 (iv) 1- (2,4-dimethoxyphenyl) -3- (4- (3-methylpyridyl))-2-butene-1 instead of phenyl) -3- (4-pyridyl) -2-buten-1-one The same reaction was performed using -one (168.0 mg) to obtain the title compound (148.8 mg, 0.50 mmol, yield 77% (2 steps)).

MS (ESI, POS) m / z: 300 [M + H] ⁺

Example 16
Production of (+)-1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one The racemate produced in Example 12 was prepared using CHIRALCEL OD (radius 0.46 cm, length). 25 cm, column temperature 35 ° C.), hexane-isopropyl alcohol (9/1) was eluted as a moving bed at a flow rate of 0.6 ml / min, and a peak having a retention time of 35.65 minutes was collected. Measurement of this compound with a polarimeter (PERKIN-ELMER 241 POLARIMETER) showed a positive (+) optical rotation angle.

Example 17
Production of (−)-1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) butan-1-one The racemate produced in Example 12 was prepared using CHIRALCEL OD (radius 0.46 cm, length). 25 cm, column temperature 35 ° C.), and eluted with hexane-isopropyl alcohol (9/1) · as a moving bed at a flow rate of 0.6 ml / min, and a peak having a retention time of 43.58 minutes was collected.

Example 18
Preparation of 1- (6-methoxy-2-naphthyl) -3- (4-pyridyl) butan-1-one (i) 1- (6-methoxy-2-naphthyl) -3- (4-pyridyl) -2 -Production of propen-1-one To a methanol solution (10 ml) of potassium hydroxide (337 mg, 6.0 mmol), 6-methoxy-2-acetylnaphthalene (1.0 g, 5.0 mmol), 4- Pyridinecarboxaldehyde (536 mg, 5.0 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified with concentrated hydrochloric acid, and the reaction solution was concentrated under reduced pressure. Ethyl acetate and 10% aqueous hydrochloric acid were added to the residue and stirred well. The aqueous layer was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, the residue was purified by silica gel chromatography (eluted with ethyl acetate / hexane = 4/1), and the obtained solid was washed with diethyl ether to give the title compound (165 mg, 0 .57 mmol, yield 11%).

MS (ESI, POS) m / z: 290 [M + H] ⁺

(Ii) Preparation of 1- (6-methoxy-2-naphthyl) -3- (4-pyridyl) butan-1-one Copper (I) chloride (79.2 mg, 0.8 mmol) was added to tetrahydrofuran (2 ml). To the suspension, methylmagnesium bromide (3 M solution, 0.53 ml, 1.6 mmol) was added at −20 ° C., stirred for 43 minutes, and then 1- (6-methoxy-2-naphthyl) -3- ( A tetrahydrofuran solution (2 ml) of 4-pyridyl) -2-propen-1-one (57.9 mg, 0.2 mmol) was added and stirring was continued for another 2 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with ethyl acetate / hexane = 1/1), and further purified by preparative HPLC to give the title compound (3.9 mg, 0.01 mmol, yield 6.4). %).

¹ H-NMR (CDCl ₃ ) ppm: 1.39 (3H, d, J = 6.9 Hz), 3.36 (2H, dd, J = 7.6, 12.8 Hz), 3.58 (1H, m), 3.95 (3H, s), 7.1-7.3 (4H, m), 7.76 (1H, d, J = 8.7 Hz), 7.84 (1H, d, J = 8.9 Hz), 7.96 (1H, dd, J = 8.6, 1.8 Hz), 8.36 (1H, s), 8.53 (2H, brs).

Example 19
Preparation of 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -butan-1-one oxime 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -butane-1- On (33 mg, 0.12 mmol) was suspended in water (2 ml), hydroxylamine hydrochloride (26 mg, 0.37 mmol), sodium acetate (51 mg, 0.62 mmol) were added, and 50 ° C. And stirred for 4 days. After completion of the reaction, methylene chloride (5 m) and water (5 ml) were added for extraction, and the organic layer was washed with saturated brine (5 ml) and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 20/1) to obtain the title compound (30 mg, 0.10 mmol, yield 87%).

MS (ESI, POS) m / z: 301 [M + H] ⁺

Example 20
1- (2,4-Dimethoxyphenyl) -3- (4-pyridyl) -butan-1-one Preparation of O-methyloxime 1- (2,4-Dimethoxyphenyl) -3- (4-pyridyl) -butane -1-one (34 mg, 0.13 mmol) was suspended in water (0.5 ml) and methoxylamine hydrochloride (26 mg, 0.31 mmol), 10% aqueous sodium hydroxide (0.05). ml) and stirred at room temperature for 3 days. After completion of the reaction, methylene chloride (7 m) and water (5 ml) were added for extraction, and the organic layer was washed with saturated brine (5 ml) and dried over sodium sulfate. After the solvent was distilled off, the residue was vacuum-dried to obtain the title compound (39 mg, 0.13 mmol, yield 98%).

MS (ESI, POS) m / z: 315 [M + H] ⁺

Example 21
1- (2,4-Dimethoxyphenyl) -3- (4-pyridyl) -butan-1-one Preparation of O-ethyloxime 1- (2,4-Dimethoxyphenyl) -3- (4-pyridyl) -butane -1-one (26 mg, 0.093 mmol) was dissolved in ethanol (5 ml), and ethoxylamine hydrochloride (43 mg, 0.44 mmol), 1% aqueous sodium hydroxide solution (1.8 ml) was added. In addition, the mixture was stirred at 60 ° C. for 1 day and at 80 ° C. for 1 day. After completion of the reaction, methylene chloride (5 m) and saturated aqueous sodium hydrogen carbonate (3 ml) were added for extraction, and the organic layer was washed with saturated brine (5 ml) and dried over sodium sulfate. After removing the solvent, the residue was purified by thin layer chromatography (developed with methylene chloride / methanol = 10/1) to obtain the title compound (3.4 mg, 0.01 mmol, yield 11%).

¹ H-NMR (CDCl ₃ ) ppm: 1.19 (3H, d, J = 6.7 Hz), 1.28 (3H, t, J = 7.0 Hz), 2.91 (2H, m), 3 .07 (1H, m), 3.78 (3H, s), 3.80 (3H, s), 4.11 (1H, dd, J = 1.7, 7.0 Hz), 4.18 (1H , Dd, J = 1.9, 7.0 Hz), 6.38 (1H, dd, J = 2.3, 8.1 Hz), 6.42 (1H, d, J = 2.2 Hz), 6. 88 (1H, d, J = 8.1 Hz), 7.03 (2H, m), 8.43 (2H, m).
MS (ESI, POS) m / z: 329 [M + H] ⁺

Example 22
Synthesis of (1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -1-butylideneaminooxy) acetic acid 1- (2,4-dimethoxyphenyl) -3- (4-pyridyl) -butane -1-one (80 mg, 0.28 mmol), carbomethoxyamine 1/2 hydrochloride (77 mg, 0.70 mmol), sodium acetate (115 mg, 1.40 mmol) in ethanol / water = 2 / 1 (2.4 ml) and stirred at 100 ° C. for 4 hours. After completion of the reaction, methylene chloride (10 m) and water (7 ml) were added for extraction, and the organic layer was washed with saturated brine (5 ml) and dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (eluted with methylene chloride / methanol = 30/1) to obtain the title compound (61 mg, 0.17 mmol, yield 61%).

¹ H-NMR (CDCl ₃ ) ppm: 1.27 (3H, d, J = 1.3 Hz), 2.97 (2H, m), 3.63 (1H, m), 3.75 (3H, s ), 3.80 (3H, s), 4.72 (1H, d, J = 16.5 Hz), 4.85 (1H, d, J = 16.5 Hz), 6.24 (1H, dd, J = 2.3, 8.4 Hz), 6.41 (1H, d, J = 2.3 Hz), 6.57 (1H, d, J = 8.4 Hz), 7.47 (2H, m), 8 .63 (2H, m), 9.20 (1H, brs).
MS (ESI, POS) m / z: 359 [M + H] ⁺

Test Example 1 Measurement of C17-20 Lyase Inhibitory Activity The measurement of C17-20 lyase inhibitory activity was carried out according to Grigoryev, DN et al. (1999), Analytical Biochemistry, 267, p. 319-330, Barnes, H .; J. et al. et. al. (1991), Proceedings of the National Academy of Sciences of the U.S. S. A. , 88, p. 5597-5601 and Imai, T .; et. al. (1993), Journal of Biological Chemistry, 268, p. It was carried out according to the method described in 1961-119689.

Isolation of the human lyase gene, construction of a human lyase gene expression vector, and preparation of human lyase-expressing cells were performed as follows.
The human lyase gene (GenBank accession # M14564) was isolated from the 5′UTR to the stop codon by RT-PCR using total RNA extracted from NCI-H295 (ATCC). At that time, since the primer used for RT-PCR was registered as GenBank # M14564, the following design was performed with reference to the gene sequence. That is, the forward primer is 5′-TTT AAA CTC CAC TGC TGT CTA TCT TGC CTG CCG GC-3 ′, and the reverse primer is 5′-TTT AAT TAG GTG CTA CCC TCA GCC TGG GCT TCC CT-3 ′. After the sequence of the isolated human lyase gene was confirmed, an expression vector for mammalian cells was constructed by the GATEWAY system (Invitrogene). The produced expression vector was transiently expressed in HEK293 cells using Lipofectamine PLUS (Invitrogene) and human lyase enzyme activity was confirmed. As a result, the enzyme activity of lyase was confirmed. Expression was confirmed. Next, using the prepared human lyase expression vector, a cell that constantly expresses the human lyase enzyme was prepared. Since the aforementioned human lyase expression vector has a neomycin resistance gene, the human lyase is constitutively expressed by introducing the human lyase expression vector into HEK293 cells and selecting the drug-resistant cells by treatment with 800 μg / ml of G418. I got the cells. When the human lyase enzyme activity of the obtained cells was measured, the lyase activity was confirmed.

  The enzyme was prepared as follows. The above human lyase-expressing cells were collected after culturing, and ultrasonically disrupted in 50 mM potassium phosphate buffer (pH 7.4) containing 20% glycerin and 10 mM magnesium acetate, and the supernatant obtained by centrifugation was used as the crude enzyme solution. And stored at -80 ° C.

  The evaluation method was performed as follows. The crude enzyme solution was thawed and diluted to the set enzyme concentration using the aforementioned buffer solution. The compound of the present invention was diluted to an appropriate concentration, 4 μl thereof was added to an Eppendorf tube, and then 400 μl of the prepared enzyme solution was added, followed by treatment at 37 ° C. for 10 minutes. Next, 100 μl of a substrate solution prepared in 25 μM 17α-hydroxyprogesterone and 4 mM β-NADPH with 50 mM potassium phosphate buffer solution (pH 7.4) containing 20% glycerin is added to the compound / enzyme mixture solution previously treated at 37 ° C. The enzyme reaction was carried out at 37 ° C for an additional 4 hours. The reaction was stopped by adding 0.6 ml of dichloromethane containing 0.3 μM internal standard. After extraction with shaking, the dichloromethane layer was separated and concentrated to dryness with a centrifugal evaporator. The obtained solid was dissolved in 30 μl of acetonitrile and diluted with 30 μl of water. 50 μl of this solution was injected into a high performance liquid chromatography using an ODS column and analyzed, and the peak size corresponding to the position of androstenedione was determined.

  An androstenedione solution with various concentrations was analyzed under the same conditions, and a calibration curve was prepared in advance. The amount of androstenedione produced by the enzymatic reaction was determined from the analysis results of each sample. A similar analysis was performed on the sample to which the compound of the present invention was not added, and the amount of produced androstenedione was determined.

Subsequently, C17-20 lyase inhibitory activity (%) was calculated | required using following formula (1). In formula (1), s represents the amount of produced androstenedione of the sample to which the present compound was added, and b represents the amount of produced androstenedione of the sample to which the present compound was not added.
Inhibitory activity (%) = ((ba) / b) × 100 Formula (1)

By variously examining the concentration of the compound of the present invention, the concentration that finally inhibits the enzyme activity by 50% was determined and used as the IC ₅₀ value.

Table 3
Human lyase 50% inhibitory activity value of the compound (IC ₅₀ value, μM)
Example 1 0.024
Example 2 0.1
Example 3 0.026
Example 4 0.031
Example 5 0.051
Example 6 0.12
Example 7 0.081
Example 8 0.015
Example 9 0.019
Example 10 0.022
Example 11 0.025
Example 12 0.028
Example 13 0.068
Example 14 0.11
Example 15 0.036
Example 16 0.022
Example 17 0.04
Example 18 0.0057
Example 19 1.1
Example 20 0.075
Example 21 0.072

  As is apparent from Table 3, since all of the compounds of the present invention have excellent C17-20 lyase inhibitory activity, they can be used as pharmaceuticals, particularly effective pharmaceuticals for diseases that exhibit effects by C17-20 lyase inhibitory activity. The possibility is shown.

Claims (16)

The following general formula (1)

[Wherein A represents the following general formula (2)

Or the following general formula (3)

X represents an oxygen atom or N-OR ₁₁ , and R ₁ and R ₂ may be the same or different and each represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group. , R ₃ and R ₄ may be the same or different and each represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group (provided that R ₃ and R ₄ are both hydrogen atoms) R ₅ , R ₆ and R ₇ may be the same or different from each other, and each may have a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted lower alkyl group or a substituent. Or a group arbitrarily selected from the group consisting of an optionally substituted lower alkoxy group, acyl group, acyloxy group, optionally substituted amino group, or R ₅ , R ₆ , R Any two groups of ₇ are methylenedioxy groups or Represents an ethylenedioxy group, and R ₈ , R ₉ and R ₁₀ may be the same or different from each other, and may have a hydrogen atom, a hydroxyl group, a halogen atom or a substituent. An alkyl group, an optionally substituted lower alkoxy group, an acyl group, an acyloxy group, a group arbitrarily selected from the group consisting of an optionally substituted amino group, or Any two groups of R ₈ , R ₉ and R ₁₀ form a methylenedioxy group or an ethylenedioxy group, and R ₁₁ represents a hydrogen atom, a lower alkyl group or a carboxyalkyl group (provided that When it has a substituent, the substituent of the lower alkyl group and the lower alkoxy group is an aryl group or a halogen atom, and the substituent of the amino group is substituted with a lower acyl group, an aryl group or a halogen atom. Which may be a lower alkyl group, an aryl group, benzyloxycarbonyl group, or a tert- butyloxycarbonyl group.). Or a pharmacologically acceptable salt thereof. The pyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A in the general formula (1) is the general formula (2). The pyridine derivative or a pharmacologically acceptable salt thereof according to claim ₂ , wherein in formula (1), R ₁ and R ₂ are both hydrogen atoms. The pyridine derivative or a pharmacologically acceptable salt thereof according to claim ₃ , wherein in general formula (1), either R ₃ or R ₄ is a lower alkyl group, and the other is a hydrogen atom. In the general formula (1), R ₅ , R ₆ and R ₇ each represents a group arbitrarily selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, or further R ₅ A pyridine derivative or a pharmacologically acceptable salt thereof according to claim 4, wherein any two of R ₆ , R ₆ and R ₇ form a methylenedioxy group or an ethylenedioxy group. In general formula (1), R ₅ , R ₆ and R ₇ are groups arbitrarily selected from the group consisting of a hydroxyl group, a methyl group, an ethyl group, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group and an isopropoxy group. The pyridine derivative according to claim 5, wherein X represents an oxygen atom, or indicates that any two groups of R ₅ , R ₆ and R ₇ form a methylenedioxy group or an ethylenedioxy group. Or a pharmacologically acceptable salt thereof. The pyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein A in the general formula (1) is the general formula (3). The pyridine derivative or a pharmacologically acceptable salt thereof according to claim 7, wherein in formula (1), R ₁ and R ₂ are both hydrogen atoms. The pyridine derivative or a pharmacologically acceptable salt thereof according to claim 8, wherein, in the general formula (1), either R ₃ or R ₄ is a lower alkyl group and the other is a hydrogen atom. In the general formula (1), R ₈ , R ₉ and R ₁₀ each represents a group arbitrarily selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, or further R ₈ A pyridine derivative or a pharmaceutically acceptable salt thereof according to claim 9, wherein any two groups of R ₉ , R ₉ and R ₁₀ form a methylenedioxy group or an ethylenedioxy group. In the general formula (1), R ₈ , R ₉ and R ₁₀ are arbitrarily selected from the group consisting of a hydroxyl group, a methyl group, a fluorine atom, a methoxy group, an ethoxy group or an isopropoxy group, and X is an oxygen atom. The pyridine derivative according to 10, or a pharmacologically acceptable salt thereof.   The pharmaceutical which uses the pyridine derivative as described in any one of Claims 1 thru | or 11, or its pharmacologically acceptable salt as an active ingredient.   The antitumor agent which uses the pyridine derivative as described in any one of Claims 1 thru | or 11, or its pharmacologically acceptable salt as an active ingredient.   A prophylactic or therapeutic agent for prostate cancer or breast cancer comprising the pyridine derivative according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.   A prophylactic or therapeutic agent for sex hormone excess, comprising the pyridine derivative according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.   The C17-20 lyase inhibitor which uses the pyridine derivative as described in any one of Claims 1 thru | or 11, or its pharmacologically acceptable salt as an active ingredient.