WO2005005390A1 - Novel enzyme inhibitor - Google Patents

Novel enzyme inhibitor Download PDF

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Publication number
WO2005005390A1
WO2005005390A1 PCT/JP2004/009630 JP2004009630W WO2005005390A1 WO 2005005390 A1 WO2005005390 A1 WO 2005005390A1 JP 2004009630 W JP2004009630 W JP 2004009630W WO 2005005390 A1 WO2005005390 A1 WO 2005005390A1
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Prior art keywords
group
acceptable salt
prodrug
hydrogen atom
naphthalene derivative
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PCT/JP2004/009630
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French (fr)
Japanese (ja)
Inventor
Masashi Nagai
Hiroshi Sato
Keiichirou Yamamoto
Takamichi Sato
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Nippon Kayaku Kabushiki Kaisha
Akiyama, Yuji
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Priority to JP2005511517A priority Critical patent/JPWO2005005390A1/en
Publication of WO2005005390A1 publication Critical patent/WO2005005390A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens

Definitions

  • the present invention relates to a novel naphthalene derivative useful as a drug, particularly as a C17-20 lyase inhibitor.
  • Diseases that are known to cause onset or exacerbation due to excess sex hormones include diseases caused by excess androgen such as prostate cancer, prostatic hypertrophy, hirsutism, and virilization signs, breast cancer, and ovaries. Diseases caused by excess female hormones such as cancer, uterine cancer, mastopathy, endometriosis, and uterine fibroids are known.
  • Treatment of these diseases may be antagonists or agonists of luteinizing hormone-releasing hormone (LHRH), which stops the synthesis of sex hormones, inhibitors of sex steroid biosynthesis (5 ⁇ -reductase, aromatase inhibitors, etc.), or Sex steroid receptor antagonists are currently used (Japanese clinical, vol. 58 (extra number, diagnosis and treatment of breast cancer), 311-333 (2000) and Japanese clinical, vol. 58 (extra number, diagnosis of prostate cancer) 176-182 (2000)).
  • LHRH luteinizing hormone-releasing hormone
  • Sex steroid receptor antagonists Sex steroid receptor antagonists
  • C17-20 lyase is one of sex hormone biosynthetic enzymes. It is present 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 sex hormone biosynthesis, drugs that inhibit this enzyme become new endocrine therapies that inhibit sex hormone biosynthesis, and are used in medical practice as therapeutic or prophylactic drugs. (Japanese Clinical Journal, Vol. 58 (Special Issue, Diagnosis and Treatment of Prostate Cancer), 317-319 (2000)).
  • Steroid inhibitors and non-steroid inhibitors have been reported as C17-20 lyase inhibitors.
  • As the former for example, compounds described in JP-A-7-505377 and US Pat. No. 5,994,335 have been reported.
  • As the latter for example, JP-A-2001-187784, JP-A-2002-80458, compounds having an imidazole ring such as WO 01/87875, and Patent Document JP-A-2002-234843, international Compounds having a pyridine ring have been reported, such as WO 92/16507 and WO 93/23375.
  • the present invention provides a C17-20 lyase inhibitor useful as a medicament.
  • the present invention relates to the following (1) to (14).
  • R and R are each independently the same or different and may be a hydrogen atom or a halogen atom;
  • R, R and R represent a group arbitrarily selected from the group consisting of a substituent, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkoxy group, and an amino group which may have a substituent.
  • 3 4 represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group, each of which may be the same or different, provided that R and R are both hydrogen atoms, R
  • R each independently represent a hydrogen atom, a halogen atom, a lower
  • R and R are both lower alkyl groups, and R and R are both hydrogen.
  • the naphthalene derivative according to (2) which is an atom, or a pharmaceutically acceptable salt or a salt thereof.
  • R and R represent a hydrogen atom, a halogen atom, a lower alkoxy group
  • R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
  • R and R are both hydrogen atoms, and the substitution position of the carboxy group from the naphthalene ring is 2-position
  • R and R represent a hydrogen atom, a halogen atom, a lower alkoxy group
  • a naphthalene derivative, or a pharmaceutically acceptable salt thereof or a prodrug thereof is a naphthalene derivative, or a pharmaceutically acceptable salt thereof or a prodrug thereof,
  • R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
  • naphthalene derivative according to (8) wherein the carboxy group is substituted at the 2-position from the naphthalene ring, or a pharmaceutically acceptable salt thereof or a prodrug thereof; (10) a medicament comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient;
  • an antitumor agent comprising, as an active ingredient, the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof;
  • An agent for preventing or treating prostate cancer or breast cancer comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient.
  • a prophylactic or therapeutic agent for excessive sex hormone comprising the naphthalene derivative according to any one of (1) to (9) or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient;
  • a C17-20 lyase inhibitor comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient.
  • 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 agent for hypergonadism. Or it is useful as a therapeutic agent.
  • the lower alkyl group of R 1, R 2, R 3, R 4, R 5, R 6 and R 7 is a straight-chain alkyl group having 116 carbon atoms
  • a chain or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, amyl, isopentyl, 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, 2ethyl Examples thereof include a butyl group, a 1,1,2-tri
  • the lower alkoxy group of R, R, R, R is the above-mentioned lower alkyl group
  • preferred groups include a methoxy group and an ethoxy group.
  • the lower acyl group of R, R, R, R is a lower acyl group.
  • a lower alkoxy group represents a carbonyl group to which the above-mentioned lower alkyl group is bonded.
  • Examples of the lower acyloxy group include an acetoxy group and a propionyloxy group.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and the like.
  • the optionally substituted amino group refers to an unsubstituted amino group, a lower acryl group, a lower alkyl group or a benzyloxycarbonyl group.
  • An amino group for example, formylamino group, propionylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-dipropylamino group, N, N-diisopropylamino group, N , N-di-n-butylamino group and the like.
  • the naphthalene derivative in the present invention may form a salt with an acid in some cases.
  • the salt with an acid examples 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 organic acids such as acid, tartaric acid, methanesulfonic acid, and p_toluenesulfonic acid. These salts can be produced by a conventional method.
  • naphthalene derivative or a salt thereof has hydrates and optical isomers, all hydrates, racemates and optical isomers are included.
  • the present invention also provides a prodrug of the naphthalene derivative of the present invention and a salt thereof.
  • a prodrug is an enzymatic reaction or a physiological reaction under physiological conditions. Is a compound which is converted into a compound represented by the general formula (1) by decomposition by a chemical reaction under acidic conditions or the like.
  • the prodrug of the naphthalene derivative of the present invention include compounds in which the amino group and the hydroxyl group are arylcarbonylated, for example, benzoylated in the general formula (1); , Leucylated compound, or aminocarbonylation, for example, [1,4 '] bipiperidinyl-1-carbonylated compound.
  • Examples of the compound represented by the general formula (1) include the following compounds.
  • the compounds of this invention can be manufactured as follows, for example c
  • novel naphthalene derivative represented by the general formula (1) is, for example, (R, R, R, R, R
  • a compound represented by a carboxy group or a reactive derivative thereof) can be easily produced by condensation, that is, an esterification reaction.
  • the compound represented by the general formula (A) is commercially available or can be easily synthesized.
  • Examples of the synthesis method include Synthesis (1983), vol. 5, p. 385, J. Chem. So (1941), p. 393, and U.S. Pat. No. 3,822,294. They can be converted into reactive derivatives of carboxylic acids according to a conventional method.
  • As the reactive derivative of carboxylic acid for example, acid halide, active amide compound, active ester and the like are used.
  • acid halide for example, acid chloride, acid bromide and the like are used.
  • active amide compound for example, an acid amide with imidazole, pyrazole, 4-substituted imidazole, dimethylvirazole, triazole, tetrazole, benzothiazo-nore and the like are used.
  • active ester an ester with 4-nitrophenol, 2,4-dinitrophenol, 1-hydroxybenzotriazole or the like is used.
  • a compound in which both 3 and R are substituted with a lower alkyl group is converted to a 4-acylpyridine derivative.
  • a condensing agent when Z is a carboxy group, a condensing agent can be used for the esterification reaction with the compound represented by the general formula (B).
  • condensing agents include N ,, '-dicyclohexylcarbodiimide (DCC), 1-ethyl-3_ (3-dimethylaminopropyl) force rubodiimide (EDC), ⁇ -cyclohexyl ⁇ -morpholinoethylcarbodiimide And 1-alkyl 1-2-halopyridinium salts.
  • the esterification reaction may be carried out in the presence of a base, for example, in the presence of an organic tertiary amine.
  • organic tertiary amine include triethylamine, N, N-dimethylaniline, pyridine and the like.
  • the solvent used for the esterification reaction is not particularly limited, but a solvent that dissolves the raw material and does not easily react with these is desirable, for example, pyridine, tetrahydrofuran, dioxane, benzene, ether, methylene chloride. , Dimethylformamide, toluene, or a mixed solvent of two or more selected from them. Use The solvent used is 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 the range of 140 ° C. to the reflux temperature of the solvent.
  • the reaction time is usually from 5 minutes to 120 hours, but may be arbitrarily selected depending on the type of the starting compound, the solvent, the reaction temperature and the like.
  • the naphthalene derivative represented by the general formula (1) or a pharmaceutically acceptable salt when used as a medicament, it may be used alone or in a pharmaceutically acceptable form such as a carrier, an excipient, a diluent, and a solubilizing agent. It is safe for oral or parenteral administration (systemic administration, topical administration, etc.) in the form of powders, granules, tablets, cablets, capsules, injections, suppositories, ointments, etc. by mixing with the resulting additives. Is given to Although the content of the compound of the present invention or a pharmaceutically acceptable salt in the preparation varies depending on the preparation, it is usually preferably 0.1% by weight.
  • the dosage varies depending on the route of administration, the age of the patient, and the actual condition to be prevented or treated.
  • the daily dose of the active ingredient is 0.01 mg to 2000 mg, preferably 0.1 mg to 2000 mg. mg—can be 1000 mg and can be administered in several divided doses daily.
  • the naphthalene derivative represented by the general formula (1) or a pharmaceutically acceptable salt has a C17-20 lyase inhibitory action, and is a medicament, particularly an agent for preventing or treating prostate cancer or breast cancer, Is useful as a preventive or therapeutic agent for excessive sex hormone.
  • 1,6-Dimethoxy_2_naphthoic acid methyl ester (38 mg) is dissolved in methanol (3.8 ml), 2M aqueous sodium hydroxide solution (1.5 ml) is added, and the mixture is heated and stirred at 70 ° C for 1 hour and 30 minutes. did. After cooling to room temperature, 2 M hydrochloric acid (1 ml) was used to make the aqueous solution acidic, followed by extraction with methylene chloride. The solvent was concentrated to obtain the title compound (35 mg).
  • Test Example 1 Measurement of CI 7-20 Lyase Inhibitory Activity
  • the human lyase gene (GenBank accession # M14564) was isolated from the 5'UTR to the termination codon by RT-PCR using NCI-H295 (ATCC) extracted total RNA by RT-PCR. At that time, since the primers used for RT-PCR were 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 TA G GTG CTA CCC TCA GCC TGG GCT TCC CT-3' .
  • an expression vector for mammalian cells was constructed using the GATEWAY system (Invitrogene).
  • the resulting expression vector was transiently expressed in HEK293 cells using Lipofectamine PL US (Invitrogene), and the enzyme activity of human lyase was confirmed. The enzyme activity of lyase was confirmed. Was confirmed to express human lyase.
  • cells that constantly expressed the human lyase enzyme were prepared.
  • human lyase expression vector described above has a neomycin resistance gene
  • human lyase can be constantly expressed by introducing a human lyase expression vector into HEK293 cells and selecting drug-resistant cells by treatment with 800 xg / mL G418. Expressing cells were obtained. When the lyase activity of the obtained cells was measured, the lyase activity was confirmed.
  • the enzyme was prepared as follows. The above human lyase expressing cells are collected after culturing, and Ultrasonic crushing was performed in a 50 mM potassium phosphate buffer ( ⁇ 7.4) containing glycerin and 10 mM magnesium acetate, and the supernatant obtained by centrifugation was stored at ⁇ 80 ° C. as a crude enzyme solution.
  • the evaluation method was as follows. The crude enzyme solution was melted and diluted to the set enzyme concentration using the buffer described above.
  • the compound of the present invention was diluted to an appropriate concentration, and 4 zL thereof and then 400 zL of the prepared enzyme solution were added to an eppendorf type tube and treated at 37 ° C for 10 minutes. Next, 100 ⁇ L of a substrate solution prepared in 25 ⁇ 17-hydroxyprogesterone and 4 mM / 3-NADPH in 50 mM potassium phosphate buffer (pH 7.4) containing 20% glycerin was treated at 37 ° C. in advance. Compound • Added to the enzyme mixture and enzymatic reaction was performed at 37 ° C for another 4 hours. 0.6 mL of dichloromethane containing 0.3 ⁇ of the internal standard substance was used to stop the reaction.
  • Inhibitory activity (%) ((a-b) Za) X 100 Formula (1)
  • the concentration of the compound of the present invention that finally inhibits the enzyme activity by 50% was determined and defined as an IC value.
  • the compounds of the examples of the present invention all have excellent C17-2 lyase inhibitory activity.

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Abstract

A novel naphthalene derivative that is useful as a medicinal drug, especially C17-20 lyase inhibitor. The C17-20 lyase is one of enzymes for sex hormone biosynthesis which are present in the testicle, ovary and adrenal cortex. The C17-20 lyase produces dehydroepiandrosterone and androstenedione from 17-hydroxyprognenolone and 17-hydroxyprogesterone as substrates. The biosynthesis by this enzyme is used only in biosynthesis of sex hormone, so that the novel naphthalene derivative capable of inhibiting the enzyme presents a novel endocrinotherapeutic agent capable of inhibiting the biosynthesis of sex hormone and is useful as a therapeutic or preventive drug.

Description

明 細 書  Specification
新規酵素阻害剤  New enzyme inhibitors
技術分野  Technical field
[0001] 本発明は、医薬、特に C17-20リアーゼ阻害剤として有用な新規ナフタレン誘導体 に関する。  [0001] The present invention relates to a novel naphthalene derivative useful as a drug, particularly as a C17-20 lyase inhibitor.
背景技術  Background art
[0002] 性ホルモンの過剰が原因で発症や増悪を起こすことが知られている疾患としては、 前立腺癌、前立腺肥大、多毛症、男化徴候等の男性ホルモン過剰により引き起こさ れる疾患、乳癌、卵巣癌、子宮癌、乳腺症、子宮内膜症、子宮筋腫等の女性ホルモ ン過剰により引き起こされる疾患が知られている。これらの疾患の治療法としては、性 ホルモンの生合成を止める黄体形成ホルモン放出ホルモン（LHRH)のアンタゴニス トまたはァゴニスト、性ステロイド生合成阻害剤（5 α—レダクターゼ、ァロマターゼ阻 害剤等）、または性ステロイド受容体拮抗剤等が現在用いられている（日本臨床、 58 卷 (増刊号、乳癌の診断と治療）、 311 - 333 (2000)及び日本臨床、 58卷 (増刊号、 前立腺癌の診断と治療）、 176-182 (2000)参照）。  [0002] Diseases that are known to cause onset or exacerbation due to excess sex hormones include diseases caused by excess androgen such as prostate cancer, prostatic hypertrophy, hirsutism, and virilization signs, breast cancer, and ovaries. Diseases caused by excess female hormones such as cancer, uterine cancer, mastopathy, endometriosis, and uterine fibroids are known. Treatment of these diseases may be antagonists or agonists of luteinizing hormone-releasing hormone (LHRH), which stops the synthesis of sex hormones, inhibitors of sex steroid biosynthesis (5α-reductase, aromatase inhibitors, etc.), or Sex steroid receptor antagonists are currently used (Japanese clinical, vol. 58 (extra number, diagnosis and treatment of breast cancer), 311-333 (2000) and Japanese clinical, vol. 58 (extra number, diagnosis of prostate cancer) 176-182 (2000)).
[0003] C17—20リアーゼは、性ホルモンの生合成酵素の一つである。精巣、卵巣及び副 腎皮質に存在しており、 17—ヒドロキシプログネノロン及び 17—ヒドロキシプロゲステロ ンを基質として、デヒドロェピアンドロステロン及びアンドロステンジオンを生成する。こ の酵素による生成物は性ホルモンの生合成のみに用いられるため、この酵素を阻害 する薬剤は、性ホルモンの生合成を阻害する新しい内分泌療法剤となり、治療薬あ るいは予防薬として医療現場に提供できることが期待される (日本臨床、 58卷 (増刊 号、前立腺癌の診断と治療）、 317 - 319 (2000)参照)。  [0003] C17-20 lyase is one of sex hormone biosynthetic enzymes. It is present 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 sex hormone biosynthesis, drugs that inhibit this enzyme become new endocrine therapies that inhibit sex hormone biosynthesis, and are used in medical practice as therapeutic or prophylactic drugs. (Japanese Clinical Journal, Vol. 58 (Special Issue, Diagnosis and Treatment of Prostate Cancer), 317-319 (2000)).
[0004] C17—20リアーゼ阻害剤としては、ステロイド系の阻害剤と非ステロイド系の阻害剤 が報告されている。前者としては、例えば特開平 7-505377号公報、米国特許第 59 94335号公報記載の化合物が報告されている。後者としては、例えば特開 2001-1 87784号公報、特開 2002-80458号公報、国際公開第 01/87875号公報のよう なイミダゾール環を有する化合物、また特許文献特開 2002-234843号公報、国際 公開第 92/16507号公報、国際公開第 93/23375号公報のようなピリジン環を有 する化合物が報告されている。 [0004] Steroid inhibitors and non-steroid inhibitors have been reported as C17-20 lyase inhibitors. As the former, for example, compounds described in JP-A-7-505377 and US Pat. No. 5,994,335 have been reported. As the latter, for example, JP-A-2001-187784, JP-A-2002-80458, compounds having an imidazole ring such as WO 01/87875, and Patent Document JP-A-2002-234843, international Compounds having a pyridine ring have been reported, such as WO 92/16507 and WO 93/23375.
しかし、現在まで C17-20リアーゼ阻害剤として市販されている化合物はなぐ臨床 現場からリアーゼ阻害剤開発が渴望されている（日本臨床、 58卷 (増刊号、前立腺 癌の診断と治療）、 312—316 (2000)参照）。  However, the development of a lyase inhibitor is expected from clinical sites that are currently marketed as C17-20 lyase inhibitors (Japanese clinical study, Vol. 58, extra number, diagnosis and treatment of prostate cancer). 316 (2000)).
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] 本発明は、医薬として有用な C17— 20リアーゼ阻害剤を提供するものである。 [0005] The present invention provides a C17-20 lyase inhibitor useful as a medicament.
課題を解決するための手段  Means for solving the problem
[0006] 本発明者は鋭意研究を重ねた結果、ナフタレン誘導体またはその薬理学的に許容 されうる塩若しくはそのプロドラッグが C17—20リアーゼを阻害することを見出し、本発 明を完成した。 [0006] As a result of intensive studies, the present inventors have found that a naphthalene derivative or a pharmaceutically acceptable salt thereof or a prodrug thereof inhibits C17-20 lyase, and thus completed the present invention.
すなわち、本発明は以下の（1)から（14)に関するものである。  That is, the present invention relates to the following (1) to (14).
(1)下記一般式（1)  (1) The following general formula (1)
[0007] [化 1] [0007] [Formula 1]
Figure imgf000003_0001
Figure imgf000003_0001
[式中、 R、 Rはそれぞれ独立に同一か又は異なってもよぐ水素原子、ハロゲン原 [Wherein, R and R are each independently the same or different and may be a hydrogen atom or a halogen atom;
1 2  1 2
子、低級アルキル基、水酸基、低級アルコキシ基、低級ァシルォキシ基、及び置換 基を有していてもよいアミノ基から成る群より任意に選択される基を示し、 R、 Rはそ  R, R and R represent a group arbitrarily selected from the group consisting of a substituent, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkoxy group, and an amino group which may have a substituent.
3 4 れぞれ独立に同一か又は異なってもよぐ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、 R、 Rが共に水素原子である場合を除く）、 R  3 4 represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group, each of which may be the same or different, provided that R and R are both hydrogen atoms, R
3 4 5 3 4 5
、 Rはそれぞれ独立に同一か又は異なってもよぐ水素原子、ハロゲン原子、低級ァAnd R each independently represent a hydrogen atom, a halogen atom, a lower
6 6
ルキル基、低級アルコキシ基、水酸基、及び置換基を有していてもよいアミノ基から 成る群より任意に選択される基を示す。 ]で表されるナフタレン誘導体、またはその薬 理学的に許容される塩若しくはそのプロドラッグ、 (2)—般式（1)において、 R、Rが共に低級アルキル基である（1)記載のナフタレンAnd a group arbitrarily selected from the group consisting of an alkyl group, a lower alkoxy group, a hydroxyl group, and an amino group which may have a substituent. Or a pharmaceutically acceptable salt thereof or a prodrug thereof, (2) The naphthalene according to (1), wherein in formula (1), R and R are both lower alkyl groups.
3 4 3 4
誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ、 Derivatives, or pharmacologically acceptable salts or prodrugs thereof,
(3)—般式（1)において、 R、 Rが共に低級アルキル基であり、 R、 Rが共に水素  (3) In the general formula (1), R and R are both lower alkyl groups, and R and R are both hydrogen.
3 4 5 6  3 4 5 6
原子である（2)記載のナフタレン誘導体、またはその薬理学的に許容される塩若しく The naphthalene derivative according to (2), which is an atom, or a pharmaceutically acceptable salt or a salt thereof.
(4)一般式（1)において、 R、 Rが水素原子、ハロゲン原子、低級アルコキシ基、水 (4) In the general formula (1), R and R represent a hydrogen atom, a halogen atom, a lower alkoxy group,
1 2  1 2
酸基、低級ァシルォキシ基から成る群より任意に選ばれ、 R、 Rが共に低級アルキ Arbitrarily selected from the group consisting of an acid group and a lower alkoxy group;
3 4  3 4
ル基であり、 R、 Rが共に水素原子である、（3)記載のナフタレン誘導体、またはそ The naphthalene derivative according to (3), wherein R and R are both hydrogen atoms, or
5 6  5 6
の薬理学的に許容される塩若しくはそのプロドラッグ、 A pharmacologically acceptable salt or a prodrug thereof,
(5)—般式（1)において、 R、 Rが水素原子、メトキシ基、エトキシ基、ァセトキシ基、  (5) In the general formula (1), R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
1 2  1 2
水酸基から成る群より任意に選ばれ、 R、 Rが共にメチル基またはェチル基であり、 Arbitrarily selected from the group consisting of a hydroxyl group, wherein R and R are both a methyl group or an ethyl group,
3 4  3 4
R、 Rが共に水素原子であり、ナフタレン環からのカルボキシ基の置換位置が 2位で R and R are both hydrogen atoms, and the substitution position of the carboxy group from the naphthalene ring is 2-position
5 6 5 6
ある（4)記載のナフタレン誘導体、またはその薬理学的に許容される塩若しくはその (4) The naphthalene derivative according to (4), or a pharmacologically acceptable salt thereof or a salt thereof.
(6)—般式（1)において、 Rまたは Rのいずれか一方が水素原子である（1)記載の (6) The general formula (1), wherein one of R and R is a hydrogen atom.
3 4  3 4
ナフタレン誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ、A naphthalene derivative, or a pharmacologically acceptable salt thereof, or a prodrug thereof,
(7)—般式（1)において、 Rまたは Rのいずれか一方が水素原子であり、 R、 Rが (7) In the general formula (1), one of R and R is a hydrogen atom, and R and R are
3 4 5 6 共に水素原子である（6)記載のナフタレン誘導体、またはその薬理学的に許容され る塩若 1  3 4 5 6 The naphthalene derivative according to (6), wherein both are hydrogen atoms, or a pharmacologically acceptable salt thereof.
(8)—般式（1)において、 R、 Rが水素原子、ハロゲン原子、低級アルコキシ基、水  (8) In the general formula (1), R and R represent a hydrogen atom, a halogen atom, a lower alkoxy group,
1 2  1 2
酸基、低級ァシルォキシ基から成る群より任意に選ばれ、 R、 Rのいずれか一方が Arbitrarily selected from the group consisting of an acid group and a lower acyloxy group, wherein one of R and R is
3 4  3 4
水素原子で他方が低級アルキル基であり、 R、 Rが共に水素原子である、（7)記載 (7) The hydrogen atom and the other is a lower alkyl group, and R and R are both hydrogen atoms.
5 6  5 6
のナフタレン誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ、A naphthalene derivative, or a pharmaceutically acceptable salt thereof or a prodrug thereof,
(9)一般式（1)において、 R、 Rが水素原子、メトキシ基、エトキシ基、ァセトキシ基、 (9) In the general formula (1), R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
1 2  1 2
水酸基から成る群より任意に選ばれ、 Rが水素原子であり、 R、 Rのいずれか一方 Arbitrarily selected from the group consisting of a hydroxyl group, wherein R is a hydrogen atom, and either R or R
2 3 4  2 3 4
が水素原子で他方力 Sメチル基またはェチル基であり、 R、 Rが共に水素原子であり Is a hydrogen atom and the other is an S-methyl group or an ethyl group, and R and R are both hydrogen atoms
5 6  5 6
、ナフタレン環からのカルボキシ基の置換位置が 2位である（8)記載のナフタレン誘 導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ、 (10) (1)から（9)のいずれか一項に記載のナフタレン誘導体、またはその薬理学的 に許容される塩若しくはそのプロドラッグを有効成分とする医薬、 The naphthalene derivative according to (8), wherein the carboxy group is substituted at the 2-position from the naphthalene ring, or a pharmaceutically acceptable salt thereof or a prodrug thereof; (10) a medicament comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient;
(11) (1)から（9)のいずれか一項に記載のナフタレン誘導体、またはその薬理学的 に許容される塩若しくはそのプロドラッグを有効成分とする抗腫瘍剤、  (11) an antitumor agent comprising, as an active ingredient, the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof;
(12) (1)から（9)のいずれか一項に記載のナフタレン誘導体、またはその薬理学的 に許容される塩若しくはそのプロドラッグ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、  (12) An agent for preventing or treating prostate cancer or breast cancer comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient. ,
(13) (1)から（9)のいずれか一項に記載のナフタレン誘導体、またはその薬理学的 に許容される塩若しくはそのプロドラッグ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、  (13) A prophylactic or therapeutic agent for excessive sex hormone, comprising the naphthalene derivative according to any one of (1) to (9) or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient;
(14) (1)から（9)のいずれか一項に記載のナフタレン誘導体、またはその薬理学的 に許容される塩若しくはそのプロドラッグを有効成分とする C17— 20リアーゼ阻害剤、 に関する。  (14) A C17-20 lyase inhibitor comprising the naphthalene derivative according to any one of (1) to (9), or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient.
発明の効果  The invention's effect
[0008] 本発明記載の化合物は優れた C17-20リアーゼ阻害活性を示した。よって、本発 明記載の化合物またはその薬理学的に許容される塩を有効成分として含有する薬 剤組成物は医薬、特に前立腺癌若しくは乳癌の予防または治療剤、或いは性ホル モン過剰症の予防または治療剤として有用である。  [0008] The compound according to the present invention exhibited 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 agent for hypergonadism. Or it is useful as a therapeutic agent.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0009] 以下に本発明の詳細を述べる。 The details of the present invention are described below.
本発明において、 R 、 R、 R 、 R、 R、 Rの低級アルキル基とは炭素数 1一 6の直  In the present invention, the lower alkyl group of R 1, R 2, R 3, R 4, R 5, R 6 and R 7 is a straight-chain alkyl group having 116 carbon atoms
1 2 3 4 5 6  1 2 3 4 5 6
鎖もしくは分岐状のアルキル基を示し、例えばメチル基、ェチル基、 n プロピル基、 イソプロピル基、 n ブチル基、 sec-ブチル基、 tert-ブチル基、 n ペンチル基、アミ ル基、イソペンチル基、ネオペンチル基、 tert ペンチル基、 1 メチルブチル基、 2— メチルブチル基、 1、 2—ジメチルプロピル基、 n—へキシル基、イソへキシル基、 1ーメ チルペンチル基、 2—メチルペンチル基、 3—メチルペンチル基、 1, 1 ジメチルブチ ル基、 1 , 2—ジメチルブチル基、 2, 2—ジメチルブチル基、 1 , 3—ジメチルブチル基、 2, 3—ジメチルブチル基、 3， 3—ジメチルブチル基、 1_ェチルブチル基、 2 ェチル ブチル基、 1 , 1 , 2-トリメチルプロピル基、 1 , 2, 2-トリメチルプロピル基、 1 ェチル _1 メチルプロピル基、 1ーェチルー 2—メチルプロピル基を挙げることができる。これら のうち、好ましい基としてはメチル基、ェチル基を挙げることができる。 A chain or branched alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, amyl, isopentyl, 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, 2ethyl Examples thereof include a butyl group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1ethyl_1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. Among these, preferred groups include a methyl group and an ethyl group.
[0010] 本発明において、 R、 R、 R、 Rの低級アルコキシ基とは、前述の低級アルキル基 [0010] In the present invention, the lower alkoxy group of R, R, R, R is the above-mentioned lower alkyl group
1 2 5 6  1 2 5 6
を結合したォキシ基を示し、例えばメトキシ基、エトキシ基、イソプロポキシ基、 n—ブト キシ基、イソブトキシ基、 t一ブトキシ基などを挙げることができる。これらのうち好ましい 基としてはメトキシ基、エトキシ基を挙げることができる。  Represents, for example, a methoxy group, an ethoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a t-butoxy group and the like. Among these, preferred groups include a methoxy group and an ethoxy group.
[0011] 本発明において、 R、 R、 R、 Rの低級ァシルォキシ基とは、低級ァシル基が結 [0011] In the present invention, the lower acyl group of R, R, R, R is a lower acyl group.
1 2 5 6  1 2 5 6
合したォキシ基を示し、低級アシノレ基とは前述の低級アルキル基を結合したカルボ 二ル基を示す。低級ァシルォキシ基の例としては、ァセトキシ基、プロピオニルォキシ 基を挙げることができる。  A lower alkoxy group represents a carbonyl group to which the above-mentioned lower alkyl group is bonded. Examples of the lower acyloxy group include an acetoxy group and a propionyloxy group.
[0012] 本発明において、ハロゲン原子とはフッ素原子、塩素原子、臭素原子などが挙げら れる。  In the present invention, the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and the like.
[0013] 本発明において、置換基を有していてもよいァミノ基とは、無置換のアミノ基、また は前述の低級ァシル基、前述の低級アルキル基若しくはべンジルォキシカルボニル 基で置換されたアミノ基を示し、例えばホルミルアミノ基、プロピオニルァミノ基、 N, N -ジメチルァミノ基、 N, N-ジェチルァミノ基、 N, N-ジプロピルアミノ基、 N, N-ジィ ソプロピルアミノ基、 N, N—ジー n—ブチルァミノ基などを挙げることができる。  [0013] In the present invention, the optionally substituted amino group refers to an unsubstituted amino group, a lower acryl group, a lower alkyl group or a benzyloxycarbonyl group. An amino group, for example, formylamino group, propionylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-dipropylamino group, N, N-diisopropylamino group, N , N-di-n-butylamino group and the like.
[0014] 本発明におけるナフタレン誘導体は酸と塩を形成する場合もあり、本発明は化合物  [0014] The naphthalene derivative in the present invention may form a salt with an acid in some cases.
(1)の塩をも含有する。酸との塩としては、例えば塩酸塩、臭化水素酸塩、硫酸塩等 の無機酸塩や、酢酸、トリフルォロ酢酸、プロピオン酸、乳酸、コハク酸、フマル酸、マ レイン酸、クェン酸、安息香酸、酒石酸、メタンスルホン酸、 p_トルエンスルホン酸等 の有機酸との塩を挙げることができる。これらの塩は、定法によって製造することがで きる。  It also contains the salt of (1). Examples of the salt with an 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 organic acids such as acid, tartaric acid, methanesulfonic acid, and p_toluenesulfonic acid. These salts can be produced by a conventional method.
[0015] また、本発明においてナフタレン誘導体またはその塩に水和物及び光学異性が存 在する場合には、水和物、ラセミ体、光学異性体全てが含まれる。  In the present invention, when a naphthalene derivative or a salt thereof has hydrates and optical isomers, all hydrates, racemates and optical isomers are included.
[0016] さらに、本発明においては、本発明のナフタレン誘導体及びその塩のプロドラッグも 提供される。本発明においてプロドラッグとは、生理的条件下において酵素反応また は酸性条件等による化学反応による分解により一般式（1)に示す化合物に変換する 化合物をいう。本発明のナフタレン誘導体のプロドラッグとしては、一般式（1)におい て、アミノ基ゃ水酸基がァリールカルボニル化、例えばベンゾィル化された化合物、 アミノ酸の残基でァシル化、例えばァラニル化、バリル化、ロイシル化された化合物、 またはァミノカルボニル化、例えば [1 , 4' ]ビピペリジニルー 1_カルボニル化された化 合物等が挙げられる。これらのプロドラッグは定法によって製造することができる。 Further, the present invention also provides a prodrug of the naphthalene derivative of the present invention and a salt thereof. In the present invention, a prodrug is an enzymatic reaction or a physiological reaction under physiological conditions. Is a compound which is converted into a compound represented by the general formula (1) by decomposition by a chemical reaction under acidic conditions or the like. Examples of the prodrug of the naphthalene derivative of the present invention include compounds in which the amino group and the hydroxyl group are arylcarbonylated, for example, benzoylated in the general formula (1); , Leucylated compound, or aminocarbonylation, for example, [1,4 '] bipiperidinyl-1-carbonylated compound. These prodrugs can be manufactured by a conventional method.
[0017] 一般式（1)で表される化合物としては、例えば、以下の様な化合物が挙げられる。  Examples of the compound represented by the general formula (1) include the following compounds.
[0018] [表 1-1] [0018] [Table 1-1]
Figure imgf000008_0001
1-2] ナフチル基の
Figure imgf000008_0001
1-2] of the naphthyl group
化合物 R2 R3 R4 R5 ReCompound R 2 R 3 R 4 R 5 Re
36 2— OH H CH3 H H H 36 2— OH H CH 3 HHH
1One
37 1 4-F H CH3 H H H37 1 4-FH CH 3 HHH
38 4-N(CH3)2 38 4-N (CH 3 ) 2
1 H CH3 H H H 1 H CH 3 HHH
39 2-OCH2CH3 39 2-OCH 2 CH 3
1 H CH3 H H H 1 H CH 3 HHH
40 CH3 40 CH 3
1 H H H H 1 HHHH
41 2 6— Bェr H CH3 H H H ェ 41 2 6—Ber H CH 3 HHH
42 2 H CH3 H H H42 2 H CH 3 HHH
43 2 3-OH 7— Br CH3 H H H43 2 3-OH 7— Br CH 3 HHH
44 2 1一 OH 4-Br CH3 H H H44 2 1 OH 4-Br CH 3 HHH
45 1 8-NH2 H CH3 H H H45 1 8-NH 2 H CH 3 HHH
46 1 8— Br H CH3 H H H46 1 8— Br H CH 3 HHH
47 2 1一 OH H CH3 H 2-CH3 6— CI47 2 1 OH H CH 3 H 2-CH3 6— CI
48 2 1 -OH H CH3 H 2-OCHg 6— CI48 2 1 -OH H CH 3 H 2-OCHg 6— CI
49 2 1 -OH H CH3 H 2— CI H49 2 1 -OH H CH 3 H 2— CI H
50 2 1 -OH H CH3 H 2-CI 6— CI ω 50 2 1 -OH H CH 3 H 2-CI 6— CI ω
51 2 1一 OH H CH3 H 3-O oCH3 H ェ 51 2 1 OH H CH 3 H 3-O oCH3 H
52 2 1 -OH H CH3 H ェ H52 2 1 -OH H CH 3 H H
53 2 1 -OH H CH3 H 2-CI H53 2 1 -OH H CH 3 H 2-CI H
54 2 1一 OH H CH3 H 2-CI 6— CI54 2 1 OH H CH 3 H 2-CI 6— CI
55 2 1一 OH H CH3 H H55 2 1 OH H CH 3 HH
56 2 H H CH3 H H H56 2 HH CH 3 HHH
57 2 3-OH 7— OH CH3 H H H57 2 3-OH 7— OH CH 3 HHH
58 2 3-OH 5— OH CH3 H H H58 2 3-OH 5— OH CH 3 HHH
59 2 1一 OH 6— OH CH3 H H H59 2 1 OH 6— OH CH 3 HHH
60 2 3-OH 7-OCH3 CH3 H H H60 2 3-OH 7-OCH3 CH 3 HHH
61 2 1 -OH 6-OCH3 CH3 H H H61 2 1 -OH 6-OCH3 CH 3 HHH
62 2 1 -OCH3 6-OCHg CH3 H H H62 2 1 -OCH 3 6-OCHg CH 3 HHH
63 2 1一 OH H CH3 CH3 H H63 2 1 OH H CH 3 CH 3 HH
64 2 6-OCH3 H CH3 CH3 H H64 2 6-OCH3 H CH 3 CH 3 HH
65 2 6-OCOCH3 H CH3 CH3 H H65 2 6-OCOCH3 H CH 3 CH 3 HH
66 2 3-OH H CH3 CH3 H H66 2 3-OH H CH 3 CH 3 HH
67 1 2— OH H CH3 CH3 H H67 1 2— OH H CH 3 CH 3 HH
68 1 4-F H CH3 CH3 H H68 1 4-FH CH 3 CH 3 HH
69 1 4-N(CH3)2 H CH3 CH3 H H69 1 4-N (CH 3 ) 2 H CH 3 CH 3 HH
70 1 2-OCH2CH3 H CH3 CH3 H H [0020] [表 1-3] 70 1 2-OCH 2 CH 3 H CH 3 CH 3 HH [0020] [Table 1-3]
Figure imgf000010_0002
Figure imgf000010_0002
[0021] 本発明の化合物は、例えば以下のように製造することができる c [0021] The compounds of this invention can be manufactured as follows, for example c
[0022] [化 2] [0022] [Formula 2]
Figure imgf000010_0001
Sheme 1
Figure imgf000010_0001
Sheme 1
[0023] 一般式（1)で表される新規ナフタレン誘導体は、例えば（Shemel中 R、 R、 R、 R  [0023] The novel naphthalene derivative represented by the general formula (1) is, for example, (R, R, R, R
1 3 、 R 、 Rは一般式（1)に同じ。）で表される一般式 (B)の化合物と、一般式 (A) は13 , R and R are the same as those in the general formula (1). ) And the compound of the general formula (A)
4 5 6 4 5 6
カルボキシ基またはその反応性誘導体を示す)で表される化合物を縮合、すなわち エステル化反応により容易に製造することができる。  A compound represented by a carboxy group or a reactive derivative thereof) can be easily produced by condensation, that is, an esterification reaction.
[0024] 一般式 (A)で表される化合物は市販または容易に合成可能である。合成法として は、例えば、 Synthesis (1983)、 5卷、 385頁、 J. Chem. So （1941)、 393頁、 米国特許第 3822294号公報等が挙げられる。それらを定法に従いカルボン酸の反 応性誘導体へと変換することができる。カルボン酸の反応性誘導体としては、例えば 酸ハライド、活性アミド化合物、活性エステルなどが用いられる。  The compound represented by the general formula (A) is commercially available or can be easily synthesized. Examples of the synthesis method include Synthesis (1983), vol. 5, p. 385, J. Chem. So (1941), p. 393, and U.S. Pat. No. 3,822,294. They can be converted into reactive derivatives of carboxylic acids according to a conventional method. As the reactive derivative of carboxylic acid, for example, acid halide, active amide compound, active ester and the like are used.
[0025] 酸ハライドとしては、例えば酸クロリド、酸プロミド等が用いられる。活性アミド化合物 としては、例えばイミダゾ—ル、ピラゾ—ル、 4—置換イミダゾ—ル、ジメチルビラゾ—ル、ト リアゾ—ル、テトラゾ—ル、ベンゾチアゾ—ノレ等との酸アミドが用いられる。活性エステル としては、 4—ニトロフエノール、 2， 4—ジニトロフエノール、 1—ヒドロキシベンゾトリアゾ一 ル等とのエステルが用いられる。  As the acid halide, for example, acid chloride, acid bromide and the like are used. As the active amide compound, for example, an acid amide with imidazole, pyrazole, 4-substituted imidazole, dimethylvirazole, triazole, tetrazole, benzothiazo-nore and the like are used. As the active ester, an ester with 4-nitrophenol, 2,4-dinitrophenol, 1-hydroxybenzotriazole or the like is used.
[0026] 一般式 (B)で表される化合物は、市販または容易に合成可能である。例えば、 R  [0026] The compound represented by the general formula (B) is commercially available or can be easily synthesized. For example, R
3 及び Rが共に低級アルキル基で置換された化合物は、 4一ァシルピリジン誘導体に A compound in which both 3 and R are substituted with a lower alkyl group is converted to a 4-acylpyridine derivative.
4 やメチルリチウム等を反応させることにより、容易に製造することができる。 It can be easily produced by reacting 4 or methyl lithium.
[0027] 一般式 (A)におレ、て、 Zがカルボキシ基の場合は、一般式 (B)で表される化合物と のエステルイ匕反応には縮合剤を用いることができる。縮合剤の例としては、 N, Ν'-ジ シクロへキシルカルボジイミド（DCC)、 1—ェチルー 3_ (3しジメチルァミノプロピル）力 ルボジイミド（EDC)、 Ν—シクロへキシルー Ν—モルホリノェチルカルボジイミド、 1—ァ ルキル一 2—ハロピリジニゥム塩等を挙げることができる。 In the general formula (A), when Z is a carboxy group, a condensing agent can be used for the esterification reaction with the compound represented by the general formula (B). Examples of condensing agents include N ,, '-dicyclohexylcarbodiimide (DCC), 1-ethyl-3_ (3-dimethylaminopropyl) force rubodiimide (EDC), 、 -cyclohexyl Ν-morpholinoethylcarbodiimide And 1-alkyl 1-2-halopyridinium salts.
[0028] エステル化反応は、塩基存在下、例えば有機三級ァミンの存在下に実施しても良 レ、。有機三級ァミンの例としてはトリエチルァミン、 N, N—ジメチルァニリン、ピリジン 等を挙げることができる。エステル化反応に使用する溶媒は特に限定されないが、原 料物質を溶解し、かつこれらと容易に反応しない溶媒が望ましぐ例えばピリジン、テ トラヒドロフラン、ジォキサン、ベンゼン、ェ—テル、塩化メチレン、ジメチルホルムアミド 、トルエン、あるいはこれらから選ばれた 2種以上の混合溶媒等が利用され得る。使 用される溶媒はここに挙げたものに限定されるものものではない。反応温度は反応が 進行する限り特に限定されないが、通常一 40度から溶媒の還流温度の範囲内で反 応を行うことができる。反応時間は通常 5分一 120時間であるが、原料化合物の種類 、溶媒、反応温度等によって任意に選ばれる。 [0028] The esterification reaction may be carried out in the presence of a base, for example, in the presence of an organic tertiary amine. Examples of the organic tertiary amine include triethylamine, N, N-dimethylaniline, pyridine and the like. The solvent used for the esterification reaction is not particularly limited, but a solvent that dissolves the raw material and does not easily react with these is desirable, for example, pyridine, tetrahydrofuran, dioxane, benzene, ether, methylene chloride. , Dimethylformamide, toluene, or a mixed solvent of two or more selected from them. Use The solvent used is 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 the range of 140 ° C. to the reflux temperature of the solvent. The reaction time is usually from 5 minutes to 120 hours, but may be arbitrarily selected depending on the type of the starting compound, the solvent, the reaction temperature and the like.
[0029] 一般式（1 )で表されるナフタレン誘導体または製薬上許容し得る塩を医薬として使 用する場合は、単独または担体、賦形剤、希釈剤、溶解補助剤等の製薬上許容し得 る添加剤と混合して粉剤、顆粒剤、錠剤、カブレット剤、カプセル剤、注射剤、座剤、 軟膏剤等の製剤形態で、経口または非経口的 (全身投与、局所投与等）に安全に投 与される。製剤中の本発明化合物または製薬上許容し得る塩の含量は、製剤により 種々異なるが、通常 0. 1 100重量％であることが好ましい。投与量は投与経路、患 者の年齢並びに予防または治療すべき実際の症状等により異なるが、例えば成人に 経口投与する場合、有効成分として 1日 0. 01 mg— 2000 mg、好ましくは 0. 1 mg— 1000 mgとすることができ、 1日 1一数回に分けて投与できる。  When the naphthalene derivative represented by the general formula (1) or a pharmaceutically acceptable salt is used as a medicament, it may be used alone or in a pharmaceutically acceptable form such as a carrier, an excipient, a diluent, and a solubilizing agent. It is safe for oral or parenteral administration (systemic administration, topical administration, etc.) in the form of powders, granules, tablets, cablets, capsules, injections, suppositories, ointments, etc. by mixing with the resulting additives. Is given to Although the content of the compound of the present invention or a pharmaceutically acceptable salt in the preparation varies depending on the preparation, it is usually preferably 0.1% by weight. The dosage varies depending on the route of administration, the age of the patient, and the actual condition to be prevented or treated. For example, when administered orally to an adult, the daily dose of the active ingredient is 0.01 mg to 2000 mg, preferably 0.1 mg to 2000 mg. mg—can be 1000 mg and can be administered in several divided doses daily.
[0030] 一般式（1 )で表されるナフタレン誘導体または製薬上許容し得る塩は、 C 17-20リ ァーゼ阻害作用を有し、医薬、特に前立腺癌若しくは乳癌の予防または治療剤、或 いは性ホルモン過剰症の予防または治療剤として有用である。  [0030] The naphthalene derivative represented by the general formula (1) or a pharmaceutically acceptable salt has a C17-20 lyase inhibitory action, and is a medicament, particularly an agent for preventing or treating prostate cancer or breast cancer, Is useful as a preventive or therapeutic agent for excessive sex hormone.
[0031] (実施例） (Example)
以下に本発明化合物の製造例について、実施例に基づいてさらに詳細に説明す る力 本発明はこれらの例によって何ら制限されるものではなレ、。また、本発明化合 物の有効性を示すために、本発明の代表化合物の薬理試験結果を試験例に示す。 なお、実施例の NMRは BARIAN GEMA200を、 MS (ESI)は、 SHIMADZU LCMS-QP8000 aを使用し測定した値である。  Hereinafter, the production examples of the compound of the present invention will be described in more detail based on examples. The present invention is not limited to these examples. In addition, in order to show the effectiveness of the compound of the present invention, the results of pharmacological tests of representative compounds of the present invention are shown in Test Examples. In the examples, NMR was measured using BARIAN GEMA200, and MS (ESI) was measured using SHIMADZU LCMS-QP8000a.
実施例 1  Example 1
[0032] ( 1 S) _1_ (4_ピリジル）ェチル 1_ハイドロキシナフタレン— 2_カルボキシレートの製 造  [0032] (1S) _1_ (4_pyridyl) ethyl 1_hydroxynaphthalene-2_carboxylate production
1_ハイド口キシ— 2_ナフトェ酸（68 mg, 0. 36 mmol)、（S) _ (_) _l_ (4_ピリジ ノレ）エタノール（37 mg, 0. 30 mmol)、ジシクロへキシルカルボジイミド（DCC) (7 4 mg, 0. 36 mmol)、ジメチルァミノピリジン（12 mg, 0. 10 mmol)の DMF (3 mL)懸濁液を室温で一昼夜撹拌した。反応液をろ過した後、ろ液を MP— Ts〇H Cartridge 500mg (Argonaut社）にて精製し、標題化合物（58· 5 mg)を得た。 1_Hide mouth xy- 2_Naphthoic acid (68 mg, 0.36 mmol), (S) _ (_) _ l_ (4_pyridinole) ethanol (37 mg, 0.30 mmol), dicyclohexylcarbodiimide ( DCC) (74 mg, 0.36 mmol), dimethylaminopyridine (12 mg, 0.10 mmol) in DMF (3 mL) suspension was stirred overnight at room temperature. After filtering the reaction solution, the filtrate was purified with MP-Ts〇H Cartridge 500 mg (Argonaut) to obtain the title compound (58.5 mg).
[0033] NMR(DMSO-d )ppm:l.74(3H、d、J = 6.7Hz)、6.37 (1H、 q、 J = 6.7Hz) [0033] NMR (DMSO-d) ppm: l.74 (3H, d, J = 6.7Hz), 6.37 (1H, q, J = 6.7Hz)
6  6
、 7.52(1H、 d、 J = 9.0Hz)、 7.57—7.79(2H、 m)、 7.97(1H、 d、 J = 7.7Hz) 、 7.98(1H、 d、J = 9.0Hz)、 8.13(2H、 d、J = 6.6Hz), 8.31 (1H、 d、J = 7.3 Hz)、 8.92(2H、 d、J = 6.6Hz), 11.60(1H、 s)。  , 7.52 (1H, d, J = 9.0Hz), 7.57-7.79 (2H, m), 7.97 (1H, d, J = 7.7Hz), 7.98 (1H, d, J = 9.0Hz), 8.13 (2H, d, J = 6.6 Hz), 8.31 (1H, d, J = 7.3 Hz), 8.92 (2H, d, J = 6.6 Hz), 11.60 (1H, s).
MS (ESI, P〇S)mZz:294[M + H]+。 MS (ESI, PS) mZz: 294 [M + H] < +>.
実施例 2  Example 2
[0034] (1R)_1_(4_ピリジル）ェチル 1_ハイドロキシナフタレン— 2_カルボキシレートの 実施例 1と同様に、 1—ハイドロキシ _2—ナフトェ酸（68 mg, 0.36 mmol)と（R)— (+ )_1_(4_ピリジル）エタノール（37 mg, 0.30 mmol)を、ジシクロへキシルカ ルボジイミド（DCC) (74 mg, 0.36 mmol)、ジメチルァミノピリジン（12 mg, 0. 10 mmol)を用いて縮合させ、表題化合物 (47.8 mg)を得た。  [0034] (1R) _1_ (4_pyridyl) ethyl 1_hydroxynaphthalene-2-carboxylate In the same manner as in Example 1, 1-hydroxy-2-naphthoic acid (68 mg, 0.36 mmol) and (R)-( +) Condensation of) _1_ (4_pyridyl) ethanol (37 mg, 0.30 mmol) with dicyclohexylcarbodiimide (DCC) (74 mg, 0.36 mmol) and dimethylaminopyridine (12 mg, 0.10 mmol) The title compound (47.8 mg) was obtained.
[0035] NMR(DMSO-d )ppm:l.74(3H、d、J = 6.7Hz)、6.37 (1H、 q、 J = 6.7Hz) [0035] NMR (DMSO-d) ppm: l.74 (3H, d, J = 6.7Hz), 6.37 (1H, q, J = 6.7Hz)
6  6
、 7.52(1H、 d、 J = 8.9Hz), 7.57-7.78(2H、 m)、 7.96(1H、 d, J = 7.7Hz) 、 7.98(1H、 d、 J = 8.9Hz), 8.12(2H、 d、 J = 6.6Hz), 8.32(1H、 d、J = 7.3 Hz)、 8.92(2H、 d、J = 6.6Hz), 11.60(1H、 s)。  , 7.52 (1H, d, J = 8.9Hz), 7.57-7.78 (2H, m), 7.96 (1H, d, J = 7.7Hz), 7.98 (1H, d, J = 8.9Hz), 8.12 (2H, d, J = 6.6 Hz), 8.32 (1H, d, J = 7.3 Hz), 8.92 (2H, d, J = 6.6 Hz), 11.60 (1H, s).
MS (ESI, P〇S)mZz:294[M + H]+。 MS (ESI, PS) mZz: 294 [M + H] < +>.
実施例 3  Example 3
[0036] 1—メチノレー 1_(4_ピリジル）ェチル 1_ハイドロキシナフタレン _2_カルボキシレート の製造  [0036] Production of 1-methinole 1_ (4_pyridyl) ethyl 1_hydroxynaphthalene_2_carboxylate
[0037] 実施例 1と同様に、 1_ハイド口キシー 2_ナフトェ酸（68 mg, 0.36 mmol)と 2_(4 —ピリジル）プロパン _2_オール（41 mg, 0.30 mmol)を、ジシクロへキシルカル ボジイミド（DCC) (74 mg, 0.36 mmol)、ジメチルァミノピリジン（12 mg, 0.10 mmol)を用いて縮合させ、表題化合物（45.0 mg)を得た。  [0037] In the same manner as in Example 1, 1_hide mouth xy 2_naphthoic acid (68 mg, 0.36 mmol) and 2_ (4-pyridyl) propan_2_ol (41 mg, 0.30 mmol) were added to dicyclohexylcarbodiimide. (DCC) (74 mg, 0.36 mmol) and dimethylaminopyridine (12 mg, 0.10 mmol) were condensed to give the title compound (45.0 mg).
[0038] NMR(DMSO-d )ppm:l.97(6H、 s)、 7.51(1H、 d、J = 8.8Hz)、 7.55-7.  [0038] NMR (DMSO-d) ppm: l. 97 (6H, s), 7.51 (1H, d, J = 8.8Hz), 7.55-7.
6  6
77(2H、 m)、 7.94(1H、 d、 J = 8.8Hz), 7.96(1H、 d、 J = 7.7Hz), 8.05 (2H 、 dd、 J=l.4、 5.2Hz)、 8.28(1H、 d、J = 8.4Hz)、 8.89(2H、 dd、 J=l.4、 577 (2H, m), 7.94 (1H, d, J = 8.8Hz), 7.96 (1H, d, J = 7.7Hz), 8.05 (2H , Dd, J = l.4, 5.2Hz), 8.28 (1H, d, J = 8.4Hz), 8.89 (2H, dd, J = l.4, 5
.2Hz)、 11.44(1H、 s)。 .2Hz), 11.44 (1H, s).
MS (ESI, P〇S)m/z:308[M + H]+。  MS (ESI, PS) m / z: 308 [M + H] +.
実施例 4  Example 4
[0039] (1S)_1_(4_ピリジル）ェチル 6_メトキシナフタレン— 2_カルボキシレートの製造  Production of (1S) _1_ (4_pyridyl) ethyl 6_methoxynaphthalene-2-carboxylate
6—メトキシ _2_ナフトェ酸（30 mg、0. 15 mmol)、（S)_(_)_l_(4_ピリジル） エタノール（12 mg、 0.10 mmol)、 1—ェチルー 3_ (3しジメチルァミノプロピル）力 ルボジイミド塩酸塩 (WSC'HCl) (29 mg、0.15 mmol)の塩化メチレン（3 mL) 懸濁液に PS—DMAPレジン (ARGONAUT) (35 mg)を加え、室温で一昼夜撹拌 した。レジンを除去した後、反応液を水および飽和 NaHC〇3水溶液で洗浄し、有機 層を無水 MgS04で乾燥した。溶媒を留去後、残渣を分取 HPLC(20%-90% ァ セトニトリノレ 0.1%トリフルォロ酢酸含有）にて精製し、標題化合物（9.1 mg)を得 た。  6-methoxy_2_naphthoic acid (30 mg, 0.15 mmol), (S) _ (_) _ l_ (4_pyridyl) ethanol (12 mg, 0.10 mmol), 1-ethyl-3_ (3-dimethylaminopropyl ) Force PS-DMAP resin (ARGONAUT) (35 mg) was added to a suspension of rubodiimide hydrochloride (WSC'HCl) (29 mg, 0.15 mmol) in methylene chloride (3 mL), and the mixture was stirred at room temperature for 24 hours. After removing the resin, the reaction solution was washed with water and a saturated aqueous solution of NaHC〇3, and the organic layer was dried over anhydrous MgS04. After evaporating the solvent, the residue was purified by preparative HPLC (containing 20% -90% acetonitrile 0.1% trifluoroacetic acid) to obtain the title compound (9.1 mg).
[0040] NMR(DMSO-d )ppm:l.68(3H、 d、J = 6.7Hz)、 3.96 (3H、 s)、 6.19 (1  [0040] NMR (DMSO-d) ppm: l.68 (3H, d, J = 6.7 Hz), 3.96 (3H, s), 6.19 (1
6  6
H、 q、 J = 6.7Hz)、 7.29(1H、 dd、 J = 2.5、 9.0Hz)、 7.46(1H、 d、 J = 2.5Hz )、 7.82(2H、 dd、J=l.5、 4.9Hz)、 7.92—8.13(3H、 m)、 8.67(1H、 m)、 8 .75(2H、 dd、 J=l.5、 4.9Hz)。  H, q, J = 6.7Hz), 7.29 (1H, dd, J = 2.5, 9.0Hz), 7.46 (1H, d, J = 2.5Hz), 7.82 (2H, dd, J = 1.5, 4.9Hz) ), 7.92-8.13 (3H, m), 8.67 (1H, m), 8.75 (2H, dd, J = 1.5, 4.9 Hz).
MS (ESI, P〇S)mZz:308[M + H]+。 MS (ESI, PS) mZz: 308 [M + H] < +>.
実施例 5  Example 5
[0041] 6_[2_((1S)_1_(4—ピリジル）ェチル）ォキシカルボニル]ナフチル アセテートの 実施例 4と同様に、 6—ァセトキシ一 2_ナフトェ酸（35 mg, 0.15 mmol)と（S)_( 一)一 1一（4一ピリジル）エタノール（12 mg, 0.10 mmol)を縮合させ、表題化合物（ 11.6 mg)を得た。  [0041] Similarly to Example 4 of 6_ [2 _ ((1S) _1_ (4-pyridyl) ethyl) oxycarbonyl] naphthyl acetate, 6-acetoxy-12-naphthoic acid (35 mg, 0.15 mmol) and (S ) _ (I) 1-1 (4-Pyridyl) ethanol (12 mg, 0.10 mmol) was condensed to give the title compound (11.6 mg).
[0042] MS(ESI、 P〇S)m/z:336[M + H]+。 MS (ESI, P〇S) m / z: 336 [M + H] + .
実施例 6  Example 6
[0043] (1S)_1_(4_ピリジル）ェチル 3_ハイドロキシナフタレン— 2_カルボキシレートの製 実施例 4と同様に、 3_ハイド口キシー 2_ナフトェ酸（28 mg、0. 15 mmol)と（S) 一 (一) _1_(4一ピリジル）エタノール（12 mg、0.10 mmol)を縮合させ、表題化合 物（1.5 mg)を得た。 Production of (1S) _1_ (4_pyridyl) ethyl 3_hydroxynaphthalene-2_carboxylate In the same manner as in Example 4, 3_hide mouth xy 2_naphthoic acid (28 mg, 0.15 mmol) was condensed with (S) -1- (1-) _ 1_ (4-pyridyl) ethanol (12 mg, 0.10 mmol). Thus, the title compound (1.5 mg) was obtained.
[0044] MS(ESI、 P〇S)mZz:294[M + H]+。 [0044] MS (ESI, PS) mZz: 294 [M + H] < +>.
実施例 7  Example 7
[0045] (1S)_1_(4_ピリジル）ェチル 2_ハイドロキシナフタレン— 1_カルボキシレートの製 造  Production of (1S) _1_ (4_pyridyl) ethyl 2_hydroxynaphthalene-1_carboxylate
実施例 4と同様に、 2_ハイド口キシー 1_ナフトェ酸（28 mg, 0.15 mmol)と（S)_( 一)一 1一（4一ピリジル）エタノール（12 mg, 0.10 mmol)を縮合させ、表題化合物（ 12.0 mg)を得た。  In the same manner as in Example 4, 2_hydridoxyl_l_naphthoic acid (28 mg, 0.15 mmol) was condensed with (S) _ (I) -111 (4-pyridyl) ethanol (12 mg, 0.10 mmol). The title compound (12.0 mg) was obtained.
[0046] MS(ESI、 P〇S)m/z:294[M + H]+。 MS (ESI, P〇S) m / z: 294 [M + H] + .
実施例 8  Example 8
[0047] (1S)_1_(4_ピリジル）ェチル ナフタレン— 2_カルボキシレートの製造  Production of (1S) _1_ (4_pyridyl) ethyl naphthalene-2_carboxylate
実施例 1と同様に、 2—ナフトェ酸（21 mg, 0.12 mmol)と（S)— (― )— 1— (4—ピリ ジル）エタノール（12 mg, 0.10 mmol)を縮合させ、表題化合物（5.1 mg)を得 た。  As in Example 1, 2-naphthoic acid (21 mg, 0.12 mmol) was condensed with (S) — (—)-1- (4-pyridyl) ethanol (12 mg, 0.10 mmol) to give the title compound ( 5.1 mg).
[0048] MS(ESI、 P〇S)mZz:278[M + H]+。 [0048] MS (ESI, PS) mZz: 278 [M + H] < +>.
実施例 9  Example 9
[0049] (1S)_1_(4_ピリジル）ェチル 3、 7—ジハイドロキシナフタレン一 2_カルボキシレー トの製造  Production of (1S) _1_ (4_pyridyl) ethyl 3,7-dihydroxynaphthalene-2-carboxylate
実施例 1と同様に、 3、 7—ジハイド口キシ— 2_ナフトェ酸（25 mg, 0.12 mmol)と (S)_(_)_l_(4_ピリジル）エタノール（12 mg, 0. 10 mmol)を縮合させ、表題 化合物（5.6 mg)を得た。  As in Example 1, 3,7-dihydric xy-2-naphthoic acid (25 mg, 0.12 mmol) and (S) _ (_) _ l_ (4_pyridyl) ethanol (12 mg, 0.10 mmol) Was condensed to give the title compound (5.6 mg).
[0050] MS(ESI、 P〇S)mZz:310[M + H]+。 [0050] MS (ESI, PS) mZz: 310 [M + H] < +>.
実施例 10  Example 10
[0051] (1S)_1_(4_ピリジル）ェチル 3、 5—ジハイドロキシナフタレン一 2_カルボキシレー トの製造 実施例 1と同様に、 3、 5—ジハイドロキシ -2_ナフトェ酸（25 mg、0.12 mmol)と (S)— (一)一 1一 (4一ピリジル）エタノール（12 mg、0. 10 mmol)を縮合させ、表題 化合物（7.2 mg)を得た。 Production of (1S) _1_ (4_pyridyl) ethyl 3,5-dihydroxynaphthalene-2-carboxylate As in Example 1, 3,5-dihydroxy-2_naphthoic acid (25 mg, 0.12 mmol) and (S)-(1-1) 1-1 (4-pyridyl) ethanol (12 mg, 0.10 mmol) ) Was condensed to give the title compound (7.2 mg).
[0052] MS(ESI、 P〇S)mZz:310[M + H]+。 [0052] MS (ESI, PS) mZz: 310 [M + H] < +>.
実施例 11  Example 11
[0053] (1S)_1_(4_ピリジル）ェチル 3_ハイド口キシ— 7—メトキシナフタレン _2_カルボキ シレートの製造  (0053) Production of (1S) _1_ (4_pyridyl) ethyl 3_hydric xy-7-methoxynaphthalene_2_carboxylate
実施例 1と同様に、 3_ハイドロキシ -7-メトキシ -2—ナフトェ酸（26 mg, 0.12 m mol)と（S)—(—)— 1_(4_ピリジル）エタノール（12 mg, 0.10 mmol)を縮合させ 、表題化合物（6.6 mg)を得た。  As in Example 1, 3_hydroxy-7-methoxy-2-naphthoic acid (26 mg, 0.12 mmol) and (S)-(—)-1_ (4_pyridyl) ethanol (12 mg, 0.10 mmol) Was condensed to give the title compound (6.6 mg).
[0054] MS(ESI、 P〇S)m/z:324[M + H]+。 MS (ESI, P〇S) m / z: 324 [M + H] + .
実施例 12  Example 12
[0055] (1S)_1_(4_ピリジル）ェチル 1、 6—ジハイドロキシナフタレン _2_カルボキシレー トの製造  Production of (1S) _1_ (4_pyridyl) ethyl 1,6-dihydroxynaphthalene_2_carboxylate
実施例 1と同様に、 1、 6—ジハイド口キシ— 2_ナフトェ酸（42 mg, 0.20 mmol)と (S)_(_)_l_(4_ピリジル）エタノール（21 mg, 0. 17 mmol)を縮合させ、表題 化合物（4.2 mg)を得た。  As in Example 1, 1,6-dihydridoxyl-2-naphthoic acid (42 mg, 0.20 mmol) and (S) _ (_) _ l_ (4_pyridyl) ethanol (21 mg, 0.17 mmol) Was condensed to give the title compound (4.2 mg).
[0056] MS(ESI、 P〇S)mZz:310[M + H]+。 MS (ESI, P〇S) mZz: 310 [M + H] + .
実施例 13  Example 13
[0057] (1S)_1_(4_ピリジル）ェチル 1_ハイド口キシー 6—メトキシナフタレン一 2_カルボキ シレートの製造  (1S) _1_ (4_Pyridyl) ethyl 1_Hydroxy 6-methoxynaphthalene 1_2_Carboxylate Production
実施例 1と同様に、 1_ハイドロキシ _6—メトキシ _2_ナフトェ酸（37 mg, 0.17 m mol)と（S)_(_)_(4_ピリジル）エタノール（17 mg, 0.14 mmol)を縮合させ、表 題化合物（29 mg)を得た。  In the same manner as in Example 1, 1-hydroxy-6-methoxy_2_naphthoic acid (37 mg, 0.17 mmol) and (S) _ (_) _ (4_pyridyl) ethanol (17 mg, 0.14 mmol) were condensed. The title compound (29 mg) was obtained.
[0058] MS(ESI、 P〇S)mZz:324[M + H]+。 MS (ESI, P〇S) mZz: 324 [M + H] + .
実施例 14  Example 14
[0059] (1S)_1_(4_ピリジル）ェチル 1、 6—ジメトキシナフタレン一 2_カルボキシレートの 実施例 1と同様に、 1, 6—ジメトキシ一 2_ナフトェ酸（30 mg、0.13 mmol)と（S) 一 (一) _1_(4一ピリジル）エタノール（13 mg、0.11 mmol)を縮合させ、表題化合 物（13 mg)を得た。 [0059] (1S) _1_ (4_pyridyl) ethyl 1,6-dimethoxynaphthalene-1-carboxylate In the same manner as in Example 1, 1,6-dimethoxy-12-naphthoic acid (30 mg, 0.13 mmol) was condensed with (S) -1- (1-) _ 1_ (4-pyridyl) ethanol (13 mg, 0.11 mmol), The title compound (13 mg) was obtained.
[0060] MS(ESI、 P〇S)mZz:338[M + H]+。 [0060] MS (ESI, P〇S) mZz: 338 [M + H] + .
[0061] 参考例 1 [0061] Reference Example 1
1, 6—ジハイド口キシ— 2_ナフトェ酸の製造  Production of 1, 6-dihydric xy-2_ naphthoic acid
1, 6—ジヒドロキシナフタレン（5.0 g、 31.22 mmol)とナトリウムメトキシド（3.64 g、 67.43 mmol)の DMF(45 ml)懸濁液に炭酸ガスを吹き込みながら 160°C で 11時間加熱攪拌した。氷冷後、塩酸、氷水をカ卩ぇ液性を酸性にした後、塩化メチ レンで抽出した。溶媒を濃縮後、残渣をシリカゲルカラムクロマトグラフィー、セフアデ ックス LH— 20 (フアルマシア社製）にて精製し、表題化合物（0.52 g)を得た。  A suspension of 1,6-dihydroxynaphthalene (5.0 g, 31.22 mmol) and sodium methoxide (3.64 g, 67.43 mmol) in DMF (45 ml) was heated with stirring at 160 ° C. for 11 hours while blowing carbon dioxide gas. After cooling with ice, hydrochloric acid and ice water were used to make the syrup acidic, followed by extraction with methylene chloride. After concentration of the solvent, the residue was purified by silica gel column chromatography and Sephadex LH-20 (manufactured by Pharmacia) to obtain the title compound (0.52 g).
[0062] NMR(DMSO-d )ppm:3.18(1H、 s)、 7.09(1H、 d、J = 2.4Hz)、 7.11 (1H [0062] NMR (DMSO-d) ppm: 3.18 (1H, s), 7.09 (1H, d, J = 2.4 Hz), 7.11 (1H
6  6
、 dd、 J = 2.4、 7.5Hz)、 7.15(1H、 d、J = 7.2Hz)、 7.62(1H、 d、 J = 8.8Hz) 、 8. 14(1H、 m)、 10.22(1H、 brs)。  , Dd, J = 2.4, 7.5Hz), 7.15 (1H, d, J = 7.2Hz), 7.62 (1H, d, J = 8.8Hz), 8.14 (1H, m), 10.22 (1H, brs) .
MS (ESI, P〇S)m/z:205[M + H]+。 MS (ESI, PS) m / z: 205 [M + H] < +>.
[0063] 参考例 2  [0063] Reference Example 2
1一ハイド口キシー 6—メトキシ _2—ナフトェ酸 メチルエステルの製造  1-Hydroxy 6-methoxy-2-naphthoic acid methyl ester
1, 6—ジハイド口キシ一 2—ナフトェ酸（100 mg, 0.49 mmol)のメタノーノレーアセト 二トリル混合溶液（1:9)にジイソプロピルェチルァミン（127 mg, 0.98 mmol)、ト リメチルシリルジァゾメタン（490 mg, 0.98 mmol)を加え室温でー晚攪拌した。 溶媒を濃縮後、塩化メチレンを加えろ過にて不溶物を除去した。溶媒を濃縮後、残 渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物（33 mg)を得た。  To a solution of 1,6-dihydridoxyl-2-naphthoic acid (100 mg, 0.49 mmol) in methanolic acetonitrile (1: 9) was added diisopropylethylamine (127 mg, 0.98 mmol) and trimethylsilyl. Diazomethane (490 mg, 0.98 mmol) was added and the mixture was stirred at room temperature. After concentrating the solvent, methylene chloride was added and insolubles were removed by filtration. After concentration of the solvent, the residue was purified by silica gel column chromatography to give the title compound (33 mg).
[0064] NMR(CDC1 )ppm:3.94(3H、 s)、 3.98(3H、 s)、 7.06(1H、 d、J = 2.6Hz),  [0064] NMR (CDC1) ppm: 3.94 (3H, s), 3.98 (3H, s), 7.06 (1H, d, J = 2.6 Hz),
3  Three
7.15(1H、 dd、J = 2.6、 9.2Hz), 7.17(1H、 d、 J = 8.4Hz), 7.74(1H、 d、J =8.8Hz)、 8.31(1H、 d、J = 9.2Hz)、 11.95(1H、 s)。  7.15 (1H, dd, J = 2.6, 9.2Hz), 7.17 (1H, d, J = 8.4Hz), 7.74 (1H, d, J = 8.8Hz), 8.31 (1H, d, J = 9.2Hz), 11.95 (1H, s).
MS (ESI, P〇S)mZz:233[M + H]+。 MS (ESI, PS) mZz: 233 [M + H] < +>.
参考例 3 1_ハイド口キシー 6—メトキシ— 2_ナフトェ酸の製造 Reference example 3 1_Hydroxy 6-methoxy-2_Naphthoic acid
1_ハイド口キシー 6—メトキシ _2_ナフトェ酸 メチルエステル（0· 47 mg)をメタノー ノレ（5 ml)に溶解し、 2M 水酸化ナトリウム水溶液（5 ml)を加え、 70°Cで 9時間加 熱攪拌した。室温に冷却後、 2M 塩酸（11 ml)をカ卩ぇ液性を酸性にした後、塩化メ チレンで抽出した。溶媒を濃縮して表題化合物 (43 mg)を得た。 1-Hydroxoxy 6-methoxy_2_naphthoic acid methyl ester (0.47 mg) was dissolved in methanol (5 ml), 2 M aqueous sodium hydroxide solution (5 ml) was added, and the mixture was heated at 70 ° C for 9 hours. Stirred hot. After cooling to room temperature, 2M hydrochloric acid (11 ml) was used to acidify the syrup, followed by extraction with methylene chloride. The solvent was concentrated to obtain the title compound (43 mg ).
[0065] NMR(DMSO-d )ppm:3.90(3H、 s)、 7.20(1H、 dd、J = 2.5、 9. lHz)、 7. [0065] NMR (DMSO-d) ppm: 3.90 (3H, s), 7.20 (1H, dd, J = 2.5, 9.lHz), 7.
6  6
29(1H、 d、J = 8.8Hz), 7.33(1H、 d、 J = 2.4Hz)、 7.70(1H、 d、 J = 8.8Hz) 、 8. 18(1H、 d、 J = 9.2Hz), 12.70(1H、 brs)。  29 (1H, d, J = 8.8Hz), 7.33 (1H, d, J = 2.4Hz), 7.70 (1H, d, J = 8.8Hz), 8.18 (1H, d, J = 9.2Hz), 12.70 (1H, brs).
MS (ESI, P〇S)mZz:219[M + H]+。 MS (ESI, PS) mZz: 219 [M + H] < +>.
[0066] 参考例 4 [0066] Reference Example 4
1, 6—ジメトキシ一 2_ナフトェ酸 メチルエステルの製造  Manufacture of 1,6-dimethoxy-1-2-naphthoic acid methyl ester
1, 6—ジハイド口キシ— 2—ナフトェ酸（100 mg, 0.49 mmol)の DMF溶液（2.5 ml)に炭酸カリウム（135 mg, 0.98 mmol)、ョードメタン（139 mg, 0.98 mm ol)を加え室温で一晩攪拌した。塩化メチレンをカ卩えろ過にて不溶物を除去後、溶媒 を濃縮した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物（28 mg)を得た。  To a DMF solution (2.5 ml) of 1,6-dihydric xy-2-naphthoic acid (100 mg, 0.49 mmol) was added potassium carbonate (135 mg, 0.98 mmol) and iodomethane (139 mg, 0.98 mmol) at room temperature. Stirred overnight. After removing the insoluble matter by filtration and filtration of methylene chloride, the solvent was concentrated. The residue was purified by silica gel column chromatography to give the title compound (28 mg).
[0067] NMR(CDC1 )ppm:3.94(3H、 s)、 3.97(3H、 s)、 4.04(3H、 s)、 7.13(1H、  [0067] NMR (CDC1) ppm: 3.94 (3H, s), 3.97 (3H, s), 4.04 (3H, s), 7.13 (1H, s)
3  Three
d、J = 2.5Hz)、 7.20(1H、 dd、J = 2.5、 9.2Hz)、 7.50(1H、 d、J = 8.8Hz)、 7.86(1H、 d、 J = 8.7Hz)、 8.19(1H、 d、J = 9.2Hz)。  d, J = 2.5Hz), 7.20 (1H, dd, J = 2.5, 9.2Hz), 7.50 (1H, d, J = 8.8Hz), 7.86 (1H, d, J = 8.7Hz), 8.19 (1H, d, J = 9.2 Hz).
MS (ESI, P〇S)m/z:247[M + H]+。  MS (ESI, PS) m / z: 247 [M + H] +.
[0068] 参考例 5 [0068] Reference Example 5
1, 6—ジメトキシ— 2—ナフトェ酸の製造  Production of 1,6-dimethoxy-2-naphthoic acid
1, 6—ジメトキシ _2_ナフトェ酸 メチルエステル（38 mg)をメタノール（3.8 ml)に 溶解し、 2M 水酸化ナトリウム水溶液（1.5 ml)をカ卩え、 70°Cで 1時間 30分加熱攪 拌した。室温に冷却後、 2M 塩酸（1 ml)をカ卩ぇ液性を酸性にした後、塩化メチレン で抽出した。溶媒を濃縮して表題化合物（35 mg)を得た。  1,6-Dimethoxy_2_naphthoic acid methyl ester (38 mg) is dissolved in methanol (3.8 ml), 2M aqueous sodium hydroxide solution (1.5 ml) is added, and the mixture is heated and stirred at 70 ° C for 1 hour and 30 minutes. did. After cooling to room temperature, 2 M hydrochloric acid (1 ml) was used to make the aqueous solution acidic, followed by extraction with methylene chloride. The solvent was concentrated to obtain the title compound (35 mg).
[0069] NMR(DMSO-d )ppm:3.90(3H、 s)、 7.94(3H、 s)、 7.25(1H、 dd、J = 2.6 [0069] NMR (DMSO-d) ppm: 3.90 (3H, s), 7.94 (3H, s), 7.25 (1H, dd, J = 2.6
6  6
、 9.2Hz), 7.39(1H、 d、J = 2.5Hz)、 7.61(1H、 d、 J = 8.4Hz)、 7.76(1H、 d、 J = 8. 6Hz)、 8. 11 (1H、 d、 J = 9. 2z)。 , 9.2Hz), 7.39 (1H, d, J = 2.5Hz), 7.61 (1H, d, J = 8.4Hz), 7.76 (1H, d, J = 8.6 Hz), 8.11 (1H, d, J = 9.2z).
MS (ESI, P〇S) m/z : 233 [M + H] +。  MS (ESI, P〇S) m / z: 233 [M + H] +.
[0070] 試験例 1 CI 7-20リアーゼ阻害活性測定  Test Example 1 Measurement of CI 7-20 Lyase Inhibitory Activity
C17—20リアーゼ阻害活性測定は Grigoryev, D.N.et.al. (1999) , Analytical Biochemistry, 267, p. 319—330、 Barnes, H. J. et. al. (1991)， Proceeding s of the National Academy of Sciences of the U. S. A. , 88， p. 55 97—5601並びに Imai, T. et. al. (1993) , Journal of Biological Chemistry , 268, p. 19681_19689ίこ記載の方法 ίこ従って以下のよう ίこ行った。ヒ卜リアーゼ 遺伝子の単離、ヒトリアーゼ遺伝子発現ベクターの構築、及びヒトリアーゼ発現細胞 の作成は以下の通り行った。  C17-20 Lyase inhibitory activity was measured by Grigoryev, DNet.al. (1999), Analytical Biochemistry, 267, p. 319-330, Barnes, HJ et. Al. (1991), Proceeding s of the National Academy of Sciences of The method described in the USA, 88, p. 55 97-5601 and Imai, T. et. al. (1993), Journal of Biological Chemistry, 268, p. 19681_19689, was carried out as follows. 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.
[0071] ヒトリアーゼ遺伝子（GenBank accession # M14564)は NCI— H295 (ATCC )力 抽出した全 RNAを用いて RT— PCRにより 5'UTRから終始コドンまでを増幅し 単離した。その際、 RT— PCRに使用したプライマーは GenBank # M14564として 登録されていることから、その遺伝子配列を参考にして以下のデザインを行った。す なわち、フォワードプライマーが 5し TTT AAA CTC CAC TGC TGT CTA TCT TGC CTG CCG GC—3'で、リバースプライマーが 5'—TTT AAT TA G GTG CTA CCC TCA GCC TGG GCT TCC CT— 3'である。）単離し たヒトリアーゼ遺伝子は配列確認後、 GATEWAYシステム（Invitrogene)により、哺 乳類細胞用発現ベクターを構築した。作成した発現ベクターを Lipofectamine PL US (Invitrogene)を用いて、 HEK293細胞に一過性に発現させヒトリアーゼ酵素 活性の確認を行ったところ、リアーゼの酵素活性が確認されたことから、この発現べク ターはヒトリアーゼを発現することが確認された。次に、作成したヒトリアーゼ発現べク ターを用いて、ヒトリアーゼ酵素を恒常的に発現している細胞の作成を行った。先述 のヒトリアーゼ発現べクタ一は neomycin耐性遺伝子を持つことから、 HEK293細胞 にヒトリアーゼ発現ベクターをにより導入し、 800 x g/mLの G418処理によって薬 剤耐性細胞を選択することにより、ヒトリアーゼを恒常的に発現している細胞を得た。 得られた細胞のヒトリアーゼ酵素活性を測定したところ、リアーゼ活性が確認された。  [0071] The human lyase gene (GenBank accession # M14564) was isolated from the 5'UTR to the termination codon by RT-PCR using NCI-H295 (ATCC) extracted total RNA by RT-PCR. At that time, since the primers used for RT-PCR were 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 TA G GTG CTA CCC TCA GCC TGG GCT TCC CT-3' . After confirming the sequence of the isolated human lyase gene, an expression vector for mammalian cells was constructed using the GATEWAY system (Invitrogene). The resulting expression vector was transiently expressed in HEK293 cells using Lipofectamine PL US (Invitrogene), and the enzyme activity of human lyase was confirmed.The enzyme activity of lyase was confirmed. Was confirmed to express human lyase. Next, using the prepared human lyase expression vector, cells that constantly expressed the human lyase enzyme were prepared. Since the human lyase expression vector described above has a neomycin resistance gene, human lyase can be constantly expressed by introducing a human lyase expression vector into HEK293 cells and selecting drug-resistant cells by treatment with 800 xg / mL G418. Expressing cells were obtained. When the lyase activity of the obtained cells was measured, the lyase activity was confirmed.
[0072] 酵素の調製は次のように行った。上記ヒトリアーゼ発現細胞を培養後採集し、 20% グリセリン及び 10mM酢酸マグネシウムを含む 50mMリン酸カリウム緩衝液（ρΗ7· 4 )中で超音波破砕し、遠心分離することにより得た上清を粗酵素液として- 80度に保 存した。 [0072] The enzyme was prepared as follows. The above human lyase expressing cells are collected after culturing, and Ultrasonic crushing was performed in a 50 mM potassium phosphate buffer (ρΗ7.4) containing glycerin and 10 mM magnesium acetate, and the supernatant obtained by centrifugation was stored at −80 ° C. as a crude enzyme solution.
[0073] 評価方法は次のように行った。粗酵素液を融解し、前述の緩衝液を用いて設定酵 素濃度に希釈調製した。  [0073] The evaluation method was as follows. The crude enzyme solution was melted and diluted to the set enzyme concentration using the buffer described above.
[0074] 本発明化合物を適当濃度に希釈し、エツペンドルフ型チューブにその 4 z Lを、 次いで調製酵素液 400 z Lをカロえ、 37度で 10分間処理した。次に 20%グリセリン 添加 50mMリン酸カリウム緩衝液（pH7. 4)で 25 μ Μ 17ひ—ヒドロキシプロゲステロ ン、 4mM /3—NADPHに調製した基質液 100 μ Lを、予め 37度処理した化合物 •酵素混合液に加え、 37度で更に 4時間酵素反応を行った。 0. 3 μ Μの内部標準物 質を含むジクロロメタン 0. 6 mLをカ卩ぇ反応を停止した。振とう抽出後にジクロロメタ ン層を分取し、遠心エバポレータで濃縮乾固した。得られた固体をァセトニトリル 30 μ Lで溶解し、水 30 μ Lで希釈した。この溶液のうち 50 μ Lを ODSカラムを用い た高速液体クロマトグラフィーに注入して分析し、アンドロステンジオンの位置に相当 するピークの大きさを求めた。  [0074] The compound of the present invention was diluted to an appropriate concentration, and 4 zL thereof and then 400 zL of the prepared enzyme solution were added to an eppendorf type tube and treated at 37 ° C for 10 minutes. Next, 100 μL of a substrate solution prepared in 25 μΜ17-hydroxyprogesterone and 4 mM / 3-NADPH in 50 mM potassium phosphate buffer (pH 7.4) containing 20% glycerin was treated at 37 ° C. in advance. Compound • Added to the enzyme mixture and enzymatic reaction was performed at 37 ° C for another 4 hours. 0.6 mL of dichloromethane containing 0.3 μΜ of the internal standard substance was used to stop the reaction. After shaking extraction, the dichloromethane layer was separated and concentrated to dryness using 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 size of the peak corresponding to the position of androstenedione was determined.
[0075] 同一条件にて様々な濃度のアンドロステンジオン溶液を分析し、検量線を事前に 作成した。各サンプルの分析結果から酵素反応で生成したアンドロステンジオン量を 求めた。本発明化合物非添加サンプルも同様な分析を行い、生成アンドロステンジ オン量を求めた。次いで下記の式（1)を用いて C17-20リアーゼ阻害活性（％)を求 めた。式（1)中、 aは本発明化合物非添加サンプノレの生成アンドロステンジオン量を 、bは本発明化合物添加サンプノレの生成アンドロステンジオン量をそれぞれ示す。  [0075] Androstenedione solutions of various concentrations were analyzed under the same conditions, and calibration curves were prepared in advance. From the analysis results of each sample, the amount of androstenedione produced by the enzyme reaction was determined. The same analysis was carried out for the sample to which the compound of the present invention was not added, and the amount of produced androstenedione was determined. Next, C17-20 lyase inhibitory activity (%) was determined using the following formula (1). In the formula (1), a represents the amount of androstenedione produced in the sample without the compound of the present invention, and b represents the amount of androstenedione produced in the sample with the compound of the present invention.
[0076] 阻害活性（％) = ( (a— b) Za) X 100 式（1)  [0076] Inhibitory activity (%) = ((a-b) Za) X 100 Formula (1)
[0077] 本発明化合物の濃度を種々検討することにより、最終的に酵素活性を 50%阻害す る本発明化合物の濃度を求め、 IC 値とした。  [0077] By variously examining the concentration of the compound of the present invention, the concentration of the compound of the present invention that finally inhibits the enzyme activity by 50% was determined and defined as an IC value.
50  50
[0078] 表 2  [0078] Table 2
化合物のヒトリアーゼ 50%阻害活性値 (IC 値）  Human lyase 50% inhibitory activity (IC value) of compound
50  50
実施例 IC 値（μ Μ)  Example IC value (μΜ)
50  50
0. 013 3 0. 015 0.013 3 0. 015
4 0. 013  4 0.013
5 0. 010  5 0. 010
6 0. 013  6 0. 013
7 0. 025  7 0. 025
8 0. 0069  8 0.0069
9 0. 034 9 0.034
0 0. 0470 0. 047
1 0. 0171 0. 017
2 0. 122 0.12
3 0. 00623 0.0062
4 0. 016 4 0. 016
表 2において明らかなように、本発明の実施例の化合物はいずれも優れた C17— 2 リアーゼ阻害活性を有する。 As is clear from Table 2, the compounds of the examples of the present invention all have excellent C17-2 lyase inhibitory activity.

Claims

請求の範囲 The scope of the claims
[1] 下記一般式 (1)  [1] The following general formula (1)
Figure imgf000022_0001
Figure imgf000022_0001
[式中、 R、 Rはそれぞれ独立に同一か又は異なってもよぐ水素原子、ハロゲン原 [Wherein, R and R are each independently the same or different and may be a hydrogen atom or a halogen atom;
1 2  1 2
子、低級アルキル基、水酸基、低級アルコキシ基、低級ァシルォキシ基、及び置換 基を有していてもよいアミノ基から成る群より任意に選択される基を示し、 R、 Rはそ  R, R and R represent a group arbitrarily selected from the group consisting of a substituent, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkoxy group, and an amino group which may have a substituent.
3 4 れぞれ独立に同一か又は異なってもよぐ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、 R、 Rが共に水素原子である場合を除く）、 R  3 4 represents a group arbitrarily selected from the group consisting of a hydrogen atom and a lower alkyl group, each of which may be the same or different, provided that R and R are both hydrogen atoms, R
3 4 5 3 4 5
、 Rはそれぞれ独立に同一か又は異なってもよぐ水素原子、ハロゲン原子、低級ァAnd R each independently represent a hydrogen atom, a halogen atom, a lower
6 6
ルキル基、低級アルコキシ基、水酸基、及び置換基を有していてもよいアミノ基から 成る群より任意に選択される基を示す。 ]で表されるナフタレン誘導体、またはその薬 理学的に許容される塩若しくはそのプロドラッグ。  And a group arbitrarily selected from the group consisting of an alkyl group, a lower alkoxy group, a hydroxyl group, and an amino group which may have a substituent. Or a pharmacologically acceptable salt thereof or a prodrug thereof.
[2] 一般式（1)において、 R、 Rが共に低級アルキル基である請求項 1記載のナフタレ  [2] The naphthalene according to claim 1, wherein in the general formula (1), R and R are both lower alkyl groups.
3 4  3 4
ン誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ。  Or a pharmacologically acceptable salt thereof or a prodrug thereof.
[3] 一般式（1)において、 R、 Rが共に低級アルキル基であり、 R、 Rが共に水素原子  [3] In the general formula (1), R and R are both lower alkyl groups, and R and R are both hydrogen atoms
3 4 5 6  3 4 5 6
である請求項 2記載のナフタレン誘導体、またはその薬理学的に許容される塩若しく はそのプロドラッグ。  3. The naphthalene derivative according to claim 2, which is or a pharmacologically acceptable salt thereof, or a prodrug thereof.
[4] 一般式（1)において、 R、 Rが水素原子、ハロゲン原子、低級アルコキシ基、水酸基  [4] In the general formula (1), R and R are a hydrogen atom, a halogen atom, a lower alkoxy group, a hydroxyl group
1 2  1 2
、低級ァシルォキシ基から成る群より任意に選ばれ、 R、 Rが共に低級アルキル基  , Is selected from the group consisting of a lower alkoxy group and R and R are both lower alkyl groups.
3 4  3 4
であり、 R、 Rが共に水素原子である、請求項 3記載のナフタレン誘導体、またはそ  4. The naphthalene derivative according to claim 3, wherein R and R are both hydrogen atoms, or
5 6  5 6
の薬理学的に許容される塩若しくはそのプロドラッグ。  Or a pharmacologically acceptable salt thereof or a prodrug thereof.
[5] 一般式（1)において、 R、 Rが水素原子、メトキシ基、エトキシ基、ァセトキシ基、水  [5] In the general formula (1), R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
1 2  1 2
酸基から成る群より任意に選ばれ、 R、 Rが共にメチル基またはェチル基であり、 R  Arbitrarily selected from the group consisting of an acid group, wherein R and R are both a methyl group or an ethyl group;
3 4 5 3 4 5
、 Rが共に水素原子であり、ナフタレン環からのカルボキシ基の置換位置が 2位であAnd R are both hydrogen atoms, and the substitution position of the carboxy group from the naphthalene ring is 2-position.
6 6
る請求項 4記載のナフタレン誘導体、またはその薬理学的に許容される塩若しくはそ [6] 一般式（1)において、 Rまたは Rのいずれか一方が水素原子である請求項 1記載の The naphthalene derivative according to claim 4, or a pharmacologically acceptable salt or a salt thereof. [6] The method according to claim 1, wherein in formula (1), one of R and R is a hydrogen atom.
3 4  3 4
ナフタレン誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ。  A naphthalene derivative, a pharmacologically acceptable salt thereof, or a prodrug thereof.
[7] 一般式（1)において、 Rまたは Rのいずれか一方が水素原子であり、 R、 Rが共に [7] In the general formula (1), one of R and R is a hydrogen atom, and R and R are both
3 4 5 6 水素原子である請求項 6記載のナフタレン誘導体、またはその薬理学的に許容され る塩若しくはそのプロドラッグ。  7. The naphthalene derivative according to claim 6, which is a hydrogen atom, or a pharmacologically acceptable salt thereof or a prodrug thereof.
[8] 一般式（1)において、 R、 Rが水素原子、ハロゲン原子、低級アルコキシ基、水酸基 [8] In the general formula (1), R and R are a hydrogen atom, a halogen atom, a lower alkoxy group, a hydroxyl group
1 2  1 2
、低級ァシルォキシ基から成る群より任意に選ばれ、 R、 Rのいずれか一方が水素  , Is selected arbitrarily from the group consisting of lower alkoxy groups, and one of R and R is hydrogen.
3 4  3 4
原子で他方が低級アルキル基であり、 R、 Rが共に水素原子である、請求項 7記載  The other of the atoms is a lower alkyl group, and R and R are both hydrogen atoms.
5 6  5 6
のナフタレン誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ。  Or a pharmacologically acceptable salt thereof or a prodrug thereof.
[9] 一般式（1)において、 R、 Rが水素原子、メトキシ基、エトキシ基、ァセトキシ基、水 [9] In the general formula (1), R and R represent a hydrogen atom, a methoxy group, an ethoxy group, an acetyloxy group,
1 2  1 2
酸基から成る群より任意に選ばれ、 Rが水素原子であり、 R、 Rのいずれか一方が  Arbitrarily selected from the group consisting of an acid group, wherein R is a hydrogen atom, and one of R and R is
2 3 4  2 3 4
水素原子で他方がメチル基またはェチル基であり、 R、 Rが共に水素原子であり、  A hydrogen atom and the other is a methyl group or an ethyl group; R and R are both hydrogen atoms;
5 6  5 6
ナフタレン環からのカルボキシ基の置換位置が 2位である請求項 8記載のナフタレン 誘導体、またはその薬理学的に許容される塩若しくはそのプロドラッグ。  9. The naphthalene derivative according to claim 8, wherein the carboxy group is substituted at the 2-position from the naphthalene ring, or a pharmaceutically acceptable salt thereof or a prodrug thereof.
[10] 請求項 1から請求項 9のいずれか一項に記載のナフタレン誘導体、またはその薬理 学的に許容される塩若しくはそのプロドラッグを有効成分とする医薬。 [10] A medicament comprising the naphthalene derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
[11] 請求項 1から請求項 9のいずれか一項に記載のナフタレン誘導体、またはその薬理 学的に許容される塩若しくはそのプロドラッグを有効成分とする抗腫瘍剤。 [11] An antitumor agent comprising the naphthalene derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
[12] 請求項 1から請求項 9のいずれか一項に記載のナフタレン誘導体、またはその薬理 学的に許容される塩若しくはそのプロドラッグ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。 [12] A prophylactic or therapeutic agent for prostate cancer or breast cancer, comprising the naphthalene derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.
[13] 請求項 1から請求項 9のいずれか一項に記載のナフタレン誘導体、またはその薬理 学的に許容される塩若しくはそのプロドラッグ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。  [13] An agent for preventing or treating excess sex hormone, comprising the naphthalene derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.
[14] 請求項 1から請求項 9のいずれか一項に記載のナフタレン誘導体、またはその薬理 学的に許容される塩若しくはそのプロドラッグを有効成分とする C17— 20リアーゼ阻  [14] A C17-20 lyase inhibitor comprising the naphthalene derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.
PCT/JP2004/009630 2003-07-09 2004-07-07 Novel enzyme inhibitor WO2005005390A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07506588A (en) * 1992-05-15 1995-07-20 ブリテイツシユ・テクノロジー・グループ・リミテツド Substituted pyridines and their production and pharmaceutical uses
JPH10291981A (en) * 1997-02-21 1998-11-04 Takeda Chem Ind Ltd Condensed ring compound, its production and use
JP2000007658A (en) * 1998-04-23 2000-01-11 Takeda Chem Ind Ltd Naphthalene derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07506588A (en) * 1992-05-15 1995-07-20 ブリテイツシユ・テクノロジー・グループ・リミテツド Substituted pyridines and their production and pharmaceutical uses
JPH10291981A (en) * 1997-02-21 1998-11-04 Takeda Chem Ind Ltd Condensed ring compound, its production and use
JP2000007658A (en) * 1998-04-23 2000-01-11 Takeda Chem Ind Ltd Naphthalene derivative

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