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WO2005005390A1 - Inhibiteur d'enzyme - Google Patents

Inhibiteur d'enzyme 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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WO
WIPO (PCT)
Prior art keywords
group
acceptable salt
prodrug
hydrogen atom
naphthalene derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/009630
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English (en)
Japanese (ja)
Inventor
Masashi Nagai
Hiroshi Sato
Keiichirou Yamamoto
Takamichi Sato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Priority to JP2005511517A priority Critical patent/JPWO2005005390A1/ja
Publication of WO2005005390A1 publication Critical patent/WO2005005390A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un dérivé de naphtalène utile en tant que médicament, notamment un inhibiteur de C17-20 lyase. La C17-20 lyase est une des enzymes de la biosynthèse des hormones sexuelles se trouvant dans les testicules, les ovaires et le cortex surrénal. Cette C17-20 lyase produit de la déhydroépiandrostérone et de l'androsténédione à partir de la 17-hydroxyprégnénolone et de la 17-hydroxyprogestérone en tant que substrats. La biosynthèse de cette enzyme sert seulement dans la biosynthèse de l'hormone sexuelle, de sorte que le nouveau dérivé de naphtalène capable d'inhiber cette enzyme comporte un nouvel agent endocrinothérapeutique apte à inhiber la biosynthèse de l'hormone sexuelle, ce dérivé étant utile comme médicament de prévention ou de traitement.
PCT/JP2004/009630 2003-07-09 2004-07-07 Inhibiteur d'enzyme Ceased WO2005005390A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005511517A JPWO2005005390A1 (ja) 2003-07-09 2004-07-07 新規酵素阻害剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003272189A JP2006160605A (ja) 2003-07-09 2003-07-09 新規酵素阻害剤
JP2003-272189 2003-07-09

Publications (1)

Publication Number Publication Date
WO2005005390A1 true WO2005005390A1 (fr) 2005-01-20

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PCT/JP2004/009630 Ceased WO2005005390A1 (fr) 2003-07-09 2004-07-07 Inhibiteur d'enzyme

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JP (2) JP2006160605A (fr)
TW (1) TW200507843A (fr)
WO (1) WO2005005390A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07506588A (ja) * 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 置換ピリジン及びその製造と医薬的使用
JPH10291981A (ja) * 1997-02-21 1998-11-04 Takeda Chem Ind Ltd 縮合環化合物、その製造法および用途
JP2000007658A (ja) * 1998-04-23 2000-01-11 Takeda Chem Ind Ltd ナフタレン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07506588A (ja) * 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 置換ピリジン及びその製造と医薬的使用
JPH10291981A (ja) * 1997-02-21 1998-11-04 Takeda Chem Ind Ltd 縮合環化合物、その製造法および用途
JP2000007658A (ja) * 1998-04-23 2000-01-11 Takeda Chem Ind Ltd ナフタレン誘導体

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JP2006160605A (ja) 2006-06-22
JPWO2005005390A1 (ja) 2006-10-26

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