WO2006109680A1 - Use of 3,5-diphenylpyrazole analogue as anti-tumor agent - Google Patents

Use of 3,5-diphenylpyrazole analogue as anti-tumor agent Download PDF

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WO2006109680A1
WO2006109680A1 PCT/JP2006/307346 JP2006307346W WO2006109680A1 WO 2006109680 A1 WO2006109680 A1 WO 2006109680A1 JP 2006307346 W JP2006307346 W JP 2006307346W WO 2006109680 A1 WO2006109680 A1 WO 2006109680A1
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group
hydrogen atom
halogeno
groups
atoms
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PCT/JP2006/307346
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French (fr)
Japanese (ja)
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Shunsuke Kuroiwa
Sakiko Maruyama
Yoshikazu Suzuki
Hiroko Yamazaki
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Nippon Kayaku Kabushiki Kaisha
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the use of a 3,5 diphenyl-rubirazole analogue and a pharmacologically acceptable salt thereof, particularly as an antitumor agent.
  • a malignant tumor is a group of cells that deviate from normal biological mechanisms and continue to grow in vivo and, if not treated, can cause the death of the host.
  • surgical excision, radiation, hormonal therapy or chemotherapy is common, and surgical treatment is the first choice especially for the treatment of malignant solid tumors.
  • Radiation therapy, hormonal therapy, and pharmacotherapy are commonly used to treat malignant solid tumors that cannot be treated with adjuvant or surgery before or after surgery.
  • Hormone therapy, chemotherapy, etc. are used to narrow the scope of surgery and to reduce or eliminate tumors that cannot be removed by surgery to prevent recurrence.
  • Patent Document 1 an estrogen receptor negative (MDA) of a pyrazole derivative is used.
  • MB-233 A growth inhibitory effect on cells has been reported (for example, Example 5). That is, the compound described in Patent Document 1 exhibits a growth inhibitory effect on estrogen receptor negative cells. However, it has been shown that pyrazole derivatives have no growth inhibitory effect on estrogen receptor positive cells (T47D).
  • Patent Document 2 reports a number of compounds in which a hydroxyl group is substituted at the ortho position of the benzene ring directly connected to the 5-position of the pyrazole ring, but its use is for bronchial asthma and alleles. It is intended for dermatologic skin diseases, and no reports have been made on its use with the cell growth inhibitory activity as an index.
  • Patent Document 3 reports a pyrazole compound having an action of regulating an ATP-binding cassette (hereinafter abbreviated as ABC) transporter, and a method for treating a disease mediated by ABC transporter using the compound.
  • ABC ATP-binding cassette
  • Patent Document 3 In the background of the invention of Patent Document 3 ([0003] and [0016] items), many target diseases mediated by ABC transporters are described, and cancer is also mentioned among them. However, although Patent Document 3 shows in a working example that a pyrazole compound has a function of regulating membrane potential, it specifically discloses the growth inhibitory action of tumor cells. .
  • Patent Document 1 EP1398029A1 Publication
  • Patent Document 2 DE4126543 A1 Publication
  • Patent Document 3 International Publication No. 2004Z080972A1
  • the present inventors have found that 3,5-diphenylazole analogues and pharmaceutically acceptable salts thereof have tumor cell growth inhibitory activity.
  • the present invention has been completed.
  • the 3,5-diphenylbiazole analog used in the present invention is a functional group on the benzene ring directly connected to the 3-position (or 5-position) of the pyrazole ring, with a hydroxyl group or at the ortho-position of at least one benzene ring.
  • the protective group is characterized by having a hydroxyl group.
  • a tumor cell growth inhibitor comprising, as an active ingredient, a 3,5-diphenylavirazole analog represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
  • the group A represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom); Or an optionally substituted lower alkyl group; or an amino group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent.
  • both of G and Z are hydrogen atoms; halogeno groups; or one is a hydrogen atom and the other is a halogeno group
  • groups D and E , L, Q, X and Y are each independently a hydrogen atom; may be substituted with an aminocarbonyl group; a lower alkoxycarbonyl group; a carboxyl group; a -tolyl group; a nitro group
  • Both the base and the base may form a 5- to 6-membered heterocycle with up to two atoms, which are independently selected from nitrogen, oxygen or sulfur nuclear power.
  • the group represents a hydrogen atom, a carbonyl group, or a sulfol group, and 3 ⁇ 4 [represents a straight chain, branched chain, or ring structure composed of 1 to 6 carbon atoms.
  • Each of the groups G and Z independently has a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a carboxyl group at the end, and may have a carbon number of 2
  • An alkylsyloxy group composed of 5 except for the case of G and Z !, both of which are hydrogen atoms; a nonogeno group; or one is a hydrogen atom and the other is a halogeno group), E, L, Q, X and Y are each independently a hydrogen atom; may have a substituent.
  • the group A represents a hydrogen atom; a carbo ol group; or a sulfo group, and 3 ⁇ 4 [is a straight chain, branched chain or ring structure composed of 1 to 6 carbon atoms.
  • Each of the groups D, E, L, Q, X, and Y is independently a hydrogen atom; a methylaminocarbol group
  • the group represents a hydrogen atom or a carbo group
  • 3 ⁇ 4 [represents a methyl group
  • Groups G and Z are each independently a hydrogen atom (except when both G and Z are hydrogen atoms); a hydroxyl group; a lower alkoxy group, and groups D, E, L, Q, X and Y
  • both group Q and group ⁇ ⁇ ⁇ may form a 5- or 6-membered heterocyclic ring with one or more nitrogen atoms, or a 3,5-diphenyl-birazole analog or a pharmacology thereof.
  • a tumor cell growth inhibitor according to any one of (1) and (3), wherein a salt that is pharmaceutically acceptable is an active ingredient.
  • tumor cell growth inhibitor according to any one of (1) and (5), wherein the tumor cell is selected from the group power of breast cancer cells, lung cancer cells, and colon cancer cells.
  • tumor cell proliferation inhibitor according to (6) wherein the tumor cell is a breast cancer cell expressing an estrogen receptor, endometrial cancer, endometrial cancer, uterine fibroid cell, or ovarian tumor cell.
  • an antitumor agent comprising as an active ingredient the 3,5-difur-rubirazole analogue or the pharmacologically acceptable salt thereof described in 1 above.
  • a group represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom). Or an optionally substituted lower alkyl group; or an amino group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent.
  • the groups D, E, L, and X are each independently a hydrogen atom; may have a substituent, an aminocarbo group; Carboxy group; nitrile group; nitro group; halogeno group; lower alkyl group; halogeno-substituted lower alkyl group; lower alkoxy group; lower alkylthio group; lower alkyl sulfoxyl group;
  • substituents which may be an aminosulfonyl group
  • ring C is a 5- to 6-membered ring containing up to 2 atoms independently selected from nitrogen, oxygen or sulfur atoms Indicates a heterocycle.
  • a novel 3,5-diphenyl-rubiazole analog or a physiologically acceptable salt thereof and a 3,5-diphenyl-rubirazole analog or a physiologically acceptable salt thereof It is possible to provide a tumor cell growth inhibitor, particularly an antitumor agent, containing a salt as an active ingredient.
  • a tumor cell growth inhibitor particularly an antitumor agent
  • cells that express estrogen receptor have a strong and antiproliferative effect, and a therapeutic effect is expected for diseases such as breast cancer and endometrial cancer that are strongly associated with them.
  • the 3,5-diphenylazole analogue used in the present invention is a potent cell growth inhibitory agent against breast cancer cells, lung cancer cells, large intestine cancer cells, etc., regardless of the expression of estrogen receptor in tumor cells. It has an effect and is useful as an antitumor agent inhibitor.
  • the present invention provides a tumor cell using a 3,5-diphenylazole analog comprising a compound represented by the above general formula (1) as a main component, or a pharmacologically acceptable salt thereof.
  • the present invention relates to an antiproliferative agent, a method for reducing a malignant tumor, an antitumor agent, and a novel 3,5-diphenyl-birazole analogue or a physiologically acceptable salt thereof.
  • tumors expressing the estrogen receptor include breast cancer, endometrial cancer, endometrial cancer, uterine fibroid, ovarian tumor and the like.
  • the group A represents a hydrogen atom (in this case, a substituted group [not present) of the group A; a carbonyl group; or a sulfonyl group; when the group A is a hydrogen atom, Including its tautomers.
  • Particularly preferred as group A is a hydrogen atom or a carbonyl group.
  • [0014] in the present invention [[having a substituent may be a lower alkyl group; or having a substituent!] / Take it! / Indicates an amino group.
  • 3 ⁇ 4 [has a substituent, and in the case of a lower alkyl group, the alkyl group may have a straight chain, a branched chain, or a ring structure, and the carbon number is 1 to: LO
  • LO are preferred.
  • a linear or branched alkyl group a methyl group, an ethyl group, an n-propyl group, an isopyl pill group, an n-butyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a non- Group, decyl group and the like.
  • cyclic alkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.
  • a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is preferred, and a methyl group is preferred.
  • the substituent of the lower alkyl group includes a substituted or unsubstituted amino group, a hydroxyl group, and a lower alkoxy. Ci group is mentioned.
  • the substituted amino group include acyclic or cyclic amino groups.
  • a straight chain, branched chain or cyclic alkyl group having 1 to 3 carbon atoms is preferred, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclo group.
  • a propyl group is exemplified, and a methyl group is particularly preferable.
  • acyclic substituted amino group examples include methylamino group, dimethylamino group, ethylamino group, jetylamino group, methylethylamino group, n-propylamino group, cyclopropylamino group, and isopropylamino group. More preferably, they are a methylamino group and a dimethylamino group.
  • the cyclic amino group include monocyclic or condensed ring, alicyclic or aromatic groups, and may contain atoms other than carbon atoms and nitrogen atoms. Of these, a heteroalicyclic amino group having a 5- to 6-membered ring structure is preferable.
  • pyrrolidinyl group examples include a pyrrolidinyl group, a piperidyl group, a 4-piperazyl group, a 4-methylbiperazyl group, and a 4 morpholinyl group. Particularly preferred are pyrrolidine 1-yl and 4 morpholine 4-yl.
  • examples of the substituted amino group include an acyclic or cyclic amino group.
  • Preferred examples of the substituent for the acyclic amino group include a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, a substituted benzene, and a heteroaromatic ring having a 5- to 6-membered ring structure.
  • Preferred substituents of 1 to 3 substituents for benzene include methyl group, methoxy group, fluorine atom, chlorine atom, nitrile group, methoxycarbol group, carboxyl group, triazolyl group, etc. Preferred are a fluorine atom and a -tolyl group.
  • Preferred examples of the heteroaromatic ring having a 5- to 6-membered ring structure include pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • acyclic substituted amino group examples include methylamino group, dimethylamino group, ethylamino group, jetylamino group, methylethylamino group, n -propylamino group, cyclopropylamino group, isopropylamino group, and the like.
  • One is a methylamino group and a dimethylamino group.
  • Cyclic amino groups are monocyclic or condensed Examples thereof include a ring, an alicyclic group and an aromatic group, and may contain atoms other than carbon atoms and nitrogen atoms.
  • heteroalicyclic amino group having a 5- to 6-membered ring structure is preferred.
  • Specific examples include a pyrrolidyl group, piperidinyl group, 4-piperazyl group, 4-methylbiperazyl group, 4 morpholinyl group and the like.
  • Particularly preferred are pyrrolidine 1-yl and 4 morpholine 4-yl.
  • Preferred as a combination of groups A to J! / which is a acetyl group, a methanesulfonyl group, an aminocarbonyl group, an aminosulfol group, a methylaminocarbonyl group, a methylaminosulfol group, dimethyl
  • examples thereof include an aminocarbonyl group and a dimethylaminosulfonyl group, and particularly preferred V is a acetyl group.
  • a tautomer may exist as a feature of the pyrazole ring. In this case,!, Any tautomers and mixtures of tautomers are also included in the present invention.
  • the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent, which may be a lower acyloxy group (provided that both of G and Z are hydrogen atoms). Atoms; except for halogeno groups). Of these, one in which one of the groups G and Z is a hydrogen atom and the other is not a combination of a halogeno group is preferred.
  • the lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, an isobutyroxy group, a tert-butoxy group, a bentoxy group, a hexyloxy group, and a cyclohexyl group.
  • Xyloxy group and the like can be mentioned, and in the present invention, a methoxy group is preferable among alkoxy groups having 1 to 3 carbon atoms.
  • Preferred examples of the group G or Z in the general formula (1) include a hydrogen atom, a hydroxyl group, a methoxy group, and a succinoxy group.
  • Particularly preferred combinations of G—Z or Z—G include a hydrogen atom hydroxyl group, a hydrogen atom-methoxy group combination.
  • halogeno group examples include a fluorine atom, a chlorine atom, a bromine atom, and the like. In the present invention, a chlorine atom is preferable.
  • the lower acyloxy group is a saturated aliphatic monocarboxylic acid such as formyloxy group, acetyloxy group, propio-oxy group, butyryloxy group, isoptyryloxy group, valeryloxy group, isovaleryloxy group, saturated fatty acid, etc.
  • Zikaru Examples thereof include an oxalyloxy group, a malonyloxy group, a succinyloxy group, a glutaryloxy group, etc., which are an acyl group of a boric acid, and a fumaryloxy group, which is an acyloxy group of an unsaturated aliphatic dicarboxylic acid.
  • the acyloxy group is preferably a succinyloxy group among the saturated aliphatic dicarboxylic acids.
  • Substituents of the lower acyloxy group include linear, branched or cyclic alkyl groups having 1 to 3 carbon atoms, substituted benzene and a 5- or 6-membered heteroaromatic ring, halogeno Groups are preferred.
  • Examples of the linear, branched, or cyclic alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclohexyl group, and a methyl group is particularly preferable. .
  • substituents for benzene are preferred and preferred substituents include methyl, methoxy, fluorine, chlorine, nitryl, methoxycarbol, triazolyl, etc.
  • fluorine atom and -tolyl group Preferred examples of heteroaromatic rings having a 6-membered ring structure include pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. Particularly preferred are pyridine and thiazole.
  • the halogeno group include a fluorine atom, a chlorine atom, a bromine atom and the like, and particularly preferred are a fluorine atom and a chlorine atom.
  • the groups D, E, L, Q, X and Y are each independently a hydrogen atom; may have a substituent, V-amino carbo group; a lower alkoxy carbo group; a carboxyl group; A tolyl group; a nitrogen group; a halogeno group; a lower alkyl group; a halogeno-substituted lower alkyl group; a lower alkoxy group; a lower alkylthio group; a lower alkylsulfoxyl group; a lower alkylsulfone group; or a substituted or unsubstituted aminosulfol group.
  • Both the group D and the group L and both ⁇ or the group Q and the group ⁇ are, for example, two carbon atoms on the aromatic ring to which they are bonded, as shown in the following general formula (1 ').
  • a 5- or 6-membered heterocyclic ring (ring C) may be formed together with the above heteroatoms, and a heterocyclic ring may be formed together with the aromatic ring to which each is bonded.
  • a hetero atom refers to a nitrogen atom, an oxygen atom or a sulfur atom. Up to two atoms can be selected independently from these heteroatoms.
  • the 5-membered heterocycles that can be used in the present invention include those containing one heteroatom, such as Ru, furan, thiophene, those containing two heteroatoms of the same type, such as pyrazole, imidazole, those containing two heterogeneous heteroatoms, such as oxazole, isoxazole, thiazole, isothiazole and the like.
  • Examples of the 6-membered heterocyclic ring that can be used in the present invention include pyridine, pyridazine, pyrimidine, and pyrazine. Particularly preferred in the present invention is pyridine, which is preferably a 6-membered heterocyclic ring.
  • the substituent of the aminocarbonyl group is a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclo A propyl group etc. are mentioned.
  • the number of substituents is 1 or 2.
  • the lower alkoxycarbo group is a linear, branched or cyclic alkyl group composed of 1 to 10 carbon atoms, preferably a linear, branched chain or ring composed of 1 to 6 carbon atoms.
  • the alkyl group of a structure is shown.
  • Examples of the alkoxy of the lower alkoxycarbo group include alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, n-butoxy, isobutyloxy, tert-butoxy, pentoxy, hexyloxy, cyclohexyloxy, etc. In the invention, methoxy is preferred.
  • halogeno group examples include a fluorine atom, a chlorine atom, and a bromine atom.
  • the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, Examples thereof include a pentyl group, a neopentyl group, a hexyl group, or a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • straight chain, branched chain, and cyclic alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group are preferable, and particularly preferable.
  • the lower alkyl group include a methyl group.
  • the halogeno-substituted lower alkyl group refers to a group in which at least one hydrogen of the lower alkyl group is substituted with the halogeno group, for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group.
  • a trifluoromethyl group is preferred among the halogeno-substituted lower alkyl groups having 1 to 3 carbon atoms.
  • the lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, an isobutyroxy group, a tert-butoxy group, a bentoxy group, a hexyloxy group, and a cyclohexyl group.
  • Xyloxy group and the like can be mentioned, and in the present invention, a methoxy group is preferable among alkoxy groups having 1 to 3 carbon atoms.
  • the lower alkylthio group, the lower alkylsulfoxyl group, the lower alkylsulfone group, and the lower alkyl are linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, Examples thereof include isopropyl, n-butyl, tert-butyl, pentyl, neopentyl, hexyl, or cyclic alkyl having 1 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • straight-chain, branched-chain, and cyclic alkyls having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • Particularly preferred lower alkyls are methyl and And cyclopropyl.
  • the lower alkylthio group includes methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, tert-butylthio group, n-pentylthio group, neopentylthio group, hexylthio group, cyclopropylthio group.
  • the lower alkylsulfoxyl group includes methylsulfoxyl group, ethylsulfoxyl group, n-propylsulfoxyl group, isopropylsulfoxyl group, n-butylsulfoxyl group, tert-butylsulfoxyl group, n-pentylsulfo group.
  • Xyl group, neopentyl examples include a sulfoxyl group, a hexylsulfoxyl group, a cyclopropylsulfoxyl group, a cyclobutylsulfoxyl group, a cyclopentylsulfoxyl group, a cyclohexylsulfoxyl group, and the like. Among them, a methylsulfoxyl group is preferred.
  • the lower alkyl sulfone group includes methyl sulfone group, ethyl sulfone group, n-propyl sulfone group, isopropyl sulfone group, n-butyl sulfone group, tert-butyl sulfone group, n-pentyl sulfone group, neopentyl sulfone group, Examples thereof include a xylsulfone group, a cyclopropylsulfone group, a cyclobutylsulfone group, a cyclopentylsulfone group, and a cyclohexylsulfone group. Of these, a methylsulfone group is preferred.
  • the aminosulfol group may be a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, such as a substituent. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group.
  • the number of substituents is 1 or 2.
  • preferable as the groups D, E, L, Q, X and Y are hydrogen atom, nitrile group, nitro group, chlorine atom, fluorine atom, trifluoromethyl group, methoxy group , A methyl group, a cyclopropyl group, a methylthio group, a methylsulfoxyl group, a methylsulfone group, and a methanesulfol group.
  • Particularly preferred are a hydrogen atom, a nitrile group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a methyl group.
  • the 3, 5 diphenylbirazole analogues represented by the above general formula (1) or general formula (1 ') are:
  • the 3, 5 diphenylbirazole analogues represented by the following general formula (1 ") are:
  • the compounds listed in Table 12 below are:
  • Physiologically acceptable salts in the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, succinic acid, fumaric acid, maleic acid, citrate, benzoic acid, tartaric acid, methanesulfonic acid.
  • mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, succinic acid, fumaric acid, maleic acid, citrate, benzoic acid, tartaric acid, methanesulfonic acid.
  • salts with organic acids such as p-toluenesulfonic acid.
  • these salts are easily prepared by subjecting them to a normal salt formation reaction.
  • the agent having an inhibitory effect on cell proliferation used in the present invention is a 3,5-diphenyl-biazole analogue or a physiologically acceptable salt thereof alone or mixed with an excipient or a carrier.
  • Suspension, emulsion, injection, inhalation, tablet, pill, granule, fine granule, powder, capsule, oral solution, suppository, transdermal solution, transdermal patch, ointment It can be administered orally or parenterally as a formulation such as a transmucosal fluid or transmucosal attachment.
  • additives such as excipients or carriers, pharmaceutically acceptable ones are selected, and their types and compositions are determined by the administration route and administration method.
  • saccharides such as sodium chloride, glucose and mannitol are generally desirable.
  • Magnesium stearate and the like are desirable. If desired, auxiliaries, stabilizers, wetting agents, or emulsifiers, buffers and other commonly used additives may be included in the preparation.
  • the content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to L00 wt%, preferably 1 to 98 wt%.
  • the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight.
  • an oral preparation it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives.
  • Capsules, tablets, granules and powders generally contain 5 to: L00% by weight, preferably 25 to 98% by weight of active ingredient.
  • the dosage is determined by the patient's age, sex, weight, symptoms, therapeutic purpose, etc., but the therapeutic dosage is usually 0.001 to 100 mg ZkgZ days for parenteral administration, and 0. 01 to 500 mg / kg / ⁇ , preferably 0.1 to: LOOmgZkgZ ⁇ , which is administered once or in 2 to 4 divided doses.
  • the 3,5-diphenyl-rubyrazole analog of the present invention and the 3,5-diphenylrubazole analog used in the present invention can be synthesized, for example, according to the method shown in the following scheme 1. It is.
  • the compound represented by the general formula (7) that is, the 2-hydroxyacetophenone derivative used as a raw material is commercially available.
  • Non-commercial derivatives can be synthesized by subjecting the corresponding phenol derivative and salt acetyl or acetylbenzene derivative to the Friedel-Crafts reaction.
  • the compound of the general formula (9) may be isolated, but after confirming the formation of the general formula (9) as a condensation reaction product, potassium t-butoxide or the like may be contained in the reaction system without isolation and purification. By removing the base, it is possible to obtain the compound of the general formula (10) as a one-pot reaction.
  • a compound of the general formula (11) can be obtained by subjecting the compound of the general formula (10) and hydrazine to a condensation reaction.
  • the compound of the general formula (11) may have a tautomer as described above. In the above scheme 1, only one isomer is described for simplicity.
  • the compound of general formula (12) can be synthesized by condensing the compound of (11) with an acid salt of ⁇ J-A (except when A is a hydrogen atom).
  • an acid salt of ⁇ J-A except when A is a hydrogen atom.
  • a condensation reaction is performed with a compound of general formula (11) using a salt acetyl group, which corresponds to general formula (12). It is possible to synthesize acetyl derivatives.
  • ESI is an abbreviation for Electron Spray Ionization, and is one of the ionic methods in molecular weight measurement.
  • (ER +) represents a cell expressing the estrogen receptor
  • (ER ⁇ ) represents a cell not expressing the estrogen receptor.
  • Tetrahydrofuran (5 ml) was added to the residue obtained by evaporating the organic layer and heated to 50-60 degrees Celsius to form a solution. After hydrazine hydrate (0.1 ml) was added and stirred for 17.5 hours, the reaction solution was transferred to a separatory funnel with ethyl acetate and washed sequentially with saturated saline Z tap water (1Z1) and saturated saline. did. Isopropyl ether (5 ml) was added to the solid residue obtained by evaporation of the organic layer, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain the target compound (114. lmg).
  • Example 1 the same compound (110. lmg) was obtained by carrying out the same reaction using 4-cyanobenzoyl chloride (139 mg) instead of 3-cyanobenzoyl chloride. Obtained.
  • Example 2 the same compound (84.8 mg) was obtained by performing the same reaction using 3 methylbenzoyl chloride (112 1) instead of 3 (trifluoromethyl) benzoyl chloride.
  • Example 5 3 (2 hydroxy-1 5 ⁇ 1) file 5— (3 fluoro) file 1
  • Example 2 the same compound (9) was obtained by carrying out the same reaction using 3 fluorobenzoyl chloride (104 1) instead of 3 (trifluoromethyl) benzoyl chloride.
  • This compound was synthesized in the following two steps.
  • Example 2 the target compound was obtained by conducting the same reaction using 4 (trifluoromethyl) benzoyl chloride instead of 3 (trifluoromethyl) benzoyl chloride.
  • the reaction mixture was transferred to a separatory funnel with ethyl acetate and washed with tap water (5 times) and saturated brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated to obtain the target compound (13.5 mg).
  • Example 9 1—Dimethylaminocarbole— 3— (2-Hydroxy—Black) Fale— Synthesis of 5- (4 (trifluoromethyl)) fluoropyrazole (Compound No. 41) This compound was synthesized in the following four steps using Compound No. 6 as a reaction raw material.
  • Example 9 The same procedure as in 2) and 4) in Example 9 was carried out using methanesulfuryl chloride in place of phenol chloroformate, thereby producing 3- [2- (t-butyldimethylsilyloxy). 5) (Black mouth) phenol 1— (4- (trifluoromethyl)) phenol 1 (1H) -virazole (148 mg) was also obtained in 2 steps to obtain the target compound (6.7 mg). .
  • This compound was synthesized in the following three steps.
  • the compound of Compound No. 46 was synthesized by carrying out the same reaction using 2′-hydroxy-1-5′-fluoroacetophenone instead of 3-acetyl 4-hydroxy-methylbenzoate. .
  • Example 12 a compound of Compound No. 50 was synthesized by carrying out the same reaction using 2′-hydroxy 5′-methylsulfo-lucatophenone in place of 3-acetyl 4-hydroxy-methyl benzoate.
  • This compound was synthesized in the following two steps.
  • Example 19 1—Methyl 3— (2-methyloxy-5-chloro) 1-methyl 5- (4 trifluoromethyl) phenol-pyrazole (Compound No. 47) and 3— (2 methyloxy) —5—Black mouth) Fuel 5— Synthesis of (4-Trifluoromethyl) phenol (1H) -pyrazole (Compound No. 48)
  • This compound was synthesized in the following four steps.
  • toluene (16 ml) and triethylamine (2951) were added to the compound represented by the general formula (13) (305 mg), and the mixture was heated and stirred at 110 ° C.
  • Diphenylphosphoryl azide (228 ⁇ 1) was added dropwise, and the mixture was stirred at the same temperature for 2 hours.
  • the reaction mixture was ice-cooled, poured into water (80 ml), and stirred for 1 hour.
  • Ethyl acetate (250 ml) and water (100 ml) were added for liquid separation. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate.
  • This compound was synthesized in the following three steps.
  • the compound was synthesized according to the method described in the following reference: Journal of Medicinal Chemistry, 23 (3), pp335-338 (198 0). That is, 8-acetoxyquinoline (general formula (17), 11. 83g), salt-potassium (7.30g), anhydrous salt-aluminum (26.5g) are mixed and 170 ° C under nitrogen flow. For 1 hour and 15 minutes. After cooling with ice, 2N hydrochloric acid (253 ml) was added dropwise over 30 minutes. The mixture was heated and stirred at 70 ° C for 2 hours and 30 minutes. After cooling to room temperature, the mixture was stirred at the same temperature. The precipitated crystals were collected by filtration, washed with water, and dried under vacuum to obtain the desired compound (5.714 g).
  • Example 1 In Example 1, 4 (trifluoromethyl) benzoyl chloride (0.42 ml) was used instead of 3 cyanobenzoyl chloride, 7 ′ acetylyl 8 ′ instead of 2′-hydroxy 1-5′-chloro 1acetophenone.
  • Compound No. 53 (166.3 mg) was obtained using hydroxyquinoline hydrochloride (general formula (18), 532.5 mg).
  • Example 21 Compound No. 54 (8.9 mg) was obtained using 3 trifluoromethylbenzoyl chloride (0.48 ml) instead of 4- (trifluoromethyl) benzoyl chloride.
  • ER + and MDA—MB 453 (ER-) were added with compounds Nos. 1 to 54 and 157360 as a comparative example.
  • MCF—7 (ER +) — MDA—MB—231 (ER—), H s0578T NCI—H460 and HCT116 were supplemented with Compound No. 6 and further cultured for 3 days.
  • the cells were stained with 0.05% Methylene Blue solution, and the absorbance at 660 nM was measured with a microphone plate reader (Benchmark Plus-BIO RAD).
  • the growth inhibition rate was determined by the following formula, and the 50% cell growth inhibitory concentration (IC50) of each compound is shown in Table 2 and Table 3 in units of / z gZmL.
  • the compound group represented by the general formula (1) has an antitumor effect on breast cancer cells, which suppresses the growth of breast cancer cells regardless of whether they are estrogen receptor positive or negative. It can be seen that Among these compound groups, those with particularly high IC50 were Compound Nos. 1, 3, 4, 5, 6, 7, 31, 38 and 54. In addition, as shown in Table 3, Compound No. 6 has an antitumor effect of inhibiting the growth of lung cancer cells and colon cancer cells that are not limited to breast cancer cells, and the compound group represented by the general formula (1) is a cancer cell. In contrast, it has a broad anti-cancer spectrum.

Abstract

A growth inhibitory agent for tumor cells comprising a 3,5-diphenylpyrazole analogue represented by the general formula (1) or a pharmacologically acceptable salt thereof as the active ingredient: (1) wherein the group A represents a hydrogen atom, a carbonyl group or a sulfonyl group; the group J represents a lower alkyl group which may have a substituent or an amino group which may have a substituent; the groups G and Z independently represent a hydrogen atom, a hydroxyl group or the like; and the groups D, E, L, Q, X and Y independently represent a hydrogen atom, an aminocarbonyl group which may have a substituent, a lower alkoxycarbonyl group or the like.

Description

明 細 書  Specification
3， 5—ジフエ二ルビラゾール類縁体の抗腫瘍剤としての用途  3,5-Use of diphenylbirazole analogs as antitumor agents
技術分野  Technical field
[0001] 本発明は、 3, 5 ジフエ-ルビラゾール類縁体およびその薬理学的に許容される 塩の用途、特に抗腫瘍剤としての用途に関する。  [0001] The present invention relates to the use of a 3,5 diphenyl-rubirazole analogue and a pharmacologically acceptable salt thereof, particularly as an antitumor agent.
背景技術  Background art
[0002] 悪性腫瘍とは正常の生体機構からはずれて生体内で増殖を続け、治療をしなけれ ば宿主の死を招くような細胞群である。悪性腫瘍の治療は、外科的な切除、放射線 照射、ホルモン療法又は化学療法が一般的であり、特に悪性固形腫瘍の治療にお いては外科的手術が第一選択となっている。放射線療法、ホルモン療法およびィ匕学 療法は、手術前又は手術後の補助療法あるいは手術による治療が不可能と判断さ れた悪性固形腫瘍の治療に用いられるのが一般的である。ホルモン療法や化学療 法等は、手術で切除する範囲を狭め、また、手術によって切除しきれない腫瘍を縮 小又は消失させ再発を予防するために使用されている。し力しながら、手術は癌患 者に対して肉体的及び精神的な苦痛を与え、更に、腫瘍が転移していれば切除は 広範囲にわたることとなり手技的にも困難を極めているのが現状である。従って正常 な細胞増殖を抑制せず、正常の生体機構カゝらはずれて生体内で増殖を続ける悪性 腫瘍の細胞増殖を選択的に抑制する方法が求められている。  [0002] A malignant tumor is a group of cells that deviate from normal biological mechanisms and continue to grow in vivo and, if not treated, can cause the death of the host. For the treatment of malignant tumors, surgical excision, radiation, hormonal therapy or chemotherapy is common, and surgical treatment is the first choice especially for the treatment of malignant solid tumors. Radiation therapy, hormonal therapy, and pharmacotherapy are commonly used to treat malignant solid tumors that cannot be treated with adjuvant or surgery before or after surgery. Hormone therapy, chemotherapy, etc. are used to narrow the scope of surgery and to reduce or eliminate tumors that cannot be removed by surgery to prevent recurrence. However, surgery presents physical and mental distress to cancer patients, and if the tumor has metastasized, the resection is widespread, making it extremely difficult to perform manually. is there. Accordingly, there is a need for a method that selectively suppresses the cell growth of malignant tumors that do not suppress normal cell growth and that deviate from normal biological mechanisms and continue to grow in vivo.
[0003] 特許文献 1にお 、ては、ピラゾール誘導体のエストロゲン受容体ネガティブ (MDA  [0003] In Patent Document 1, an estrogen receptor negative (MDA) of a pyrazole derivative is used.
MB— 233)細胞に対する増殖抑制効果が報告されて 、る（例えば実施例 5)。す なわち、特許文献 1記載の化合物は、エストロゲン受容体ネガティブ細胞に関しては 増殖抑制効果を示して 、る。し力しながらエストロゲン受容体ポジティブ細胞 (T47D )に対しては、ピラゾール誘導体は増殖抑制効果が無いことが示されている。  MB-233) A growth inhibitory effect on cells has been reported (for example, Example 5). That is, the compound described in Patent Document 1 exhibits a growth inhibitory effect on estrogen receptor negative cells. However, it has been shown that pyrazole derivatives have no growth inhibitory effect on estrogen receptor positive cells (T47D).
[0004] また特許文献 2には、ピラゾール環の 5位に直結したベンゼン環のオルト位に、水 酸基が置換したィ匕合物が多数報告されているが、その用途は気管支喘息やアレル ギー性皮膚疾患を目的としたものであり、細胞増殖の抑制活性を指標とした用途に 関して報告はされていない。 [0005] さらに特許文献 3では、 ATP—バインディングカセット（以下 ABCと省略）トランスポ ータの調節作用を持つピラゾール化合物、ならびにその化合物を用いた ABCトラン スポータが介在する疾患の治療法が報告されて 、る。特許文献 3の発明の背景（ [0 003]および [0016]項）の中では、 ABCトランスポーターが介在する多くの対象疾 患が記載されており、その中には癌も挙げられている。しかしながら特許文献 3には ピラゾールイ匕合物が膜電位の調節機能を有することを実施例において示されている ものの、腫瘍細胞の増殖抑制作用につ 、ては具体的には開示されて 、な 、。 [0004] Patent Document 2 reports a number of compounds in which a hydroxyl group is substituted at the ortho position of the benzene ring directly connected to the 5-position of the pyrazole ring, but its use is for bronchial asthma and alleles. It is intended for dermatologic skin diseases, and no reports have been made on its use with the cell growth inhibitory activity as an index. [0005] Further, Patent Document 3 reports a pyrazole compound having an action of regulating an ATP-binding cassette (hereinafter abbreviated as ABC) transporter, and a method for treating a disease mediated by ABC transporter using the compound. RU In the background of the invention of Patent Document 3 ([0003] and [0016] items), many target diseases mediated by ABC transporters are described, and cancer is also mentioned among them. However, although Patent Document 3 shows in a working example that a pyrazole compound has a function of regulating membrane potential, it specifically discloses the growth inhibitory action of tumor cells. .
[0006] 特許文献 1 :EP1398029A1号公報  [0006] Patent Document 1: EP1398029A1 Publication
特許文献 2： DE4126543 A 1号公報  Patent Document 2: DE4126543 A1 Publication
特許文献 3：国際公開第 2004Z080972A1号公報  Patent Document 3: International Publication No. 2004Z080972A1
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
[0007] 上述のように化学療法が悪性固形腫瘍に対して主たる治療方法ではな!/ヽことの理 由は、悪性固形腫瘍に対する広い抗癌スペクトルを持ち、且つ重篤な副作用がない 有効な抗腫瘍剤が存在しなカゝつたカゝらである。従って、悪性固形腫瘍に対して優れ た抗腫瘍効果を示す抗腫瘍剤が望まれて!/ヽる。 [0007] As mentioned above, chemotherapy is not the main treatment method for malignant solid tumors! The reason is that it has a broad anticancer spectrum for malignant solid tumors and has no serious side effects. There are no anti-tumor agents. Therefore, an antitumor agent exhibiting an excellent antitumor effect against malignant solid tumors is desired!
課題を解決するための手段  Means for solving the problem
[0008] 上記課題を解決するために鋭意検討した結果、本発明者等は 3, 5—ジフエ-ルビ ラゾール類縁体およびその薬学的に許容し得る塩が、腫瘍細胞の増殖抑制活性を 有することを見出し、本発明を完成した。特に本発明において用いられる 3, 5—ジフ ェ-ルビラゾール類縁体は、ピラゾール環の 3位 (又は 5位）に直結したベンゼン環上 の官能基に関して、少なくとも一方のベンゼン環のオルト位に水酸基又は保護基の っ 、た水酸基を有することを特徴としたものである。  [0008] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that 3,5-diphenylazole analogues and pharmaceutically acceptable salts thereof have tumor cell growth inhibitory activity. The present invention has been completed. In particular, the 3,5-diphenylbiazole analog used in the present invention is a functional group on the benzene ring directly connected to the 3-position (or 5-position) of the pyrazole ring, with a hydroxyl group or at the ortho-position of at least one benzene ring. The protective group is characterized by having a hydroxyl group.
[0009] 即ち、本発明は  [0009] That is, the present invention provides
(1)下記一般式（1)で表される 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学 的に許容される塩を有効成分とする、腫瘍細胞の増殖抑制剤。
Figure imgf000005_0001
(1) A tumor cell growth inhibitor comprising, as an active ingredient, a 3,5-diphenylavirazole analog represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
Figure imgf000005_0001
[式中、基 Aは水素原子；カルボ-ル基；又はスルホ二ル基を示し (基 Aが水素原子 の場合にはその互変異性体を含む。）、 ¾ [は置換基を有していてもよい低級アルキ ル基；又は置換基を有して 、てもよ 、アミノ基を示し、基 Gおよび Zはそれぞれ独立に 、水素原子；水酸基；低級アルコキシ基；ハロゲノ基；又は置換基を有して 、てもよ ヽ 低級ァシルォキシ基を示し (但し Gおよび Zの ヽずれもが水素原子；ハロゲノ基；又は 一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、 Q、 Xおよび Yはそ れぞれ独立に、水素原子；置換基を有して ヽてもよ ヽァミノカルボニル基；低級アルコ キシカルボ-ル基；カルボキシル基；-トリル基；ニトロ基；ハロゲノ基；低級アルキル 基；ハロゲノ置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級ァ ルキルスルホキシル基；低級アルキルスルホン基；又は置換基を有して!/、てもよ 、アミ ノスルホニル基を示し、基 Dと基 Lの両者及び Ζ又は基 Qと基 Υの両者は、窒素原子 、酸素原子又は硫黄原子力も独立に選択される 2個までの原子と共に 5ないし 6員環 の複素環を形成してもよい。 ]  [In the formula, the group A represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom); Or an optionally substituted lower alkyl group; or an amino group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent. And represents a lower acyloxy group (provided that both of G and Z are hydrogen atoms; halogeno groups; or one is a hydrogen atom and the other is a halogeno group), and groups D and E , L, Q, X and Y are each independently a hydrogen atom; may be substituted with an aminocarbonyl group; a lower alkoxycarbonyl group; a carboxyl group; a -tolyl group; a nitro group A halogeno group; a lower alkyl group; a halogeno-substituted lower alkyl group; a lower alkoxy group; A lower alkylthio group; a lower alkylsulfoxyl group; a lower alkylsulfone group; or having a substituent! /, Which may represent an aminosulfonyl group, both a group D and a group L, and Ζ or a group Q Both the base and the base may form a 5- to 6-membered heterocycle with up to two atoms, which are independently selected from nitrogen, oxygen or sulfur nuclear power. ]
(2)一般式（1)において、基 Αは水素原子；カルボ-ル基；又はスルホ -ル基を示し 、 ¾ [は炭素数 1から 6で構成される直鎖、分岐鎖ないしは環構造を有するアルキル 基；無置換アミノ基；非環状の置換アミノ基；又は環構成員子として窒素および酸素か ら選択される原子を 2個まで含んで 、ても良 、5な 、し 6員環構造を有する環状アミノ 基を示し、基 Gおよび Zはそれぞれ独立に、水素原子;水酸基;低級アルコキシ基;ハ 口ゲノ基；又は末端にカルボキシル基を有して 、ても良 、、炭素数 2から 5で構成され るアルキルァシルォキシ基を示し（但し Gおよび Zの!、ずれもが水素原子；ノヽロゲノ基 ；又は一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、 Q、 Xおよび Yはそれぞれ独立に、水素原子；置換基を有して ヽてもよ ヽァミノカルボ-ル基；低級 アルコキシカルボ-ル基；カルボキシル基；-トリル基；ニトロ基；ハロゲノ基；低級アル キル基；フッ素置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級 アルキルスルホキシル基；低級アルキルスルホン基；又は無置換アミノスルホ -ル基 を示し、基 Dと基 Lの両者及び Z又は基 Qと基 Yの両者は、窒素原子又は酸素原子 力も独立に選択される 2個までの原子と共に 5ないし 6員環の複素環を形成していて もよい、 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学的に許容される塩を有 効成分とする、（1)に記載の腫瘍細胞の増殖抑制剤。 (2) In the general formula (1), the group represents a hydrogen atom, a carbonyl group, or a sulfol group, and ¾ [represents a straight chain, branched chain, or ring structure composed of 1 to 6 carbon atoms. An alkyl group having; an unsubstituted amino group; an acyclic substituted amino group; or containing up to two atoms selected from nitrogen and oxygen as ring members, which may be 5, 6 or 6 membered ring structures Each of the groups G and Z independently has a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a carboxyl group at the end, and may have a carbon number of 2 An alkylsyloxy group composed of 5 (except for the case of G and Z !, both of which are hydrogen atoms; a nonogeno group; or one is a hydrogen atom and the other is a halogeno group), E, L, Q, X and Y are each independently a hydrogen atom; may have a substituent. Aminocarbol group; lower alkoxycarbol group; carboxyl group; -tolyl group; nitro group; halogeno group; A fluorine group-substituted lower alkyl group; a lower alkoxy group; a lower alkylthio group; a lower alkylsulfoxyl group; a lower alkylsulfone group; or an unsubstituted aminosulfur group, both a group D and a group L and Z or a group Q And group Y may form a 5- to 6-membered heterocycle with up to 2 atoms, the nitrogen or oxygen atom of which are also independently selected, a 3,5-diphenyl-biazole analogue or The tumor cell growth inhibitor according to (1), comprising a pharmacologically acceptable salt as an active ingredient.
(3)—般式（1)において、基 Aは水素原子；カルボ-ル基；又はスルホ -ル基を示し 、 ¾ [は炭素数 1から 6で構成される直鎖、分岐鎖ないしは環構造を有するアルキル 基；無置換アミノ基；炭素数 1から 3で構成されるアルキル基を 1な ヽし 2個置換基とし て有する、非環状アミノ基;又はピロリジニル基、ピベリジ-ル基、 4ーピペラジニル基 、 4—メチルビペラジ-ル基、 4—モルホリニル基力 なる群より選択される環状アミノ 基を示し、基 Gおよび Zはそれぞれ独立に、水素原子;水酸基；低級アルコキシ基； ハロゲノ基;又はァセチルォキシ基、ォキサリルォキシ基、マロニルォキシ基、スクシ -ルォキシ基およびダルタミニルォキシ基カゝらなる群より選択される基を示し (但し G および Zの 、ずれもが水素原子;ノ、口ゲノ基；又は一方が水素原子で他方がハロゲノ 基の場合を除く）、基 D、 E、 L、 Q、 Xおよび Yはそれぞれ独立に、水素原子;メチル ァミノカルボ-ル基、ジメチルァミノカルボ-ル基、無置換アミノカルボ-ル基;メトキ シカルボニル基、エトキシカルボ-ル基、プロピルォキシカルボ-ル基、イソプロピル ォキシカルボ-ル基、シクロプロピルォキシカルボ-ル基；カルボキシル基； -トリル 基；ニトロ基；ノヽロゲノ基;メチル基、ェチル基、プロピル基、イソプロピル基、シクロプ 口ピル基；トリフルォロメチル基;メトキシ基、エトキシ基、プロピルォキシ基、イソプロピ ルォキシ基、シクロプロピルォキシ基；メチルチオ基；メチルスルホキシル基；メタンス ルホニル基及び無置換アミノスルホ -ル基カゝらなる群より選択される基を示し、基 Dと 基 Lの両者及び Ζ又は基 Qと基 Υの両者は、窒素原子又は酸素原子から独立に選 択される 2個までの原子と共に 5ないし 6員環の複素環を形成していてもよい、 3, 5— ジフエ二ルビラゾール類縁体又はその薬理学的に許容される塩を有効成分とする、 ( 1)又は（2)に記載の腫瘍細胞の増殖抑制剤。  (3) —in the general formula (1), the group A represents a hydrogen atom; a carbo ol group; or a sulfo group, and ¾ [is a straight chain, branched chain or ring structure composed of 1 to 6 carbon atoms. An unsubstituted amino group; an acyclic amino group having 1 to 3 alkyl groups each having 1 to 3 carbon atoms as a substituent; or a pyrrolidinyl group, a piperidyl group, 4-piperazinyl A cyclic amino group selected from the group consisting of a 4-methylbiperazyl group and a 4-morpholinyl group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or an acetyloxy group , An oxalyloxy group, a malonyloxy group, a succinyloxy group, and a daltaminyloxy group, each of which represents a group selected from the group consisting of a hydrogen atom; Is a hydrogen source Each of the groups D, E, L, Q, X, and Y is independently a hydrogen atom; a methylaminocarbol group, a dimethylaminocarbol group, an unsubstituted aminocarbo- group. Group; methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, cyclopropyloxycarboxyl group; carboxyl group; -tolyl group; nitro group; Methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group; trifluoromethyl group; methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy group; methylthio group; methylsulfoxyl group A group selected from the group consisting of a methanesulfonyl group and an unsubstituted aminosulfol group, both a group D and a group L and Ζ or Both group Q and group と 共 に may form a 5- to 6-membered heterocycle with up to two atoms independently selected from nitrogen or oxygen atoms, 3, 5-diphenylbiazole The growth inhibitor of tumor cells according to (1) or (2), comprising an analog or a pharmacologically acceptable salt thereof as an active ingredient.
(4)一般式（1)において、基 Αは水素原子；又はカルボ-ル基を示し、 ¾ [はメチル基 を示し、基 Gおよび Zはそれぞれ独立に水素原子（但し Gおよび Zのいずれもが水素 原子の場合を除く）；水酸基;低級アルコキシ基を示し、基 D、 E、 L、 Q、 Xおよび Yは それぞれ独立に、水素原子；二トリル基；フルォロ基；クロ口基；トリフルォロメチル基； 又は無置換アミノスルホ -ル基カゝらなる群より選択される基を示し、基 Dと基 Lの両者 又は基 Qと基 Υの両者は、 1個以上の窒素原子と共に 5な 、し 6員環の複素環を形成 していてもよい、 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学的に許容される 塩を有効成分とする、 (1)な 、し (3)の 、ずれか一項に記載の腫瘍細胞の増殖抑制 剤。 (4) In the general formula (1), the group represents a hydrogen atom or a carbo group, and ¾ [represents a methyl group Groups G and Z are each independently a hydrogen atom (except when both G and Z are hydrogen atoms); a hydroxyl group; a lower alkoxy group, and groups D, E, L, Q, X and Y Each independently represents a group selected from the group consisting of a hydrogen atom; a nitrile group; a fluoro group; a black mouth group; a trifluoromethyl group; or an unsubstituted aminosulfol group; Or both group Q and group と 共 に may form a 5- or 6-membered heterocyclic ring with one or more nitrogen atoms, or a 3,5-diphenyl-birazole analog or a pharmacology thereof. A tumor cell growth inhibitor according to any one of (1) and (3), wherein a salt that is pharmaceutically acceptable is an active ingredient.
(5)腫瘍細胞が、エストロゲン受容体を発現して!/、る細胞である（1)な 、し (4)の 、ず れか一項に記載の腫瘍細胞の増殖抑制剤。  (5) The tumor cell growth inhibitor according to any one of (1) and (4), wherein the tumor cell is a cell that expresses an estrogen receptor!
(6)腫瘍細胞が、乳癌細胞、肺癌細胞、大腸癌細胞力 なる群力 選ばれる（1)ない し（5)の 、ずれか一項に記載の腫瘍細胞の増殖抑制剤。  (6) The tumor cell growth inhibitor according to any one of (1) and (5), wherein the tumor cell is selected from the group power of breast cancer cells, lung cancer cells, and colon cancer cells.
(7)腫瘍細胞が、エストロゲン受容体を発現している乳癌細胞、子宮体癌、子宮内膜 癌、子宮筋腫細胞、卵巣腫瘍細胞である（6)に記載の腫瘍細胞の増殖抑制剤。 (7) The tumor cell proliferation inhibitor according to (6), wherein the tumor cell is a breast cancer cell expressing an estrogen receptor, endometrial cancer, endometrial cancer, uterine fibroid cell, or ovarian tumor cell.
(8) (1)ないし（7)のいずれ力 1項に記載の 3, 5—ジフ -ルビラゾール類縁体又は その薬理学的に許容される塩を有効成分とする、抗腫瘍剤。 (8) Any one of (1) to (7), an antitumor agent comprising as an active ingredient the 3,5-difur-rubirazole analogue or the pharmacologically acceptable salt thereof described in 1 above.
(9)下記一般式（1')で表される 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学 的に許容される塩。  (9) 3,5-Diphenyl-birazole analogue represented by the following general formula (1 ') or a pharmacologically acceptable salt thereof.
Figure imgf000007_0001
Figure imgf000007_0001
[式中、基 Αは水素原子；カルボ-ル基；又はスルホ二ル基を示し (基 Aが水素原子 の場合にはその互変異性体を含む。）、 ¾ [は置換基を有していてもよい低級アルキ ル基；又は置換基を有して 、てもよ 、アミノ基を示し、基 Gおよび Zはそれぞれ独立に 、水素原子；水酸基；低級アルコキシ基；ハロゲノ基；又は置換基を有して 、てもよ ヽ 低級ァシルォキシ基を示し (但し Gおよび Zの ヽずれもが水素原子；ハロゲノ基；又は 一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、および Xはそれぞ れ独立に、水素原子；置換基を有して ヽてもよ 、ァミノカルボ-ル基；低級アルコキシ カルボ-ル基；カルボキシル基；二トリル基；ニトロ基；ハロゲノ基；低級アルキル基；ハ ロゲノ置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級アルキル スルホキシル基；低級アルキルスルホン基；又は置換基を有して!/ヽてもよ 、アミノスル ホニル基を示し、環 Cは、窒素原子、酸素原子又は硫黄原子から独立に選択される 2 個までの原子を含む 5ないし 6員環の複素環を示す。 ] [In the formula, a group represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom). Or an optionally substituted lower alkyl group; or an amino group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent. And represents a lower acyloxy group (provided that both of G and Z are a hydrogen atom; a halogeno group; or Except that one is a hydrogen atom and the other is a halogeno group), the groups D, E, L, and X are each independently a hydrogen atom; may have a substituent, an aminocarbo group; Carboxy group; nitrile group; nitro group; halogeno group; lower alkyl group; halogeno-substituted lower alkyl group; lower alkoxy group; lower alkylthio group; lower alkyl sulfoxyl group; With substituents, which may be an aminosulfonyl group, ring C is a 5- to 6-membered ring containing up to 2 atoms independently selected from nitrogen, oxygen or sulfur atoms Indicates a heterocycle. ]
(10)下記一般式（2)、（3)、（4)、 (5)又は（6)で表される 3, 5—ジフ 二ルビラゾー ル類縁体又はその薬理学的に許容される塩。  (10) A 3,5-dihydrobiazole analog represented by the following general formula (2), (3), (4), (5) or (6) or a pharmacologically acceptable salt thereof.
Figure imgf000008_0001
に関する。
Figure imgf000008_0001
About.
発明の効果 The invention's effect
本発明により、新規 3, 5—ジフエ-ルビラゾール類縁体又はその生理学的に許容 される塩、及び 3, 5—ジフエ-ルビラゾール類縁体又はその生理学的に許容される 塩を有効成分とする、腫瘍細胞の増殖抑制剤、特に抗腫瘍剤を提供する事ができる 。特に本発明にお ヽてはエストロゲン受容体を発現する細胞にぉ 、ても強 、増殖抑 制効果が示され、これらと強く関与する乳癌、子宮体癌などの疾患に治療効果が期 待される。更には、本発明において用いられる 3, 5—ジフエ-ルビラゾール類縁体は 、腫瘍細胞におけるエストロゲン受容体の発現に関わらず、乳癌細胞、肺癌細胞、大 腸癌細胞等に対して強力な細胞増殖抑制作用を示し、抗腫瘍剤抑制として有用で ある。 According to the present invention, a novel 3,5-diphenyl-rubiazole analog or a physiologically acceptable salt thereof, and a 3,5-diphenyl-rubirazole analog or a physiologically acceptable salt thereof It is possible to provide a tumor cell growth inhibitor, particularly an antitumor agent, containing a salt as an active ingredient. Particularly, in the present invention, cells that express estrogen receptor have a strong and antiproliferative effect, and a therapeutic effect is expected for diseases such as breast cancer and endometrial cancer that are strongly associated with them. The Furthermore, the 3,5-diphenylazole analogue used in the present invention is a potent cell growth inhibitory agent against breast cancer cells, lung cancer cells, large intestine cancer cells, etc., regardless of the expression of estrogen receptor in tumor cells. It has an effect and is useful as an antitumor agent inhibitor.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0011] 本発明は、上記一般式（1)で表される化合物を主成分とする 3, 5—ジフエ-ルビラ ゾール類縁体、又はその薬理学的に許容される塩を用いた、腫瘍細胞の増殖抑制 剤、悪性腫瘍を縮小する方法および抗腫瘍剤、及び新規 3, 5—ジフエ-ルビラゾー ル類縁体又はその生理学的に許容される塩に関する。  [0011] The present invention provides a tumor cell using a 3,5-diphenylazole analog comprising a compound represented by the above general formula (1) as a main component, or a pharmacologically acceptable salt thereof. The present invention relates to an antiproliferative agent, a method for reducing a malignant tumor, an antitumor agent, and a novel 3,5-diphenyl-birazole analogue or a physiologically acceptable salt thereof.
[0012] また、エストロゲン受容体を発現している腫瘍としては乳癌、子宮体癌、子宮内膜癌 、子宮筋腫、卵巣腫瘍などが挙げられる。  [0012] Examples of tumors expressing the estrogen receptor include breast cancer, endometrial cancer, endometrial cancer, uterine fibroid, ovarian tumor and the like.
[0013] 本発明において、基 Aは水素原子 (但しこの場合基 Aの置換 ¾ [は存在しない）；カ ルポ二ル基;又はスルホ二ル基を示し、基 Aが水素原子の場合にはその互変異性体 を含む。基 Aとして特に好まし 、ものは水素原子又はカルボ-ル基である。  [0013] In the present invention, the group A represents a hydrogen atom (in this case, a substituted group [not present) of the group A; a carbonyl group; or a sulfonyl group; when the group A is a hydrogen atom, Including its tautomers. Particularly preferred as group A is a hydrogen atom or a carbonyl group.
[0014] 本発明にお 、て ¾ [は置換基を有して 、てもよ 、低級アルキル基；又は置換基を有 して！/、てもよ！/、アミノ基を示す。  [0014] In the present invention, [[having a substituent may be a lower alkyl group; or having a substituent!] / Take it! / Indicates an amino group.
[0015] ¾ [が置換基を有して 、てもよ 、低級アルキル基の場合、アルキル基としては直鎖、 分岐鎖又は環構造のいずれをとつてもよぐ炭素数が 1〜： LOのものが好ましい。例え ば、直鎖又は分岐鎖アルキル基としてはメチル基、ェチル基、 n—プロピル基、イソプ 口ピル基、 n—ブチル基、 tert—ブチル基、ペンチル基、へキシル基、ォクチル基、ノ -ル基、デシル基などが挙げられる。環状アルキル基としてはシクロプロピル基、シク ロブチル基、シクロペンチル基、シクロへキシル基、シクロォクチル基、シクロノニル基 、シクロデシル基等が挙げられる。本発明においては炭素数が 1〜6の直鎖、分岐鎖 又は環状アルキル基が好ましぐさらにはメチル基が好ましい。  [0015] ¾ [has a substituent, and in the case of a lower alkyl group, the alkyl group may have a straight chain, a branched chain, or a ring structure, and the carbon number is 1 to: LO Are preferred. For example, as a linear or branched alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopyl pill group, an n-butyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a non- Group, decyl group and the like. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group. In the present invention, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is preferred, and a methyl group is preferred.
[0016] 低級アルキル基の置換基としては置換又は無置換アミノ基、水酸基、低級アルコキ シ基が挙げられる。置換アミノ基としては、非環状又は環状のァミノ基が挙げられる。 非環状アミノ基の置換基としては炭素数 1から 3で構成される直鎖、分岐鎖又は環構 造のアルキル基が好ましぐメチル基、ェチル基、 n—プロピル基、イソプロピル基、シ クロプロピル基が挙げられ、特に好ましいものはメチル基である。非環状置換アミノ基 として好ましいものはメチルァミノ基、ジメチルァミノ基、ェチルァミノ基、ジェチルアミ ノ基、メチルェチルァミノ基、 n—プロピルアミノ基、シクロプロピルアミノ基、イソプロピ ルァミノ基などが挙げられ、特に好まし 、ものはメチルァミノ基およびジメチルァミノ基 である。環状アミノ基としては単環又は縮合環のもの、脂環式又は芳香族のものが挙 げられ、炭素原子及び窒素原子以外の原子を含んでいてもよい。中でも、 5ないし 6 員環構造を有する複素脂環式ァミノ基が好ましい。具体的には例えば、ピロリジニル 基、ピベリジ-ル基、 4ーピペラジ-ル基、 4ーメチルビペラジ-ル基、 4 モルホリニ ル基等が挙げられる。特に好ましいものはピロリジン 1ーィルおよび 4 モルホリン 4ーィルである。 [0016] The substituent of the lower alkyl group includes a substituted or unsubstituted amino group, a hydroxyl group, and a lower alkoxy. Ci group is mentioned. Examples of the substituted amino group include acyclic or cyclic amino groups. As the substituent for the acyclic amino group, a straight chain, branched chain or cyclic alkyl group having 1 to 3 carbon atoms is preferred, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclo group. A propyl group is exemplified, and a methyl group is particularly preferable. Preferred examples of the acyclic substituted amino group include methylamino group, dimethylamino group, ethylamino group, jetylamino group, methylethylamino group, n-propylamino group, cyclopropylamino group, and isopropylamino group. More preferably, they are a methylamino group and a dimethylamino group. Examples of the cyclic amino group include monocyclic or condensed ring, alicyclic or aromatic groups, and may contain atoms other than carbon atoms and nitrogen atoms. Of these, a heteroalicyclic amino group having a 5- to 6-membered ring structure is preferable. Specific examples include a pyrrolidinyl group, a piperidyl group, a 4-piperazyl group, a 4-methylbiperazyl group, and a 4 morpholinyl group. Particularly preferred are pyrrolidine 1-yl and 4 morpholine 4-yl.
¾ [が置換基を有して 、てもよ 、ァミノ基の場合、置換アミノ基としては、非環状又は 環状のァミノ基が挙げられる。非環状アミノ基の置換基としては炭素数 1から 3で構成 される直鎖、分岐鎖又は環構造のアルキル基、置換ベンゼンおよび 5ないし 6員環構 造を有する複素芳香環が好ましぐメチル基、ェチル基、 n プロピル基、イソプロピ ル基、シクロプロピル基が挙げられ、特に好ましいものはメチル基である。ベンゼンの 置換基は 1〜3個が好ましぐ好ましい置換基としてメチル基、メトキシ基、フッ素原子 、塩素原子、二トリル基、メトキシカルボ-ル基、カルボキシル基、トリァゾリル基などが 挙げられ、特に好ましいものはフッ素原子および-トリル基である。 5ないし 6員環構 造を有する複素芳香環の好ましい例としてはピロール、フラン、チォフェン、ピラゾー ル、イソキサゾール、イソチアゾール、イミダゾール、ォキサゾール、チアゾール、ピリ ジン、ピリダジン、ピリミジン、ピラジン等が挙げられ、特に好ましいものはピリジンおよ びチアゾールである。非環状置換アミノ基として好ましいものはメチルァミノ基、ジメチ ルァミノ基、ェチルァミノ基、ジェチルァミノ基、メチルェチルァミノ基、 n—プロピルァ ミノ基、シクロプロピルアミノ基、イソプロピルアミノ基などが挙げられ、特に好ましいも のはメチルァミノ基およびジメチルァミノ基である。環状アミノ基としては単環又は縮 合環のもの、脂環式又は芳香族のものが挙げられ、炭素原子及び窒素原子以外の 原子を含んでいてもよい。中でも、 5ないし 6員環構造を有する複素脂環式ァミノ基が 好ましい。具体的には例えば、ピロリジ -ル基、ピペリジニル基、 4ーピペラジ-ル基 、 4ーメチルビペラジ-ル基、 4 モルホリニル基等が挙げられる。特に好ましいもの はピロリジン 1ーィルおよび 4 モルホリン 4 ィルである。 In the case of an amino group, examples of the substituted amino group include an acyclic or cyclic amino group. Preferred examples of the substituent for the acyclic amino group include a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, a substituted benzene, and a heteroaromatic ring having a 5- to 6-membered ring structure. Group, ethyl group, n-propyl group, isopropyl group and cyclopropyl group, and particularly preferred is methyl group. Preferred substituents of 1 to 3 substituents for benzene include methyl group, methoxy group, fluorine atom, chlorine atom, nitrile group, methoxycarbol group, carboxyl group, triazolyl group, etc. Preferred are a fluorine atom and a -tolyl group. Preferred examples of the heteroaromatic ring having a 5- to 6-membered ring structure include pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. Particularly preferred are pyridine and thiazole. Preferred examples of the acyclic substituted amino group include methylamino group, dimethylamino group, ethylamino group, jetylamino group, methylethylamino group, n -propylamino group, cyclopropylamino group, isopropylamino group, and the like. One is a methylamino group and a dimethylamino group. Cyclic amino groups are monocyclic or condensed Examples thereof include a ring, an alicyclic group and an aromatic group, and may contain atoms other than carbon atoms and nitrogen atoms. Of these, a heteroalicyclic amino group having a 5- to 6-membered ring structure is preferred. Specific examples include a pyrrolidyl group, piperidinyl group, 4-piperazyl group, 4-methylbiperazyl group, 4 morpholinyl group and the like. Particularly preferred are pyrrolidine 1-yl and 4 morpholine 4-yl.
[0018] 基 A—Jの組合せとして好まし!/、ものはァセチル基、メタンスルホ-ル基、ァミノカル ボニル基、アミノスルホ -ル基、メチルァミノカルボ-ル基、メチルアミノスルホ -ル基 、ジメチルァミノカルボニル基、ジメチルアミノスルホニル基等が挙げられ、特に好まし V、基としてはァセチル基が挙げられる。  [0018] Preferred as a combination of groups A to J! /, Which is a acetyl group, a methanesulfonyl group, an aminocarbonyl group, an aminosulfol group, a methylaminocarbonyl group, a methylaminosulfol group, dimethyl Examples thereof include an aminocarbonyl group and a dimethylaminosulfonyl group, and particularly preferred V is a acetyl group.
[0019] 基 Aが水素原子の場合には、ピラゾール環の特徴として互変異性体が存在する場 合がある。この場合には!、ずれの互変異性体および互変異性体の混合物であっても 本発明に含まれる。  [0019] When the group A is a hydrogen atom, a tautomer may exist as a feature of the pyrazole ring. In this case,!, Any tautomers and mixtures of tautomers are also included in the present invention.
[0020] 基 Gおよび Zはそれぞれ独立に、水素原子;水酸基;低級アルコキシ基;ハロゲノ基 ；又は置換基を有して 、てもよ 、低級ァシルォキシ基 (但し Gおよび Zの 、ずれもが 水素原子;ハロゲノ基の場合を除く）を示す。中でも基 Gおよび Zの一方が水素原子 で他方がハロゲノ基の組み合わせでな 、ものが好まし 、。  [0020] The groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent, which may be a lower acyloxy group (provided that both of G and Z are hydrogen atoms). Atoms; except for halogeno groups). Of these, one in which one of the groups G and Z is a hydrogen atom and the other is not a combination of a halogeno group is preferred.
[0021] 低級アルコキシ基としては炭素数 1〜6のアルコキシ基、例えばメトキシ基、エトキシ 基、プロポキシ基、 n—ブチロキシ基、イソブチロキシ基、 tert—ブチロキシ基、ベント キシ基、へキシロキシ基、シクロへキシロキシ基等が挙げられ、本発明においては炭 素数 1〜3のアルコキシ基が好ましぐ中でもメトキシ基が好ましい。上記一般式（1) において基 G又は Zとして好ましいものは水素原子、水酸基、メトキシ基、スクシ-ル ォキシ基が挙げられる。 G—Zあるいは Z—Gの特に好ましい組合せとしては、水素原 子 水酸基、水素原子ーメトキシ基の組合せが挙げられる。  [0021] The lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, an isobutyroxy group, a tert-butoxy group, a bentoxy group, a hexyloxy group, and a cyclohexyl group. Xyloxy group and the like can be mentioned, and in the present invention, a methoxy group is preferable among alkoxy groups having 1 to 3 carbon atoms. Preferred examples of the group G or Z in the general formula (1) include a hydrogen atom, a hydroxyl group, a methoxy group, and a succinoxy group. Particularly preferred combinations of G—Z or Z—G include a hydrogen atom hydroxyl group, a hydrogen atom-methoxy group combination.
[0022] ハロゲノ基としてはフッ素原子、塩素原子、臭素原子等が挙げられ、本発明にお 、 ては塩素原子が好ましい。  [0022] Examples of the halogeno group include a fluorine atom, a chlorine atom, a bromine atom, and the like. In the present invention, a chlorine atom is preferable.
[0023] 低級ァシルォキシ基としては飽和脂肪族モノカルボン酸のァシルォキシ基であるホ ルミルォキシ基、ァセチルォキシ基、プロピオ-ルォキシ基、ブチリルォキシ基、イソ プチリルォキシ基、バレリルォキシ基、イソバレリルォキシ基など、飽和脂肪族ジカル ボン酸のァシル基であるォキサリルォキシ基、マロニルォキシ基、スクニシルォキシ 基、グルタリルォキシ基等、不飽和脂肪族ジカルボン酸のァシルォキシ基であるフマ リルォキシ基等が挙げられる。本発明にお 、てァシルォキシ基としては飽和脂肪族 ジカルボン酸のァシルォキシ基が好ましぐ中でもスクニシルォキシ基が好ましい。低 級ァシルォキシ基の置換基としては、炭素数 1から 3で構成される直鎖、分岐鎖また は環構造のアルキル基、置換ベンゼンおよび 5な ヽし 6員環構造を有する複素芳香 環、ハロゲノ基が好ましい。炭素数 1から 3で構成される直鎖、分岐鎖または環構造の アルキル基としてはメチル基、ェチル基、 n—プロピル基、イソプロピル基、シクロプロ ピル基が挙げられ、特に好ましくはメチル基である。ベンゼンの置換基は 1〜3個が 好ましぐ好ましい置換基としてはメチル基、メトキシ基、フッ素原子、塩素原子、二トリ ル基、メトキシカルボ-ル基、トリァゾリル基などが挙げられ、特に好ましいのはフッ素 原子及び-トリル基である。 5な 、し 6員環構造を有する複素芳香環の好ま 、例とし てはピロール、フラン、チォフェン、ピラゾール、イソキサゾール、イソチアゾール、イミ ダゾール、ォキサゾール、チアゾール、ピリジン、ピリダジン、ピリミジン、ピラジン等が 挙げられ、特に好ましいものはピリジンおよびチアゾールである。ハロゲノ基としては フッ素原子、塩素原子、臭素原子等が挙げられ、特に好ましいものはフッ素原子及 び塩素原子である。 [0023] The lower acyloxy group is a saturated aliphatic monocarboxylic acid such as formyloxy group, acetyloxy group, propio-oxy group, butyryloxy group, isoptyryloxy group, valeryloxy group, isovaleryloxy group, saturated fatty acid, etc. Zikaru Examples thereof include an oxalyloxy group, a malonyloxy group, a succinyloxy group, a glutaryloxy group, etc., which are an acyl group of a boric acid, and a fumaryloxy group, which is an acyloxy group of an unsaturated aliphatic dicarboxylic acid. In the present invention, the acyloxy group is preferably a succinyloxy group among the saturated aliphatic dicarboxylic acids. Substituents of the lower acyloxy group include linear, branched or cyclic alkyl groups having 1 to 3 carbon atoms, substituted benzene and a 5- or 6-membered heteroaromatic ring, halogeno Groups are preferred. Examples of the linear, branched, or cyclic alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclohexyl group, and a methyl group is particularly preferable. . 1 to 3 substituents for benzene are preferred and preferred substituents include methyl, methoxy, fluorine, chlorine, nitryl, methoxycarbol, triazolyl, etc. Are fluorine atom and -tolyl group. Preferred examples of heteroaromatic rings having a 6-membered ring structure include pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. Particularly preferred are pyridine and thiazole. Examples of the halogeno group include a fluorine atom, a chlorine atom, a bromine atom and the like, and particularly preferred are a fluorine atom and a chlorine atom.
[0024] 基 D、 E、 L、 Q、 Xおよび Yはそれぞれ独立に、水素原子；置換基を有していてもよ Vヽァミノカルボ-ル基；低級アルコキシカルボ-ル基；カルボキシル基；-トリル基；二 トロ基；ハロゲノ基；低級アルキル基；ハロゲノ置換低級アルキル基；低級アルコキシ 基；低級アルキルチオ基；低級アルキルスルホキシル基；低級アルキルスルホン基； 又は置換な 、し無置換アミノスルホ-ル基を示す。  [0024] The groups D, E, L, Q, X and Y are each independently a hydrogen atom; may have a substituent, V-amino carbo group; a lower alkoxy carbo group; a carboxyl group; A tolyl group; a nitrogen group; a halogeno group; a lower alkyl group; a halogeno-substituted lower alkyl group; a lower alkoxy group; a lower alkylthio group; a lower alkylsulfoxyl group; a lower alkylsulfone group; or a substituted or unsubstituted aminosulfol group. Indicates.
[0025] 基 Dと基 Lの両者及び Ζ又は基 Qと基 Υの両者は、例えば、下記一般式（1')に示さ れるように、それぞれが結合する芳香環上の炭素原子、 2個までのヘテロ原子と共に 5な 、し 6員環の複素環 (環 C)を形成し、それぞれが結合する芳香環と共に複素縮 合環を構成してもよい。本発明においてへテロ原子とは窒素原子、酸素原子又は硫 黄原子を示す。これらへテロ原子からは独立に 2個までの原子が選択され得る。本発 明においてとり得る 5員環の複素環としてはへテロ原子を 1個含むもの、例えばピロ一 ル、フラン、チォフェン、同種のへテロ原子を 2個含むもの、たとえばピラゾール、イミ ダゾール、異種のへテロ原子を 2個含むもの、例えばォキサゾール、イソキサゾール、 チアゾール、イソチアゾール等を挙げることができる。本発明においてとり得る 6員環 の複素環としてはピリジン、ピリダジン、ピリミジン、ピラジン等を挙げることができる。 本発明にお 、ては 6員環の複素環が好ましぐピリジンが特に好ま 、。 [0025] Both the group D and the group L and both Ζ or the group Q and the group Υ are, for example, two carbon atoms on the aromatic ring to which they are bonded, as shown in the following general formula (1 '). A 5- or 6-membered heterocyclic ring (ring C) may be formed together with the above heteroatoms, and a heterocyclic ring may be formed together with the aromatic ring to which each is bonded. In the present invention, a hetero atom refers to a nitrogen atom, an oxygen atom or a sulfur atom. Up to two atoms can be selected independently from these heteroatoms. The 5-membered heterocycles that can be used in the present invention include those containing one heteroatom, such as Ru, furan, thiophene, those containing two heteroatoms of the same type, such as pyrazole, imidazole, those containing two heterogeneous heteroatoms, such as oxazole, isoxazole, thiazole, isothiazole and the like. Examples of the 6-membered heterocyclic ring that can be used in the present invention include pyridine, pyridazine, pyrimidine, and pyrazine. Particularly preferred in the present invention is pyridine, which is preferably a 6-membered heterocyclic ring.
Figure imgf000013_0001
Figure imgf000013_0001
[0027] ァミノカルボニル基の置換基とは炭素数 1〜3で構成される直鎖、分岐鎖まもしくは 環構造のアルキル基、例えばメチル基、ェチル基、 n—プロピル基、イソプロピル基、 シクロプロピル基などが挙げられる。置換基の個数は 1又は 2個である。  [0027] The substituent of the aminocarbonyl group is a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclo A propyl group etc. are mentioned. The number of substituents is 1 or 2.
[0028] 低級アルコキシカルボ-ル基とは炭素数 1から 10で構成される直鎖、分岐鎖または 環構造のアルキル基、好ましくは炭素数 1から 6で構成される直鎖、分岐鎖または環 構造のアルキル基を示す。低級アルコキシカルボ-ル基のアルコキシとしては炭素 数 1〜6のアルコキシ、例えばメトキシ、エトキシ、プロポキシ、 n—ブチロキシ、イソブ チロキシ、 tert—ブチロキシ、ペントキシ、へキシロキシ、シクロへキシロキシ等が挙げ られ、本発明においてはメトキシが好ましい。  [0028] The lower alkoxycarbo group is a linear, branched or cyclic alkyl group composed of 1 to 10 carbon atoms, preferably a linear, branched chain or ring composed of 1 to 6 carbon atoms. The alkyl group of a structure is shown. Examples of the alkoxy of the lower alkoxycarbo group include alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, n-butoxy, isobutyloxy, tert-butoxy, pentoxy, hexyloxy, cyclohexyloxy, etc. In the invention, methoxy is preferred.
[0029] ハロゲノ基としてはフッ素原子、塩素原子、臭素原子等が挙げられる。  [0029] Examples of the halogeno group include a fluorine atom, a chlorine atom, and a bromine atom.
[0030] 低級アルキル基とは炭素数が 1から 6である直鎖又は分岐鎖アルキル基、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、 tert—ブチル基 、ペンチル基、ネオペンチル基、へキシル基、又は炭素数が 3から 6である環状アル キル基、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシ ル基等が挙げられる。本発明においては好ましくは炭素数 1〜3の直鎖、分岐鎖、お よび環状のアルキル基例えばメチル基、ェチル基、プロピル基、イソプロピル基、シク 口プロピル基等が挙げられ、特に好まし 、低級アルキル基としてはメチル基が挙げら れる。 [0031] ハロゲノ置換低級アルキル基としては前記低級アルキル基の水素が少なくとも 1つ 以上が前記ハロゲノ基で置換されたものを指し、例えばフルォロメチル基、クロロメチ ル基、ブロモメチル基、ジフルォロメチル基、ジクロロメチル基、ジブロモメチル基、トリ フルォロメチル基、トリクロロメチル基、トリブロモメチル基、フルォロェチル基、クロ口 ェチル基、ブロモェチル基、ジフルォロェチル基、ジクロロェチル基、ジブ口モェチ ル基、トリフルォロェチル基、ペンタフルォロェチル基等が挙げられる。本発明にお いては炭素数が 1〜3であるハロゲノ置換低級アルキル基が好ましぐ中でもトリフル ォロメチル基が好ましい。 [0030] The lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, Examples thereof include a pentyl group, a neopentyl group, a hexyl group, or a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. In the present invention, straight chain, branched chain, and cyclic alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group are preferable, and particularly preferable. Examples of the lower alkyl group include a methyl group. [0031] The halogeno-substituted lower alkyl group refers to a group in which at least one hydrogen of the lower alkyl group is substituted with the halogeno group, for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group. , Dibromomethyl group, trifluoromethyl group, trichloromethyl group, tribromomethyl group, fluorethyl group, chloroethyl group, bromoethyl group, difluoroethyl group, dichloroethyl group, dibumethyl group, trifluoroethyl group, pentafluoro group And a loetyl group. In the present invention, among the halogeno-substituted lower alkyl groups having 1 to 3 carbon atoms, a trifluoromethyl group is preferred.
[0032] 低級アルコキシ基としては炭素数 1〜6のアルコキシ基、例えばメトキシ基、エトキシ 基、プロポキシ基、 n—ブチロキシ基、イソブチロキシ基、 tert—ブチロキシ基、ベント キシ基、へキシロキシ基、シクロへキシロキシ基等が挙げられ、本発明においては炭 素数 1〜3のアルコキシ基が好ましぐ中でもメトキシ基が好ましい。  [0032] The lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, an isobutyroxy group, a tert-butoxy group, a bentoxy group, a hexyloxy group, and a cyclohexyl group. Xyloxy group and the like can be mentioned, and in the present invention, a methoxy group is preferable among alkoxy groups having 1 to 3 carbon atoms.
[0033] 低級アルキルチオ基、低級アルキルスルホキシル基、低級アルキルスルホン基に ぉ 、て低級アルキルとは炭素数が 1から 6である直鎖もしくは分岐鎖アルキル、例え ばメチル、ェチル、 n—プロピル、イソプロピル、 n—ブチル、 tert—ブチル、ペンチル 、ネオペンチル、へキシル、又は炭素数が 1から 6である環状アルキル、例えばシクロ プロピル、シクロブチル、シクロペンチル、シクロへキシル等が挙げられる。本発明に おいては好ましくは炭素数 1〜3の直鎖、分岐鎖、および環状のアルキル例えばメチ ル、ェチル、プロピル、イソプロピル、シクロプロピル等が挙げられ、特に好ましい低 級アルキルとしてはメチルおよびシクロプロピルが挙げられる。  [0033] The lower alkylthio group, the lower alkylsulfoxyl group, the lower alkylsulfone group, and the lower alkyl are linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, Examples thereof include isopropyl, n-butyl, tert-butyl, pentyl, neopentyl, hexyl, or cyclic alkyl having 1 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. In the present invention, preferred are straight-chain, branched-chain, and cyclic alkyls having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl, and cyclopropyl. Particularly preferred lower alkyls are methyl and And cyclopropyl.
[0034] 低級アルキルチオ基としてはメチルチオ基、ェチルチオ基、 n—プロピルチオ基、ィ ソプロピルチオ基、 n—ブチルチオ基、 tert—ブチルチオ基、 n—ペンチルチオ基、 ネオペンチルチオ基、へキシルチオ基、シクロプロピルチオ基、シクロプチルチオ基 、シクロペンチルチオ基、シクロへキシルチオ基等が挙げられ、中でもメチルチオ基 が好ましい。 [0034] The lower alkylthio group includes methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, tert-butylthio group, n-pentylthio group, neopentylthio group, hexylthio group, cyclopropylthio group. Group, cycloptylthio group, cyclopentylthio group, cyclohexylthio group and the like, among which methylthio group is preferable.
[0035] 低級アルキルスルホキシル基としてはメチルスルホキシル基、ェチルスルホキシル 基、 n—プロピルスルホキシル基、イソプロピルスルホキシル基、 n—ブチルスルホキ シル基、 tert—ブチルスルホキシル基、 n—ペンチルスルホキシル基、ネオペンチル スルホキシル基、へキシルスルホキシル基、シクロプロピルスルホキシル基、シクロブ チルスルホキシル基、シクロペンチルスルホキシル基、シクロへキシルスルホキシル 基等が挙げられ、中でもメチルスルホキシル基が好まし 、。 [0035] The lower alkylsulfoxyl group includes methylsulfoxyl group, ethylsulfoxyl group, n-propylsulfoxyl group, isopropylsulfoxyl group, n-butylsulfoxyl group, tert-butylsulfoxyl group, n-pentylsulfo group. Xyl group, neopentyl Examples include a sulfoxyl group, a hexylsulfoxyl group, a cyclopropylsulfoxyl group, a cyclobutylsulfoxyl group, a cyclopentylsulfoxyl group, a cyclohexylsulfoxyl group, and the like. Among them, a methylsulfoxyl group is preferred.
[0036] 低級アルキルスルホン基としてはメチルスルホン基、ェチルスルホン基、 n—プロピ ルスルホン基、イソプロピルスルホン基、 n—ブチルスルホン基、 tert—ブチルスルホ ン基、 n—ペンチルスルホン基、ネオペンチルスルホン基、へキシルスルホン基、シク 口プロピルスルホン基、シクロブチルスルホン基、シクロペンチルスルホン基、シクロへ キシルスルホン基等が挙げられ、中でもメチルスルホン基が好まし ヽ。  [0036] The lower alkyl sulfone group includes methyl sulfone group, ethyl sulfone group, n-propyl sulfone group, isopropyl sulfone group, n-butyl sulfone group, tert-butyl sulfone group, n-pentyl sulfone group, neopentyl sulfone group, Examples thereof include a xylsulfone group, a cyclopropylsulfone group, a cyclobutylsulfone group, a cyclopentylsulfone group, and a cyclohexylsulfone group. Of these, a methylsulfone group is preferred.
[0037] 置換基を有して!/、てもよ 、アミノスルホ -ル基にぉ 、て置換基とは炭素数 1〜3で 構成される直鎖、分岐鎖又は環構造のアルキル基、例えばメチル基、ェチル基、 n— プロピル基、イソプロピル基、シクロプロピル基等が挙げられる。置換基の個数は 1又 は 2個である。  [0037] With a substituent! /, The aminosulfol group may be a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, such as a substituent. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group. The number of substituents is 1 or 2.
[0038] 上記一般式（1)において基 D、 E、 L、 Q、 Xおよび Yとして好ましいものは水素原子 、二トリル基、ニトロ基、塩素原子、フッ素原子、トリフルォロメチル基、メトキシ基、メチ ル基、シクロプロピル基、メチルチオ基、メチルスルホキシル基、メチルスルホン基、メ タンスルホ-ル基が挙げられる。特に好ましいものとしては水素原子、二トリル基、塩 素原子、フッ素原子、トリフルォロメチル基、メチル基が挙げられる。  In the above general formula (1), preferable as the groups D, E, L, Q, X and Y are hydrogen atom, nitrile group, nitro group, chlorine atom, fluorine atom, trifluoromethyl group, methoxy group , A methyl group, a cyclopropyl group, a methylthio group, a methylsulfoxyl group, a methylsulfone group, and a methanesulfol group. Particularly preferred are a hydrogen atom, a nitrile group, a chlorine atom, a fluorine atom, a trifluoromethyl group, and a methyl group.
[0039] 下記一般式（1)で表される 3, 5 ジフヱ-ルビラゾール類縁体とは、例えば以下の 表 1 1に挙げる化合物群である。  [0039] The 3,5 difluoro-rubirazole analogs represented by the following general formula (1) are, for example, a group of compounds listed in Table 11 below.
[0040]  [0040]
Figure imgf000015_0001
化合物番号 し
Figure imgf000015_0001
Compound number
- -
--
- -
--
― -
- -
--
--
--
--
--
--
--
--
- 一 -One
- -
--
--
--
― -
- -
--
--
--
--
--
- 咖 -咖
--
--
--
--
--
- 上記一般式（1)又は一般式（ 1 ')で表される 3, 5 ジフエ二ルビラゾール類縁体の うち、下記一般式（1")で表される 3, 5 ジフエ二ルビラゾール類縁体は、例えば以 下の表 1 2に挙げる化合物群である。
Figure imgf000017_0001
-Of the 3, 5 diphenylbirazole analogues represented by the above general formula (1) or general formula (1 '), the 3, 5 diphenylbirazole analogues represented by the following general formula (1 ") are: For example, the compounds listed in Table 12 below.
Figure imgf000017_0001
[0044] 表 1一;[0044] Table 1;
Figure imgf000017_0002
Figure imgf000017_0002
[0045] 本発明における生理学的に許容される塩としては、塩酸、硫酸等の鉱酸との塩、酢 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 [0045] Physiologically acceptable salts in the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, succinic acid, fumaric acid, maleic acid, citrate, benzoic acid, tartaric acid, methanesulfonic acid.
、 p—トルエンスルホン酸等の有機酸との塩等が挙げられる。また、これらの塩は通常 の造塩反応に付すことにより容易に調製される。 And salts with organic acids such as p-toluenesulfonic acid. In addition, these salts are easily prepared by subjecting them to a normal salt formation reaction.
[0046] 本発明で用いられる細胞増殖阻害効果を有する薬剤は、 3, 5—ジフエ-ルビラゾ ール類縁体又はその生理学的に許容される塩を単独又は賦形剤あるいは担体と混 合して懸濁液、乳剤、注射剤、吸入剤、錠剤、丸剤、顆粒剤、細粒剤、散剤、カプセ ル剤、経口用液剤、座剤、経皮用液剤、経皮用貼付剤、軟膏剤、経粘膜液剤、経粘 膜添付剤等の製剤とし、経口的に、又は非経口的に投与される。賦形剤又は担体等 の添加剤としては薬剤学的に許容されるものが選ばれ、その種類および組成は投与 経路や投与方法によって決まる。例えば注射剤の場合、一般に食塩、グルコースや マン-トール等の糖類が望ましい。経口剤の場合、でんぷん、乳糖、結晶セルロース [0046] The agent having an inhibitory effect on cell proliferation used in the present invention is a 3,5-diphenyl-biazole analogue or a physiologically acceptable salt thereof alone or mixed with an excipient or a carrier. Suspension, emulsion, injection, inhalation, tablet, pill, granule, fine granule, powder, capsule, oral solution, suppository, transdermal solution, transdermal patch, ointment It can be administered orally or parenterally as a formulation such as a transmucosal fluid or transmucosal attachment. As additives such as excipients or carriers, pharmaceutically acceptable ones are selected, and their types and compositions are determined by the administration route and administration method. For example, in the case of injections, saccharides such as sodium chloride, glucose and mannitol are generally desirable. For oral preparations, starch, lactose, crystalline cellulose
、ステアリン酸マグネシウム等が望ましい。所望に応じて上記製剤中に助剤、安定剤 、湿潤剤、又は乳化剤、緩衝液およびその他の通常使用される添加剤が含まれてい てもよい。 Magnesium stearate and the like are desirable. If desired, auxiliaries, stabilizers, wetting agents, or emulsifiers, buffers and other commonly used additives may be included in the preparation.
[0047] 製剤中における本ィ匕合物の含量は製剤により種々異なるが、通常、 0. 1〜： L00重 量％、好ましくは 1〜98重量％である。例えば注射剤の場合には、通常、 0. 1〜30 重量％、好ましくは 1〜10重量％の有効成分を含むようにすることがよい。経口剤の 場合には、添加剤とともに錠剤、カプセル剤、散剤、顆粒剤、液剤、ドライシロップ剤 等の形態で用いられる。カプセル剤、錠剤、顆粒、散剤は一般に 5〜： L00重量％、好 ましくは 25〜98重量％の有効成分を含む。 [0048] 投与量は、患者の年令、性別、体重、症状、治療目的等により決定されるが、治療 量は通常、非経口投与で 0. 001〜100mgZkgZ日であり、経口投与では 0. 01〜 500mg/kg/曰、好ましくは 0. 1〜： LOOmgZkgZ曰、これを 1回で、あるいは 2〜4 回に分けて投与する。 [0047] The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to L00 wt%, preferably 1 to 98 wt%. For example, in the case of injections, the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of an oral preparation, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives. Capsules, tablets, granules and powders generally contain 5 to: L00% by weight, preferably 25 to 98% by weight of active ingredient. [0048] The dosage is determined by the patient's age, sex, weight, symptoms, therapeutic purpose, etc., but the therapeutic dosage is usually 0.001 to 100 mg ZkgZ days for parenteral administration, and 0. 01 to 500 mg / kg / 曰, preferably 0.1 to: LOOmgZkgZ 曰, which is administered once or in 2 to 4 divided doses.
[0049] 本発明の 3, 5—ジフヱ-ルビラゾール類縁体、および本発明に使用される 3, 5— ジフエ二ルビラゾール類縁体は、例えば以下のスキーム 1で示される方法に準じて合 成が可能である。  [0049] The 3,5-diphenyl-rubyrazole analog of the present invention and the 3,5-diphenylrubazole analog used in the present invention can be synthesized, for example, according to the method shown in the following scheme 1. It is.
[0050] スキー A 1 [0050] Ski A 1
Figure imgf000018_0001
Figure imgf000018_0001
[0051] [式中、 A、 J、 D、 E、 L、 Q、 X、 Yおよび Zは一般式（1)に同じ。ただし簡便のため、 一般式（1)において Zは水酸基として記載している。 ] [0051] [In the formula, A, J, D, E, L, Q, X, Y and Z are the same as those in the general formula (1). However, for simplicity, Z is described as a hydroxyl group in general formula (1). ]
[0052] 一般式（7)で示される化合物、すなわち原料として用いる 2—ヒドロキシァセトフエノ ン誘導体は市販品として入手が可能である。また市販されていない誘導体に関して は対応するフエノール誘導体と塩ィ匕ァセチル、もしくはァセトキシベンゼン誘導体をフ リーデル一クラフツ反応に供する事により合成することが可能である。  [0052] The compound represented by the general formula (7), that is, the 2-hydroxyacetophenone derivative used as a raw material is commercially available. Non-commercial derivatives can be synthesized by subjecting the corresponding phenol derivative and salt acetyl or acetylbenzene derivative to the Friedel-Crafts reaction.
[0053] 一般式 (7)および、一般式 (8)で示される酸塩化物又は安息香酸誘導体とを縮合 反応に供する事により、一般式（9)で示されるエステル体へと導く。 [0053] Condensation with general formula (7) and acid chloride or benzoic acid derivative represented by general formula (8) By subjecting to reaction, it leads to the ester body represented by the general formula (9).
[0054] 一般式 (9)の化合物は単離しても良いが、縮合反応成績体として一般式 (9)の生 成を確認後、単離精製することなく反応系内にカリウム t ブトキシドなどの塩基を カロえる事により、 1ポットの反応として一般式（10)の化合物を得ることも十分に可能で ある。 [0054] The compound of the general formula (9) may be isolated, but after confirming the formation of the general formula (9) as a condensation reaction product, potassium t-butoxide or the like may be contained in the reaction system without isolation and purification. By removing the base, it is possible to obtain the compound of the general formula (10) as a one-pot reaction.
[0055] 一般式（10)の化合物およびヒドラジンとを縮合反応に供する事により、一般式（11 )の化合物を得ることが出来る。一般式（11)の化合物は前述の通り互変異性体の存 在する可能性がある力 簡便のため上記スキーム 1中では一方の異性体のみを記載 している。  [0055] A compound of the general formula (11) can be obtained by subjecting the compound of the general formula (10) and hydrazine to a condensation reaction. As described above, the compound of the general formula (11) may have a tautomer as described above. In the above scheme 1, only one isomer is described for simplicity.
[0056] 一般式（12)の化合物を得るには、次の方法を用いる事が出来る。すなわち一般式  [0056] In order to obtain the compound of the general formula (12), the following method can be used. That is, the general formula
(11)の化合物 ^J—A(Aが水素原子の場合を除く）の酸塩ィ匕物などとを縮合すること により、一般式（12)の化合物を合成することが可能である。例え «Jカ^チル基、 Aが カルボニル基であるような場合には塩ィ匕ァセチルを用いて一般式（11)の化合物と縮 合反応を行うことにより、一般式（12)に相当するァセチル誘導体を合成することが出 来る。  The compound of general formula (12) can be synthesized by condensing the compound of (11) with an acid salt of ^ J-A (except when A is a hydrogen atom). For example, in the case where «J-catyl group and A is a carbonyl group, a condensation reaction is performed with a compound of general formula (11) using a salt acetyl group, which corresponds to general formula (12). It is possible to synthesize acetyl derivatives.
実施例  Example
[0057] 以下に合成例（実施例および参考例)及び実験例を挙げて本発明を具体的に説明 する力 本発明はこれらにより限定されるものではない。  [0057] The ability to specifically describe the present invention with reference to synthesis examples (Examples and Reference Examples) and experimental examples below. The present invention is not limited thereto.
[0058] 本合成例において、 ESIとは Electron Spray Ionizationの略であり、分子量測 定におけるイオンィ匕法の 1つである。また、本実験例において (ER+)はエストロゲン 受容体を発現する細胞を、 (ER-)はエストロゲン受容体の発現していない細胞をそ れぞれ表す。 [0058] In this synthesis example, ESI is an abbreviation for Electron Spray Ionization, and is one of the ionic methods in molecular weight measurement. In this experimental example, (ER +) represents a cell expressing the estrogen receptor, and (ER−) represents a cell not expressing the estrogen receptor.
[0059] 実施例 1 3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (3 シァノ）フエ-ル一（1 H)ーピラゾール (ィ匕合物番号 1)の合成  [0059] Example 1 Synthesis of 3— (2 hydroxy-1 5-mouth) phenol 1— (3 cyano) phenol (1 H) -pyrazole (Compound No. 1)
5'—クロ口一 2'—ヒドロキシァセトフエノン（129. 8mg)をジメチルホルムアミド（1. 5 ml)に溶解し、 3 シァノベンゾイルクロリド（139mg)、次いでピリジン（80 μ 1)を加え て室温で 20時間攪拌した。氷水冷却下、反応液にカリウム— t—ブトキシド（198mg) を加えた。反応系が不均一となったためワンミキサーを掛けた後、室温で更に 5時間 攪拌した。 2規定塩酸および酢酸ェチルを加えて不溶物を濾別した後、濾液を分液 ロートへ移した。水層を除去した後、水道水（6回)で洗浄した。 Dissolve 5'-black 2'-hydroxyacetophenone (129.8 mg) in dimethylformamide (1.5 ml), add 3 cyanobenzoyl chloride (139 mg), and then add pyridine (80 μ 1). Stir at room temperature for 20 hours. Under cooling with ice water, potassium t-butoxide (198 mg) was added to the reaction solution. Since the reaction system became heterogeneous, after 5 minutes at room temperature after applying one mixer Stir. 2N Hydrochloric acid and ethyl acetate were added to separate insoluble matters, and the filtrate was transferred to a separatory funnel. After removing the aqueous layer, it was washed with tap water (6 times).
[0060] 有機層をエバポレートして得られた残渣にテトラヒドロフラン（5ml)を加えて摂氏 50 —60度に加熱して溶液とした。ヒドラジン水和物（0. 1ml)をカ卩えて 17. 5時間攪拌し た後、反応溶液を酢酸ェチルで分液ロートへ移し、飽和食塩水 Z水道水（1Z1)、 飽和食塩水で順次洗浄した。有機層をエバポレートして得られた固体性残渣にイソ プロピルエーテル（5ml)をカ卩え、室温で 3時間攪拌した。析出固体を濾取して乾燥 することにより、 目的化合物（114. lmg)を得た。  [0060] Tetrahydrofuran (5 ml) was added to the residue obtained by evaporating the organic layer and heated to 50-60 degrees Celsius to form a solution. After hydrazine hydrate (0.1 ml) was added and stirred for 17.5 hours, the reaction solution was transferred to a separatory funnel with ethyl acetate and washed sequentially with saturated saline Z tap water (1Z1) and saturated saline. did. Isopropyl ether (5 ml) was added to the solid residue obtained by evaporation of the organic layer, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain the target compound (114. lmg).
[0061] MS (ESI) :m/z 296 [M+H]+  [0061] MS (ESI): m / z 296 [M + H] +
[0062] 実施例 2 3— (2—ヒドロキシ一 5—クロ口）フエ-ル一 5— (4—シァノ）フエ-ル一（1 [0062] Example 2 3— (2-hydroxy-5-chloro) 1--5- (4-cyanol) 1 (1
H)ーピラゾール (化合物番号 5)の合成 Synthesis of H) -pyrazole (Compound No. 5)
実施例 1にお 、て、 3—シァノベンゾイルク口リドの替わりに 4 -シァノベンゾイルク口 リド（139mg)を用いて同様の反応を行うことにより、 目的の化合物（110. lmg)を得 た。  In Example 1, the same compound (110. lmg) was obtained by carrying out the same reaction using 4-cyanobenzoyl chloride (139 mg) instead of 3-cyanobenzoyl chloride. Obtained.
[0063] MS (ESI) :m/z 296 [M+H]+  [0063] MS (ESI): m / z 296 [M + H] +
[0064] 実施例 3 3—（2—ヒドロキシー5—クロ口）フエ-ルー 5—（3—（トリフルォロメチル）） フ 二ルー (1H)ーピラゾール（ィ匕合物番号 2)の合成  Example 3 3— (2-Hydroxy-5-black mouth) ferro-5- (3- (trifluoromethyl)) Fluoro (1H) -pyrazole (Compound No. 2) synthesis
2—ヒドロキシ一 5—クロロアセトフエノン（128. 4mg)をジメチルホルムアミド（0. 8m 2-Hydroxy-1-5-chloroacetophenone (128.4 mg) with dimethylformamide (0.8 m
I)に溶解し、 3— (トリフルォロメチル）ベンゾイルクロリド（123 μ 1)、次いでピリジン（7 9 1)をカ卩えて室温で 20時間攪拌した。氷水冷却下、反応液にカリウム— t—ブトキ シド（198mg)をカ卩えた。反応系が不均一となったためワンミキサーを掛けた後、室温 で更に 5時間攪拌した。 2規定塩酸および酢酸ェチルを加えて反応液を分液ロート へ移した。水層を除去した後、水道水（6回)で洗浄した。 Dissolved in I), 3- (trifluoromethyl) benzoyl chloride (123 μ1) and then pyridine (79 1) were added and stirred at room temperature for 20 hours. Under ice water cooling, potassium t-butoxide (198 mg) was added to the reaction solution. Since the reaction system became heterogeneous, it was stirred for 5 hours at room temperature after applying one mixer. 2N hydrochloric acid and ethyl acetate were added, and the reaction solution was transferred to a separatory funnel. After removing the aqueous layer, it was washed with tap water (6 times).
有機層をエバポレートして得られた残渣をテトラヒドロフラン（3ml)に溶解し、ヒドラ ジン水和物（0. 1ml)をカ卩えて 17. 5時間攪拌した。反応溶液を酢酸ェチルで分液口 ートへ移し、飽和食塩水 Z水道水（1Z1)、飽和食塩水で順次洗浄した。有機層を エバポレートして得られた固体性残渣にイソプロピルエーテル（3ml)を加え、室温で 3時間攪拌した。析出固体を濾取して乾燥することにより、 目的化合物（37. 7mg)を 得た。 The residue obtained by evaporating the organic layer was dissolved in tetrahydrofuran (3 ml), hydrazine hydrate (0.1 ml) was added, and the mixture was stirred for 17.5 hours. The reaction solution was transferred to a separation port with ethyl acetate, and washed successively with saturated brine Z tap water (1Z1) and saturated brine. Isopropyl ether (3 ml) was added to the solid residue obtained by evaporating the organic layer, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain the target compound (37.7 mg). Obtained.
[0065] MS (ESI) :m/z 339 [M+H]+  [0065] MS (ESI): m / z 339 [M + H] +
[0066] 実施例 4 3— (2 ヒドロキシー5 クロ口）フエ-ルー 5— (3—メチル）フエ-ルー（1 [0066] Example 4 3— (2 hydroxy-5 black mouth) ferro 5— (3-methyl) ferro (1
H)ーピラゾール (化合物番号 3)の合成 Synthesis of H) -pyrazole (Compound No. 3)
実施例 2において、 3 （トリフルォロメチル）ベンゾイルク口リドの替わりに 3 メチル ベンゾイルクロリド（112 1)を用いて同様の反応を行うことにより、 目的の化合物（84 . 8mg)を得た。  In Example 2, the same compound (84.8 mg) was obtained by performing the same reaction using 3 methylbenzoyl chloride (112 1) instead of 3 (trifluoromethyl) benzoyl chloride.
[0067] MS (ESI) :m/z 285 [M+H]+ [0067] MS (ESI): m / z 285 [M + H] +
[0068] 実施例 5 3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (3 フルォロ）フエ-ル一（ [0068] Example 5 3— (2 hydroxy-1 5 × 1) file 5— (3 fluoro) file 1
1H)ーピラゾール (ィ匕合物番号 4)の合成 1H) -Pyrazole (Compound No. 4)
実施例 2において、 3 （トリフルォロメチル）ベンゾイルク口リドの替わりに 3 フルォ 口べンゾイルクロリド（104 1)を用いて同様の反応を行うことにより、 目的の化合物（9 In Example 2, the same compound (9) was obtained by carrying out the same reaction using 3 fluorobenzoyl chloride (104 1) instead of 3 (trifluoromethyl) benzoyl chloride.
1. 4mg)を得た。 1. 4 mg) was obtained.
[0069] MS (ESI) :m/z 289 [M+H]+ [0069] MS (ESI): m / z 289 [M + H] +
[0070] 実施例 6 3— (2—ヒドロキシ一 5 クロ口）フエ-ルー 5— (4—アミノスルホ -ル）フエ 二ルー（1H)—ピラゾール（ィ匕合物番号 8)の合成  Example 6 3—Synthesis of 2- (2-hydroxy-5-cyclo) -phenol 5 -— (4-aminosulfo) phenol di- (1H) -pyrazole (Compound No. 8)
本ィ匕合物は以下の 2工程で合成を行った。  This compound was synthesized in the following two steps.
I) 4 アミノスルホ-ルー（2' ァセチルー 4' クロ口）フエ-ルペンゾエート（スキー ム 1の一般式（9)において、 D = SO NH、E = G=Y=H、X=C1)の合成  I) Synthesis of 4 aminosulfo-luo (2 'acetyl 4' black mouth) phenol penzoate (in Scheme 1, general formula (9), D = SO NH, E = G = Y = H, X = C1)
2 2  twenty two
2 -ヒドロキシ 5 クロロアセトフエノン（ 194. Omg)および 4 -カルボキシベンゼ ンスルホンアミド（228. 3mg)をジメチルホルムアミド（1. 1ml)に溶解し、 1—ジメチ ルァミノプロピル 3 ェチルカルボジイミド塩酸塩（26 lmg)および 4 ジメチルアミ ノビリジン (69mg)をカ卩えて室温で 18時間攪拌した。 2規定塩酸および酢酸ェチルを 加えて反応液を分液ロートへ移した。水層を除去した後、水道水（3回）および飽和 食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートして得られ た固体性残渣に酢酸ェチル (4ml)を加え、摂氏 50度で溶液とした。  2-Hydroxy-5 chloroacetophenone (194. Omg) and 4-carboxybenzensulfonamide (228.3 mg) were dissolved in dimethylformamide (1.1 ml) and 1-dimethylaminopropyl 3-ethylcarbodiimide hydrochloride (26 lmg) and 4dimethylaminoviridine (69mg) were added and stirred at room temperature for 18 hours. 2N Hydrochloric acid and ethyl acetate were added and the reaction mixture was transferred to a separatory funnel. The aqueous layer was removed, and then washed with tap water (3 times) and saturated brine. After drying over anhydrous sodium sulfate, ethyl acetate (4 ml) was added to the solid residue obtained by evaporating the organic layer to make a solution at 50 degrees Celsius.
溶液を室温に戻し、へキサン（16ml)を加えて 3時間攪拌した。析出固体を濾取し て乾燥することにより、 目的化合物（287. 2mg)を得た。 [0071] MS (ESI) :m/z 354 [M+H]+ The solution was returned to room temperature and hexane (16 ml) was added and stirred for 3 hours. The precipitated solid was collected by filtration and dried to obtain the target compound (287.2 mg). [0071] MS (ESI): m / z 354 [M + H] +
[0072] 2) 3 - (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (4 アミノスルホ -ル）フエ-ル一（ 1H)ーピラゾール (化合物番号 8)の合成  [0072] 2) Synthesis of 3-(2 Hydroxy-5-Phenol) Phenol 5 -— (4 Aminosulfol) Phenol (1H) -Pyrazole (Compound No. 8)
4 アミノスルホ-ルー（2'—ァセチルー 4'—クロ口）フエ-ルペンゾエート（287. 2m g)をジメチルホルムアミド（1. 6ml)に溶解し、氷水冷却下、カリウム t—ブトキシド（21 lmg)をカ卩えて 16時間攪拌した。 2規定塩酸および酢酸ェチルを加えて反応液を分 液ロートへ移した。水層を除去した後、水道水（2回)で洗浄した。有機層からは固体 が析出していた力 固体ごと有機層をエバポレートした後、残渣にメタノール（5ml)を 加えて摂氏 60度に加熱した。ヒドラジン水和物（0. 2ml)をカ卩えて 17. 5時間攪拌し た後、室温で 5時間攪拌した。析出固体を濾取して乾燥することにより、 目的化合物（ 19. 7mg)を得た。  4 Aminosulfolulu (2'-acetyl 4'-black) phenol penzoate (287.2 mg) was dissolved in dimethylformamide (1.6 ml), and potassium t-butoxide (21 lmg) was dissolved in ice water. Stir for 16 hours. 2N hydrochloric acid and ethyl acetate were added, and the reaction mixture was transferred to a separatory funnel. After removing the aqueous layer, it was washed with tap water (twice). The force from which a solid was precipitated from the organic layer After the organic layer was evaporated together with the solid, methanol (5 ml) was added to the residue and heated to 60 degrees Celsius. Hydrazine hydrate (0.2 ml) was added and stirred for 17.5 hours, then at room temperature for 5 hours. The precipitated solid was collected by filtration and dried to obtain the target compound (19.7 mg).
[0073] MS (ESI) :m/z 350 [M+H]+ [0073] MS (ESI): m / z 350 [M + H] +
[0074] 実施例 7 3—（2 ヒドロキシー5 クロ口）フエ-ルー 5—（4 （トリフルォロメチル）） フ 二ルー (1H)ーピラゾール（ィ匕合物番号 6)の合成  Example 7 Synthesis of 3— (2 hydroxy-5 black mouth) ferro-5— (4 (trifluoromethyl)) fluor (1H) -pyrazole (Compound No. 6)
実施例 2において、 3 （トリフルォロメチル）ベンゾイルク口リドの替わりに 4 （トリフ ルォロメチル)ベンゾイルク口リドを用いて同様の反応を行うことにより、 目的の化合物 In Example 2, the target compound was obtained by conducting the same reaction using 4 (trifluoromethyl) benzoyl chloride instead of 3 (trifluoromethyl) benzoyl chloride.
(96. 7mg)を得た。 (96.7 mg) was obtained.
[0075] MS (ESI) :m/z 339 [M+H]+ [0075] MS (ESI): m / z 339 [M + H] +
[0076] 実施例 8 1—ァセチル— 3— (2 ヒドロキシ— 5 クロ口）フエ-ル— 5— (4— (トリフ ルォロメチル） )フエ-ルーピラゾール（化合物番号 7)の合成  Example 8 Synthesis of 1-Acetyl-3- (2 Hydroxy-5 Chromium) Phenol-5- (4- (Trifluoromethyl)) Phenolupyrazole (Compound No. 7)
3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (4— (トリフルォロメチル））フエ-ル 一（1H)—ピラゾール（11. 8m)をピリジン（0. 2ml)に溶解し、無水酢酸（0. 2ml)を 加えて室温で 2時間攪拌した。  3— (2 Hydroxy-1 5) Methyl 5- (4- (Trifluoromethyl)) 1-Hole (1H) -Pyrazole (11.8m) dissolved in Pyridine (0.2ml) Acetic anhydride (0.2 ml) was added and stirred at room temperature for 2 hours.
反応液を酢酸ェチルで分液ロートへ移し、水道水（5回）および飽和食塩水で洗浄 した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートすることにより目的化合物 (13. 5mg)を得た。  The reaction mixture was transferred to a separatory funnel with ethyl acetate and washed with tap water (5 times) and saturated brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated to obtain the target compound (13.5 mg).
[0077] MS (ESI) :m/z 381 [M+H]+ [0077] MS (ESI): m / z 381 [M + H] +
[0078] 実施例 9 1—ジメチルァミノカルボ-ル— 3— (2—ヒドロキシ— 5 クロ口）フエ-ル— 5—（4 （トリフルォロメチル））フ 二ルーピラゾール（ィ匕合物番号 41)の合成 本化合物は反応原料として化合物番号 6の化合物を用い、以下の 4工程で合成を 行った。 Example 9 1—Dimethylaminocarbole— 3— (2-Hydroxy—Black) Fale— Synthesis of 5- (4 (trifluoromethyl)) fluoropyrazole (Compound No. 41) This compound was synthesized in the following four steps using Compound No. 6 as a reaction raw material.
[0079] 1) 3— [2 （tーブチルジメチルシリルォキシ）ー5 クロ口]フエ-ルー 5—（4 （トリ フルォロメチル））フエ-ルー（1H)—ピラゾールの合成  [0079] 1) 3— [2 (t-Butyldimethylsilyloxy) -5 Chromium] Ferru 5— (4 (Trifluoromethyl)) Ferru (1H) —Synthesis of pyrazole
3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (4— (トリフルォロメチル））フエ-ル 一（1H)—ピラゾール（ィ匕合物番号 6、 1. OOg)およびイミダゾール（402mg)をジメチ ルホルムアミド（1. 5ml)に加え、摂氏 4度で tーブチルジメチルクロロシラン（50重量 %のトルエン溶液、 1. 23ml)を加えた。 5分後に室温へ昇温した後、 3時間攪拌を続 けた。反応溶液を酢酸ェチルで希釈し、水道水で洗浄した。無水硫酸ナトリウムで乾 燥後、有機層をエバポレートした。得られた残渣をシリカゲルカラムクロマトグラフィー (シリカゲル 30g、へキサン Z酢酸ェチル = 5Z1次 、でへキサン Z酢酸ェチル Zメ タノール =3ZlZ0. 1)で精製することにより、 目的化合物（1. 08g)を得た。  3— (2 Hydroxy-5-chloro) 1- 5- (4- (Trifluoromethyl)) 1- (1H) -Pyrazole (Compound No. 6, 1. OOg) and Imidazole ( 402 mg) was added to dimethylformamide (1.5 ml) and t-butyldimethylchlorosilane (50 wt% toluene solution, 1.23 ml) was added at 4 degrees Celsius. After 5 minutes, the temperature was raised to room temperature and stirring was continued for 3 hours. The reaction solution was diluted with ethyl acetate and washed with tap water. After drying over anhydrous sodium sulfate, the organic layer was evaporated. The obtained residue was purified by silica gel column chromatography (silica gel 30 g, hexane Z ethyl acetate = 5Z primary, hexane Z ethyl acetate Z methanol = 3 ZlZ0.1) to give the target compound (1.08 g). Obtained.
[0080] MS (ESI) :m/z 453 [M+H]+  [0080] MS (ESI): m / z 453 [M + H] +
[0081] 2) 1 フエ-ルォキシカルボ-ルー 3— [2 （tーブチルジメチルシリルォキシ） 5 クロ口]フエ-ルー 5—（4 （トリフルォロメチル））フエ-ルーピラゾールの合成 [0081] 2) Synthesis of 1-phenylcarboxyl 3— [2 (t-butyldimethylsilyloxy) 5 black mouth] Fuel 5— (4 (trifluoromethyl)) phenol-pyrazole
3— [2 （tーブチルジメチルシリルォキシ）ー5 クロ口]フエ-ルー 5—（4 （トリフ ルォロメチル） )フエ-ル一 (1H)—ピラゾール（0. 60g)をピリジン（3ml)に溶解し、 摂氏 4度でフエ-ルクロロホルメート（0. 24g)をカ卩えた。 35分後に室温へ昇温し、一 晚攪拌を続けた。反応溶液を酢酸ェチルで希釈し、水道水で洗浄した。無水硫酸ナ トリウムで乾燥後、有機層をエバポレートして得られた残渣をシリカゲルクロマトグラフ ィー（シリカゲル 18g、へキサン Z酢酸ェチル = 10Zl)で精製する事により、 目的化 合物 (0. 77g)を得た。 3— [2 (t-Butyldimethylsilyloxy) -5 Chromium] Fuel 5— (4 (Trifluoromethyl)) phenol (1H) -Pyrazole (0.60 g) into pyridine (3 ml) Dissolve and ferrule chloroformate (0.24 g) at 4 degrees Celsius. After 35 minutes, the temperature was raised to room temperature and stirring was continued. The reaction solution was diluted with ethyl acetate and washed with tap water. After drying over anhydrous sodium sulfate, the organic layer was evaporated and the residue obtained was purified by silica gel chromatography (silica gel 18 g, hexane Z ethyl acetate = 10 Zl) to give the desired compound (0.777 g). )
[0082] MS (ESI) :m/z 573 [M+H]+  [0082] MS (ESI): m / z 573 [M + H] +
[0083] 3) 1ージメチルァミノカルボ-ルー 3— [2 （tーブチルジメチルシリルォキシ） 5— クロ口]フエ-ルー 5—（4 （トリフルォロメチル））フエ-ルーピラゾールの合成 メタノール（2ml)に、 1 フエ-ルォキシカルボ-ルー 3— [2 （tーブチルジメチル シリルォキシ） 5—クロ口]フエ-ル一 5— (4— (トリフルォロメチル））フエ-ル一ビラ ゾール（273mg)およびジメチルァミン (40重量％水溶液、 0. 06ml)を摂氏 4度で加 えた。 1. 5時間後、反応液をエバポレートして得られた残渣を、シリカゲルカラムクロ マトグラフィー（シリカゲル 27g、へキサン Z酢酸ェチル = 10Z1から 3Z1)で精製す る事により、 目的化合物（156mg)を得た。 [0083] 3) 1-Dimethylaminocarboru 3— [2 (t-butyldimethylsilyloxy) 5— black mouth] Ferro 5— (4 (trifluoromethyl)) Synthesis In methanol (2 ml), 1-phenylcarboxyl 3— [2 (t-butyldimethylsilyloxy) 5—black] methanol 1— (4— (trifluoromethyl)) solvent Zole (273 mg) and dimethylamine (40 wt% aqueous solution, 0.06 ml) were added at 4 degrees Celsius. 1. After 5 hours, the reaction mixture was evaporated, and the residue obtained was purified by silica gel column chromatography (silica gel 27 g, hexane Z ethyl acetate = 10Z1 to 3Z1) to give the target compound (156 mg). Obtained.
[0084] MS (ESI) : m/z 524 [M +H]+ [0084] MS (ESI): m / z 524 [M + H] +
[0085] 4) 1—ジメチルァミノカルボ-ル一 3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (4 （トリフルォロメチル））フ 二ルーピラゾール（ィ匕合物番号 41)の合成  [0085] 4) 1-Dimethylaminocarboxyl 3— (2 Hydroxy 1 5 Chloro) 1-Diphenyl 5 — (4 (Trifluoromethyl)) 2-dipyrazole (Compound No. 41) )
1 ジメチルァミノカルボ-ル 3— [ 2 （t ブチルジメチルシリルォキシ） 5 ク ロロ]フエ-ルー 5— (4— (トリフルォロメチル））フエ-ルーピラゾール（150mg)をテト ラヒドロフラン（3ml)に溶解し、摂氏 4度でテトラ一 n—プチルアンモ -ゥムフルオリド（ 0. 34ml)を加えて、室温で一晩攪拌した。反応液を酢酸ェチルで希釈し、水道水で 洗浄した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートして得られた残渣を シリカゲルカラムクロマトグラフィー（シリカゲル 4. 5g、へキサン Z酢酸ェチル = 10Z 1から lZl)で精製する事により、 目的化合物（52mg)を得た。
Figure imgf000024_0001
1 Dimethylaminocarbole 3— [2 (t-butyldimethylsilyloxy) 5 chloro] ferro-5- (4- (trifluoromethyl)) ferro-pyrazole (150 mg) with tetrahydrofuran (3 ml ), Tetra-n-butylammofluoride (0.34 ml) was added at 4 degrees Celsius, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and washed with tap water. After drying over anhydrous sodium sulfate, the organic layer was evaporated and the resulting residue was purified by silica gel column chromatography (silica gel 4.5 g, hexane Z ethyl acetate = 10Z 1 to lZl) to give the target compound (52 mg) Got.
Figure imgf000024_0001
3. 20 (3H, s)、 3. 85 (3H, s)、 7. 02 (2H, d, J = 8. 8Hz)、 7. 29 ( 1H, dd, J = 2 . 7, 8. 8Hz)、 7. 39 ( 1H, s)、 7. 75 ( 1H, d, J = 8. 1Hz) , 7. 83— 7. 90 ( 1H,さ らに 1Hがオーバーラップ)。  3.20 (3H, s), 3.85 (3H, s), 7.02 (2H, d, J = 8.8Hz), 7.29 (1H, dd, J = 2.7, 8.8Hz ), 7.39 (1H, s), 7.75 (1H, d, J = 8.1 Hz), 7.83—7.90 (1H and 1H overlap).
[0087] MS (ESI) : m/z 410 [M +H]+ [0087] MS (ESI): m / z 410 [M + H] +
[0088] 実施例 10 1—ジメチルアミノスルホ-ルー 3— (2 ヒドロキシ一 5 クロ口）フエ-ル  Example 10 1-Dimethylaminosulfolulu 3-
5—（4 （トリフルォロメチル））フ 二ルーピラゾール（ィ匕合物番号 42)の合成 Synthesis of 5- (4 (Trifluoromethyl)) furipyrazole (Compound No. 42)
3— [2 （tーブチルジメチルシリルォキシ）ー5 クロ口]フエ-ルー 5—（4 （トリフ ルォロメチル））フエ-ルー（1H)—ピラゾール（180mg)をピリジン（lml)に溶解し、 摂氏 4度でジメチルアミノスルホニルクロリド（608 μ 1)を加えて 7時間加熱還流した。 反応液を室温へ冷却した後、反応液をエバポレートして得られた残渣をシリカゲルク 口マトグラフィー（シリカゲル 27g、塩化メチレンのみ、次いで塩化メチレン Zメタノー ル = 10Zl)で精製する事により、 目的化合物（3. 7mg)を得た。またこの時の主生 成物は 1 ジメチルアミノスルホ -ル 3—（5 クロロー 2— t—ブチルジメチルシリル ォキシ）フエ-ルー 5—（4 （トリフルォロメチル））フエ-ルーピラゾール（41mg)だつ た。 3— [2 (t-butyldimethylsilyloxy) -5 black mouth] ferro 5— (4 (trifluoromethyl)) ferro (1H) -pyrazole (180 mg) is dissolved in pyridine (lml), Dimethylaminosulfonyl chloride (608 μ1) was added at 4 degrees Celsius and heated to reflux for 7 hours. After cooling the reaction solution to room temperature, the residue obtained by evaporating the reaction solution is purified by silica gel chromatography (silica gel 27 g, methylene chloride alone, then methylene chloride Z methanol = 10 Zl) to give the target compound (3.7 mg) was obtained. The main product at this time is 1 dimethylaminosulfol 3- (5 chloro-2-t-butyldimethylsilyl Oxy) Fu-Lu 5— (4 (Trifluoromethyl)) Fu-Lupyrazole (41 mg).
[0089] MS (ESI) :m/z 560 [M+H]+  [0089] MS (ESI): m / z 560 [M + H] +
[0090] 実施例 11 1—メチルスルホ -ル一 3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— ( 4 （トリフルォロメチル））フ 二ルーピラゾール（ィ匕合物番号 43)の合成  Example 11 1—Methylsulfol 1- (2-hydroxy-5-chloro) 1-methyl 4- (4 (trifluoromethyl)) 2-nitropyrazole (Compound No. 43) Composition
フエ-ルクロロホルメートの替わりにメタンスルホユルク口リドを用い、実施例 9におけ る 2)および 4)と同様の操作を行うことにより、 3— [2— (t—ブチルジメチルシリルォキ シ） 5 クロ口]フエ-ル一 5— (4— (トリフルォロメチル））フエ-ル一（1H)—ビラゾ ール（148mg)力も 2工程で目的化合物（6. 7mg)を得た。  The same procedure as in 2) and 4) in Example 9 was carried out using methanesulfuryl chloride in place of phenol chloroformate, thereby producing 3- [2- (t-butyldimethylsilyloxy). 5) (Black mouth) phenol 1— (4- (trifluoromethyl)) phenol 1 (1H) -virazole (148 mg) was also obtained in 2 steps to obtain the target compound (6.7 mg). .
[0091] MS (ESI) :m/z 417 [M+H]+  [0091] MS (ESI): m / z 417 [M + H] +
[0092] 実施例 12 3— (2 ヒドロキシ一 5—メトキシカルボ-ル）フエ-ルー 5— (4— (トリフ ルォロメチル） )フエ二ルー (1H)ーピラゾール（ィ匕合物番号 44)の合成  Example 12 3—Synthesis of (2 Hydroxy-5-methoxycarbol) Ferru 5— (4— (Trifluoromethyl)) Fenirrou (1H) -Pyrazole (Compound No. 44)
本化合物は、以下の 3工程で合成した。  This compound was synthesized in the following three steps.
[0093] 1) 4 トリフルォロメチル一（2'—ァセチル一 4'—メトキシカルボ-ル）フエ-ルペンゾ エートの合成  [0093] 1) Synthesis of 4 trifluoromethyl mono (2'-acetyl mono 4'-methoxycarbol) phenol penzoate
3 ァセチルー 4 ヒドロキシ一メチルベンゾエート（500mg)およびピリジン（0. 27 ml)をジメチルホルムアミド（1. 3ml)に溶解し、摂氏 10度以下の温度を保ちながら 4 —(トリフルォロメチル)ベンゾイルクロリド (0. 46ml)を滴下した。 1時間攪拌を続けた 後、反応液を酢酸ェチルで希釈し、 10%硫酸水素カリウム水溶液、水道水、飽和食 塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートして得ら れた残渣をシリカゲルカラムクロマトグラフィー（シリカゲル 50g、へキサン Z酢酸ェチ ル= 10Z1から 3Z1)で精製する事により、 目的化合物（931mg)を得た。  3 Acetyl- 4 hydroxy monomethylbenzoate (500 mg) and pyridine (0.27 ml) are dissolved in dimethylformamide (1.3 ml) and 4 — (trifluoromethyl) benzoyl chloride ( 0.46 ml) was added dropwise. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate and washed successively with 10% aqueous potassium hydrogen sulfate solution, tap water, and saturated saline. After drying over anhydrous sodium sulfate, the organic layer was evaporated and the residue obtained was purified by silica gel column chromatography (silica gel 50 g, hexane Z acetate = 10Z1 to 3Z1) to give the target compound (931 mg) Got.
[0094] 'H -NMR CCDCI )  [0094] 'H -NMR CCDCI)
3  Three
2. 61 (3H, s)、 3. 98 (3H, s)、 7. 34 (1H, d, J = 8. 4Hz)、 7. 80 (2H, d, J = 8. 4Hz)、 8. 25-8. 37 (2H,さらに 1Hとオーバーラップ）、 8. 56 (1H, d, J = 2. 1H z) 0 2.61 (3H, s), 3.98 (3H, s), 7.34 (1H, d, J = 8.4Hz), 7.80 (2H, d, J = 8.4Hz), 8. 25-8. 37 (overlap with 2H and 1H), 8. 56 (1H, d, J = 2.1H z) 0
[0095] 2) 1— (2 ヒドロキシ一 5—メトキシカルボ-ル）フエ-ルー 3— (4— (トリフルォロメチ ル））フエ-ルプロパン— 1, 3 ジオンの合成 4 トリフルォロメチルー（2' ァセチルー 4'ーメトキシカルボニル）フエニルベンゾ エート（904mg)をジメチルホルムアミド（2. 5ml)に溶解し、摂氏 10度以下の温度を 保ちながらカリウム一 t—ブトキシド（1モル一テトラヒドロフラン溶液、 3. 7ml)を滴下し た。 1. 5時間攪拌した後、反応液を酢酸ェチルで希釈し、 10%硫酸水素カリウム水 溶液、水道水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、有機層を エバポレートすることにより、固体性残渣を得た。得られた残渣を熱へキサンで懸濁 精製することにより、 目的化合物 (449mg)を得た。この化合物はさらに精製すること なぐ次の反応に用いた。 [0095] 2) 1— (2 Hydroxy-5-methoxycarbol) felt 3— (4— (trifluoromethyl)) phenol propane — 1, 3 dione synthesis 4 Dissolve trifluoromethyl- (2'-acetyl-4'-methoxycarbonyl) phenylbenzoate (904mg) in dimethylformamide (2.5ml) and maintain the temperature below 10 degrees Celsius with potassium tert-butoxide (1 mol Tetrahydrofuran solution, 3.7 ml) was added dropwise. 1. After stirring for 5 hours, the reaction solution was diluted with ethyl acetate and washed successively with 10% aqueous potassium hydrogen sulfate solution, tap water, and saturated brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated to obtain a solid residue. The obtained residue was suspended and purified with hot hexane to obtain the desired compound (449 mg). This compound was used in the next reaction without further purification.
[0096] 3) 3 - (2 ヒドロキシ一 5—メトキシカルボ-ル）フエ-ル一 5— (4— (トリフルォロメチ ル））フ 二ルー ( 1H)ーピラゾール（ィ匕合物番号 44)の合成  [0096] 3) Synthesis of 3-(2 Hydroxy-5-methoxycarbol) phenol 1- (4- (Trifluoromethyl)) furyru (1H) -pyrazole (Compound No. 44)
1 （2 ヒドロキシー5—メトキシカルボ-ル）フエ-ルー 3—（4 （トリフルォロメチ ル））フエ-ルプロパン— 1 , 3 ジオン（200mg)を n—プロパノール（1ml)およびテト ラヒドロフラン (0. 5ml)に懸濁し、ヒドラジン水和物（64 μ 1)を加えて摂氏 65度で 2時 間攪拌した。加熱を停止して室温へ冷却した後、反応液を酢酸ェチルで希釈し、飽 和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートして固体 性残渣を得た。得られた固体を熱へキサンで懸濁精製することにより、 目的化合物（ 130mg)を得た。
Figure imgf000026_0001
1 (2Hydroxy-5-methoxycarbol) phenol 3- (4 (trifluoromethyl)) phenolpropane-1,3 dione (200mg) into n-propanol (1ml) and tetrahydrofuran (0.5ml) The suspension was suspended, hydrazine hydrate (64 μ1) was added, and the mixture was stirred at 65 ° C. for 2 hours. After stopping the heating and cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with saturated Japanese brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated to obtain a solid residue. The obtained solid was suspended and purified with hot hexane to obtain the target compound (130 mg).
Figure imgf000026_0001
3. 85 (3H, s)、 7. 09 ( 1H, d, J = 8. 6Hz)、 7. 45 ( 1H, s)、 7. 83 (2H,さらに 1 Hとオーバーラップ）、 8. 12 (2H, d, J = 8. lHz)、8. 40 ( 1H, d, J = 2. OHz)。  3. 85 (3H, s), 7.09 (1H, d, J = 8.6Hz), 7.45 (1H, s), 7.83 (overlap with 2H, then 1H), 8.12 (2H, d, J = 8. lHz), 8.40 (1H, d, J = 2. OHz).
[0098] MS (ESI) : m/z 363 [M +H]+ [0098] MS (ESI): m / z 363 [M + H] +
[0099] 実施例 13 3— (2 ヒドロキシ一 5 クロ口）フエ-ルー 5— (4— (トリフルォロメチル） [0099] Example 13 3— (2 hydroxy-l 5 black mouth) ferro- 5— (4— (trifluoromethyl)
)フエ二ルー（1H)—ピラゾール（ィ匕合物番号 6)の合成 ) Synthesis of Fenirrou (1H) -pyrazole (Compound No. 6)
実施例 12の方法に従!、、 3 ァセチル 4 ヒドロキシーメチルベンゾエートの替 わりに 2' ヒドロキシ 5 '—クロローァセトフエノンを用いて同様の反応を行うことによ り、化合物番号 6の化合物を合成した。  According to the method of Example 12 !, the same reaction was carried out using 2′-hydroxy 5′-chloroacetophenone instead of 3-acetyl 4-hydroxy-methyl benzoate. Synthesized.
[0100] MS (ESI) : m/z 339 [M +H]+ [0100] MS (ESI): m / z 339 [M + H] +
[0101] 実施例 14 3— (2 ヒドロキシ一 5 フルォロ）フエ-ル一 5— (4— (トリフルォロメチ ル））フ 二ルー（1H)—ピラゾール（ィ匕合物番号 46)の合成 [0101] Example 14 3— (2 Hydroxy-5 fluoro) phenol 5— (4— (Trifluoromethi Lu)) Synthesis of two roux (1H) -pyrazole (compound No. 46)
実施例 12の方法に従!、、 3 ァセチル 4 ヒドロキシーメチルベンゾエートの替 わりに 2' ヒドロキシ一 5' フルオローァセトフエノンを用いて同様の反応を行うこと により、化合物番号 46の化合物を合成した。  According to the method of Example 12, the compound of Compound No. 46 was synthesized by carrying out the same reaction using 2′-hydroxy-1-5′-fluoroacetophenone instead of 3-acetyl 4-hydroxy-methylbenzoate. .
[0102] MS (ESI) :m/z 323 [M+H]+ [0102] MS (ESI): m / z 323 [M + H] +
[0103] 実施例 15 3— (2 ヒドロキシ一 4, 5 ジフルォロ）フエ-ルー 5— (4— (トリフルォ ロメチル））フ 二ルー（1H)—ピラゾール（ィ匕合物番号 49)の合成  Example 15 3—Synthesis of (2 hydroxy-1,4,5 difluoro) ferro- 5— (4- (trifluoromethyl)) fluoro (1H) -pyrazole (Compound No. 49)
実施例 12の方法に従!、、 3 ァセチル 4 ヒドロキシーメチルベンゾエートの替 わりに 2' ヒドロキシー4', 5' ジフルオローァセトフエノンを用いて同様の反応を行 うことにより、化合物番号 49の化合物を合成した。  According to the method of Example 12 !, the same reaction was carried out using 2′-hydroxy-4 ′, 5′-difluoro-acetophenone instead of 3-acetyl 4-hydroxy-methylbenzoate. Was synthesized.
[0104] MS (ESI) :m/z 341 [M+H]+  [0104] MS (ESI): m / z 341 [M + H] +
[0105] 実施例 16 3— (2 ヒドロキシ一 5—メチルスルホ -ル）フエ-ルー 5— (4— (トリフル ォロメチル））フ 二ルー（1H)—ピラゾール（ィ匕合物番号 50)の合成  Example 16 Synthesis of 3— (2 Hydroxy-5-methylsulfol) ferro-5 -— (4- (Trifluoromethyl)) fluoro (1H) -pyrazole (Compound No. 50)
実施例 12の方法に従!、、 3 ァセチル 4 ヒドロキシーメチルベンゾエートの替 わりに 2' ヒドロキシ 5'—メチルスルホ -ルァセトフエノンを用いて同様の反応を行 うことにより、化合物番号 50の化合物を合成した。  According to the method of Example 12, a compound of Compound No. 50 was synthesized by carrying out the same reaction using 2′-hydroxy 5′-methylsulfo-lucatophenone in place of 3-acetyl 4-hydroxy-methyl benzoate.
[0106] MS (ESI) :m/z 383 [M+H]+  [0106] MS (ESI): m / z 383 [M + H] +
[0107] 実施例 17 3— (2 ヒドロキシ一 5—カルボキシ）フエ-ルー 5— (4— (トリフルォロメ チル））フ 二ルー（1H)—ピラゾール（ィ匕合物番号 45)の合成  Example 17 Synthesis of 3— (2 Hydroxy-5-carboxy) phenol 5 -— (4- (Trifluoromethyl)) fluoro (1H) -pyrazole (Compound No. 45)
3—（2 ヒドロキシー5—メトキシカルボ-ル）フエ-ルー 5—（4 （トリフルォロメチ ル)）フエ-ルー（1H)—ピラゾール (ィ匕合物番号 44、 2. 98g)および水酸ィ匕ナトリウ ム（2. 06g)を 50%含水 1 プロパノール（8. 2ml)に加え、摂氏 65度で 4時間加熱 攪拌した。室温へ冷却した後、反応液を酢酸ェチルで希釈し、 10%硫酸水素力リウ ム、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、有機層をエバポレートし て固体性残渣を得た。得られた残渣を熱へキサンで懸濁精製する事により、 目的化 合物（2. 68g)を得た。  3— (2 Hydroxy-5-methoxycarbol) ferro 5— (4 (trifluoromethyl)) ferro (1H) —pyrazole (compound number 44, 2.98 g) and hydroxya sodium (2.06 g) was added to 1% propanol (8.2 ml) containing 50% water, and the mixture was heated and stirred at 65 ° C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with 10% lithium hydrogen sulfate and saturated brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated to obtain a solid residue. The obtained residue was suspended and purified with hot hexane to obtain the desired compound (2.68 g).
[0108] ^-NMRCDMSO-d )  [0108] ^ -NMRCDMSO-d)
6  6
7. 07 (1H, d, J = 8. 6Hz) , 7. 45 (1H, s)、 7. 79— 7. 84 (2H,さらに 1Hと才ー ノ ーラップ）、 8. 11 (2H, d, J = 8. 1Ηζ)、 8. 38 (1H, br. d, J= l. 7Hz)、 11. 23 (1H, br. s)。 7. 07 (1H, d, J = 8.6 Hz), 7. 45 (1H, s), 7. 79— 7. 84 (2H, then 1H Norlap), 8.11 (2H, d, J = 8.1 Ηζ), 8.38 (1H, br. D, J = l. 7Hz), 11. 23 (1H, br. S).
[0109] MS (ESI) :m/z 349 [M+H]+ [0109] MS (ESI): m / z 349 [M + H] +
[0110] 実施例 18 3— (2 ヒドロキシ— 5 シァノ）フエ-ルー 5— (4— (トリフルォロメチル） )フエ二ルー（1H)—ピラゾール（ィ匕合物番号 51)の合成  [0110] Example 18 Synthesis of 3— (2 Hydroxy-5 Ciano) Fueru 5— (4— (Trifluoromethyl)) Feniru (1H) -pyrazole (Compound No. 51)
本化合物は、以下の 2工程で合成した。  This compound was synthesized in the following two steps.
[0111] 1) 3— (2 ヒドロキシ一 5—カルボキシ）フエ-ルー 5— (4— (トリフルォロメチル））フ ェ-ルー（1H)—ピラゾール（ィ匕合物番号 45、 42mg)を N、 N ジメチルホルムアミド (0. 5ml)に溶解し、 1ージメチルァミノプロピルー3 ェチルカルボジイミド塩酸塩（3 5mg)、 N—ヒドロキシスクシンイミド（21mg)をカ卩え、室温で 4時間攪拌した。 2規定ァ ンモユア—メタノール溶液 (0. 5ml)をカ卩え、同温で終夜攪拌した。反応液に酢酸ェ チル、 10%硫酸水素カリウムを加えて反応を停止した。水層と有機層を分離後、有 機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残 渣を薄層クロマトグラフィー（酢酸ェチルで展開）で精製し、 3— (2 ヒドロキシ— 5— 力ルバモイル）フエ-ルー 5—（4 （トリフルォロメチル））フエ-ルー（1H)—ピラゾー ル（22. 3mg)を得た。  [0111] 1) 3— (2 Hydroxy-5-carboxy) phenol 5 -— (4- (trifluoromethyl)) ferro (1H) -pyrazole (Compound No. 45, 42 mg) Dissolve in N, N dimethylformamide (0.5 ml), and add 1-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (35 mg) and N-hydroxysuccinimide (21 mg) and stir at room temperature for 4 hours. . 2N ammonia-methanol solution (0.5 ml) was added and stirred overnight at the same temperature. Ethyl acetate and 10% potassium hydrogen sulfate were added to the reaction solution to stop the reaction. After separating the aqueous layer and the organic layer, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solvent, the residue was purified by thin-layer chromatography (development with ethyl acetate), and 3- (2 hydroxy-5-strong rubamoyl) felt 5— (4 (trifluoromethyl)) felt-loop (1H) -pyrazole (22.3 mg) was obtained.
[0112] MS (ESI) :m/z 348 [M+H]+  [0112] MS (ESI): m / z 348 [M + H] +
[0113] 2) 3— (2 ヒドロキシ一 5 シァノ）フエ-ル一 5— (4 トリフルォロメチル）フエ-ル  [0113] 2) 3— (2 Hydroxy-5 Cyanol) 1- 5- (4 Trifluoromethyl)
(1H)ーピラゾール (ィ匕合物番号 51)の合成  Synthesis of (1H) -pyrazole (Compound No. 51)
2) 3— (2 ヒドロキシ— 5—力ルバモイル）フエ-ル— 5— (4— (トリフルォロメチル） )フエ-ルー（1H)—ピラゾール（22. 3mg)を N、 N—ジメチルホルムアミド（0. 5ml) に溶解し、塩ィ匕チォ-ル（3滴）を加え、室温で終夜攪拌した。反応液を酢酸ェチル で希釈後、水、 5%重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。 溶媒を減圧留去後、残渣を薄層クロマトグラフィー（へキサン Z酢酸ェチル Zメタノー ル =20Z15Z3で展開）で精製し、 目的の化合物（15. lmg)を得た。  2) 3— (2 Hydroxy-5-force rubamoyl) phenol — 5— (4— (trifluoromethyl)) Ferro (1H) -pyrazole (22.3 mg) with N, N-dimethylformamide ( 0.5 ml), added with sodium chloride (3 drops), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, 5% aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer chromatography (developed with hexane Z ethyl acetate Z methanol = 20Z15Z3) to obtain the desired compound (15. lmg).
[0114] MS (ESI) :m/z 330 [M+H]+  [0114] MS (ESI): m / z 330 [M + H] +
[0115] 実施例 19 1—メチル 3— (2—メチルォキシ 5 クロ口）フエ-ル一 5— (4 トリ フルォロメチル）フエ-ルーピラゾール（ィ匕合物番号 47)および 3—（2 メチルォキシ —5—クロ口）フエ-ル一 5— (4—トリフルォロメチル）フエ-ル一（1H)—ピラゾール（ 化合物番号 48)の合成 Example 19 1—Methyl 3— (2-methyloxy-5-chloro) 1-methyl 5- (4 trifluoromethyl) phenol-pyrazole (Compound No. 47) and 3— (2 methyloxy) —5—Black mouth) Fuel 5— Synthesis of (4-Trifluoromethyl) phenol (1H) -pyrazole (Compound No. 48)
3— (2 ヒドロキシ一 5 クロ口）フエ-ル一 5— (4— (トリフルォロメチル））フエ-ル (1H)ーピラゾール (ィ匕合物番号 6、 96. 7mg)、炭酸カリウム（118mg)およびヨウ ィ匕メチル（180 1)をジメチルホルムアミド (0. 6ml)に加え、室温でー晚攪拌した。反 応液に酢酸ェチルを加えて希釈し、水道水、飽和食塩水で順次洗浄した。無水硫酸 ナトリウムで乾燥後、有機層をエバポレートして得られた残渣を分取薄層クロマトダラ フィー（0. 5mm厚、 20cmX20cm、 2枚、へキサン Z酢酸ェチル =3ZDで精製す る事により、化合物番号 47 (71. 7mg)およびィ匕合物番号 48 (23. 4mg)を得た。  3— (2 Hydroxyl 5 x 5) Phenol 5— (4— (Trifluoromethyl)) Phenol (1H) -Pyrazole (Compound No. 6, 96.7 mg), Potassium carbonate (118 mg ) And iodomethyl (1801) were added to dimethylformamide (0.6 ml) and stirred at room temperature. The reaction solution was diluted by adding ethyl acetate, and washed successively with tap water and saturated brine. After drying over anhydrous sodium sulfate and evaporating the organic layer, the resulting residue was purified by preparative thin layer chromatography (0.5 mm thickness, 20 cm x 20 cm, 2 sheets, hexane Z ethyl acetate = 3 ZD). No. 47 (71.7 mg) and Compound No. 48 (23.4 mg) were obtained.
[0116] 化合物番号 47 : MS (ESI)  [0116] Compound No. 47: MS (ESI)
m/z 367 [M+H]+  m / z 367 [M + H] +
[0117] 化合物番号 48 : MS (ESI)  [0117] Compound No. 48: MS (ESI)
m/z 353 [M+H]+  m / z 353 [M + H] +
[0118] 実施例 20 3— (2 ヒドロキシ一 5—メタンスルホンアミド）フエ-ル一 5— (4— (トリフ ルォロメチル） )フエ二ルー (1H)ーピラゾール（化合物番号 52)の合成  Example 20 3— (2 Hydroxy-5-methanesulfonamido) phenol 1—Synthesis of 5- (4- (trifluoromethyl)) phenyl (1H) -pyrazole (Compound No. 52)
本化合物は、以下の 4工程で合成した。 This compound was synthesized in the following four steps.
[0119] スキーム 2 [0119] Scheme 2
Figure imgf000030_0001
Figure imgf000030_0001
(15) (16) 化合物番号 52  (15) (16) Compound No. 52
[0120] 1) 1—ァセチルー 3— (2—ァセトキシ— 5—カルボキシ）フエ-ルー 5— (4— (トリフル ォロメチル））フ 二ルー（1H)—ピラゾール（一般式（13) )の合成 [0120] 1) Synthesis of 1-acetylyl 3- (2-acetoxy-5-carboxy) ferro- 5-(4- (trifluoromethyl)) fluoro (1H) -pyrazole (general formula (13))
3— (2—ヒドロキシ一 5—カルボキシ）フエ-ルー 5— (4— (トリフルォロメチル））フエ 二ルー（1H)—ピラゾール（ィ匕合物番号 45、 400mg)にピリジン（2. Oml)、無水酢酸 (2. Oml)を加え、室温で 5時間攪拌した。反応液を酢酸ェチルで希釈し、 10%硫酸 水素カリウム、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧 留去後、残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン Zメタノール = 100 Z1から 20Z1で溶出）で精製し、一般式（13) (70mg)及び 1—ァセチル— 3— (2 —ァセトキシ一 5—ァセトカルボキシ）フエ二ルー 5— (4— (トリフルォロメチル））フエ 二ルー（1H)—ピラゾール（一般式（14)、 422mg)を得た。  3— (2-Hydroxy-1-5-carboxy) felu 5— (4— (trifluoromethyl)) 2 di (1H) -pyrazole (compound number 45, 400 mg) to pyridine (2. Oml ) And acetic anhydride (2. Oml) were added and stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate, washed with 10% potassium hydrogen sulfate, water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methylene chloride Z methanol = 100 Z1 to 20Z1) to obtain the general formula (13) (70 mg) and 1-acetyl-3- (2-acetoxy 5-acetocarboxy) phenyl 5- (4- (trifluoromethyl)) phenyl (1H) -pyrazole (general formula (14), 422 mg) was obtained.
[0121] 一般式（14)で表される化合物 (422mg)をテトラヒドロフラン（5. 5ml)に溶解し、水  [0121] The compound represented by the general formula (14) (422 mg) was dissolved in tetrahydrofuran (5.5 ml),
(2. 5ml)を加えて室温で一晩攪拌した。反応液を酢酸ェチルで希釈し、水、飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、一般式（13)で 表される化合物（274mg)を得た。 (2.5 ml) was added and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the general formula (13) The compound represented (274 mg) was obtained.
[0122] MS (ESI) :m/z 433 [M+H]+ [0122] MS (ESI): m / z 433 [M + H] +
[0123] ^-NMRCDMSO-d ) [0123] ^ -NMRCDMSO-d)
6  6
2. 09 (3H, s)、 2. 77 (3H, s)、 7. 32 (1H, s)、 7. 44 (1H, d, J = 8. 3Hz)、 7. 8 4 (2H, m)、 8. 02 (1H, d, J = 2. lHz)、 8. 04 (1H, dd, J = 2. 1, 8. 3Hz)、 8. 2 1 (2H, m)、 12. 80 (1H, brs)。  2.09 (3H, s), 2.77 (3H, s), 7.32 (1H, s), 7.44 (1H, d, J = 8.3Hz), 7.8 4 (2H, m ), 8.02 (1H, d, J = 2. lHz), 8.04 (1H, dd, J = 2.1, 8. 3Hz), 8.2 1 (2H, m), 12. 80 ( 1H, brs).
[0124] MS (ESI) :m/z 474 [M]+ 、475 [M+H]+ 、433 [M - Ac + 2H]+ [0124] MS (ESI): m / z 474 [M] +, 475 [M + H] +, 433 [M-Ac + 2H] +
[0125] 2) 1—ァセチルー 3— (2—ァセトキシ— 5—ァミノ）フエ-ルー 5— (4— (トリフルォロ メチル））フ 二ルー（1H)—ピラゾール（一般式（15) )の合成 [0125] 2) Synthesis of 1-acetylyl 3— (2—acetoxy-5-amino) ferro 5— (4- (trifluoromethyl)) fluor (1H) -pyrazole (general formula (15))
アルゴン雰囲気下、一般式（13)で表される化合物（305mg)にトルエン（16ml)、ト リエチルァミン（295 1)を加え、 110°Cで加熱攪拌した。ジフエ-ルホスホリルアジド (228 μ 1)を滴下し、同温で 2時間攪拌した。反応液を氷冷の後、水（80ml)に注ぎ、 1時間攪拌した。酢酸ェチル（250ml)、水（100ml)を加え分液した。水層と有機層 を分離し、有機層を飽和食塩水で洗浄の後、無水硫酸ナトリウムで乾燥した。溶媒を 減圧留去し、得られた残渣をシリカゲルクロマトグラフィー (塩化メチレン Zメタノール = 100/1から 20/1で溶出）で精製し、粗生成物を得た。再びシリカゲルクロマトグ ラフィー（へキサン Z酢酸ェチル = 7Z2で溶出）で精製し、 目的の化合物（24mg)を 得た。  In an argon atmosphere, toluene (16 ml) and triethylamine (2951) were added to the compound represented by the general formula (13) (305 mg), and the mixture was heated and stirred at 110 ° C. Diphenylphosphoryl azide (228 μ1) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was ice-cooled, poured into water (80 ml), and stirred for 1 hour. Ethyl acetate (250 ml) and water (100 ml) were added for liquid separation. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution with methylene chloride Zmethanol = 100/1 to 20/1) to obtain a crude product. The product was purified again by silica gel chromatography (eluting with hexane Z ethyl acetate = 7Z2) to obtain the desired compound (24 mg).
[0126] MS (ESI) :m/z 404 [M+H]+  [0126] MS (ESI): m / z 404 [M + H] +
[0127] ^-NMRCDMSO-d ) [0127] ^ -NMRCDMSO-d)
6  6
1. 96 (3H, s)、 2. 75 (3H, s)、 5. 20 (2H, brs)、 6. 59— 6. 66 (2H,オーバーラ ップ）、 6. 87 (1H, m)、 7. 86 (2H, m)、 8. 20 (2H, m)。  1. 96 (3H, s), 2.75 (3H, s), 5.20 (2H, brs), 6.59— 6.66 (2H, overlap), 6.87 (1H, m ), 7.86 (2H, m), 8.20 (2H, m).
[0128] 3) 1—ァセチルー 3— (2—ァセトキシ— 5—メタンスルホ-ルアミド）フエ-ルー 5— (4 [0128] 3) 1-Acetyl 3— (2—Acetoxy-5—Methanesulfuramide) Fuel 5— (4
- (トリフルォロメチル)）フ -ル一（1H)—ピラゾール（一般式（16) )の合成 一般式（15)で表される化合物（12. 4mg)をピリジン (0. 5ml)に溶解し、氷冷下攪 拌した。メタンスルホユルクロリド（2. 5 1)を加え、同温で 3時間攪拌した。酢酸ェチ ル（7ml)で希釈し、水（5ml)を加えて反応を停止した。水層と有機層を分離後、有 機層を水、 10%硫酸水素カリウム、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥 した。溶媒を濃縮後、残渣を薄層クロマトグラフィー (塩化メチレン Zメタノール =ιοSynthesis of-(trifluoromethyl)) furyl (1H) -pyrazole (general formula (16)) Dissolve compound (12.4 mg) represented by general formula (15) in pyridine (0.5 ml) The mixture was stirred under ice cooling. Methanesulfur chloride (2.5 1) was added and stirred at the same temperature for 3 hours. The reaction was stopped by diluting with ethyl acetate (7 ml) and adding water (5 ml). After separating the aqueous and organic layers, the organic layer is washed with water, 10% potassium hydrogen sulfate, and saturated saline, and dried over anhydrous sodium sulfate. did. After concentrating the solvent, the residue was subjected to thin-layer chromatography (methylene chloride Zmethanol = ιοο
Z1で展開)で精製し、目的の化合物 (4. 4mg)を得た。 Purification with Z1) gave the desired compound (4.4 mg).
[0129] MS (ESI) :m/z 480 [M—H]— [0129] MS (ESI): m / z 480 [M—H] —
[0130] ^-NMRCDMSO-d ) [0130] ^ -NMRCDMSO-d)
6  6
2. 03 (3H, s)、 2. 76 (3H, s)、 3. 05 (3H, s)、 7. 23— 7. 29 (4H,ォーノーラッ プ）、 7. 87 (2H, m)、 8. 21 (2H, m)、 10. 00 (1H, brs；)。  2.03 (3H, s), 2.76 (3H, s), 3.05 (3H, s), 7.23— 7.29 (4H, monolap), 7.87 (2H, m), 8. 21 (2H, m), 10. 00 (1H, brs;).
[0131] 4) 3 - (2 ヒドロキシ一 5—メタンスルホンアミド）フエ-ル一 5— (4— (トリフルォロメ チル））フ 二ルー（1H)—ピラゾール（ィ匕合物番号 52)の合成  [0131] 4) Synthesis of 3- (2 Hydroxy-5-methanesulfonamido) phenol 5- (4- (Trifluoromethyl)) furyl (1H) -pyrazole (Compound No. 52)
一般式（16)で表される化合物 (4. 4mg)をメタノール (0. 5ml)に溶解し、氷冷下 攪拌した。 2規定水酸ィ匕ナトリウム水溶液 (0. 5ml)を加え、同温で 20分間攪拌した。 室温に昇温の後、さらに 2時間攪拌した。飽和塩ィ匕アンモ-ゥム水溶液（5ml)、酢酸 ェチル（15ml)を加えて反応を停止した。水層と有機層を分離後、有機層を飽和食 塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物番号 52 ( The compound represented by the general formula (16) (4.4 mg) was dissolved in methanol (0.5 ml) and stirred under ice cooling. 2N sodium hydroxide aqueous solution (0.5 ml) was added, and the mixture was stirred at the same temperature for 20 minutes. After warming to room temperature, the mixture was further stirred for 2 hours. Saturated aqueous ammonium salt solution (5 ml) and ethyl acetate (15 ml) were added to stop the reaction. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give Compound No. 52 (
3. 5mg)を得た。 3. 5 mg) was obtained.
[0132] MS (ESI) :m/z 398 [M+H]+
Figure imgf000032_0001
[0132] MS (ESI): m / z 398 [M + H] +
Figure imgf000032_0001
2. 93 (3H, s)、 6. 95 (1H, d, J = 8. 6Hz) , 7. 14 (1H, dd, J = 2. 6, 8. 6Hz) , 7. 20 (1H, s)、 7. 62 (1H, d, J = 2. 6Hz) , 7. 76 (2H, m)、 8. 01 (2H, m)。  2.93 (3H, s), 6.95 (1H, d, J = 8.6Hz), 7.14 (1H, dd, J = 2.6, 8. 6Hz), 7.20 (1H, s ), 7.62 (1H, d, J = 2.6 Hz), 7.76 (2H, m), 8.01 (2H, m).
[0134] 実施例 21 3— ( (8 ヒドロキシ）キノリン一 7—ィル） 5— (4— (トリフルォロメチル） )フエ二ルー（1H)—ピラゾール（ィ匕合物番号 53)の合成 Example 21 Synthesis of 3 — ((8-hydroxy) quinoline 7-yl) 5— (4- (trifluoromethyl)) phenyl (1H) -pyrazole (Compound No. 53)
本化合物は、以下の 3工程で合成した。 This compound was synthesized in the following three steps.
[0135] スキーム 3 [0135] Scheme 3
Figure imgf000033_0001
Figure imgf000033_0001
化合物番号 53  Compound No. 53
[0136] 1) 8—ァセトキシキノリン (一般式（17) )の合成  [0136] 1) Synthesis of 8-acetoxyquinoline (general formula (17))
8—ヒドロキシキノリン（10. 41g)にピリジン（34. 8ml)、無水酢酸（20. 3ml)を加え 、室温で 5時間攪拌した。反応液を減圧留去し、得られた残渣を酢酸ェチルで希釈 した。水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、 目的の化合物を粗精製物（11. 83g)として得た。この化合物はさらに精製することな く次の反応に用いた。  Pyridine (34.8 ml) and acetic anhydride (20.3 ml) were added to 8-hydroxyquinoline (10.41 g), and the mixture was stirred at room temperature for 5 hours. The reaction solution was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound as a crude product (11.83 g). This compound was used in the next reaction without further purification.
[0137] 2) 7—ァセチル一 8—ヒドロキシキノリン塩酸塩（一般式（18) )の合成  [0137] 2) Synthesis of 7-acetylyl 8-hydroxyquinoline hydrochloride (general formula (18))
次の参考文献: Journal of Medicinal Chemistry, 23(3), pp335— 338 (198 0) に記載の方法に従って合成した。すなわち、 8—ァセトキシキノリン（一般式（17) 、 11. 83g)、塩ィ匕カリウム（7. 30g)、無水塩ィ匕アルミニウム（26. 5g)を混合し、窒素 気流下 170°Cで 1時間 15分加熱した。氷冷の後、 2規定塩酸（253ml)を 30分間か けて滴下した。 70°Cで 2時間 30分加熱攪拌した。室温に冷却の後、同温でー晚攪 拌した。析出した結晶を濾取し、水で洗浄し、真空乾燥して目的の化合物（5. 714g )を得た。  The compound was synthesized according to the method described in the following reference: Journal of Medicinal Chemistry, 23 (3), pp335-338 (198 0). That is, 8-acetoxyquinoline (general formula (17), 11. 83g), salt-potassium (7.30g), anhydrous salt-aluminum (26.5g) are mixed and 170 ° C under nitrogen flow. For 1 hour and 15 minutes. After cooling with ice, 2N hydrochloric acid (253 ml) was added dropwise over 30 minutes. The mixture was heated and stirred at 70 ° C for 2 hours and 30 minutes. After cooling to room temperature, the mixture was stirred at the same temperature. The precipitated crystals were collected by filtration, washed with water, and dried under vacuum to obtain the desired compound (5.714 g).
[0138] 化合物番号 — NMR(CD OD)  [0138] Compound Number — NMR (CD OD)
3  Three
2. 80 (3H, s)、 8. 24 (1H, dd, J = 5. 4, 8. 9Hz)、 8. 61 (1H, d, J = 8. 4Hz) , 9. 15 (1H, dd, J= l. 5, 5. 4Hz) , 9. 85 (1H, dd, J= l. 5, 8. 9Hz) , 10. 26 (1 H, dd, J= l. 5, 8. 9Hz)。 2.80 (3H, s), 8.24 (1H, dd, J = 5.4, 8. 9Hz), 8.61 (1H, d, J = 8.4Hz), 9. 15 (1H, dd , J = l. 5, 5. 4Hz), 9. 85 (1H, dd, J = l. 5, 8. 9Hz), 10. 26 (1 H, dd, J = l. 5, 8. 9 Hz).
[0139] 3) 3— ( (8 ヒドロキシ）キノリン一 7—ィル） 5— (4— (トリフルォロメチル））フエ-ル [0139] 3) 3— (7-yl (8-hydroxy) quinoline) 5— (4-— (Trifluoromethyl)) methanol
(1H)ーピラゾール (ィ匕合物番号 53)の合成  Synthesis of (1H) -pyrazole (I Compound No. 53)
実施例 1において、 3 シァノベンゾイルク口リドの替わりに 4 （トリフルォロメチル） ベンゾイルクロリド（0. 42ml)を、 2'—ヒドロキシ一 5'—クロ口一ァセトフエノンの替わり に 7 ァセチル一 8 ヒドロキシキノリン塩酸塩（一般式（18)、 532. 5mg)を用いて 化合物番号 53 (166. 3mg)を得た。  In Example 1, 4 (trifluoromethyl) benzoyl chloride (0.42 ml) was used instead of 3 cyanobenzoyl chloride, 7 ′ acetylyl 8 ′ instead of 2′-hydroxy 1-5′-chloro 1acetophenone. Compound No. 53 (166.3 mg) was obtained using hydroxyquinoline hydrochloride (general formula (18), 532.5 mg).
[0140] 化合物番号 53 — NMR(DMSO— d ) [0140] Compound No. 53 — NMR (DMSO— d)
6  6
7. 20 (2H,ォーノ 一ラップ）、 7. 65 (2H, m)、 7. 82 (2H, m)、 8. 13 (2H, m)、 8 7. 20 (2H, mono lap), 7. 65 (2H, m), 7. 82 (2H, m), 8. 13 (2H, m), 8
. 60 (1H, brs)、 8. 93 (1H, dd, J= l. 4, 4. 4Hz) , 13. 44 (1H, brs；)。 60 (1H, brs), 8.93 (1H, dd, J = l. 4, 4. 4Hz), 13. 44 (1H, brs;).
[0141] 実施例 22 3— ( (8 ヒドロキシ）キノリン一 7—ィル） 5— (3— (トリフルォロメチル）[0141] Example 22 3— ((8-hydroxy) quinoline 7-yl) 5— (3— (trifluoromethyl)
)フエ二ルー（1H)—ピラゾール（ィ匕合物番号 54)の合成 ) Synthesis of Phenol (1H) -Pyrazole (Compound No. 54)
実施例 21において、 4— (トリフルォロメチル）ベンゾイルク口リドの替わりに 3 トリフ ルォ口べンゾイルクロリド（0. 48ml)を用いて化合物番号 54 (8. 9mg)を得た。  In Example 21, Compound No. 54 (8.9 mg) was obtained using 3 trifluoromethylbenzoyl chloride (0.48 ml) instead of 4- (trifluoromethyl) benzoyl chloride.
[0142] MS (ESI) :m/z 356 [M+H]+
Figure imgf000034_0001
[0142] MS (ESI): m / z 356 [M + H] +
Figure imgf000034_0001
7. 02 (1H, s)、 7. 21 (1H, d, J = 8. 0Hz) , 7. 53— 7. 72 (4H,ォーノ 一ラップ） 、 8. 06— 8. 23 (2H,ォーノ 一ラップ）、 8. 60 (1H, brs) , 8. 83— 8. 90 (2H, m)  7. 02 (1H, s), 7. 21 (1H, d, J = 8.0 Hz), 7. 53— 7. 72 (4H, ono lap), 8. 06— 8. 23 (2H, ono 1 lap), 8. 60 (1H, brs), 8. 83— 8. 90 (2H, m)
[0144] 参考例 1 1—メチル—3— (4—ヒドロキシ）フエ-ルー 5— (2, 5 ジメチル）フエ-ル 一（ 1H) ピラゾール（157360 :—般式（19) )の合成 [0144] Reference Example 1 Synthesis of 1-methyl-3- (4-hydroxy) phenol 5— (2,5 dimethyl) phenol mono (1H) pyrazole (157360: —general formula (19))
本化合物は、以下の 2工程で合成した。 [0145] スキーム 4 This compound was synthesized in the following two steps. [0145] Scheme 4
Figure imgf000035_0001
Figure imgf000035_0001
[0146] 1) 2, 5 ジメチルァセトフエノン（1. 012g)、 4 ヒドロキシベンズアルデヒド（0. 834 g)、パラートルエンスルホン酸水和物（0. 26g)をトルエン（6. 8ml)〖こ懸濁させ、摂 氏 100度で 19時間攪拌した。室温に冷却の後、反応液を塩化メチレンで希釈し、水 で洗浄した。無水硫酸ナトリウムで乾燥の後、溶媒を減圧留去して得られた残渣をシ リカゲルカラムクロマトグラフィー（へキサン Z酢酸ェチル = 2Z1で溶出）で精製し、 粗精製物を得た。再びシリカゲルカラムクロマトグラフィー（へキサン Z酢酸ェチル = 3Z1で溶出）で精製し、 1— (2, 5 ジメチルフエ-ル）— 3— (4—ヒドロキシフエ-ル )プロべノン（一般式（20)、 786mg)を得た。  [0146] 1) 2, 5 Dimethylacetophenone (1.012 g), 4 Hydroxybenzaldehyde (0.834 g), Para-toluenesulfonic acid hydrate (0.26 g) in toluene (6.8 ml) Turbid and stirred at 100 degrees Celsius for 19 hours. After cooling to room temperature, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with hexane Z ethyl acetate = 2Z1) to obtain a crude product. Purify again by silica gel column chromatography (eluting with hexane Z ethyl acetate = 3Z1), 1— (2,5 dimethylphenol) — 3— (4-hydroxyphenol) probenone (general formula (20) 786 mg).
[0147] 2) 1 - (2, 5 ジメチルフエ-ル） 3—（4ーヒドロキシフエ-ル）プロべノン（一般式（  [0147] 2) 1-(2,5 Dimethylphenol) 3- (4-hydroxyphenol) probenone (general formula (
20)、 786mg)をトルエン（3ml)に溶解し、摂氏 60度で N—メチルヒドラジン（0. 2ml )を加え、同温で 4日間攪拌した。室温に冷却の後、溶媒を減圧留去して得られた残 渣をシリカゲルカラムクロマトグラフィー（へキサン Z酢酸ェチル = 2Z1で溶出）で精 製し、 目的物を含むフラクションを濃縮した。へキサンを加え、 50°Cで 1時間懸濁の 後、室温で終夜放置した。沈殿した固体を濾取し、 1ーメチルー 3—（4ーヒドロキシ） フエ-ルー 5— (2, 5 ジメチル）フエ-ルー（1H)—ピラゾール（ィ匕合物番号 15736 0、 179mg)を得た。  20), 786 mg) was dissolved in toluene (3 ml), N-methylhydrazine (0.2 ml) was added at 60 degrees Celsius, and the mixture was stirred at the same temperature for 4 days. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with hexane Z ethyl acetate = 2Z1), and the fraction containing the desired product was concentrated. Hexane was added and suspended at 50 ° C for 1 hour, and then allowed to stand overnight at room temperature. The precipitated solid was collected by filtration to obtain 1-methyl-3- (4-hydroxy) phenol 5- (2,5 dimethyl) ferro- (1H) -pyrazole (Compound No. 157360, 179 mg).
[0148] MS (ESI) :m/z 279 [M+H]+ 3 [0148] MS (ESI): m / z 279 [M + H] + Three
2. 17, 2. 32 (s, total 3H) , 2. 36, 2. 45 (s, total 3H) , 3. 68, 3. 90 (s, total 3H)、 6. 39, 6. 41 (s, total 1H)、 6. 55 (1H, brs) , 6. 85, 6. 91 (m, total 2 H) , 7. 03, 7. 07 (m, total 1H, ) , 7. 18 (2H, m)、 7. 32, 7. 68 (m, total 2 H)。  2. 17, 2. 32 (s, total 3H), 2. 36, 2.45 (s, total 3H), 3.68, 3.90 (s, total 3H), 6. 39, 6. 41 ( s, total 1H), 6.55 (1H, brs), 6. 85, 6. 91 (m, total 2 H), 7. 03, 7. 07 (m, total 1H,), 7. 18 (2H , m), 7.32, 7.68 (m, total 2 H).
[0150] 試験例 1  [0150] Test Example 1
乳癌細胞である MCF— 7 (ER+)、 MDA—MB— 453 (ER—）、 MDA—MB— 23 1 (ER )および Hs0578T(ER—）、ならびに肺癌細胞 NCI— H460、大腸癌細胞 HCT116を用いた in vitroにおける抗腫瘍効果  For breast cancer cells MCF-7 (ER +), MDA-MB-453 (ER-), MDA-MB- 23 1 (ER) and Hs0578T (ER-), and lung cancer cell NCI- H460, colon cancer cell HCT116 In vitro antitumor effect
1500個の NCI— H460、 2000個の MCF— 7 (ER+)および HCT116、 4000個 の MDA— MB— 453 (ER—）、 MDA— MB— 231 (ER— )および Hs0578Tを 10 %牛胎児血清添加の RPMI 1640培地 (旭テクノクラス社)を用い 96穴プレートに播 種した。各細胞を 37°C、 5%CO Z95%Airの条件下で 24時間培養後、 MCF— 7 (  1500 NCI—H460, 2000 MCF—7 (ER +) and HCT116, 4000 MDA—MB—453 (ER—), MDA—MB—231 (ER—) and Hs0578T with 10% fetal bovine serum Of RPMI 1640 medium (Asahi Techno Class) was seeded in a 96-well plate. After culturing each cell under conditions of 37 ° C, 5% CO Z95% Air for 24 hours, MCF-7 (
2  2
ER + )および MDA—MB 453 (ER-)には化合物番号 1から 54の化合物および 比較例として 157360を添加し、 MCF— 7 (ER + )ゝ MDA— MB— 231 (ER—）、 H s0578T、 NCI— H460および HCT116には化合物番号 6を添カ卩し、更に 3日間培 養した。細胞を 0. 05%の Methylene Blue溶液で染色し、 660nMの吸光度をマ イク口プレートリーダー（Benchmark Plus -BIO RAD製）で測定した。増殖抑制 率は下記式で求め、各化合物の 50%細胞増殖抑制濃度 (IC50)を/ z gZmLの単 位で表 2及び表 3に示した。  ER +) and MDA—MB 453 (ER-) were added with compounds Nos. 1 to 54 and 157360 as a comparative example. MCF—7 (ER +) — MDA—MB—231 (ER—), H s0578T NCI—H460 and HCT116 were supplemented with Compound No. 6 and further cultured for 3 days. The cells were stained with 0.05% Methylene Blue solution, and the absorbance at 660 nM was measured with a microphone plate reader (Benchmark Plus-BIO RAD). The growth inhibition rate was determined by the following formula, and the 50% cell growth inhibitory concentration (IC50) of each compound is shown in Table 2 and Table 3 in units of / z gZmL.
[0151] 増殖抑制率 = (1 薬剤添加群の吸光度 ÷対照群の吸光度） X 100 [0151] Growth inhibition rate = (1 drug added group absorbance ÷ control group absorbance) X 100
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0001
Figure imgf000037_0002
[0153] 1C50 (〃 g/mL)  [0153] 1C50 (〃 g / mL)
表 3
Figure imgf000037_0003
Table 3
Figure imgf000037_0003
[0154] 表 2に挙げた結果より、一般式（1)で表される化合物群は乳癌細胞に対し、エストロ ゲン受容体ポジティブ及びネガティブに関わらず、乳癌細胞の増殖を抑制する抗腫 瘍効果を有していることがわかる。これら化合物群のうち、 IC50が特に効果の高いも のは、ィ匕合物番号 1、 3、 4、 5、 6、 7、 31、 38および 54であった。また、表 3に示すよ うに、化合物番号 6は乳癌細胞だけでなぐ肺癌細胞及び大腸癌細胞の増殖を抑制 する抗腫瘍効果を示し、一般式（1)で表される化合物群が癌細胞に対して幅広い抗 癌スペクトルを有して 、ることがわかる。  [0154] From the results listed in Table 2, the compound group represented by the general formula (1) has an antitumor effect on breast cancer cells, which suppresses the growth of breast cancer cells regardless of whether they are estrogen receptor positive or negative. It can be seen that Among these compound groups, those with particularly high IC50 were Compound Nos. 1, 3, 4, 5, 6, 7, 31, 38 and 54. In addition, as shown in Table 3, Compound No. 6 has an antitumor effect of inhibiting the growth of lung cancer cells and colon cancer cells that are not limited to breast cancer cells, and the compound group represented by the general formula (1) is a cancer cell. In contrast, it has a broad anti-cancer spectrum.

Claims

請求の範囲 The scope of the claims
下記一般式（1)で表される 3, 5 ジフエ二ルビラゾール類縁体又はその薬理学的に 許容される塩を有効成分とする、腫瘍細胞の増殖抑制剤。 A tumor cell growth inhibitor comprising, as an active ingredient, a 3,5 diphenylrubiazole analog represented by the following general formula (1) or a pharmacologically acceptable salt thereof:
Figure imgf000038_0001
Figure imgf000038_0001
[式中、基 Aは水素原子；カルボ-ル基；又はスルホ二ル基を示し (基 Aが水素原子 の場合にはその互変異性体を含む。）、 ¾ [は置換基を有していてもよい低級アルキ ル基；又は置換基を有して 、てもよ 、アミノ基を示し、基 Gおよび Zはそれぞれ独立に 、水素原子；水酸基；低級アルコキシ基；ハロゲノ基；又は置換基を有して 、てもよ ヽ 低級ァシルォキシ基を示し (但し Gおよび Zの ヽずれもが水素原子；ハロゲノ基；又は 一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、 Q、 Xおよび Yはそ れぞれ独立に、水素原子；置換基を有して ヽてもよ ヽァミノカルボニル基；低級アルコ キシカルボ-ル基；カルボキシル基；-トリル基；ニトロ基；ハロゲノ基；低級アルキル 基；ハロゲノ置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級ァ ルキルスルホキシル基；低級アルキルスルホン基；又は置換基を有して!/、てもよ 、アミ ノスルホニル基を示し、基 Dと基 Lの両者及び Ζ又は基 Qと基 Υの両者は、窒素原子 、酸素原子又は硫黄原子力も独立に選択される 2個までの原子と共に 5ないし 6員環 の複素環を形成してもよい。 ]  [In the formula, the group A represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom); Or an optionally substituted lower alkyl group; or an amino group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent. And represents a lower acyloxy group (provided that both of G and Z are hydrogen atoms; halogeno groups; or one is a hydrogen atom and the other is a halogeno group), and groups D and E , L, Q, X and Y are each independently a hydrogen atom; may be substituted with an aminocarbonyl group; a lower alkoxycarbonyl group; a carboxyl group; a -tolyl group; a nitro group A halogeno group; a lower alkyl group; a halogeno-substituted lower alkyl group; a lower alkoxy group; A lower alkylthio group; a lower alkylsulfoxyl group; a lower alkylsulfone group; or having a substituent! /, Which may represent an aminosulfonyl group, both a group D and a group L, and Ζ or a group Q Both the base and the base may form a 5- to 6-membered heterocycle with up to two atoms, which are independently selected from nitrogen, oxygen or sulfur nuclear power. ]
一般式（1)において、基 Αは水素原子；カルボ-ル基；又はスルホ -ル基を示し、 ¾[ は炭素数 1から 6で構成される直鎖、分岐鎖ないしは環構造を有するアルキル基;無 置換アミノ基；非環状の置換アミノ基；又は環構成員子として窒素および酸素から選 択される原子を 2個まで含んで 、ても良 、5な 、し 6員環構造を有する環状アミノ基を 示し、基 Gおよび Zはそれぞれ独立に、水素原子;水酸基;低級アルコキシ基;ハロゲ ノ基；又は末端にカルボキシル基を有して 、ても良 、、炭素数 2から 5で構成されるァ ルキルァシルォキシ基を示し（但し Gおよび Zの!、ずれもが水素原子；ハロゲノ基；又 は一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、 Q、 Xおよび Yは それぞれ独立に、水素原子；置換基を有して ヽてもよ ヽァミノカルボ-ル基；低級ァ ルコキシカルボ-ル基；カルボキシル基；二トリル基；ニトロ基；ハロゲノ基；低級アルキ ル基；フッ素置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級ァ ルキルスルホキシル基；低級アルキルスルホン基；又は無置換アミノスルホ-ル基を 示し、基 Dと基 Lの両者及び Ζ又は基 Qと基 Υの両者は、窒素原子又は酸素原子か ら独立に選択される 2個までの原子と共に 5ないし 6員環の複素環を形成していても よい、 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学的に許容される塩を有効 成分とする、請求項 1に記載の腫瘍細胞の増殖抑制剤。 In the general formula (1), the group represents a hydrogen atom, a carbo group, or a sulfo group, and ¾ [is an alkyl group having a straight chain, branched chain or ring structure composed of 1 to 6 carbon atoms. An unsubstituted amino group; an acyclic substituted amino group; or a cyclic member having up to two atoms selected from nitrogen and oxygen as a ring member, having a 5- or 6-membered ring structure An amino group, and the groups G and Z each independently have a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a carboxyl group at the end, and may be composed of 2 to 5 carbon atoms. An alkyl group which is an alkyl group (provided that G and Z !, both of which are hydrogen atoms; halogeno groups; Are one hydrogen atom and the other is a halogeno group), the groups D, E, L, Q, X and Y are each independently a hydrogen atom; may have a substituent. Group: lower alkoxycarbonyl group; carboxyl group; nitrile group; nitro group; halogeno group; lower alkyl group; fluorine-substituted lower alkyl group; lower alkoxy group; lower alkylthio group; lower alkylsulfoxyl group; A sulfone group; or an unsubstituted aminosulfol group, wherein both group D and group L and Ζ or group Q and group と 共 に together with up to two atoms independently selected from nitrogen or oxygen atoms The tumor cell according to claim 1, comprising a 3,5-diphenylazole analogue or a pharmacologically acceptable salt thereof, which may form a 5- to 6-membered heterocyclic ring, as an active ingredient. Growth inhibitor.
一般式（1)において、基 Αは水素原子；カルボ-ル基；又はスルホ -ル基を示し、 ¾[ は炭素数 1から 6で構成される直鎖、分岐鎖ないしは環構造を有するアルキル基;無 置換アミノ基;炭素数 1から 3で構成されるアルキル基を 1ないし 2個置換基として有 する、非環状アミノ基;又はピロリジニル基、ピベリジ-ル基、 4ーピペラジニル基、 4 —メチルビペラジ-ル基、 4—モルホリニル基力 なる群より選択される環状アミノ基 を示し、基 Gおよび Zはそれぞれ独立に、水素原子;水酸基；低級アルコキシ基;ハロ ゲノ基;又はァセチルォキシ基、ォキサリルォキシ基、マロニルォキシ基、スクシ-ル ォキシ基およびダルタミ-ルォキシ基カもなる群より選択される基を示し (但し Gおよ び Zの 、ずれもが水素原子;ハロゲノ基；又は一方が水素原子で他方がハロゲノ基の 場合を除く）、基 D、 E、 L、 Q、 Xおよび Yはそれぞれ独立に、水素原子;メチルァミノ カルボ-ル基、ジメチルァミノカルボ-ル基、無置換アミノカルボ-ル基;メトキシカル ボ-ル基、エトキシカルボ-ル基、プロピルォキシカルボ-ル基、イソプロピルォキシ カルボ-ル基、シクロプロピルォキシカルボ-ル基；カルボキシル基；ニトリル基； -ト 口基；ノヽロゲノ基;メチル基、ェチル基、プロピル基、イソプロピル基、シクロプロピル基 ；トリフルォロメチル基;メトキシ基、エトキシ基、プロピルォキシ基、イソプロピルォキシ 基、シクロプロピルォキシ基；メチルチオ基；メチルスルホキシル基；メタンスルホ-ル 基及び無置換アミノスルホニル基カゝらなる群より選択される基を示し、基 Dと基 Lの両 者及び Ζ又は基 Qと基 Υの両者は、窒素原子又は酸素原子力 独立に選択される 2 個までの原子と共に 5ないし 6員環の複素環を形成していてもよい、 In the general formula (1), the group represents a hydrogen atom, a carbo group, or a sulfo group, and ¾ [is an alkyl group having a straight chain, branched chain or ring structure composed of 1 to 6 carbon atoms. An unsubstituted amino group; an acyclic amino group having 1 to 2 alkyl groups each having 1 to 3 carbon atoms as a substituent; or a pyrrolidinyl group, a piperidyl group, a 4-piperazinyl group, 4-methylbiperazi- And a cyclic amino group selected from the group consisting of 4-morpholinyl group, wherein the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; A group selected from the group consisting of a group, a succinoxy group, and a dartamine-oxy group (wherein G and Z are both hydrogen atoms; halogeno groups; or one is a hydrogen atom and the other is a hydrogen atom). Group D, E, L, Q, X and Y are each independently a hydrogen atom; a methylaminocarbol group, a dimethylaminocarbole group, an unsubstituted aminocarbol group; a methoxycarlo Borol group, ethoxycarbon group, propyloxycarbon group, isopropyloxycarbol group, cyclopropyloxycarboro group; carboxyl group; nitrile group; ; Methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group; trifluoromethyl group; methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy group; methylthio group; methylsulfoxyl group A group selected from the group consisting of a methanesulfol group and an unsubstituted aminosulfonyl group, both a group D and a group L and Ζ or both a group Q and a group Υ May form a heterocyclic ring of 5 to 6-membered ring together with the atoms up to 2 substituents selected nitrogen atom or oxygen Nuclear independently,
3, 5—ジフエ- ルビラゾール類縁体又はその薬理学的に許容される塩を有効成分とする、請求項 1 又は請求項 2に記載の腫瘍細胞の増殖抑制剤。 3, 5—Jihue The growth inhibitor of tumor cells according to claim 1 or 2, comprising a rubilazole analog or a pharmacologically acceptable salt thereof as an active ingredient.
[4] 一般式（1)にお 、て、基 Aは水素原子；又はカルボ-ル基を示し、 ¾ [はメチル基を 示し、基 Gおよび Zはそれぞれ独立に水素原子（但し Gおよび Zのいずれもが水素原 子の場合を除く）；水酸基;低級アルコキシ基を示し、基 D、 E、 L、 Q、 Xおよび Yはそ れぞれ独立に、水素原子；二トリル基；フルォロ基；クロ口基；トリフルォロメチル基；又 は無置換アミノスルホ -ル基カゝらなる群より選択される基を示し、基 Dと基 Lの両者又 は基 Qと基 Υの両者は、 1個以上の窒素原子を含む 5な ヽし 6員環の複素環を形成し ていてもよい、 3, 5—ジフエ-ルビラゾール類縁体又はその薬理学的に許容される 塩を有効成分とする、請求項 1な!ヽし請求項 3の ヽずれか一項に記載の腫瘍細胞の 増殖抑制剤。 [4] In the general formula (1), the group A represents a hydrogen atom; or a carbo group, ¾ [represents a methyl group, and the groups G and Z each independently represent a hydrogen atom (provided that G and Z Each represents a hydrogen atom); a hydroxyl group; a lower alkoxy group; the groups D, E, L, Q, X, and Y are each independently a hydrogen atom; a nitrile group; a fluoro group A group selected from the group consisting of a chloromethyl group, a trifluoromethyl group, or an unsubstituted aminosulfol group, both a group D and a group L, or both a group Q and a group The active ingredient is a 3,5-diphenylvirazole analog or a pharmacologically acceptable salt thereof, which may form a 5- or 6-membered heterocyclic ring containing one or more nitrogen atoms. 4. The tumor cell growth inhibitor according to claim 1, wherein the tumor cell growth inhibitor is any one of claims 1 to 3.
[5] 腫瘍細胞が、エストロゲン受容体を発現して!/ヽる細胞である請求項 1な ヽし請求項 4 のいずれか一項に記載の腫瘍細胞の増殖抑制剤。  [5] The growth inhibitor of tumor cells according to any one of claims 1 to 4, wherein the tumor cells are cells that express!
[6] 腫瘍細胞が、乳癌細胞、肺癌細胞、大腸癌細胞力 なる群力 選ばれる請求項 1な[6] The claim 1, wherein the tumor cell is selected from the group consisting of breast cancer cells, lung cancer cells, and colon cancer cells.
V、し請求項 5の 、ずれか一項に記載の腫瘍細胞の増殖抑制剤。 6. The tumor cell growth inhibitor according to claim 5, wherein V is any one of the above.
[7] 腫瘍細胞が、エストロゲン受容体を発現している乳癌細胞、子宮体癌、子宮内膜癌、 子宮筋腫細胞、卵巣腫瘍細胞である請求項 6に記載の腫瘍細胞の増殖抑制剤。 7. The tumor cell growth inhibitor according to claim 6, wherein the tumor cell is a breast cancer cell expressing an estrogen receptor, endometrial cancer, endometrial cancer, uterine fibroid cell, or ovarian tumor cell.
[8] 請求項 1ないし請求項 7のいずれ力 1項に記載の 3, 5—ジフエ-ルビラゾール類縁 体又はその薬理学的に許容される塩を有効成分とする、抗腫瘍剤。 [8] An antitumor agent comprising, as an active ingredient, the 3,5-diphenylazole analog or the pharmacologically acceptable salt thereof according to any one of claims 1 to 7.
[9] 下記一般式（1 ' )で表される 3, 5—ジフエ二ルビラゾール類縁体又はその薬理学的 に許容される塩。 [9] 3,5-Diphenylbirazole analog represented by the following general formula (1 ′) or a pharmacologically acceptable salt thereof.
Figure imgf000040_0001
Figure imgf000040_0001
[式中、基 Αは水素原子；カルボ-ル基；又はスルホ二ル基を示し (基 Aが水素原子 の場合にはその互変異性体を含む。）、 ¾ [は置換基を有していてもよい低級アルキ ル基；又は置換基を有して 、てもよ 、アミノ基を示し、基 Gおよび Zはそれぞれ独立に 、水素原子；水酸基；低級アルコキシ基；ハロゲノ基；又は置換基を有して 、てもよ ヽ 低級ァシルォキシ基を示し (但し Gおよび Zの ヽずれもが水素原子；ハロゲノ基；又は 一方が水素原子で他方がハロゲノ基の場合を除く）、基 D、 E、 L、および Xはそれぞ れ独立に、水素原子；置換基を有して ヽてもよ 、ァミノカルボ-ル基；低級アルコキシ カルボ-ル基；カルボキシル基；二トリル基；ニトロ基；ハロゲノ基；低級アルキル基；ハ ロゲノ置換低級アルキル基；低級アルコキシ基；低級アルキルチオ基；低級アルキル スルホキシル基；低級アルキルスルホン基；又は置換基を有して!/ヽてもよ 、アミノスル ホニル基を示し、環 Cは、窒素原子、酸素原子又は硫黄原子から独立に選択される 2 個までの原子と共に 5ないし 6員環の複素環を示す。 ] [In the formula, a group represents a hydrogen atom; a carbonyl group; or a sulfonyl group (including a tautomer when the group A is a hydrogen atom). Lower alk An amino group, and the groups G and Z are each independently a hydrogen atom; a hydroxyl group; a lower alkoxy group; a halogeno group; or a substituent.示 し represents a lower acyloxy group (provided that both G and Z are hydrogen atoms; halogeno groups; or one is a hydrogen atom and the other is a halogeno group), and the groups D, E, L, and X are Each independently a hydrogen atom; may have a substituent, an aminocarbo group; a lower alkoxy carbo group; a carboxyl group; a nitrile group; a nitro group; a halogeno group; a lower alkyl group; Logeno-substituted lower alkyl group; lower alkoxy group; lower alkylthio group; lower alkyl sulfoxyl group; lower alkyl sulfone group; ,oxygen A 5- to 6-membered heterocyclic ring with up to 2 atoms independently selected from atoms or sulfur atoms. ]
下記一般式（2)、（3)、（4)、（5)又は（6)で表される 3, 5—ジフエ二ルビラゾール類 縁体又はその薬理学的に許容される塩。 A 3,5-diphenylvirazole analog represented by the following general formula (2), (3), (4), (5) or (6) or a pharmacologically acceptable salt thereof.
Figure imgf000041_0001
Figure imgf000041_0001
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