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WO2006109680A1 - Utilisation d'un analogue du 3,5-diphenylpyrazole en tant qu'agent antitumoral - Google Patents

Utilisation d'un analogue du 3,5-diphenylpyrazole en tant qu'agent antitumoral Download PDF

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Publication number
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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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.

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Abstract

La présente invention propose un inhibiteur de la croissance des cellules tumorales qui comprend en tant que matière active un analogue du 3,5-diphénylpyrazole représenté par la formule générale (1) ou un sel pharmacologiquement acceptable de celui-ci : (1). Dans cette formule, le groupe A représente un atome d'hydrogène, un groupe carbonyle ou un groupe sulfonyle ; le groupe J représente un groupe alkyle inférieur qui peut porter un substituant ou un groupe amino qui peut porter un substituant ; les groupes G et Z représentent indépendamment un atome d'hydrogène, un groupe hydroxyle ou des groupes similaires ; et les groupes D, E, L, Q, X et Y représentent indépendamment un atome d'hydrogène, un groupe aminocarbonyle qui peut porter un substituant, un groupe alcoxycarbonyle inférieur ou des groupes similaires.
PCT/JP2006/307346 2005-04-07 2006-04-06 Utilisation d'un analogue du 3,5-diphenylpyrazole en tant qu'agent antitumoral WO2006109680A1 (fr)

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WO2010000372A3 (fr) * 2008-06-09 2010-05-27 Ludwig-Maximilians-Universität München Nouveau médicament pour l’inhibition de l’agrégation des protéines impliquées dans des maladies associées à l’agrégation des protéines et/ou des maladies neurodégénératives
US9493439B1 (en) * 2014-04-07 2016-11-15 University Of Kentucky Research Foundation Proteasome inhibitors
CN109748873A (zh) * 2017-11-08 2019-05-14 北京嘉林药业股份有限公司 化合物及其治疗癌症的用途
CN110437220A (zh) * 2018-07-13 2019-11-12 暨南大学 三氮唑类化合物及其应用
US20220315528A1 (en) * 2019-08-21 2022-10-06 The Board Of Trustees Of The Leland Stanford Junior University Inhibitors of phospholipid synthesis and methods of use

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JP2010536922A (ja) * 2007-08-25 2010-12-02 ユニバーシテーテ デス ザールランデス ホルモン関連疾患治療用の１７ベータ−ヒドロキシステロイドデヒドロゲナーゼ１型阻害剤
WO2009027346A3 (fr) * 2007-08-25 2009-05-28 Univ Saarland Inhibiteurs 17bêta-hydroxystéroïd-déhydrogénase de type 1 pour traiter des maladies hormono-dépendantes
US10435373B2 (en) 2008-06-09 2019-10-08 Ludwig-Maximilians-Universitat Munchen Drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
US10071966B2 (en) 2008-06-09 2018-09-11 Ludwig-Maximalians-Universitat Munchen Drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
JP2011522810A (ja) * 2008-06-09 2011-08-04 ルートヴィヒ‐マクシミリアンズ‐ウニヴェルジテート・ミュンヘン タンパク質凝集関連の疾患および／または神経変性性疾患に関係するタンパク質の凝集を阻害するための新規薬物
EP2684873A1 (fr) * 2008-06-09 2014-01-15 Ludwig-Maximilians-Universität München Médicaments pour l'inhibition de l'agrégation des protéines impliquées dans des maladies associées à l'agrégation des protéines et/ou des maladies neurodégénératives
AU2009266098B2 (en) * 2008-06-09 2015-01-22 Ludwig-Maximilians-Universitat Munchen New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
CN102056903B (zh) * 2008-06-09 2015-04-15 路德维希马克西米利安慕尼黑大学 抑制与蛋白聚集有关的疾病和/或神经变性疾病中涉及的蛋白聚集的新药
WO2010000372A3 (fr) * 2008-06-09 2010-05-27 Ludwig-Maximilians-Universität München Nouveau médicament pour l’inhibition de l’agrégation des protéines impliquées dans des maladies associées à l’agrégation des protéines et/ou des maladies neurodégénératives
CN102056903A (zh) * 2008-06-09 2011-05-11 路德维希马克西米利安慕尼黑大学 抑制与蛋白聚集有关的疾病和/或神经变性疾病中涉及的蛋白聚集的新药
US9493439B1 (en) * 2014-04-07 2016-11-15 University Of Kentucky Research Foundation Proteasome inhibitors
CN109748873A (zh) * 2017-11-08 2019-05-14 北京嘉林药业股份有限公司 化合物及其治疗癌症的用途
WO2019091277A1 (fr) * 2017-11-08 2019-05-16 北京嘉林药业股份有限公司 Composé de 2-(1h-pyrazol-3-yl) phénol et son utilisation
US11332461B2 (en) * 2017-11-08 2022-05-17 Beijing Jialin Pharmaceutical Inc. 2-(1H-pyrazol-3-yl) phenol compound and use thereof
CN110437220A (zh) * 2018-07-13 2019-11-12 暨南大学 三氮唑类化合物及其应用
CN110437220B (zh) * 2018-07-13 2022-12-27 暨南大学 三氮唑类化合物及其应用
US20220315528A1 (en) * 2019-08-21 2022-10-06 The Board Of Trustees Of The Leland Stanford Junior University Inhibitors of phospholipid synthesis and methods of use

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