WO2002074296A1 - Medicaments contre le cancer solide contenant des derives de l'acide hydroxamique comme ingredient actif - Google Patents

Medicaments contre le cancer solide contenant des derives de l'acide hydroxamique comme ingredient actif Download PDF

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WO2002074296A1
WO2002074296A1 PCT/JP2002/002360 JP0202360W WO02074296A1 WO 2002074296 A1 WO2002074296 A1 WO 2002074296A1 JP 0202360 W JP0202360 W JP 0202360W WO 02074296 A1 WO02074296 A1 WO 02074296A1
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group
phenyl
tlc
nmr
methanol
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PCT/JP2002/002360
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English (en)
Japanese (ja)
Inventor
Masao Naka
Kanji Takahashi
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2002074296A1 publication Critical patent/WO2002074296A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a prophylactic and / or therapeutic agent for solid cancer containing a hydroxamic acid derivative, a nontoxic salt thereof and a prodrug thereof as an active ingredient, and a novel hydroxamic acid derivative, a nontoxic salt thereof and a prodode thereof.
  • a prophylactic and / or therapeutic agent for solid cancer containing a hydroxamic acid derivative, a nontoxic salt thereof and a prodrug thereof as an active ingredient, and a novel hydroxamic acid derivative, a nontoxic salt thereof and a prodode thereof.
  • a prophylactic and / or therapeutic agent for solid cancer comprising a hydroxamic acid derivative, a non-toxic salt thereof or a prodrug thereof as an active ingredient; And a novel compound contained in the hydroxamic acid derivative of the general formula (I),
  • the compound represented by the general formula (I) inhibits the production of interleukin-16 to produce various inflammatory diseases, sepsis, multiple myeloma, Cellular leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, cystic sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman's disease, atrial myxoma, diabetes, autoimmune disease, hepatitis, colon It is described as being effective as a prophylactic and / or therapeutic agent for inflammation, graft-versus-host disease, infectious disease, endometriosis.
  • the hydroxamic acid derivative represented by the general formula (I), a non-toxic salt thereof, and a prodrug thereof have been shown to be used in solid cancer (for example, , Brain tumor, head and neck cancer, thyroid cancer, esophageal cancer, stomach cancer, large intestine (colon, rectum) cancer, liver cancer, gallbladder and bile duct cancer, kidney cancer, lung cancer, breast cancer, cervical cancer, uterine body cancer, ovarian cancer, Prostate cancer, testicular tumor, bladder cancer, renal pelvis and ureteral tumor, adrenal cancer, neuronal tumor, glioma, bone tumor, rhabdomyosarcoma, osteosarcoma, soft tissue sarcoma, eosinophilic granuloma, malignant melanoma, skin
  • the present invention was found to be useful as a prophylactic and / or therapeutic agent for cancer, glioblasto
  • R 2 represents a hydrogen atom, a C1-8 alkyl group, a C2-9 acyl group or a Cy 1 group,
  • R 3 and R 4 each independently represent a hydrogen atom, a C 1-8 alkyl group, a C 2-9 acyl group or a Cyc 1 group,
  • R 5 is hydroxyl, C l ⁇ 8 alkyl group, C l ⁇ 8 alkoxy group, _NR 6 R 7 Motoma other represents 1 group Cyc,
  • R 6 and R 7 each independently represent a hydrogen atom, a C 1-8 alkyl group or a Cy 1 group,
  • R 1D represents a C 1-8 alkyl group or a Cy c 1 group
  • Cy c1 group is a C3-7 monocyclic carbocycle or a 5-7 membered monocyclic heterocycle containing 1-4 nitrogen atoms, 1 oxygen atom and Z or 1 sulfur atom. Represents a ring, R 11 represents a hydrogen atom, a Cl-8 alkyl group, a C2-9 acyl group or a Cyc1 group,
  • R 12 and R 13 are each independently a hydrogen atom, C L ⁇ 8 alkyl group, a C2 to 9 Ashiru group or Cy c 1 group,
  • n 0 or an integer of 1 to 5
  • Ring A contains C 3-15 monocyclic, bicyclic, tricyclic carbocyclic or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms 5-18 Member represents a monocyclic, bicyclic or tricyclic heterocycle,
  • Ring B contains C5-15 monocyclic, bicyclic, tricyclic carbocyclic aryl or 1-4 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 sulfur atoms5 Represents an 18-membered monocyclic, bicyclic, or tricyclic heteroaryl ring;
  • (g) represents a trifluoromethoxy group.
  • R 1 and R 8 may be taken together to represent a C 1-4 alkylene group.
  • n 0 or an integer of 1 to 5
  • R 9 represents a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group.
  • Hydroxamic acid derivatives their non-toxic salts or their prod
  • alkyl, alkoxy, and alkylene groups include straight-chain and branched ones.
  • a C 1-8 alkyl group refers to a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof. It is.
  • the C2-8 alkenyl group is a vinyl, probenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentagenenyl, hexenyl, heptagenyl, octagenyl, hexatrienyl, heptatrienyl, octatrienyl group and isomers thereof. It is.
  • C2-8 alkynyl groups include ethynyl, propiel, butynyl, pentenyl, hexynyl, heptynyl, octynyl, butyudiinyl, pentadiynyl, hexaziynyl, heptadinyl, octadinyl, hexatriynyl, heptatriynyl, and octatriynyl; Is an isomer of
  • Halogen atoms are fluorine, chlorine, bromine and iodine atoms.
  • the C 1-4 alkylene group is a methylene, ethylene, trimethylene, tetramethylene group and isomers thereof.
  • the C1-8 alkylene group is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group and isomers thereof.
  • the C2-9 acetyl group is an acetyl, propionyl, butyryl, paleryl, hexanoyl, heptanyl, octanoyl, nonanoyl group and isomers thereof.
  • the C1-8 alkoxy group is a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.
  • the C 3-7 monocyclic carbocycle means a C 3-7 monocyclic aromatic carbocycle, a partially saturated carbocycle and a fully saturated carbocycle.
  • a 5- to 7-membered monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom is 1 to 4 nitrogen atoms, 1 oxygen Means a 5- to 7-membered monocyclic heteroaryl containing an atom and or one sulfur atom and saturated or partially or entirely thereof.
  • C3-15 monocyclic, bicyclic, and tricyclic carbocycles are C3-15 monocyclic, bitricyclic aromatic carbocycles, partially saturated carbocycles, and all saturated carbocycles Means a carbon ring.
  • a 5- to 18-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is 1 to 5- to 18-membered mono-, bi-, and tricyclic heteroaryls containing 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and some or all thereof Means that they are saturated.
  • pyrrol imidazole, pyrazole, triazol, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (chopyran), chepin, oxazole.
  • Indazole quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, Cinnoline, benzoxazole, Benzothiazole, benzimidazole, carbazole, acridine, dibenzofuran, dibenzothiophene, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidin, tetrazolin, tetrazolidine, dihydropyridine, dihydropyrimidine Dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, dihydrodiazepine, tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, t
  • C5 to C15 monocyclic, bicyclic, and tricyclic carbocyclic aryls are cyclopentene, cyclohexadiene, cycloheptadiene, cycloheptoleline, benzene, indene, naphthalene, fluorene, and anthracene ring. And the like.
  • a 5- to 18-membered monocyclic, bicyclic or tricyclic heteroaryl ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is , Imidazole, triazole, tetrazole, pyrazole, pyridine, pyra Gin, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiane (chopyran), chepin, oxazole, isoxazole, thiazole, isothiazole, franzane, oxazine, oxazine, oxazine, oxazine, oxazine, oxazine, oxazine , Thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indo
  • ⁇ indicates that it is connected to the front side of the page (that is, ⁇
  • the present invention includes all non-toxic salts.
  • non-toxic salts For example, common salts, acid addition salts, hydrate salts and the like can be mentioned.
  • Non-toxic, water-soluble salts are preferred.
  • Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (such as tetramethylammonium, triethylamine, And salts of methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-dalcamine, and the like.
  • alkali metals such as potassium and sodium
  • salts of alkaline earth metals such as calcium and magnesium
  • ammonium salts such as tetramethylammonium, triethylamine, And salts of methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine,
  • the compounds according to the invention are converted into the corresponding acid addition salts by known methods.
  • the acid addition salts are preferably non-toxic and water-soluble.
  • Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate Such as, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, dalconate Organic acid salts.
  • the compound or a salt thereof according to the present invention can be converted to a hydrate by a known method.
  • the prodrug of the present invention is a compound of the formula (I) wherein one CO NH OH group is
  • R 14 represents a C 1-8 alkyl group or a C 1-8 alkyl group substituted by a C 1-8 alkoxy group.
  • ring A is a C3-10 monocyclic, bicyclic carbon ring or 1-4 nitrogen atoms, 1-2 oxygen atoms and / or 1-2
  • a 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing a sulfur atom is preferred.
  • a C 5-7 monocyclic carbocycle or a 5-10 membered monocyclic ring containing 1-2 nitrogen atoms, 1-2 oxygen atoms and / or 1-2 sulfur atoms, Cyclic heterocycles are preferred. More preferred are benzene, cyclohexane, benzoxazole, benzothiazole, benzimidazole, benzothiophene, and benzofuran rings.
  • the R 1, (1) C l ⁇ 8 alkyl group, (2) -OR 2 group, (3) - SR 2 group, (4) a halogen atom, (5) Cyc l, ( 6) _NR 3 R 4 Preference is given to groups or (7) a C 1-8 alkyl group substituted by an OR 2 group, an SR 2 group, a halogen atom, a Cycl, —NR 3 R 4 group.
  • a C1-8 alkyl group (2) a C1-8 alkoxy group, (3) a C1-8 alkylthio group, (4) a halogen atom, (5) 1 to 4 nitrogen atoms, 5- to 7-membered monocyclic heterocycle containing one oxygen atom and Z or one sulfur atom, (6) di (C1-8 alkyl) amino group or (7) C1-8 alkoxy
  • a C 1-8 alkyl group substituted by an amino group is preferred.
  • an R-form, an S-form or a mixture thereof is preferable.
  • an R-form or an S-form is preferable. More preferred is the S-form.
  • Ring B includes C 5-10 monocyclic, bicyclic carbocyclic aryl or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms.
  • a 15-membered monocyclic or bicyclic heteroaryl is preferred. Particularly preferred are benzene, naphthalene, pyridine, thiophene, benzofuran and benzoxazole rings.
  • R 8 is preferably a C 1-4 alkyl group. Particularly preferred is a methyl group.
  • R 9 is preferably a hydrogen atom, a C 1-4 alkyl group, a C 2-4 alkenyl group, or a C 2-4 alkynyl group. Particularly preferred are a hydrogen atom, a methyl group and an aryl group.
  • n is preferably 0 or an integer of 1 to 5. Particularly preferred is 0 or 1.
  • n is preferably 0 or an integer of 1 to 5. Particularly preferred is 0 or 1.
  • More preferred compounds for use in the present invention include the compounds described in Examples described later, the compounds shown in Tables 1 to 7 below, and salts thereof.
  • hydroxamic acid derivatives represented by the general formula (I), their non-toxic salts or their prodrugs according to the present invention can be produced by the following methods or the methods described in Examples.
  • the prodrugs represented by the general formula (IA) can be produced by the following methods (a) to (c).
  • R 1 — a has the same meaning as R 1 , provided that it does not represent a group containing an amino group, a thiol group, or a carbonyl group, and other symbols have the same meanings as described above.
  • the compound can be produced by subjecting the compound to an amidation reaction.
  • This amidation reaction is known, for example,
  • a method using an acid halide is, for example, a method in which a carboxylic acid is converted to an acid halide agent (oxalyl) in an organic solvent (chloroform, salted methylene, dimethyl ether, tetrahydrofuran, or the like) or without a solvent. Chloride and thionyl chloride) at ⁇ 20 ° C. to reflux temperature, and the resulting acid halide is reacted with amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.).
  • a tertiary amine pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.
  • reaction is carried out at 0 to 40 ° C in an inert organic solvent (eg, chloroform, methylene chloride, getyl ether, tetrahydrofuran).
  • an inert organic solvent eg, chloroform, methylene chloride, getyl ether, tetrahydrofuran.
  • the reaction can be carried out by reacting with an acid halide in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (aqueous sodium bicarbonate or sodium hydroxide solution) at a temperature of 0 to 40 ° C.
  • a method using a mixed acid anhydride includes, for example, a method in which a carboxylic acid is mixed with an tertiary amine (pyridine, triethylamine, dimethylaniline, or the like) in an organic solvent (chloroform, methylene chloride, dimethyl ether, tetrahydrofuran, or the like) or without a solvent.
  • an acid halide e.g., pivaloyl chloride
  • an acid derivative e.g., ethyl ethyl chloroformate, isobutyl chloroformate
  • the reaction is carried out by reacting the anhydride with an amine in an organic solvent (e.g., chloroform, methylene chloride, getyl ether, tetrahydrofuran) at 0 to 40 ° C.
  • the method using a condensing agent is, for example, a method in which a carboxylic acid and an amine are converted into a tertiary amine (pyridine) in an organic solvent (e.g., , bird Condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino)) in the presence or absence of ethylamine, dimethylaniline, dimethylaminopyridine, etc.)
  • DCC dicyclyclohexylcarbodiimide
  • E DC 1, 1'-Ipyldionymidazole
  • CD I 1, 1'-Ipyldionymidazole
  • 2-chloro-1 -methylpyridinium iodine 1-propanephosphonic acid cyclic anhydride
  • the reaction is carried out at 0 to 40 ° C with or without 1-hydroxybenztriazole (HOBt).
  • the reactions (1), (2) and (3) are desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • Triethylamine sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, triammonium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.
  • catalysts tetrakis (triphenyl) Phosphine) palladium CPd (PPh 3 ) 4 ), bis (triphenylphosphine) dichloride palladium (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd (0Ac) 2 ), palladium black, 1,1'-bis (Diphenylphosphine Inofue mouth) Dichloropa Indium (PdCl 2 (dppf) 2), Nishioi ⁇ Jiarirupara Jiumu (PdCl 2 (allyl) 2), iodide Fuenirubisu (triphenyl phosphine) palladium (PhP
  • R 1-c represents a group containing any one of an amino group, a thiol group, and a propyloxyl group, and the other symbols have the same meanings as described above.).
  • R 1 one al., Protected Amino group represents a group containing any of the protected thiol group or a protected force Rupokishiru group and the other symbols have the same meanings as described above.
  • Examples of the protecting group for an amino group include a benzyloxycarbonyl group, an aryloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetyl group, and a 91-fluorenylmethoxycarbonyl group.
  • Examples of the protecting group for the thiol group include a benzyl group, a methoxybenzyl group, an acetamidomethyl group, a triphenylmethyl group, and an acetyl group.
  • Examples of the protective group for the carbonyl group include a methyl group, an ethyl group, a t-butyl group, a benzyl group, and an aryl group.
  • the amino-, thiol- or carboxyl-protecting group is not particularly limited as long as it can be easily and selectively eliminated, in addition to the above.
  • those described in T. W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999 are used.
  • the deprotection reaction under the a / potassium condition is performed, for example, by using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.).
  • an alkali metal hydroxide sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • organic solvent methanol, tetrahydrofuran, dioxane, etc.
  • alkaline earth metal hydroxide barium hydroxide, calcium hydroxide, etc.
  • carbonate sodium carbonate, potassium carbonate, etc.
  • an aqueous solution thereof or a mixture thereof at 0 to 40 ° C. Done at temperature.
  • the deprotection reaction under acidic conditions can be performed, for example, in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisol, etc.), an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), or an inorganic acid. It is carried out in an acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) at a temperature of 0 to 100 ° C.
  • Deprotection reactions using hydrogenolysis include, for example, solvents (ethers (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, etc.).
  • solvents ethers (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, etc.).
  • the deprotection reaction using a metal complex is performed, for example, in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, etc.), a trapping reagent (hydrogenated triptyltin, dimedone, etc.) and z or an organic acid (acetic acid, etc.).
  • the reaction is performed at a temperature of 0 to 40 ° C. using a metal complex (such as a tetrakistriphenylphosphine palladium (0) complex) in the presence of
  • hydroxamic acid derivative represented by the general formula (I) according to the present invention can be produced by the following methods (d) and (e).
  • hydroxamic acid derivative represented by the general formula (I) can be produced by subjecting the compound represented by the general formula (IA) to a deprotection reaction.
  • This deprotection reaction of hydroxamic acid is known, for example,
  • the deprotection reaction of hydroxamic acid refers to a general deprotection reaction that can be easily understood by those skilled in the art, such as a deprotection reaction under alkaline conditions, a deprotection reaction under acid conditions, and hydrogenolysis. This means the deprotection reaction used, and the desired compound of the present invention can be easily produced by using these reactions properly. be able to.
  • hydroxamic acid protecting groups include t-butyl, —C (CH 3 ) 2 —OCH 3 and benzyl, but others are readily available.
  • the group is not particularly limited as long as it is a group which can be selectively eliminated. For example, those described in TW Greene et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999 are used.
  • the prodrug derivative represented by the general formula (IB) according to the present invention is a compound represented by the general formula (IA), wherein the R 14 group represents a 1-methoxy-11-methylethyl group, Formula (IA-3)
  • the compound can be produced by subjecting the compound to a methanol removal reaction.
  • This demethanol reaction is known, and is carried out in an organic solvent (benzene, toluene, dioxane, pyridine, etc.) at a temperature of 60 to 150 ° C.
  • organic solvent benzene, toluene, dioxane, pyridine, etc.
  • the compounds represented by the general formulas (II) and (IV) are known per se or can be easily produced by the following reaction schemes 1 and 2 or known methods. Reaction process formula 1
  • each reaction is carried out by a known method.
  • the compound represented by the general formula (X), the general formula (XIV), the general formula (III), the general formula (V) or the general formula (VI) used as a starting material is It is known per se or can be easily produced by a known method.
  • the reaction product is purified by conventional purification means, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium gayate, thin-layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, or recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.
  • conventional purification means for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium gayate, thin-layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, or recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.
  • the other starting materials and reagents in the present invention are known per se or can be produced by known methods.
  • the compounds of the general formula (I), their non-toxic salts and their prodrugs used in the present invention have very low toxicity and can be judged to be sufficiently safe for use as pharmaceuticals.
  • the compounds used in the present invention include solid cancers (for example, brain tumor, head and neck cancer, thyroid cancer, esophageal cancer, stomach cancer, large intestine (colon, rectum) cancer, liver cancer, gallbladder and bile duct cancer, kidney cancer, lung cancer, breast cancer, child cancer).
  • solid cancers for example, brain tumor, head and neck cancer, thyroid cancer, esophageal cancer, stomach cancer, large intestine (colon, rectum) cancer, liver cancer, gallbladder and bile duct cancer, kidney cancer, lung cancer, breast cancer, child cancer.
  • Cervical cancer endometrial cancer, ovarian cancer, prostate cancer, testicular tumor, bladder cancer, renal pelvis Ureteral tumor, adrenal cancer, neuronal tumor, glioma, bone tumor, rhabdomyosarcoma, osteosarcoma, soft tissue sarcoma, eosinophilic granuloma, malignant melanoma, skin cancer, glioblastoma, Wilms tumor, etc. It is useful as a prophylactic and / or therapeutic agent.
  • a non-toxic salt thereof or a prodrug thereof for the above-mentioned purpose, it is usually necessary to administer orally or parenterally, systemically or locally. It is administered in the form.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, once per day, in the range of lmg to 100mg, once to several times a day Is administered orally or parenterally (preferably intravenously) once to several times a day, in a range of 0.1 mg to 100 mg per adult per day, or It is continuously administered intravenously for 1 hour to 24 hours a day.
  • a dose smaller than the above dose may be sufficient, or may be required outside the range.
  • the compound of the present invention When the compound of the present invention is administered, it is used as a solid preparation for oral administration, a liquid preparation for oral administration, and an injection, an external preparation, a suppository and the like for parenteral administration.
  • Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • the one or more active substances may be as such or excipients (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (such as hydroxypropylcellulose, polyester). Vinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (calcium fiber monoglycolate, etc.), lubricant (magnesium stearate, etc.), It is mixed with stabilizers and solubilizers (glutamic acid, aspartic acid, etc.), etc., and used in the form of a formulation according to the usual method.
  • excipients such as lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.
  • binders such as hydroxypropylcellulose, polyester. Vinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (calcium fiber monoglycolate, etc.), lubricant (magnesium stearate, etc.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such solutions, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof). Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffer and the like.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections which are used by dissolving or suspending in a solvent before use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
  • this injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Good. They are prepared by sterilization or aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and dissolved in sterile distilled water for injection or other solvents before use.
  • compositions for parenteral administration include topical solutions, ointments, salves, inhalants, sprays, suppositories and vaginal preparations containing one or more active substances and prescribed in a conventional manner. Pessaries etc. are included.
  • Sprays include sodium bisulfite in addition to commonly used diluents. Buffers that provide isotonicity with such stabilizers, for example, isotonic agents such as sodium chloride, sodium citrate, or citrate may be included. Methods for producing spray agents are described in detail, for example, in U.S. Pat. Nos. 2,868,691 and 3,095,355. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing changes in tumor volume of mice to which the compound according to the present invention was administered.
  • FIG. 2 shows the tumor weight of a mouse to which the compound of the present invention was orally administered daily for 31 days.
  • the solvent in kakkoko indicated at the point of separation by chromatography and in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • the solvent in the kakkou indicated at the NMR indicates the solvent used for the measurement.
  • Reference example 1 The solvent in the kakkou indicated at the NMR indicates the solvent used for the measurement.
  • the reaction mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from hexane / ethyl acetate and dried to give the title compound (53.8 g) having the following physical data.
  • the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium salt of sodium chloride, dried over anhydrous sodium sulfate and concentrated.
  • the obtained residue is subjected to silica gel column chromatography.
  • Example 2 To a solution of the compound prepared in Example 1 (7.27 g) in methanol (100 ml), concentrated hydrochloric acid (2.0 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and azeotroped with ethanol. Ethyl acetate was added to the obtained residue, and the precipitated crystals were filtered and dried to give the title compound (5.55 g) having the following physical data.
  • Example 2 Using the corresponding benzene derivative in place of monochlorobiphenyl, the same operation as in Reference Example 1—Reference Example 2 ⁇ Reference Example 3—Example 1 ⁇ Example 2 was performed to obtain the title compound shown below. .
  • the reaction mixture was concentrated, diluted with ethyl acetate, washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated.
  • Tripotassium phosphate (333 mg), tetrakis (triphenylphosphine) palladium (120 mg), and benzofuran-2-boronic acid (40 mg) were added to dimethylformamide (10 ml) of the compound (440 mg) produced in Reference Example 6. .
  • the reaction mixture was stirred at 60 ° C for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated.
  • Example 2 The same operation as in Example 2 was carried out using the compound prepared in Example 4 instead of the compound prepared in Example 1, to obtain the title compound having the following physical data.
  • TLC R f 0.29 (ethyl acetate),
  • Example 5 (1) to 5 (18) -Using the corresponding boronic acid instead of 2-boronic acid, the same operation as in Example 4 ⁇ Example 5 was performed to obtain the title compound shown below.
  • Example 5 (1)
  • the extract is washed with a 1N aqueous hydrochloric acid solution, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Dried and concentrated. The obtained residue was washed with getyl ether to give the title compound (51.3 g) having the following physical data.
  • the extract was washed with a 2N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated.
  • Example 4 The same operation as in Example 4 was carried out using the compound produced in Reference Example 7 and 4-methylthiophenolpolonic acid to obtain the title compound having the following physical data.
  • Example 6 instead of the compound produced in Reference Example 9, the same operation as in Example 6 was carried out using the compound produced in Reference Example 9 (1), Reference Example 10, Reference Example 11 or Reference Example 12, and The title compound shown below was obtained.
  • Example 6 (1) the same operation as in Example 6 was carried out using the compound produced in Reference Example 9 (1), Reference Example 10, Reference Example 11 or Reference Example 12, and The title compound shown below was obtained.
  • Example 6 (1) the same operation as in Example 6 was carried out using the compound produced in Reference Example 9 (1), Reference Example 10, Reference Example 11 or Reference Example 12, and The title compound shown below was obtained.
  • Example 2 The same operation as in Example 2 was performed using the compound prepared in Example 6 to obtain the title compound having the following physical data.
  • Example 7 The same operation as in Example 7 was carried out using the compounds prepared in Examples 6 (1) to 6 (4) instead of the compound prepared in Example 6, and if desired, an acid addition was carried out by a usual method. The title compound shown below was obtained.
  • Example 7 (1) The same operation as in Example 7 was carried out using the compounds prepared in Examples 6 (1) to 6 (4) instead of the compound prepared in Example 6, and if desired, an acid addition was carried out by a usual method. The title compound shown below was obtained.
  • Example 8 (1)
  • Example 4 Reference Example 2 ⁇ Reference Example 3 ⁇ Example 1 ⁇ Example 2 using methyl 6- (3-bromophenyl) -16-oxohexanoate instead of the compound prepared in Reference Example 6.
  • the title compound having the following physical data was obtained by the same procedure as in above.
  • Example 9 The same operation as in Example 9 was carried out using methyl 6- (2-bromophenyl) -6-oxohexanoate instead of methyl 6- (3-bromophenyl) -6-oxohexanoate, and The title compound having the following physical data was obtained.
  • Example 10 (1) and 10 (2) The same operation as in Example 10 was carried out using a corresponding compound instead of styrene to obtain the title compound shown below.
  • Example 14 Using the compound produced in Reference Example 14, the same operation as in Example 1 ⁇ Example 2 was performed to obtain the title compound having the following physical properties.
  • Example 11 The same operation as in Reference Example 14 ⁇ Example 11 was performed using vinyl magnesium bromide instead of the methyl magnesium iodide getyl ether solution, to give the title compound having the following physical data.
  • the precipitated crystals are dissolved in ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous solution of sodium salt, dried over anhydrous magnesium sulfate, and concentrated.
  • the (+) form of the title compound having the following physical property values ( 2.44 g, 92.4% ee, HPLC).
  • the residue obtained by concentrating the filtrate was dissolved in ethyl acetate, washed with an aqueous solution of hydrochloric acid IN, water, and an aqueous solution of saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated.
  • the precipitated crystals are dissolved in ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. (2.88 g) of the title compound having the following physical properties is obtained. , 89.9% ee, HPL C).
  • Example 15 Using the (+) form of the compound produced in Reference Example 15, the same operation as in Example 1 ⁇ Example 2 was performed to obtain the title compound having the following physical data.
  • Example 12 The same operation as in Example 12 was carried out using the (one) form of the compound produced in Reference Example 15 to give the title compound having the following physical data.
  • Example 13 (1)
  • Reference Example 4 Reference Example using methyl 6- [4-((4- (morpholine-41-methyl) phenyl) phenyl) -1] 6-oxohexanoate instead of the compound prepared in Reference Example 1. 3 ⁇ The same operation as in Example 1 was performed to obtain the title compound having the following physical data.
  • Example 2 In place of the compound prepared in Example 1, the same operation as in Example 2 was carried out using the compound prepared in Example 15, and further converted into an acid adduct salt by a conventional method. The title compound having physical properties was obtained.
  • Example 16 The same operation as in Example 16 was performed using the compound prepared in Example 15 (1).
  • the compound was converted into an acid addition salt by a conventional method to give the title compound having the following physical data.
  • Example 2 The same operation as in Example 1 ⁇ Example 2 was performed using the compound produced in Reference Example 17 to give the title compound having the following physical data.
  • Example 17 Using the compound produced in Reference Example 17, the same operation as in Example 1-Reference Example 3-Example 2 was performed to obtain the title compound having the following physical data.
  • Example 19 Using the compound prepared in Reference Example 19 instead of the compound prepared in Reference Example 2, the same operation as in Reference Example 3—Example 1 ⁇ Example 2 was carried out to obtain the title compound having the following physical properties. Obtained.
  • Example 23 In place of the compound prepared in Example 6, the compound prepared in Example 6 (3) or 6 (4) was used, and if necessary, further converted into an acid additive salt by a usual method. The title compound shown in was obtained.
  • Example 23 (1) In place of the compound prepared in Example 6, the compound prepared in Example 6 (3) or 6 (4) was used, and if necessary, further converted into an acid additive salt by a usual method. The title compound shown in was obtained.
  • Example 23 (1) In place of the compound prepared in Example 6, the compound prepared in Example 6 (3) or 6 (4) was used, and if necessary, further converted into an acid additive salt by a usual method. The title compound shown in was obtained.
  • Example 2 In place of the compound prepared in Example 1, the same operation as in Example 2 was carried out using the compound prepared in Example 24, and further converted into an acid adduct salt by a conventional method. The title compound having physical properties was obtained.
  • Example 24 (1) Using the compound prepared in Example 24 (1), the same procedure as in Example 25 was performed, or the compound was converted to an acid addition salt by a conventional method to give the title compound having the following physical data. Obtained.
  • Example 26 The same operation as in Reference Example 1 ⁇ Reference Example 2 ⁇ Reference Example 3 ⁇ Example 1 was performed using the corresponding benzene derivative instead of 4-chlorobiphenyl to obtain the present invention compound shown below.
  • Example 26 The same operation as in Reference Example 1 ⁇ Reference Example 2 ⁇ Reference Example 3 ⁇ Example 1 was performed using the corresponding benzene derivative instead of 4-chlorobiphenyl to obtain the present invention compound shown below.
  • Example 26
  • Example 27 The same operations as in Example 2 were carried out using the compounds prepared in Examples 26 to 26 (1) instead of the compound prepared in Example 1, to obtain the following compounds of the present invention.
  • Example 27
  • A549 Human lung cancer; American Type Culture Collection (ATCC), Colon26: Mouse rectal cancer; Center for Medical Cell Resources, Tohoku University,
  • A375 Human malignant melanoma; American Type Culture Collection (ATCC),
  • PANC-1 human kidney cancer; American Type Culture Collection (ATCC),
  • KATOIII human gastric cancer; American Type Culture Collection (ATCC),
  • HepG2 Human liver cancer; American Type Culture Collection (ATCC),
  • PC14 Human lung cancer
  • the human lung cancer cells PC14 cultured in-Vito port, ImM EDTA was treated with phosphate buffer containing saline (PBS), Hank's (GIBCO- BRL Co.) solution using 2 X 1 0 7 cel ls / ml of cell suspension was prepared. Transfer the cell suspension to a 6-week-old female BALB / c nude mice (Nippon Charls River Co., Ltd.) were inoculated into two subcutaneous sites on the back at 4 ⁇ 10 6 cells / 200 L / site.
  • PBS phosphate buffer containing saline
  • GEBCO- BRL Co. Hank's
  • the tumor was divided into groups based on the tumor volume as an index, and from the next day, the compound of Example 7 (4) according to the present invention suspended in 0.5% methylcellulose (MC) was treated at a volume of 200 zL / mouse for 1 day. Oral administration every day until the day before the end of the experiment. Similarly, a control group (control) was orally administered with 0.5% MC.
  • the tumor volume of each individual was determined by measuring the minor axis and major axis of the tumor using an electronic caliper, and calculating the tumor volume based on the following equation. On the day of the experiment (day 31), tumor tissues were excised and weighed. The experiment was performed with 9 cases in each group.
  • Tumor volume (mm 3 ) minor axis (mm) 2 X major axis (mm) / 2
  • Fig. 1 shows the change in tumor volume
  • Fig. 2 shows the tumor weight
  • the following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 5 Omg of the active ingredient.
  • the solution is sterilized in the usual way, filled into ampoules in 5 ml portions, freeze-dried in the usual way, and used in an amount of 20 mg per ampoule. 100 ampoules containing a sex component were obtained.

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Abstract

L'invention concerne des médicaments prophylactiques et/ou thérapeutiques contre le cancer solide qui contiennent, comme ingrédient actif, des dérivés de l'acide hydroxamique, représentés par la formule générale (I) dans laquelle chaque symbole est tel que défini dans la description, des sels non toxiques de ceux-ci ou des promédicaments de ceux-ci. Les composés représentés par la formule générale (I), ainsi que les sels et les promédicaments de ceux-ci sont utiles en prévention et/ou en traitement du cancer solide.
PCT/JP2002/002360 2001-03-15 2002-03-13 Medicaments contre le cancer solide contenant des derives de l'acide hydroxamique comme ingredient actif WO2002074296A1 (fr)

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JP2001074949A JP2004359546A (ja) 2001-03-15 2001-03-15 ヒドロキサム酸誘導体、それらの非毒性塩およびそれらのプロドラッグ体を有効成分として含有する、固形癌の予防および／または治療剤
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011670A1 (fr) 2003-08-01 2005-02-10 Chugai Seiyaku Kabushiki Kaisha Composes heterocycliques utiles comme inhibiteurs de la malonyl-coa decarboxylase
US7786145B2 (en) 2003-08-01 2010-08-31 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-CoA decarboxylase inhibitors
JP4974905B2 (ja) * 2006-02-08 2012-07-11 株式会社静岡カフェイン工業所 サイトカイン産生阻害剤及びヘテロ環式フェノキシ誘導体
AU2006325294B2 (en) * 2005-10-31 2012-10-11 Merck Sharp & Dohme Corp. CETP inhibitors
JP2014111615A (ja) * 2006-12-19 2014-06-19 Methylgene Inc ヒストンデアセチラーゼの阻害薬及びそのプロドラッグ

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE488493T1 (de) * 2005-06-28 2010-12-15 Sigma Tau Ind Farmaceuti Biphenyl- und naphthylphenylhydroxamsäurederivate
US10550327B2 (en) * 2012-11-21 2020-02-04 Merck Patent Gmbh Polymerisable compounds and the use thereof in liquid-crystal displays
CN111393278B (zh) * 2020-04-20 2020-11-20 山西白求恩医院(山西医学科学院) 一种长松萝衍生物及其在制备治疗胆囊癌药物中的用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757984A1 (fr) * 1995-08-08 1997-02-12 Ono Pharmaceutical Co., Ltd. Dérivés d'acide hydroxamique utiles pour l'inhibition gélatinase
WO1997018188A1 (fr) * 1995-11-14 1997-05-22 Abbott Laboratories Inhibiteurs de metalloproteinases matricielles, a l'hydroxamate biphenylique
WO1997043239A1 (fr) * 1996-05-15 1997-11-20 Bayer Corporation Inhibition des metalloproteases matricielles par les acides biaryle oxobutyriques substitues
JPH10182583A (ja) * 1996-12-25 1998-07-07 Mitsui Chem Inc 新規ヒドロキサム酸誘導体
WO1999011608A1 (fr) * 1997-09-01 1999-03-11 Roche Diagnostics Gmbh Inhibiteurs de metalloprotease de matrice a base d'acide malonique
WO1999019296A1 (fr) * 1997-10-09 1999-04-22 Ono Pharmaceutical Co., Ltd. Derives d'acide aminobutanoique
WO1999061413A1 (fr) * 1998-05-27 1999-12-02 Bayer Corporation Derives d'acide 4-biarylbutyrique et 5-biarylpentanoique utilises comme inhibiteurs de metalloproteases matricielles
WO2001021583A1 (fr) * 1999-09-24 2001-03-29 Ono Pharmaceutical Co., Ltd. Derives d'acide hydroxamique, procede de production desdits derives et medicaments contenant lesdits derives comme principe actif

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757984A1 (fr) * 1995-08-08 1997-02-12 Ono Pharmaceutical Co., Ltd. Dérivés d'acide hydroxamique utiles pour l'inhibition gélatinase
WO1997018188A1 (fr) * 1995-11-14 1997-05-22 Abbott Laboratories Inhibiteurs de metalloproteinases matricielles, a l'hydroxamate biphenylique
WO1997043239A1 (fr) * 1996-05-15 1997-11-20 Bayer Corporation Inhibition des metalloproteases matricielles par les acides biaryle oxobutyriques substitues
JPH10182583A (ja) * 1996-12-25 1998-07-07 Mitsui Chem Inc 新規ヒドロキサム酸誘導体
WO1999011608A1 (fr) * 1997-09-01 1999-03-11 Roche Diagnostics Gmbh Inhibiteurs de metalloprotease de matrice a base d'acide malonique
WO1999019296A1 (fr) * 1997-10-09 1999-04-22 Ono Pharmaceutical Co., Ltd. Derives d'acide aminobutanoique
WO1999061413A1 (fr) * 1998-05-27 1999-12-02 Bayer Corporation Derives d'acide 4-biarylbutyrique et 5-biarylpentanoique utilises comme inhibiteurs de metalloproteases matricielles
WO2001021583A1 (fr) * 1999-09-24 2001-03-29 Ono Pharmaceutical Co., Ltd. Derives d'acide hydroxamique, procede de production desdits derives et medicaments contenant lesdits derives comme principe actif

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011670A1 (fr) 2003-08-01 2005-02-10 Chugai Seiyaku Kabushiki Kaisha Composes heterocycliques utiles comme inhibiteurs de la malonyl-coa decarboxylase
JP2007501232A (ja) * 2003-08-01 2007-01-25 中外製薬株式会社 マロニル−ＣｏＡデカルボキシラーゼ阻害剤として有用な複素環式化合物
US7696365B2 (en) 2003-08-01 2010-04-13 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors
US7786145B2 (en) 2003-08-01 2010-08-31 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-CoA decarboxylase inhibitors
JP4727578B2 (ja) * 2003-08-01 2011-07-20 中外製薬株式会社 マロニル−ＣｏＡデカルボキシラーゼ阻害剤として有用な複素環式化合物
AU2006325294B2 (en) * 2005-10-31 2012-10-11 Merck Sharp & Dohme Corp. CETP inhibitors
US8334290B2 (en) 2005-10-31 2012-12-18 Merck Sharp & Dohme Corp. CETP inhibitors
JP4974905B2 (ja) * 2006-02-08 2012-07-11 株式会社静岡カフェイン工業所 サイトカイン産生阻害剤及びヘテロ環式フェノキシ誘導体
JP2014111615A (ja) * 2006-12-19 2014-06-19 Methylgene Inc ヒストンデアセチラーゼの阻害薬及びそのプロドラッグ

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