WO2006013939A1 - Derives de pyrazole - Google Patents

Derives de pyrazole Download PDF

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Publication number
WO2006013939A1
WO2006013939A1 PCT/JP2005/014332 JP2005014332W WO2006013939A1 WO 2006013939 A1 WO2006013939 A1 WO 2006013939A1 JP 2005014332 W JP2005014332 W JP 2005014332W WO 2006013939 A1 WO2006013939 A1 WO 2006013939A1
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Prior art keywords
group
compound
substituted
methyl
unsubstituted
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PCT/JP2005/014332
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English (en)
Japanese (ja)
Inventor
Katsuji Kagechika
Mitsuhiro Yamaguchi
Yoshihiro Shibata
Hiroyuki Usui
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Daiichi Pharmaceutical Co., Ltd.
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Publication of WO2006013939A1 publication Critical patent/WO2006013939A1/fr

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    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a preventive / therapeutic agent for diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor a ligand (PPAR / y agonist: Peroxisome proliferator-activated a / y receptor agonist).
  • PPAR / y agonist Peroxisome proliferator-activated a / y receptor agonist
  • Diabetes mellitus is a disease that develops and develops various acute and chronic complications such as ischemic heart disease and cerebrovascular disorder, and causes a significant impairment in daily life. Therefore, it is necessary to prevent the onset and progression of these complications through early detection and strict glycemic control.
  • Type 1 diabetes and the production of insulin 'secretion is at a high level from the normal range, but it is very sensitive to the target organ and tissue of insulin. It is classified as type 2 diabetes that is reduced (ie, increased insulin resistance).
  • the main target organs and tissues of insulin are muscle, adipose tissue, and liver, which promotes glucose uptake and glycogen synthesis in muscle, and promotes uptake and utilization of dulose in adipose tissue. In the liver, it suppresses gluconeogenesis and promotes glycogen synthesis. Insulin is also involved in fat metabolism (facilitation of fat synthesis and inhibition of degradation) in adipose tissue that is not just for controlling sugar metabolism as described above.
  • Non-Patent Document 1 thiazolidinedione derivatives such as pioglitazone (pioglitazone) (Non-Patent Document 1) have been developed as drugs that improve insulin resistance, and are widely used for the treatment of type 2 diabetics, especially type 2 diabetics with obesity. RU
  • Non-patent Document 2 thiazolidinedione derivatives have been shown to be pergosomes of peroxisome proliferator-activated receptor ⁇ (PPAR y)! (Non-patent Document 2).
  • PPAR y peroxisome proliferator-activated receptor ⁇
  • Non-patent Document 2 The mechanism by which PPAR yagonists improve insulin resistance has not been fully elucidated, but it promotes apoptosis of hypertrophic adipocytes that produce and secrete free fatty acids that cause insulin resistance, and from preadipocytes to adipocytes Incorporation of free fatty acids by promoting differentiation into plants ⁇ Promoting storage is cited as a promising theory.
  • PPAR ⁇ -agonist pioglitazone
  • diabetes causes and develops complications such as ischemic heart disease and cerebrovascular disorder, so such weight gain and fluid retention are not desirable.
  • PPAR a / y agonists in which PPAR ⁇ agonists have been subjected to PPAR ⁇ agonist action. It has also been suggested that it exhibits properties as an excellent anti-diabetic drug.
  • Non-patent Document 4 For example, in a test using db / db mice, it has been shown that PPAR a / ⁇ agost KRP-297 significantly suppresses body weight gain compared to pioglitazone. . PPAR a / yagost LY465608 has been shown to increase high-density lipoprotein (HDL) in a dose-dependent manner and lower plasma triglycerides, reducing the risk of ischemic heart disease. (Non-Patent Document 5).
  • HDL high-density lipoprotein
  • Typical PPAR a / y agonists include the following compounds (Non-patent Documents 6 to 7 and Patent Documents 1 and 2).
  • Non-Patent Document 2 J. Biol. Chem., 270, 12953-12956 (1995)
  • Non-Patent Document 3 Am. J. Med., 115 (8A), 111S- 115S (2003)
  • Non-Patent Document 4 Am. J. Physiol, 284, E966-E971 (2003)
  • Non-Patent Document 5 Diabetes, 51, 1083-1087 (2002)
  • Non-Patent Document 6 Bioorg. Med. Chem. Lett., 9, 533-538 (1999)
  • Non-Patent Document 7 Chem. Pharm. Bull, 51, 138-151 (2003)
  • Patent Literature l WO2001-021602
  • Patent Document 2 WO2004—000785
  • the object of the present invention is to have a chemical structure that is different from the above-mentioned known PPAR a / y agonist, has an excellent PPAR a / y agonist action, and has desirable properties as a pharmaceutical product. Is to provide a compound.
  • X, Y, and ⁇ ⁇ each independently represent a nitrogen atom or a carbon atom.
  • n an integer of 0 to 3
  • n an integer of 1 to 3
  • Q may be substituted with one or two groups selected from among hydroxyl group, halogen atom, lower alkenyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, and substituted or unsubstituted amino group. !, Indicates a benzene ring,
  • R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group.
  • R 2 represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group,
  • R 3 and R 4 each independently represent a hydrogen atom or a lower alkyl group
  • R 5 represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted benzyl group.
  • R 6 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted
  • a compound represented by an unsubstituted amino group (provided that when m is 2 or more, two or more R 6 s may be the same or different from each other), a salt thereof, and a solvate thereof To do.
  • the present invention also provides a pharmaceutical comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the above general formula (I), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides use of a compound represented by the above general formula (I), a salt thereof or a solvate thereof for the production of a medicament.
  • the present invention provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof. It is to provide.
  • the compound represented by the general formula (I) of the present invention exhibits an excellent PPAR a Zyagost action and is useful as a prophylactic / therapeutic agent for diabetes.
  • the hydrogen atom and the rogen atom mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom is preferable.
  • An unsubstituted lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms
  • a buyl group, an allyl group, and a butenyl group can be given as typical examples.
  • An unsubstituted lower alkoxy group means an alkoxy group having a linear, branched and cyclic lower alkyl group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Typical examples include butoxy, isobutoxy, pentoxy, and cyclopentyloxy. Of these, a methoxy group is preferred, with a methoxy group and an ethoxy group being preferred.
  • Examples of the substituted lower alkoxy group include a lower alkoxy group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, a halogen atom, and a lower alkoxy group.
  • Specific examples include trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxyethoxy group, 3-hydroxypropoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 3-fluoro group.
  • Typical examples include fluoropropoxy, methoxymethoxy, 2-methoxyethoxy, and 3-methoxypropoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy.
  • Groups, 2-fluoroethoxy group, 2-chloroethoxy group, methoxymethoxy group, and 2-methoxyethoxy group are preferred trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxy group Trifluoromethoxy is more preferred, with ethoxy, 2-fluoroethoxy, methoxymethoxy, and 2-methoxyethoxy.
  • Group, 2, 2, 2-triflate Ruo b ethoxy group, 2-Furuoroetokishi group, and 2-Metokishieto alkoxy group is particularly preferred.
  • the substituted lower alkyl group includes a hydroxyl group, a halogen atom, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a carboxy group, a lower alkoxy group, a rubamoyl group, and a lower alkyl group rubamoyl.
  • the lower alkanoylamino group means an amino group substituted by an alkanoyl group having 2 to 6 carbon atoms, and specifically includes an acetylamino group, a propio-lamino group, a butyrylamino group, an isobutyryl group. Mention may be made of amino groups and valeryl amino groups.
  • substituted lower alkyl group examples include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloro group.
  • 2-fluoroethyl group aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, Rubamoylmethyl group, 2 rubamoylethyl group, Carbamoylmethyl group, 2-methylcarbamoyl E methyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoyl E methyl group, Jefferies Chi carbamoylmethyl group, a force Luba Moyle ⁇ amino methyl, methylcarbamoylamino main A trifluoromethyl group, 2, 2, 2-triflul, more preferably a til group, an ethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group
  • the substituted phenoxy group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a phenoxy substituted with 1 or 2 groups selected from the central forces of a substituted or unsubstituted amino group.
  • Groups such as fluorophenoxy, chlorophenoxy, bromophenoxy, methoxyphenoxy, ethoxyphenoxy, methylphenoxy, ethylphenoxy, trifluoromethylphenoxy, dimethylphenol
  • Representative examples include an enoxy group, a fluoromethylphenoxy group, a chloromethylphenoxy group, a difluorophenoxy group, a dichlorophenoxy group, and a black chlorophenoxy group. Of these, a fluorophenoxy group, a chlorophenoxy group, a bromophenoxy group, a methylphenoxy group, and a trifluoromethylphenoxy group are preferable.
  • the substituted phenol group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group.
  • Examples include phenyl groups substituted with 1 or 2 groups selected, such as hydroxyphenyl group, fluorophenol group, black-opened phenyl group, bromophenol group, methoxyphenyl group, and ethoxyphenol group.
  • Typical examples of mono-substituted phenyl groups are ethylaminophenol, dimethylaminophenol, dimethylaminophenol, and methylsulfophenol.
  • hydroxyphenyl group black-faced phenyl group, fluorophenol group, bromophenol group, methoxyphenyl group, methylphenol group, trifluoromethylphenol group, methylsulfur group. -Luxoxyphenyl groups and methylsulfo-aminophenol groups are preferred.
  • the substituted amino group includes a lower alkylamino group, a di-lower alkylamino group, a lower alkoxycarbolamino group, a strong ruberamoylamino group, a lower alkyl force ruberamoylamino group, a di-lower alkyl force ruberamoylamino group, and a lower alkylsulfo-amino group.
  • alkanoylamino groups such as methylamino group, ethylamino group, propylamino group, butyramino group, pentylamino group, hexylamino group, isopropylamino group, tert-butylamino group, sec-butylamino group, dimethylamino group, Jetylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, diisopropylamino group, methylethylamino group, methoxycarbolamino group, ethoxycarboamino group, force rubamoi
  • Typical examples are amino group, methylcarbamoylamino group, ethylcarbamoylamino group, dimethylcarbamoylamino group, jetylcarbamoylamino group, methylsulfolumino group,
  • a methylcarbamoylamino group, an ethylcarbamoylamino group, a dimethylcarbamoylamino group, a jetylcarbamoylamino group, a methylsulfo-lumino group, an ethylsulfo-amino group, and an acetylamino group are preferred.
  • Q may be substituted with one or two groups selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group.
  • a benzene ring which may be substituted with one or two groups selected from among halogen atoms, lower alkenyl groups, lower alkoxy groups, and substituted or unsubstituted lower alkyl groups; Preferred lower alkoxy group And a benzene ring is more preferred, when substituted with one or two groups selected from among a substituted or unsubstituted lower alkyl group.
  • the ring, trifluoromethylbenzene ring, aminobenzene ring, methylaminobenzene ring, ethylaminobenzene ring, dimethylaminobenzene ring, and jetylaminobenzene ring can be listed as typical examples of mono-substituted benzene rings.
  • Benzene ring methyl-trifluoromethylbenzene ring, fluoro-methylbenzene ring, chloro-methylbenzene ring, fluoro-hydroxybenzene ring, black-hydroxybenzene ring, difluorobenzene ring, dichlorobenzene ring, Chlorofluoro Ring, amino-fluorobenzene ring, amino-chlorobenzene ring, fluoro-methylaminominobenzene ring, chloromethylaminoaminobenzene ring, dimethylaminofluorobenzene ring, dimethylamino-chlorobenzene ring, Typical examples of the di-substituted benzene ring include a jetylamino-fluorobenzene ring, a chloro-jetylaminobenzene ring, a fluoro-methoxybenzene ring, a chloro-methoxybenzene ring, and an ethylene
  • a methylbenzene ring, a dimethylbenzene ring, and a methoxybenzene ring are more preferable, with a methylbenzene ring, a dimethylbenzene ring, a methoxybenzene ring, a fluorobenzene ring, a trifluoromethylbenzene ring, and an arylbenzene ring being preferred. .
  • R 1 will be described below.
  • R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group.
  • a substituted or unsubstituted amino group in the case of a phenyl group which may be substituted with one or two selected groups, in addition to the unsubstituted phenol group, a hydroxyphenol group, Fluorophenol group, Chlorophenol group, Bromophenol group, Buhlphenol group, Methoxyphenol group, Ethoxyphenyl group, 2-Methoxyethoxyphenyl group, Phenoxyphenyl group, Fluorophenyl group Group, chlorophenol group, biphenyl group, fluoro-furol group, methylphenol Group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylaminophenol group, jetyl
  • the aminophenyl group can be cited as a typical example of a mono-substituted phenyl group, such as a dimethylphenol group, a methyl
  • a phenol group, a fluorophenol group, a chlorophenol group, a bromophenol group, a methoxyphenol group, a methylphenol group, a trifluoromethylphenol group, a dimethylphenol group, and 2-methoxyphenyl groups are preferred, chlorophenyl, fluorophenyl, methoxyphenol, methylphenol, dimethylphenol, and 2-methoxyethoxy.
  • a phenol group is more preferred.
  • R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group.
  • a naphthyl group that may be substituted with one or two selected groups, hydroxy naphthyl group, fluoronaphthyl group, chloronaphthyl Group, bromonaphthyl group, vinyl naphthyl group, methoxy naphthyl group, ethoxy naphthyl group, methyl naphthyl group, ethyl naphthyl group, tert-butyl naphthyl group, trifluoromethyl naphthyl group, amino naphthyl group, methylamino naphthyl group, ethyl Aminonaphthyl group, dimethylaminonaphthyl group, jetylaminonaphthyl group Typical examples of the non-substituted naphthyl group include dimethyl naphthyl group, methyl monotrifluoromethyl naphthyl group, fluoromethyl naphthyl group,
  • naphthyl chloronaphthyl, chloronaphthyl, bromonaphthyl, trifluoronaphthyl, naphthyl, chloronaphthyl, and trifluoronaphthyl are more preferred.
  • R 1 is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted group.
  • a lower alkyl group and a 5- or 6-membered aromatic heterocyclic group which may be substituted with 1 or 2 groups selected from substituted or unsubstituted amino groups will be described.
  • a 5- or 6-membered aromatic heterocycle means a 5- or 6-membered aromatic ring containing one or more nitrogen, oxygen or sulfur atoms as a constituent of the ring structure.
  • Specific examples include pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, thiophene ring, furan ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring. , Triazole rings, and thiadiazol rings.
  • a pyridine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred, and a pyridine ring, a pyrimidine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred.
  • R 1 is preferably a pyridyl group, a fluoropyridyl group, a cyclopyridyl group, a bromopyridyl group, a trifluoromethylpyridyl group, a ferrobiridyl group, or a methoxypyridyl group.
  • Pyridyl group, black-and-white pyridyl group, trifluoromethyl pyridyl group, and methoxypyridyl group are more preferred.
  • R 1 represents a pyrimidyl group, a fluoropyrimidyl group, a black-opened pyrimidyl group, a bromopyrimidyl group, a trifluoromethylpyrimidyl group, Pyrimidyl, chloropyrimidyl, trifluoromethylpyrimidyl, and methoxypyrimidyl groups are more preferred, as are phenylpyrimidinyl and methoxypyrimidinyl groups.
  • R 1 represents a pyridazyl group, a fluoropyridazil group, a chloropyridazyl group, a bromopyridazyl group, a trifluoromethylpyridazil group, and A methoxypyridazinyl group is preferred, a pyridazinyl group, a chloropyridazinyl group, a trifluoromethylpyridazyl group, and a methoxypyridazyl group are more preferred.
  • R 1 is preferably a birazinyl group, a fluorobirazinyl group, a chlorobirazyl group, a bromopyrazuryl group, a trifluoromethylpyrazuryl group, or a methoxypyrazinyl group. More preferred are a pyrajur group, a chlorovirazyl group, a trifluoromethyl pyrajur group, and a methoxypyradur group.
  • R 1 represents a chael group, a fluorchael group, a black-eye chaer group, a bromochael group, a trifluoromethyl chaer group, and More preferred are a methoxy group, a chloro group, a trifluoromethyl group, and a methoxy group.
  • R 1 is preferably a furyl group, a fluorofuryl group, a chlorofuryl group, a bromofuryl group, a trifluoromethylfuryl group, or a methoxyfuryl group, and a furyl group, a chlorofuryl group , Trifluoromethylfuryl group, and methoxyfuryl group are more preferred.
  • R 1 is a pyrrolyl group, a chloropyrrolyl group, a chloropyrrolyl group, a bromopyrrolyl group, a trifluoromethylpyrrolyl group, or a methoxypyrrolyl group, and a chloropyrrole group.
  • Pyrrolyl, trifluoromethylpyrrolyl, and methoxypyrrolyl groups are more preferred.
  • R 1 is preferably an imidazolyl group, a fluorloyimidazolyl group, a chloroimidazolyl group, a bromoimidazolyl group, a trifluoromethylimidazolyl group, or a methoxyimidazolyl group. More preferred are groups, chloroimidazolyl, trifluoromethylimidazolyl, and methoxyimidazolyl.
  • R 1 is a pyrazolyl group
  • fluorovirazolyl Groups chlorovirazolyl, bromopyrazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are preferred, pyrazolyl, chlorovirazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are more preferred.
  • R 1 is preferably a thiazolyl group, a fluorothiazolyl group, a black thiazolyl group, a bromothiazolyl group, a trifluoromethylthiazolyl group, or a methoxythiazolyl group. More preferred are thiazolyl, black thiazolyl, trifluoromethylthiazolyl, and methoxythiazolyl! / ,.
  • R 1 is an isothiazolyl group, a fluoroloy thiazolyl group, a black isothiazolyl group, a bromoisothiazolyl group, a trifluoromethylisothiazolyl group, and a methoxyisothiazolyl
  • R 1 represents an oxazolyl group, a fluoroxazolyl group, a chlorooxazolyl group, a bromooxazolyl group, a trifluoromethyloxazolyl group, and a methoxyoxaxyl group.
  • oxazolyl, chlorooxazolyl, trifluoromethyloxazolyl, and methoxyoxazolyl are preferred.
  • R 1 is an isoxazolyl group, a fluoroisoxazolyl group, a chloroisoxazolyl group, a bromoisoxazolyl group, a trifluoromethylisooxazol group.
  • Izoxazolyl, chloroisoxazolyl, trifluoromethylisoxazolyl, and methoxyisoxazolyl are more preferred than zolyl and methoxyisoxazolyl ,.
  • R 1 represents an oxadiazolyl group, a fluoroxadiazolyl group, a clooxadiazolyl group, a bromooxadiazolyl group, a methyloxazia Zolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl are preferred.
  • Oxadiazolyl, chloroxadiazolyl, methyloxadi U more preferred are azolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl.
  • R 1 is a triazolyl group, a fluorotriazolyl.
  • chlorotriazolyl group, bromotriazolyl group, trifluoromethyltriazolyl group, and methoxytriazolyl group are preferred triazolyl group, chlorotriazolyl group, trifluoromethyltriazolyl group , And methoxytriazolyl groups are more preferred!
  • a phenyl group, a black-opened phenyl group, a fluorophenol group, a methoxyphenyl group, a methylphenol group, and a dimethylphenol group are particularly preferable.
  • R 2 will be described below.
  • the substituted or unsubstituted lower alkyl group means the above-mentioned alkyl group, and particularly preferable examples include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, methoxymethyl group, and 2 -Methoxyethyl group can be mentioned.
  • Examples of the substituted or unsubstituted force rubamoyl group include force rubamoyl groups which may be substituted with one or two lower alkyl groups. Specific examples include force rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, Examples include butyl carbamoyl group, jetyl carbamoyl group, propyl carbamoyl group, isopropyl carbamoyl group, butyl carbamoyl group, pentyl carbamoyl group, carbamoyl group, methyl carbamoyl group, dimethyl carbamoyl group, ethyl carbamoyl group. And a jetylcarbamoyl group are preferred.
  • the substituted or unsubstituted phenyl group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, and a substituted group.
  • an unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may be substituted with one or two selected phenyl groups. Can be mentioned.
  • Specific examples include hydroxyphenol groups, fluorophenol groups, black-and-white phenyl groups, bromophenol groups, methoxyphenol groups, ethoxyphenol groups, butylphenol groups, arylphenol groups, and methylsulfol groups.
  • Xylophyl group methylphenol group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylamino Phenyl group, jetylaminophenyl group, methylsulfoaminophenol group, phenoxyphenyl group, fluorophenol group, chlorophenol group, biphenyl group, and fluorophenol -Mono-substituted fue
  • Typical examples of the benzene group include: dimethylphenol group, methyl trifluoromethyl group, fluoromethylphenol group, chloromethylphenol group, fluoro-hydroxyphenol group, Mouth hydroxyphenol group, difluorophenol group, diclonal phenyl group, black monofluorophenol group, amino-fluorophenol group, amino-chlorophenol group, fluoromethylaminophenol -Group, chloromethylaminophenol group,
  • hydroxyphenyl group black-faced phenol group, fluorophenol group, bromophenol group, methoxyphenol group, methylphenol group, trifluoromethylphenol group, methylsulfoxyphenyl group. -Methyl group, and methylsulfolaminophenol group are preferred.
  • the substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfo-oxy group, a substituted or unsubstituted lower alkyl group, and a substituted group.
  • an unsubstituted amino group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may also be substituted with one or two groups that are also selected 5 or 6 Member aromatic heterocyclic group.
  • the 5- or 6-membered aromatic heterocycle is the same as the 5- or 6-membered aromatic heterocycle described in R 1 , and preferred examples are the same, but among them, the 5-membered aromatic heterocycle is the same.
  • Rings are preferred, and a furan ring, a thiazole ring, an oxazole ring, an isoxazole ring, and an oxaziazole ring are particularly preferred.
  • a furyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, and a methyloxazazolyl group are particularly preferable.
  • particularly preferred groups include rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, methoxymethyl group, 2-methoxyethyl group, oxazolyl group, and methyloxadiazolyl group. Can be mentioned.
  • R 3 and R 4 are a lower alkyl group, it means the aforementioned alkyl group, specifically
  • the methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group can be mentioned as representative examples, and each independently preferred is a methyl group in which a methyl group or an ethyl group is preferred.
  • R 5 is a lower alkyl group means an alkyl group described above include a methyl group, E Ji group, a propyl group, a tert- butyl group Preferred examples.
  • R 5 is a substituted or unsubstituted benzyl group, a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a nitro group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group are selected. Examples thereof include a benzyl group which may be substituted with 1 or 2 groups.
  • benzyl group examples include a benzyl group, a hydroxybenzyl group, a fluorbenzyl group, a black benzyl group, a bromobenzyl group, a methoxybenzyl group, an ethoxybenzyl group, a burbenzil group, a arrylbenzyl group, and a nitrobenzyl group.
  • mono-substituted benzyl groups dimethylbenzyl group, methyl-trifluoromethylbenzyl group, fluoro-methylbenzyl group, chloromethylbenzyl group, fluoro-hydroxybenzyl group, black-and-hydroxy group Ben Group, difluorine benzyl group, dichlorobenzil group, chlorofluorine benzyl group, amino-fluorobenzil group, amino-chloro benzyl group, fluoro-methylaminobenzil group, chloro
  • benzyl hydroxybenzyl, black benzyl, fluorbenzyl, bromobenzyl, methoxybenzyl, methylbenzyl, trifluoromethylbenzyl, and -trobenzyl are preferred. ,.
  • R 5 examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, a 4-methoxybenzyl group, or a 4-trobenzyl group. It can be done.
  • R 6 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted Although it is an unsubstituted amino group, each of those substituents is the same as described above.
  • a hydrogen atom, a chlorine atom, a methyl group, or an ethyl group preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methoxy group, or an ethoxy group.
  • An isopropyl group, a trifluoromethyl group, and a methoxy group are more preferable.
  • n is an integer of 0 to 3, preferably 1 or 2.
  • n is an integer of 1 to 3, preferably 1 or 2.
  • R 6 represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, A lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted amino group (where m is 2 In these cases, two or more R 6 s may be the same or different.
  • 5-membered aromatic heterocycle examples include a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, and a tetrazole ring.
  • R 6 substituted on the 5-membered aromatic heterocyclic ring is preferably a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted amino group, preferably 1 or 2
  • the 5-membered aromatic heterocycle substituted with R 6 includes methylpyrrole ring, trifluoromethylpyrrole ring, methylbiazole ring, trifluoromethylpyrazo ring.
  • Preferable examples are a diol ring, a methyl imidazole ring, a trifluoromethyl imidazole ring, a methyl triazole ring, a trifluoromethyl triazole ring, a fluoro ferrobiazole ring, a dimethyl pyrrole ring, a dimethyl virazole ring, and a dimethyl imidazole ring. It can be mentioned as.
  • the compound represented by the general formula (I) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers, optical isomers and Deviations of these and mixtures thereof are also included in the present invention.
  • the salt of the compound represented by the general formula (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • hydrochloride, hydrobromide, iodine examples thereof include hydrous acid salts and mineral acid salts such as sulfates, methanesulfonic acid salts, and organic sulfonic acid salts such as 2-hydroxyethanesulfonic acid salts and p-toluenesulfonic acid salts.
  • an alkali metal such as sodium or potassium, an alkaline earth metal such as magnesium or calcium, or methylamine, dimethylamine, or trimethylamine. It may be a salt of an organic base such as ethylamine, jetylamine, triethylamine, isopropylamine, diisopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine.
  • the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.
  • compound (I) a compound represented by general formula (I) of the present invention
  • R 5 represents a group other than a hydrogen atom
  • compound (la) R 5 represents a hydrogen atom.
  • the method of synthesizing the compound (lb) is described below.
  • Compound ( 3) can be synthesized by reacting aldehyde (1) and amine (2) in the presence of a reducing agent.
  • Compound (3) is obtained by producing a Schiff base from aldehyde (1) and amine (2) in the presence or absence of an acid such as acetic acid and then reacting with a reducing agent.
  • compound (3) can also be synthesized by dissolving aldehyde (1) and amine (2) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base.
  • a reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogen alkanes such as dichloromethane and chloroform.
  • the reaction temperature is up to the boiling point of the solvent that also uses 20 ° C force, preferably 0-50 ° C, and the reaction time is 15 minutes-24 hours, preferably 30 About minutes to 10 hours.
  • Synthesis of compound (la) from compound (3) can be carried out by allowing compound (4) to act on compound (3). 1 equivalent to excess, preferably 1 to 2 equivalents, of compound (4) is allowed to act on compound (3) in the presence of a base, and if necessary, such as tetrabutylammonium iodide and potassium iodide. A reaction accelerator can be used. As the base, 1 equivalent to an excess amount of tertiary amine such as triethylamine, potassium carbonate, carbonate such as cesium carbonate, or the like is used.
  • the solvent examples include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and solvents such as N, N-dimethylformamide and acetonitrile.
  • the reaction temperature is from 20 ° C to the boiling point of the solvent used, preferably from room temperature to 100 ° C, and the reaction time is from 1 hour to 7 days, preferably from about 1 to 48 hours.
  • the solvent examples include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and a mixed solvent thereof.
  • the reaction temperature is 0 to 100 ° C, preferably 0 to 60 ° C.
  • the reaction time varies depending on the type of ester, usually 1 to 72 hours, preferably about 1 to 24 hours.
  • it can be carried out by a method of reacting an acid such as trifluoroacetic acid or hydrochloric acid. Use excess amounts of trifluoroacetic acid and hydrochloric acid.
  • the solvent include solvents such as dichloromethane and dioxane.
  • the reaction temperature is from 0 ° C to the boiling point of the solvent used, preferably 0 to 30 ° C, and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
  • the compound (la) described in the above synthesis method 11 is a compound (la) as shown in the following synthesis method 12 It can also be produced by reaction of 3) with compound (5).
  • Compound (la) can be synthesized by reacting amine (3) with aldehyde (5) in the presence of a reducing agent. In the presence or absence of an acid such as acetic acid, a Schiff base is formed from amine (3) and aldehyde (5), and then a reducing agent is allowed to act to give compound (la).
  • compound (la) can also be synthesized by dissolving ammine (3) and aldehyde (5) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, 1 equivalent to excess of aldehyde (5) is used with respect to amine (3).
  • Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Among them, 1 equivalent is usually equivalent to aldehyde (5) in which sodium triacetoxyborohydride is preferred. An excess of, preferably 15 equivalents of reducing agent is used.
  • Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogenated alkanes such as dichloromethane and chloroform.
  • the reaction temperature is up to the boiling point of the solvent which also uses 20 ° C force, preferably 050 ° C, and the reaction time is about 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.
  • the compound (la) described in the synthesis method 11 can also be synthesized by the synthesis method 2 via the compound (7) as shown below.
  • Compound (7) is synthesized from compound (1) and compound (6) in the same manner as compound (3) is synthesized from compound (1) and compound (2) in Synthesis Method 1-1. It can be carried out.
  • the synthesis of compound (la) from compound (7) and compound (8) is the same as the synthesis of compound (la) from compound (3) and compound (5) in synthesis method 1-2. It can be done by the method.
  • the compound (la) described in the above synthesis method 11 can also be synthesized by the synthesis method 3-1 via the compound (9) as shown below.
  • R 30 represents a hydrogen atom or a nitro group
  • LG represents a hydroxyl group, a halogen atom, an alkylsulfo group. It represents a diloxy group or an arylsulfonyloxy group.
  • Compound (11) is synthesized from compound (2) by reacting compound (2) with 2 equivalents of compound (10) in the presence of a base.
  • a base tertiary amines such as triethylamine, pyridine, or carbonates such as sodium hydrogen carbonate are used.
  • the solvent include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether, N, N-dimethylformamide, acetonitrile, water and the like, or a mixed solvent thereof.
  • the reaction is up to the boiling point of the solvent that also uses 0 ° C. force, preferably about 0 to 30 ° C., and the reaction time is 30 minutes to 24 hours, preferably about 30 minutes to 5 hours.
  • the solvent examples include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether and tetrahydrofuran, solvents such as N, N-dimethylformamide, toluene and benzene, or a mixed solvent thereof.
  • the reaction is carried out from 0 ° C. to the boiling point of the solvent used, preferably about 0 to 30 ° C., and the reaction time is usually 10 minutes to 48 hours, preferably about 20 minutes to 10 hours.
  • the substituent LG is a halogen atom
  • 1 equivalent to an excess amount of the compound (12) is added to an excess amount of the chloride group (11) in which a chlorine atom, a bromine atom or an iodine atom is preferred as the halogen atom.
  • the base include carbonates such as potassium carbonate
  • examples of the solvent include N, N-dimethylformamide, acetonitrile, and dichloromethane.
  • the reaction temperature is up to the boiling point of the solvent that also uses 0 ° C force, preferably about 0 to 30 ° C, and the reaction time is usually about 10 minutes to 24 hours, preferably about 30 minutes to 8 hours.
  • the compound (13) can be produced under the same reaction conditions as when the substituent LG is a halogen atom.
  • a typical example of the alkylsulfo-oxy group is a methanesulfo-oxy group
  • examples of the aryl sulfo-oxy group include a benzene sulfo-oxy group and a p-toluenesulfonyloxy group.
  • Compound (13) and compound (9) were synthesized in the presence of an excess amount of potassium carbonate, a carbonate such as cesium carbonate, a tertiary amine such as triethylamine, or a base such as lithium hydroxide. It can be synthesized by reacting thiophenol or thioglycolic acid. Of these, the combination of triethylamine and thioglycolic acid is preferred.
  • the solvent include alkyl halides such as dichloromethane, N, N-dimethylformamide and the like.
  • the reaction temperature is 0 ° C force, up to the boiling point of the solvent used, preferably about 0 to 30 ° C, and the reaction time is usually 30 minutes to 24 hours, preferably about 30 minutes to 8 hours.
  • the compound (13) described in the above synthesis method 3-2 can also be synthesized by the synthesis method 3-3 shown below by the synthesis method described in the synthesis method 3-2 or a synthesis method analogous thereto. Is possible.
  • R 1 R 2 , R 6 , X, Y, Z, m, and ⁇ represent the above, R 30 represents a hydrogen atom or a nitro group, LG represents a hydroxyl group, a halogen atom, Represents an alkylsulfonoxy group or an arylsulfonyloxy group.
  • the compound (14) can be synthesized from the compound (6) according to the synthesis method of the compound (11) from the compound (2) in Synthesis Method 3-2.
  • the synthesis of compound (13) from compound (14) can be performed according to the synthesis method of compound (13) from compound (11) in synthesis method 3-2.
  • the compound (la) described in the above synthesis method 11 can also be synthesized by a synthesis route via the compound (17) as shown in the following synthesis method 4.
  • Compound (17) and compound (18) are reacted with copper iodide or acid copper salt in the presence of a base.
  • the halogen atom of compound (18) is preferably a bromine atom or an iodine atom.
  • compound (18) is used in an amount of 1 equivalent to an excess amount relative to compound (17).
  • Copper iodide or copper oxide is 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, and a palladium complex such as tetrakis (triphosphine) palladium is used instead of copper iodide or copper oxide. be able to.
  • the base 2 equivalent to excess amounts of metal carbonates such as cesium carbonate and potassium carbonate, metal phosphates such as tripotassium phosphate, and metal alkoxides such as sodium tert butoxide are used.
  • an inert solvent such as dioxane, toluene, acetonitrile, pyridine, N, N dimethylformamide, tetrahydrofuran, etc. is used, the reaction temperature is up to the boiling point of the solvent using 10 ° C force, and the reaction time is 30. Min to 48 hours, preferably 2 to 24 hours.
  • diamines such as 1,2-diaminocyclohexane and oximes such as salicylaldoxime dimethyldarioxime as reaction accelerators.
  • the compounds (4), (5), (6), and (12) used in the above synthesis differ in the length of the methylene chain depending on the number of n. Can be easily synthesized. Although the synthesis method used varies depending on the type of 5-membered heterocycle and the desired methylene chain, for example, the methylene chain can be easily extended as shown in Synthesis Method 5 below.
  • R 6 , X, Y, ⁇ , and m represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.
  • a cyano derivative (19) was synthesized by reacting the compound (18) contained in the compound (4) with cyanide sodium or cyanate potassium, followed by a reduction reaction in which an amine (20) ) Can be synthesized.
  • the cyano derivative (19) is acid or Carboxylic acid (21) can be obtained by alkaline hydrolysis, and hydroxy derivative (22) can be obtained by subsequent reduction reaction.
  • an aldehyde (23) having one extended methylene chain can be obtained.
  • a compound having a longer methylene chain can be obtained by halogenating the hydroxy derivative (22) to lead to the compound (24) and further extending the carbon chain in the same manner as described above.
  • a compound in which carbon is extended by an aldehyde (23) force Wittig reaction to extend one methylene chain can be synthesized.
  • Amine (20) is capable of catalytic reduction of compound (19) in the presence of a catalyst such as palladium-carbon or can be synthesized by reduction using lithium aluminum hydride or the like.
  • a catalyst such as palladium-carbon
  • the solvent include water, alcohol solvents such as ethanol, ether solvents such as jetyl ether, and ethyl acetate.
  • the reaction time is usually about 3 hours to 5 days, preferably about 10 hours to 2 days.
  • lithium aluminum hydride is usually used in an amount of 1 to 5 equivalents, preferably about 1 to 3 equivalents, relative to compound (19).
  • ether solvents such as jetyl ether and tetrahydrofuran are used.
  • the reaction time is usually about 1 to 10 hours, preferably about 1 to 3 hours, and the reaction temperature is usually about 0 ° C to the boiling point of the solvent used, preferably about 0 to 60 ° C.
  • Cyan derivative (19) force Hydrolysis to carboxylic acid (21) uses an acid such as sulfuric acid or hydrochloric acid, or an alkali such as sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • An excess of acid relative to the Cyan derivative (19), and usually 3 to 20 equivalents in the case of alkali, preferably 3-15 equivalents are used.
  • As the solvent water, an alcohol solvent such as ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, or a mixed solvent thereof is used.
  • the reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually from 50 ° C to the boiling point of the solvent used, preferably about 50 to 100 ° C.
  • Carboxylic acid (21) force The reduction reaction to the compound (22) can be carried out by using a borane complex such as lithium aluminum hydride or a borane-dimethylsulfide complex for the carboxylic acid (21). it can.
  • the lithium aluminum hydride or borane complex is usually used in an excess amount, preferably about 2 to 3 equivalents, relative to the carboxylic acid (21).
  • an ether solvent such as tetrahydrofuran is used.
  • the reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually 0 ° C. to the boiling point of the solvent used, preferably about 30 to 80 ° C.
  • the compound (22) force can be used in the usual acid-acid reaction.
  • Swern oxidation using oxalyl chloride and dimethyl sulfoxide SL Huang, K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978)
  • oxidation reaction using Dess-Martin periodinane DB Dess and JC Martin, Journal of America n Chemical Society, 113, 7277 (1991)
  • oxidation reaction using tetra-n-propylammonium perruthemate and 4-methylmorpholine-4-oxide WP Griffith, SL Ley, u P. Whitcombe, and AD White, Journal Chemical Society Chemical, omm unication, 1625 (1987).
  • the synthesis of the halogen derivative (24) from the compound (22) can be carried out by a normal halogen reaction.
  • a normal halogen reaction For example, chlorination with sodium chloride, bromination using boron tribromide, dibuccyl trifluorophosphine or N-bromosuccinimide and triphenylphosphine, iodination using sodium iodide and trimethylchlorosilane, etc. .
  • the compound (18) in the above synthesis method is the method described in Heterocycles, 60s, pp. 167-175, 2003, the method described in Reference Examples, or a method according to them. Can be manufactured.
  • R 3 to R 6 , Q, X, Y, Z, m and n represent the above, and R 7 and R 8 each independently represent a hydrogen atom or a lower alkyl group.
  • the compound (26) is synthesized from the compound (7) by compounding a metal hydride complex such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc. into the compound (7) and darioxylic acid (25). Preferably, it is carried out by the action of sodium triacetoxyborohydride. Usually, 1 equivalent or excess of darioxylic acid (25) is used relative to compound (7).
  • the metal hydride complex is usually used in an amount of 1 equivalent or excess, preferably 2 to 3 equivalents, relative to compound (7).
  • the reaction solvent include inert solvents such as tetrahydrofuran, dichloromethane, chloroform, etc.
  • the reaction temperature is 0 ° C. force up to 40 ° C., preferably about 0 to 30 ° C.
  • the reaction time is 1 to 48 hours. It is preferably about 1 to 10 hours.
  • Synthesis of compound (Ic) from compound (26) can be carried out by a general amide bond forming reaction.
  • compound (26) is reacted with ammine (27) in the presence of a condensing agent.
  • a condensing agent for example, 1 equivalent or excess of ammine (27) to compound (26) Is carried out in an inert solvent at ⁇ 50 ° C. until the boiling point of the solvent used in the reaction, preferably 0 to 30 ° C., in the presence of a condensing agent.
  • the reaction time is 10 minutes at 48 hours, preferably 30 minutes to 12 hours.
  • Condensation agents include N, N'-dicyclohexylcarbodiimide, 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide, cyanoethyl ethylate, benzotriazolyloxy-tris [pyrrolidino] -phospho-um hexa Fluorophosphate, 2- (1H benzotriazole 1-yl) 1, 1, 3, 3-tetramethyluronium tetrafluoroborate, etc. An equivalent to excess amount, preferably 1 to 5 equivalents is used.
  • the inert solvent include solvents such as dichloromethane, N, N dimethylformamide, tetrahydrofuran, and ethyl acetate, or mixtures thereof.
  • N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, 4-nitrophenol, 2,4 dinitrophenol, 2,4,5 triclonal phenol, pentachlorophenol Phenolic compounds such as ru can be added as a reaction accelerator.
  • the compound (Id) can be synthesized from the compound (Ic) by the same method as in the synthesis of the compound (lb) from the compound (la) in Synthesis Method 11.
  • a compound in which R 2 is a substituted or unsubstituted 1,3,4-oxadiazolyl group (wherein R 2 is substituted or unsubstituted A substituted 1, 3, 4-oxadiazolyl group, wherein R 5 is other than a hydrogen atom (Ie), R 2 is a substituted or unsubstituted 1, 3, 4 oxadiazolyl group
  • R 5 is a hydrogen atom
  • a compound (If) can also be synthesized by the following method.
  • R 3 to R 6 , Q, X, Y, ⁇ , m and ⁇ are as defined above, and R, a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted phenyl group.
  • Compound (29) can be synthesized from compound (26) and compound (28) by the same method as in the synthesis of compound (Ic) from compound (26) in synthesis method 6.
  • Compound (29) Strength Compound (Ie) can be synthesized by a conventional method, for example, a heat treatment in the presence of polyphosphoric acid or phosphorus oxychloride, or triphenylamine in the presence of a base such as triethylamine. It can be carried out by a known method such as a method in which ruphorphine and tetrasalt carbon are reacted in dichloromethane [for example, US Patent Publication No. 2004019215].
  • R 2 is a substituted or unsubstituted pyrazole ring, thiazole ring, oxazole ring, isoxazole ring, 1, 2, 4 —
  • a compound having an oxaziazole ring or a 1,2,4-triazole ring may be obtained by referring to the carboxy group of the above compound (26) in the literature [for example, W. Roger Tully et al., Journal of Medicinal Chemistry, 34, 2060-2067, (1991 ) And the like. Can be synthesized by converting to a 5-membered heterocyclic ring.
  • Compound (I) of the present invention can be administered orally using various preparations.
  • the compound (I) of the present invention used for the preparation may be any of a free form, a salt, and a hydrate or solvate thereof.
  • Examples of the oral preparation containing the compound (I) of the present invention include tablets, fine granules, powders, granules, and capsules, and tablets and capsules are preferred. These oral preparations contain pharmaceutically acceptable additives such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants and the like. It can be selected and used as needed.
  • the dosage is preferably 0.1 mg to 1500 mg per person per day, particularly 1 mg to 500 mg. This dose may be once a day or divided into 2 to 3 times.
  • Reference Example 6 The compound (322 mg) obtained in (3) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (lml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 ml), and the compound (317 mg) obtained in Reference Example 6- (1) was collected and stirred at 70 ° C. for 3.5 hours. The reaction solution was cooled to room temperature and the solvent was distilled off under reduced pressure.
  • Reference Example 7 Dissolving the compound (500 mg) obtained in (2) in anhydrous tetrahydrofuran (7 ml), adding lithium aluminum hydride (96 mg) with cooling with ice water and stirring at the same temperature for 2 hours. did. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted three times with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [4-methyl-1- (4-trifluoromethyl) -1- 1H-pyrrole-1-yl] methanol. It was.
  • Reference Example 7 The compound (600 mg) obtained in (3) was dissolved in dichloromethane (8 ml), and tritylamine (442 1) and thiodaricholic acid (222 1) were added in this order in an ice bath, The mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to give the title compound as an oil. This was used in the next reaction without purification.
  • Example 7 In the same manner as in (1), from the compound (677 mg) obtained in 1H-imidazole-3-carbaldehyde (215 mg) and Reference Example 2- (2), the title compound (771 mg) was obtained as a colorless oil.
  • Reference Example 6 In the same manner as (4), Reference Example 9— From the compound (1. Og) obtained in (2) and Reference Example 5- (1) from the compound (1.18 g) The title compound (1.43 g) was obtained as a colorless oil.
  • Reference Example 13 The compound (93 lmg) obtained in (1) was dissolved in concentrated hydrochloric acid (20 ml) and stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 ml), and borane-dimethylsulfide complex (885 1) was added in an ice bath and stirred for 1.5 hours.
  • Reference Example 6 In the same manner as (4), Reference Example 15—Compound (2. Og) obtained in (3) and Reference Example 11—Compound obtained in (1) (1.83 g) To give the title compound (3.03 g) as a pale yellow oil.
  • Reference Example 11 The compound (15.8 g) obtained in (1) was dissolved in tetrahydrofuran (300 ml), glycine tert butyl ester (9 ml) and magnesium sulfate (50 g) were added, and the mixture was heated to reflux for 4 hours. did. The reaction solution was returned to room temperature, filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (100 ml), sodium borohydride (2.3 g) was added while cooling with ice water, and the mixture was stirred at room temperature for 4 hours.
  • Reference Example 17 Compound obtained in (3) (0.230 g), acetohydrazide (0.038 g), 1-ethyl — 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.107 g) ), 1-hydroxybenzotriazole hydrate (0.085 g) was dissolved in N, N dimethylformamide (4 ml) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.163 g) as a colorless oil.
  • Acetoxyacetolide (10 g) was dissolved in acetic acid (100 ml), and an aqueous solution (50 ml) of sodium nitrite (4.67 g) was added dropwise with cooling with ice water. After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Jetyl ether was added to the residue, and insolubles were collected by filtration. The mother liquor was concentrated under reduced pressure, to the residue was added diethyl ether monohexane, and the insoluble material was collected by filtration to give the title compound (1 0.9 g) as a yellow solid.
  • Reference Example 21 The compound (1.75 g) obtained in (2) was dissolved in methoxyethanol (15 ml), and potassium hydroxide (3.4 g) was added at 140 ° C. Stir overnight. The reaction mixture was poured into concentrated hydrochloric acid-ice and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound.
  • Reference Example 17 The compound (3.5 g) obtained in (1) was dissolved in acetonitrile (30 ml), and N— (9-fluoromethoxycarbo-loxy) succinimide (3.74) was cooled with ice water. g) was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium bicarbonate, aqueous citrate solution and saturated brine in this order.
  • Example 26- (1) the title compound (1. Og) was obtained as a colorless solid from the compound (1. lg) obtained in Reference Example 22- (3). It was.
  • Reference Example 22 The compound (1. Og) obtained in (4) was dissolved in tetrahydrofuran (50 ml) and 1,8 diazabicyclo [5.4.0] undane 7 sen (2%) was cooled with ice water. Tetrahydrofuran solution (42.2 ml) was added, and the mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. Acetic acid residue The mixture was extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine.
  • Reference Example 30 Compound (0.150 g) obtained in (2) and acetohydrazine in the same manner as Reference Example 18. The title compound (0.145 g) was also obtained as a colorless oil.
  • Reference Example 15 Similar to (1), Reference Example 31—Compound (0.190 g) force obtained in (1) The compound (0.177 g) was obtained as a colorless solid.
  • Azimuth sodium (0.39 g) was added and stirred at room temperature for 18 hours.
  • the reaction mixture was poured into about 200 ml of ice water, extracted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, and then once with saturated brine.
  • the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate-hexane) to obtain the title compound (0.58 g) as a colorless oil. .
  • Reference Example 33 The compound (0.58 g) obtained in (1) was dissolved in ethyl acetate (15 ml), and 10% Radium monocarbon (0.10 g) and di-tert-butyl dicarbonate (0.999 g) were added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. 10% palladium-carbon was filtered off and washed with ethyl acetate. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to give the title compound (0.6 lg) as a colorless solid.
  • Reference Example 33 The compound (0.60 g) obtained in (2) was dissolved in dichloromethane (2 ml), 4N hydrochloric acid-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and 0.1N sodium hydroxide aqueous solution (20 ml) was added to the residue, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 2- (5-methyl-2phenol-2H— [1, 2, 3] triazol-4-yl) ethylamine (0.38 g) was dissolved as a yellow oil. I got it.
  • Reference Example 9 The compound (1.6 g) obtained in (2) was dissolved in dichloromethane (15 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Residue The compound (1.63 g) obtained in Reference Example 16- (1) was added to the residue dissolved in ethanol (20 ml), and the mixture was stirred at 80 ° C. for 6 hours.
  • Reference Example 37 The compound (0.276 g) obtained in (1) was dissolved in tetrahydrofuran (7 ml), and borane-dimethylsulfide complex (0.278 ml) was added thereto at 50 ° C. Stir for 3 hours. Water was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Reference Example 17 In the same manner as (2), Reference Example 42—Compound (0. lOOg) obtained in (2) and Reference Example 17—Compound obtained in (1) (0.166 g) The title compound (0.240 g) was also obtained as a colorless oil.
  • Reference Example 15 The compound (0.250 g) obtained in (3) was dissolved in dichloromethane (4 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure, dissolve the residue in N, N dimethylformamide (6 ml), difluoroacetic acid (0.083 ml), 1 ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.199 g), 1-hydroxybenzo Triazole hydrate (0.159 g) and N-methylmorpholine (0.286 ml) were added and stirred at room temperature for 22 hours.
  • Reference Example 44 The compound (0.124 g) obtained in (1) was dissolved in tetrahydrofuran (4 ml), and borane-dimethylsulfide complex (0.133 ml) was added thereto at 50 ° C. Stir for 23 hours. Water was added to the reaction mixture, and the mixture was stirred at 60 ° C for 1 hour, saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. Further, the compound (0.066 g) obtained in Reference Example 44- (1) was reacted and treated in the same manner as above and extracted with ethyl acetate.

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Abstract

Composé représenté par la formule générale (I), qui est utile comme agoniste des récepteurs α/Ϝ activés par les proliférateurs de peroxysome, sel du composé, et solvat de l’un ou l’autre de ceux-ci. (Dans la formule, X, Y, et Z représentent chacun un azote ou un carbone ; m est un nombre entier allant de 0 à 3 ; n est un nombre entier allant de 1 à 3 ; Q représente un cycle benzénique éventuellement substitué par un hydroxy, un halogéno, un alcényle inférieur, un alcoxy inférieur, un alkyle inférieur, et un amino ; R1 représente un groupement phényle, naphtyle, ou hétérocyclique aromatique de 5 ou 6 chaînons éventuellement substitué par un hydroxy, un halogéno, un alcényle inférieur, un alcoxy inférieur, un phénoxy, un phényle, un alkyle inférieur, et un amino ; R2 représente un alkyle inférieur, un carbamoyle, un phényle, ou un groupement hétérocyclique aromatique de 5 ou 6 chaînons ; R3 et R4 représentent chacun un hydrogène ou un alkyle inférieur ; R5 représente un hydrogène, un alkyle inférieur, ou un benzyle ; et R6 représente un hydrogène, un hydroxy, un halogéno, un alcényle inférieur, un alcoxy inférieur, un phénoxy, un phényle, un alkyle inférieur, ou un amino.) [Formule chimique 1] (I)
PCT/JP2005/014332 2004-08-05 2005-08-04 Derives de pyrazole WO2006013939A1 (fr)

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WO2009036900A1 (fr) * 2007-09-18 2009-03-26 Bayer Cropscience Ag Procédé de préparation de dérivés de 2,2-difluoréthylamine par hydratation d'amides
KR101520337B1 (ko) 2007-09-18 2015-05-14 바이엘 크롭사이언스 아게 이민 수소화에 의한 2,2-디플루오로에틸아민 유도체의 제조방법
CN106554285A (zh) * 2016-11-27 2017-04-05 天津市职业大学 一种钙钛矿太阳电池用甲基卤化铵的生产方法

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WO2002018355A1 (fr) * 2000-08-23 2002-03-07 Eli Lilly And Company Dérivés d'acide oxazolyl-aryloxyacétique et leur utilisation comme agonistes des ppar
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WO2002100403A1 (fr) * 2001-06-07 2002-12-19 Eli Lilly And Company Modulateurs des recepteurs actives par les proliferateurs du peroxisome (ppar)
WO2004000785A2 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Composes chimiques
US6723743B1 (en) * 1999-09-28 2004-04-20 Neurogen Corporation High affinity small molecule C5a receptor modulators
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US6723743B1 (en) * 1999-09-28 2004-04-20 Neurogen Corporation High affinity small molecule C5a receptor modulators
WO2001040207A1 (fr) * 1999-12-02 2001-06-07 Glaxo Group Limited Derives d'oxazoles et de thiazoles substitues en tant qu'activateurs hppar (recepteur active de proliferation du perixosome humain) alpha
WO2002018355A1 (fr) * 2000-08-23 2002-03-07 Eli Lilly And Company Dérivés d'acide oxazolyl-aryloxyacétique et leur utilisation comme agonistes des ppar
WO2002049993A2 (fr) * 2000-09-29 2002-06-27 Neurogen Corporation Petites molecules modulatrices des recepteurs c5a a haute affinite
WO2002100403A1 (fr) * 2001-06-07 2002-12-19 Eli Lilly And Company Modulateurs des recepteurs actives par les proliferateurs du peroxisome (ppar)
WO2004000785A2 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Composes chimiques
WO2005065683A1 (fr) * 2003-12-22 2005-07-21 Eli Lilly And Company Derive de triazole, oxadiazole et thiadiazole en tant que modulateurs de ppar pour le traitement du diabete

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Publication number Priority date Publication date Assignee Title
WO2009036900A1 (fr) * 2007-09-18 2009-03-26 Bayer Cropscience Ag Procédé de préparation de dérivés de 2,2-difluoréthylamine par hydratation d'amides
JP2010539201A (ja) * 2007-09-18 2010-12-16 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト アミドの水素化により２，２−ジフルオロエチルアミン誘導体を調製する方法
US8273897B2 (en) 2007-09-18 2012-09-25 Bayer Cropscience Ag Method for producing 2,2-difluoroethylamine derivative by amide hydrogenation
TWI406848B (zh) * 2007-09-18 2013-09-01 Bayer Cropscience Ag 經由醯胺氫化作用製備２，２－二氟乙胺衍生物之方法
CN101801929B (zh) * 2007-09-18 2013-10-09 拜尔农作物科学股份公司 通过酰胺氢化来制备2,2-二氟乙胺衍生物的方法
KR101520337B1 (ko) 2007-09-18 2015-05-14 바이엘 크롭사이언스 아게 이민 수소화에 의한 2,2-디플루오로에틸아민 유도체의 제조방법
KR101565391B1 (ko) 2007-09-18 2015-11-03 바이엘 크롭사이언스 악티엔게젤샤프트 아미드 수소화에 의한 2,2-디플루오로에틸아민 유도체의 제조방법
CN106554285A (zh) * 2016-11-27 2017-04-05 天津市职业大学 一种钙钛矿太阳电池用甲基卤化铵的生产方法

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