WO2001027088A1 - Potentialisateurs de lpl - Google Patents

Potentialisateurs de lpl

Info

Publication number
WO2001027088A1
WO2001027088A1 PCT/JP2000/007072 JP0007072W WO0127088A1 WO 2001027088 A1 WO2001027088 A1 WO 2001027088A1 JP 0007072 W JP0007072 W JP 0007072W WO 0127088 A1 WO0127088 A1 WO 0127088A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
tert
chloro
phenyl
butyl
Prior art date
Application number
PCT/JP2000/007072
Other languages
English (en)
Japanese (ja)
Inventor
Hisashi Shinkai
Takahisa Motomura
Noriaki Hamakawa
Original Assignee
Japan Tobacco Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Japan Tobacco Inc. filed Critical Japan Tobacco Inc.
Priority to AU76845/00A priority Critical patent/AU7684500A/en
Publication of WO2001027088A1 publication Critical patent/WO2001027088A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

  • the present invention relates to a novel LPL (lipoprotein lipase) activity enhancer comprising a compound having a 2-phenylbenzimidazole structure or a 2-phenylbenzoxazole structure as an active ingredient, It relates to therapeutic or prophylactic drugs.
  • the present invention also relates to a novel compound having a 2-phenylbenzimidazole structure or a 2-phenylbenzoxazole structure, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • hyperlipidemia is one of the risk factors for diabetes and hypertension.
  • ischemic heart disease hyperlipidemia is one of the risk factors for diabetes and hypertension.
  • a number of epidemiological studies have clarified the causal relationship between hypercholesterolemia and ischemic heart disease and have established its position as an independent risk factor.
  • hypertriglyceridemia was considered to be a risk factor, but was considered to be weak as an independent risk factor.
  • LDL low density lipoprotein
  • TG tridali ceride
  • VLDL ultra Low-density lipoprotein
  • lipid metabolism in a living body is as follows. That is, lipids taken in by the diet are absorbed in the small intestine and secreted into the blood as chylomicrons via lymphatic vessels. The secreted chylomicron is degraded into free fatty acids by the action of LPL (lipoprotein lipase) present in the capillary bed to form chylomicron remnants, which are transmitted to the liver via the chylomicron remnant receptor in the liver. It is captured. Further, in the liver, the incorporated chylomicron remnant and / or free fatty acid is converted into TG or the like by an enzyme such as acyl CoA synthetase, and is associated with apolipoprotein B to form VLDL.
  • LPL lipoprotein lipase
  • V.LDL becomes IDL (intermediate density lipoprotein) by the action of LPL, is converted to LDL by HTGL (hepatic lipase), and is distributed to peripheral tissues.
  • HTGL hepatic lipase
  • LFL binds to vascular endothelium and is a lipoprotein that is a neutral lipid-rich lipoprotein in the blood. It governs the hydrolysis of micron VLDL TG and is involved in the production of primitive HDL, which is important for cholesterol metabolism.
  • LPL plays an important role in lipid metabolism, and enhances or promotes the activity of LP, that is, promotes the production or release of LPL. By promoting or activating, TG can be reduced and HDL-cholesterol can be increased.
  • Japanese Patent Application Laid-Open Nos. 56-8368 (GB2053912) and GB2053215 disclose lipids
  • Benzimidazole derivatives such as 2- (n-pentadecyl) benzimidazole-5-methyl methyl ribonate have been disclosed as compounds having an effect of lowering the concentration of benzene.
  • the compound of the publication is characterized in that it has a linear or branched alkyl group having 7 to 2 ° carbon atoms at the 2-position of the benzimidazole ring and one CO OR 1 at the 5- or 6-position.
  • a compound having a structure such as the compound of the present invention, there is no description that it has an effect of promoting the activity of LPL, and further, there is no alertness that suggests them.
  • Japanese Patent Application Laid-Open No. Hei 2-306916 discloses a compound having a platelet adhesion inhibitory effect useful as a therapeutic or prophylactic agent for arteriosclerosis and the like, and a compound comprising 2- (2-methoxyphenyl) 16_ (triphneolomethyi).
  • 2- (2-methoxyphenyl) 16_ triphneolomethyi
  • Benzimidazole and benzazonole compounds such as 6-chloro-2- (2- (3-piperidinopropyloxy) phenyl] benzothiazol are disclosed.
  • the publication does not disclose a compound having a structure such as the compound of the present invention, but also mentions that it has an action of promoting the activity of LPL, and furthermore, does not disclose any description suggesting them.
  • WO 99/116162 discloses a compound having an antibacterial activity such as 6-amidino-2- [3- (4-methylphenoxy) phenyl] benzimidazo monole. —Substituted phenyrubenzimidazole has been disclosed. However, the compound disclosed in the publication is located at position 6 of the benzimidazole ring. It is characterized by having a toro group, an amidino group or a cyano group, and it does not disclose a compound having a structure such as the compound of the present invention, and of course does not find any description suggesting that.
  • EP 1 48431 and Japanese Patent Application Laid-Open No. 60-15676 disclose a compound having an effect on blood pressure and contractility of myocardium as' 2- (2-methoxy41-benzinoleoxy-1-pheninole)- Benzi midazoles such as 5-funoleo mouth venzi midazones are disclosed.
  • the publication does not disclose any compound having a structure as in the present invention, nor does it mention any suggestion thereof.
  • Japanese Unexamined Patent Publication No. 6-510743 discloses a compound useful as a compound useful for the treatment of inflammatory and / or immunoallergic diseases and the like.
  • (1-adamantyl) phenyl] Benzimidazole derivatives such as benzimidazole are disclosed.
  • the compound of the publication is characterized by having a substituent on the benzimidazole ring via an oxygen atom, and of course not only disclose a compound having a structure such as the compound of the present invention but also suggesting that. Is not found.
  • Japanese Patent Application Laid-Open No. H8-501133 discloses 2- [3-—4- [4-methoxyphene) as a compound having a selective inhibitory action on phosphodiesterase type IV. 2) Butoxy] 1-4-Methoxyphenyl] 1 1H-Venzimidazole-5-Rubonic acid and 2- [3- (benzyloxy)-4-methoxyphenyl] -1H-Venzimidazo Potassium mono-resin ethers such as olenoic acid are disclosed. However, the publication does not disclose a compound having a structure such as the compound of the present invention, but does not find any description suggesting this. Japanese Patent Application Laid-Open No.
  • catechol-benzimidazoles such as 2- [3- (pentinoleoxy) -14-methoxyphenyl] -1H-benzimidazono-5-potassic acid are disclosed.
  • 2- [3- (pentinoleoxy) -14-methoxyphenyl] -1H-benzimidazono-5-potassic acid are disclosed.
  • Japanese Patent Application Laid-Open No. Hei 8-109169 discloses a compound useful as a tachykinin receptor antagonist.
  • WO 97Z31635 discloses a method for preventing sleep apnea or preventing sleep apnea.
  • WO977333873 discloses a compound useful for the prevention or treatment of interstitial cystitis or urethral syndrome.
  • US Pat. No. 5,552,426 discloses a compound useful for the treatment.
  • Benzimidazole has been disclosed as a compound useful for treating or preventing amyloid peptide-related symptoms.
  • these publications do not disclose any compounds having a structure such as the compound of the present invention, nor do they mention any suggestion thereof.
  • Japanese Unexamined Patent Publication (Kokai) No. 61-65848 discloses 2- (4,1-methoxyphenyl) —4-hydroxy-17 as a compound having 5-lipoxygenase inhibitory activity.
  • Methynobenzimidazonole hydrochloride Benzimidazoles such as ethanol are disclosed.
  • JP-A-59-2785 discloses 2- (2′-methoxy) as a compound having an effect on myocardial contractility.
  • An imidazole derivative such as 4′-pendinoleoxy-pheninole) -benzimidazole is disclosed.
  • the publication does not disclose a compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.
  • Japanese Patent Application Laid-Open No. Sho 62-471 discloses a compound having an effect on blood pressure and myocardial contraction.
  • 2-arylimidazole derivatives such as 2- (2'-methoxy-4'-benzyloxy-phenyl) -15-methylmercaptobenzimidazole are disclosed.
  • the publication does not disclose any compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.
  • WO 98Z50029 discloses compounds such as [4- (1H-benzimidazo-l-5-inolecanolepoxamine) _2_fe-norebenzoinole] methionine tri.
  • the publication relates to inhibitors of protein isoprenyltransferase and the oncogene protein Ras or other related small g-proteins, which inhibits pharmacosylation or geranylgeranylation, and discloses their usefulness as LPL activity enhancers. Of course, there is no mention to suggest it.
  • the claims of the publication include, for example, a hydrogen atom and a halogen atom as R, a heterocyclic ring as R 2 (a covalent bond is defined as L n ), and a force S and R 3 as 1 to five ⁇ Norekokishi good Ariru group optionally substituted with a substituent such as group, hydrogen atom and halogen atom as a, 1 ⁇ as an L 4 one N (R S) - L s -, one L 4 —0— L s — and — L 4 — S (O).
  • — 2 — L s — is absent as L 4 and L s
  • an alkylene group having 1 to 10 carbon atoms is defined as a covalent bond as Z.
  • the present inventors have conducted intensive studies as described above to provide a compound having an activity of enhancing LPL activity, that is, a compound having an activity-enhancing activity such as promoting or activating the production or release of LPL. That is, the present inventors have found a novel compound which can reduce triglyceride and increase HDL-cholesterol and which is useful as a preventive or therapeutic agent for hyperlipidemia or arterial dysplasia, thereby completing the present invention. .
  • the present invention relates to compounds and medicaments having the LPL activating action shown in the following (1) to (28).
  • a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 substituent groups; Aryl group; or
  • R 3 , R 4 , R 5 and R 6 may be the same or different
  • R 7 is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms, and Z and may be the same or different.
  • R 7 is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms, and Z and may be the same or different.
  • R 8 is a hydrogen atom, a linear or branched ⁇ lower alkyl group having 1 to 4 carbon atoms, or having from 1 to 4 carbon straight or branched C port Gen Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient.
  • R 3 and R 4 may be the same or different
  • R 6 A hydrogen atom
  • R 3 and R 4 may be the same or different
  • 6-t ert-butynole 4-chloro-2- [4-chloro-3- [2- (trifolenormetinole) penzinoleoxy] feninole] Benzi midazo monole;
  • a therapeutic drug for hypertriglyceridemia comprising as an active ingredient the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • a prophylactic or therapeutic drug for hyperlipidemia comprising the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient.
  • a prophylactic or therapeutic drug for arteriosclerotic diseases comprising as an active ingredient the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. .
  • R is A halogen atom
  • a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is provided.
  • R 2 , R 3 and R 6 are hydrogen atoms, and R 4 is a hydrogen atom or a halogen atom
  • R 4 is a hydrogen atom or a halogen atom
  • R is a phenyl group substituted with one or two substituents selected from a halogen atom, a methyl group, a cyano group, a carbamoyl group, a methoxy group, a trifluoromethyl group, and a nitro group.
  • R is an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group or a 1,1-dimethyl-12-hydroxyxethyl group, and R 5 ′ is a halogen atom, a methyl group or a cyano group.
  • R is 2— (trifluoromethyl) phenyl group, 3— (trifluoromethyl) phenyl group, 41- (trifluoronorethynole) phenyl group, 2-phenylene 6— (Trinooleolomethinole) Phenyl group, 4-funoleol 2- (triphenylolemethinole) Phenyl group, 4-bromo-2- (trif / leolomethyl) phenyl group, 2
  • R is 2 _ (trifluoromethyl) phenyl group, 4-phenolole 2-(triphenylolemethinole) phenyl group or 5-phenolyl _ 2-(trifluoromethyl) )
  • 6-tert-butynole 4-chloro-2- [4-chloro-3- (2- (trifnorolemethinole) penzinoleoxy] phenyl benzimidazonole;
  • a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of (10) to (18), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • a method for enhancing LPL activity comprising administering an effective amount of the compound according to any one of (1) to (6).
  • (21) A method for treating hypertriglyceridemia, comprising administering to a patient an effective amount of the compound according to any one of (1) to (6).
  • (22) A method for preventing or treating hyperlipidemia, comprising administering to a patient an effective amount of the compound according to any one of (1) to (6).
  • the LPL activity enhancer according to any one of the above (1) to (6) and at least one of the hypertensives are at least one of hypertriglyceridemia, hyperlipidemia, and arteriosclerotic disease Commercial package containing documentation stating that it can or should be used for therapy.
  • a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms means an alkyl group having 1 to 4 carbon atoms which may be straight-chain or branched. It means, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group.
  • a straight-chain or branched alkyl group having 1 to 6 carbon atoms means an alkyl group having 1 to 6 carbon atoms which may be straight-chain or branched. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl, hexyl group and the like.
  • a linear or branched lower alkylene group having 1 to 4 carbon atoms means an alkylene group having 1 to 4 carbon atoms which may be linear or branched, Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, an ethylethylene group, and a dimethylmethylene group.
  • a linear or branched alkylene group having 1 to 8 carbon atoms means an alkylene group having 1 to 8 carbon atoms which may be linear or branched, Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a propylene group, an ethylethylene group, a dimethylmethylene group, and a dimethyltrimethylene group.
  • Halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a straight-chain or branched halogenated lower alkyl group having 1 to 4 carbon atoms means 1 to 3 straight-chain or branched lower alkyl groups having 1 to 4 carbon atoms.
  • the same or different halogen atoms are substituted. Specifically, it is a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group.
  • a straight-chain or branched lower alkoxy group having 1 to 4 carbon atoms means the alkoxy group having a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms described above. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an i.sopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.
  • a carbamoyl group substituted by a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms means a straight-chain or branched-chain having 1 to 4 carbon atoms as defined above for a carbamoyl group.
  • Lower alkyl group is the same or different and is substituted by 1 or 2 lower alkyl groups, specifically, methylcarbamoyl group, ethynolecanolebamoyl group, propylcanolebamoyl group, isopropynolecarbamoinole group, Butinorecanorebamoinole group, Isobutinorecanolebamoinole group, sec —butylcarbamoinole group, tert —Butilecanolebamoyl group, dimethylca Norebamoyl group, getylcarbamoyl group, dipropyl-lubamoyl group, diisobutyl-l-pyruvamoyl group, dibutylcarbamoyl group, diisobutylphenylcarbamoyl group, di-sec-butylcarbamoyl group, di-tert-butylcarbamo
  • a straight-chain or branched lower alkanoyl group having 2 to 5 carbon atoms means an alkanoyl group having 2 to 5 carbon atoms which may be straight-chain or branched, Specific examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and vivaloyl groups.
  • a straight-chain or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms means an alkoxycarbonyl group having 2 to 5 carbon atoms which may be straight-chain or branched. And specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. And the like.
  • Aryl group includes phenyl, naphthyl, biphenyl and the like.
  • a 5- to 6-membered heterocyclic group having 1 to 3 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom means 1 to 3 selected from an oxygen atom, a nitrogen atom or a sulfur atom
  • the “aryl group” for R is preferably a phenyl group.
  • a linear or branched lower alkyl group having 1 to 4 carbon atoms is preferably a methyl group or an ethyl group, particularly preferably a methyl group.
  • halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a fluorine atom.
  • the straight-chain or branched lower alkoxy group having 1 to 4 carbon atoms, which is a substituent of the aryl group in R, is preferably a methoxy group or an ethoxy group, particularly preferably It is a methoxy group.
  • the "carbamoyl group substituted with a linear or branched lower alkyl group having 1 to 4 carbon atoms" is preferably a methylcarbamoyl group, an ethylcarbamoyl group or a dimethyl group. It is a carbamoyl group.
  • the “linear or branched lower alkanoyl group having 2 to 5 carbon atoms” which is a substituent of the aryl group in R is preferably an acetyl group.
  • the aryl group may be substituted with 1 to 2 substituents.
  • the substituent of the aryl group in R is preferably a methyl group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a methoxy group, a cyano group, a nitro group or a rubamoyl group. It is an orthomethyl group or a fluorine atom.
  • the “straight or branched alkyl group having 1 to 6 carbon atoms” in 1 ⁇ is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a 1,1- It is a dimethylpropyl group, particularly preferably an isopropyl group, a tert-butyl group or a 1,1-dimethylpropyl group.
  • halogen atom which is a substituent of the alkyl group in R 1, is preferably a fluorine atom or a chlorine atom.
  • the “linear or branched lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the alkyl group in is preferably a methoxy group or an ethoxy group.
  • the “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” which is a substituent of the alkyl group in the above is preferably a methoxycarbonyl group or an ethoxycanoleboninole group.
  • the alkyl group may be substituted with 1 substituent.
  • the substituent of the alkyl group in R 1 is preferably a hydroxyl group or a carboxy group.
  • aryl group is preferably a phenyl group.
  • the "5- to 6-membered heterocyclic group having 1 to 3 complex atoms selected from oxygen atom, nitrogen atom and sulfur atom” is preferably a pyridyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group A pyrazolyl group, a morpholino group, a morpholinyl group, a piperazinyl group, a piperidino group, a piperidyl group or a pyrrolidinyl group.
  • R is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a 1,1-dimethylpropyl group, a 1.1-dimethyl-2-hydroxyshethyl group or A phenyl group, particularly preferably an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group, or a 1,1-dimethyl-2-hydroxyxethyl group.
  • linear or branched alkyl group having 1 to 6 carbon atoms for R, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a 1,1-dimethyl group
  • a propyl group particularly preferably an isopropyl group, a tert-butyl group or a 1,1-dimethylpropyl group.
  • halogen atom which is a substituent of the alkyl group in the above, is preferably a fluorine atom or a chlorine atom,
  • the “linear or branched lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the alkyl group in is preferably a methoxy group or an ethoxy group.
  • the “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” as a substituent of alkyl S in the above is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • the alkyl group may be substituted with 1 substituent.
  • the substituent of the alkyl group in R is preferably a hydroxyl group or a carboxyl group.
  • aryl group is preferably a phenyl group.
  • the "5- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur atoms" for R and ' preferably a pyridyl group, a thiazolyl group, an oxazolyl group, or a A midazolyl group, a pyrazolyl group, a morpholino group, a morpholinyl group, a piperazinyl group, a piperidino group, a piperidyl group or a pyrrolidinol group.
  • R is preferably methyl, ethyl, propyl, isopropyl A butyl group, a tert-butyl group, a 1,1-dimethylpropyl group, a 1,1-dimethyl-2-hydroxyshethyl group or a phenyl group, particularly preferably an isopropyl group, a tert-butyl group, It is a 1-dimethylpropyl group or a 1,1-dimethyl-12-hydroxyl group.
  • the “halogen atom” for R 2 is preferably a chlorine atom.
  • the “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R 2 is preferably a methyl group or an ethyl group.
  • halogen atom as a substituent for the lower alkyl group in R 2 is preferably a fluorine atom or a chlorine atom.
  • the “linear or branched lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the lower alkyl group for R 2 is preferably a methoxy group or an ethoxy group.
  • the “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” as a substituent of the lower alkyl group for R 2 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • the lower alkyl group may be substituted with 1 to 3 substituents” of the lower alkyl group for R 2, it is preferable that the lower alkyl group may be substituted with 1 substituent.
  • the substituent of the lower alkyl group for R 2 is preferably a hydroxyl group or a carboxy group.
  • R 2 is preferably a hydrogen atom or a chlorine atom.
  • halogen atom in R 3 , R 4 , R s or R 6 is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, particularly preferably a chlorine atom or a bromine atom.
  • the “linear or branched lower alkyl group having 1 to 4 carbon atoms” in R 3 , R s or R 6 is preferably a methyl group.
  • the “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” in R 3 , R 4 , R 5 or R 6 is preferably a trifluoromethyl group.
  • the R 3, R have R s or R e, is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a Shiano group.
  • R 3 is particularly preferably a hydrogen atom or a chlorine atom.
  • R is particularly preferably a hydrogen atom or a chlorine atom.
  • R 5 is particularly preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a cyano group, and more preferably a chlorine atom, a bromine atom or a cyano group.
  • R 6 is particularly preferably a hydrogen atom.
  • the “halogen atom” in R s ′ is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and particularly preferably a chlorine atom or a bromine atom.
  • the “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R 5 ′ is preferably a methyl group.
  • the “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” for R 5 ′ is preferably a trifluoromethyl group.
  • R 5 ′ is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a cyano group, and particularly preferably a chlorine atom, a bromine atom or a cyano group.
  • the “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R 7 is preferably a methyl group.
  • R 7 is preferably a hydrogen atom.
  • the “linear or branched lower alkylene group having 1 to 4 carbon atoms” in Z or is preferably a methylene group or an ethylene group.
  • the “linear or branched alkylene group having 1 to 8 carbon atoms” in X is preferably an ethylene group.
  • linear or branched lower alkyl group having 1 to 4 carbon atoms in R B, is preferably a methyl group.
  • the “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” for R 8 is preferably a chloromethyl group or a trifluoromethyl group.
  • the “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R 8 ′ is preferably a methyl group.
  • a 2- (trifluoromethyl) benzyloxy group or a 4-fluoro-1--2 (Triphenylolemethinole) benzinoleoxy group, 5-funoleoleol 2- (trifluoromethyl) benzyloxy group, 2- (trifluoromethyl) benzylamino group is a tert-butyl group as R] (or R), 1.1 —Dimethyl 2 —Hydroxyshetyl group, R 2 , R 3 , R 4 and R 6 are hydrogen atoms, R E (or R 5 ) is chlorine, bromine or cyano group, and Y is one. NH— is most preferred.
  • the compound represented by the general formula (I) includes a known compound, and is preferably a compound represented by the general formula (1 ′).
  • the compound represented by the general formula ( ⁇ ') is a novel compound. Therefore, in the present specification, the term “compound represented by the general formula (I)” refers to a compound represented by the general formula (I)
  • LPL activity is high means that LPL activity is enhanced or promoted, and more specifically, LPL production or release is promoted, activated or its activity is sustained. I do.
  • the “pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with the compound represented by the above general formula (I). Examples thereof include hydrochloride and hydrogen bromide.
  • Inorganic acid salts such as acid salts, hydroiodide salts, sulfates, nitrates, phosphates, carbonates, bicarbonates, and perchlorates; formates, acetates, trifluoroacetates, propionates, and oxalates Acid, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate, adipate, tartrate, lingate, citrate, benzoate
  • Organic acid salts such as acid salts, silicates, ascorbates, salicylates, 2-acetoxybenzoates, nicotinate, isonicotinate; methanesulphonate, ethanesulphonate, isethione Salt, benzene Sulfonates, p-s
  • the compound of the present invention has an excellent LPL activity enhancing action, and is expected as a novel type of preventive or therapeutic agent for hyperlipidemia or arteriosclerotic disease.
  • a pharmaceutically acceptable carrier known per se is usually used.
  • Excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffering agents, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, corrigents, solubilizing agents, other additives Specifically, carbohydrates such as water, vegetable oil, phenolic alcohol such as ethanol or benzyl alcohol, polyethylene glycol corn, glycerol triazetate gelatin, lactose, starch, etc., magnesium stearate, talc, lanolin, Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, and pills mixed with petrolatum, etc. Sill, suspensions, emulsions, can be administered
  • the dose may vary depending on the type and degree of the disease, the compound to be administered, the administration route, the age, sex, weight and the like of the patient.
  • the compound (I) per adult per day is usually 1 to: It is preferred to administer 100 mg, especially 50 mg to 800 mg.
  • the compound of the present invention can be produced, for example, by the following method, but it goes without saying that the method of producing the compound of the present invention is not limited thereto.
  • R 10 is water »group, merbut group, -NHR T
  • This step is for introducing a protecting group into the carboxy group, and may be carried out as needed.
  • the method is not particularly limited as long as it is a commonly used method.
  • the compound (III) R 10 is a hydroxyl group, a mercapto group, (wherein, 13 ⁇ 4 7 are as described above) one NHR 7, a halogen atom or one CHO, R "is methylcarbamoyl group, a carboxy protecting group such as Echiru group or Ariru group
  • R 3 , R 4 , RR c and Z are as described above] is the compound (II) (wherein R 3 , R 4 , R s , R 6 , R, and Z are as defined above) the presence of an acid of the a) or the like sulfuric acid, hydrochloric acid, p- toluenesulfonic acid as a R u OH (Shiki ⁇ and R u are defined as above), benzene optionally
  • the reaction can be carried
  • This step, R There hydroxyl group, a process which we used when a mercapto group or one NHR 7, i.e., the compound (IV) (wherein, R, R 3, R 4 , R 5, R 6, R u ⁇ beauty X is As described above) is a compound (III) wherein There hydroxyl, mercapto group or one NHR 7 (where, R 7 is as defined above) and, R 3, R 4, R have R 6, R u and Z are as defined above] with the compound R 12 — ⁇ , — R (where R, 2 are halogen atoms and R and Z, are as described above) and potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, etc.
  • the reaction is carried out under cooling or heating in an organic solvent such as dimethylformamide, acetone or toluene or a mixed solvent thereof in the presence of a base, or particularly when the compound (III) is used.
  • a base such as potassium carbonate
  • copper chloride or copper bromide is added.
  • R of the compound (III).
  • the compound (IV) is a compound of the formula (III) and the compound HO— — R (where R and Z are as defined above) Ether, tetrahydrofuran, dioxane, dichloromethane, dichloromethane, dichloromethane, clog form, benzene, toluene, dime It can also be synthesized by reacting in an organic solvent such as chillformamide or a mixed solvent thereof under cooling or heating.
  • the compound (III) If a guard NHR 7, the compound (IV) is, I ⁇ compound (III) with the compound OHC- - R (wherein, R and Z t are the aforementioned toe )
  • an organic solvent such as dimethinoleformamide, dioxane, toluene, dimethylsnoreoxide, methanol, ethanol, or a mixture thereof, and then sodium borohydride, sodium borohydride, and hydrogen hydride.
  • Organic solvents such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropinoleanolone, dimethoxetane, and toluene in the presence of reducing agents such as lithium borohydride, lithium aluminum hydride, trimethylsilane, and triethylsilane; It can also be synthesized by reacting in a mixed solvent under cooling or heating.
  • step 2 is X is - Z- O- Z, -, - Z- S- - and single Z- NR 7 - - is particularly useful for synthesizing the compound (IV) is.
  • This process involves: Is a step used when is a halogen atom, that is, the compound (IV) (wherein R, R 3 , R 4 , R 5 , R 6 , R restroomand X are as defined above) compound (III) (wherein, R,.
  • R 13 is a halogen atom, R 3, R 4, R 5, R 6, R u and Z are as defined above) with a compound R 13 - Z, - R [Wherein, R 13 is a hydroxyl group, a mercapto group or one NHR 7 (where R 7 is as described above), and R and 1 are as described above], and potassium carbonate, A compound capable of reacting under cooling or heating in an organic solvent such as dimethylformamide, acetone, toluene or a mixed solvent thereof in the presence of a base such as sodium carbonate, sodium hydrogen carbonate, sodium hydride or the like.
  • This process involves: Is the process used when is one CHO, that is, The compound (IV) (wherein R, R 3 , R réelle, R 5 , R 6 , R réelle and X are as described above) is a compound (III) (where R 10 is is CHO, R 3, R 4, R s, R 6, R u and Z are as defined above) with a compound R 7 HN- Z] in one R (wherein, R, R 7 ⁇ Pi is the aforementioned With dimethylformamide, dioxane, toluene, dimethylsulfoxide, methanol, ethanol and the like, or a mixed solvent thereof, and then sodium borohydride, sodium borohydride cyanide, hydrogen In the presence of reducing agents such as lithium borohydride, lithium aluminum hydride, trimethylsilane, and triethylsilane, methanol, ethanol, ether, dioxane, tetrahydrofuran, diinpropyl alcohol, dimethoxye
  • step 4 is X is _Z- NR 7 - is particularly useful for synthesizing the compound (IV) is a - Z t.
  • the compound (V) (wherein R, R 3 , R 4 , R s , R 6 and X are as described above) is obtained by preparing the compound (IV) (wherein R, R 3 , R 4 , R s , R e , R, and X are as described above), and sodium hydroxide, sodium hydroxide, sodium carbonate, carbonate base, etc. or hydrochloric acid, hydrobromic acid, etc.
  • Organic solvents such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxetane, aethenole, diisopropinoleether, and ethylene glycol, water or a mixed solvent or a non-solvent thereof in the presence of It can be synthesized by reacting under cooling or heating.
  • the compound (VI) (wherein R 14 is a halogen atom, and R, R 3 , R 4 , R 5 , R 6 and X are as described above) is a compound (V) (wherein , R, R 3 , RR s , R 6 and X are as described above) in the presence of an acid halide agent such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc.
  • Organic solvents such as black form, dimethylformamide, dichloromethane, toluene, pyridine, etc. It can be synthesized by reacting in a mixed solvent under cooling or heating.
  • R, R 2 , R s and R 1S are as described above
  • a base such as pyridine, triethylamine, N-methylmorpholine, N-methylbiperidine, and the like, dichloromethane
  • the reaction is carried out under cooling or heating in an organic solvent such as Tonolen, Athenole, Tetrahydrofuran, Dishkisan, Diisopropylether, Dimethoxetane, Hexane, etc. or in a mixed solvent or without solvent, under cooling or heating.
  • an organic solvent such as Tonolen, Athenole, Tetrahydrofuran, Dishkisan, Diisopropylether, Dimethoxetane, Hexane, etc. or in a mixed solvent or without solvent, under cooling or heating.
  • the reaction is carried out under cooling or heating in an organic solvent, water or a mixed solvent thereof or in a solvent-free condition, and if necessary, then benzene, tonylene and benzene, in the presence of an acid such as hydrochloric acid, acetic acid or p-toluenesulfonic acid.
  • Xylene, methanol, Data It can be synthesized by reacting under heating in an organic solvent such as knol, a mixed solvent thereof, or no solvent. This method is particularly effective when R 1S is a nitro group.
  • R 1S is a protected amino group or hydroxyl group
  • compound (VIII) is converted to methanol, ethanol, toluene, benzene, xylene in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, and camphorsulfonic acid. It can also be synthesized by reacting in an organic solvent such as above or a mixed solvent thereof under heating.
  • the salt addition compound of compound (I) or the hydrate or solvate of compound (I) obtained in the above step 8 can be synthesized by a conventional method after synthesizing compound (I). Can be synthesized as follows.
  • compound (I) is prepared by subjecting compound (I) to the presence of hydrochloric acid, hydrogen chloride monoether, hydrogen chloride monoethyl acetate, hydrogen chloride-dioxane, or the like, in the presence of chloroform, dichloromethane, ethyl acetate, ethanolone, methanolone, acetone, tonorenene, tetranoine. It can be synthesized by reacting under cooling or heating in an organic solvent such as drofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or without solvent.
  • compound (IV) can be synthesized by the following method, and then synthesized by the method of steps 5 to 8 described above. .
  • Compound (XI) (wherein R, R 3 , R s , R 6 , and X are as described above) is a compound (X) (where R 3 , R 5 , R 6 , R n And Z are as described above) and the compound HO——R (where R and Z are as described above), carbonated sodium, sodium carbonate, sodium hydrogencarbonate, sodium hydride, etc.
  • the reaction is carried out in an organic solvent such as dimethinolephonoremamide, acetone, dimethinolesnolefoxide, tetrahydrofuran, dimethoxetane, or a mixture thereof in the presence of a base of Can be.
  • Compound (XII) (wherein, R, R 3, R s , R 6, R “ and X are Ru der as described above) is the compound (XI) (wherein, R, R 3, R 5 , R 6 and X are as described above) in the presence of an acid such as acetic acid, ammonium chloride, or hydrochloric acid with iron, zinc, or the like, an organic solvent such as methanol, ethanol, ether, or tetrahydrofuran, water, or a mixture thereof. It can be synthesized by reacting at room temperature or under heating in a solvent or without solvent.
  • an acid such as acetic acid, ammonium chloride, or hydrochloric acid with iron, zinc, or the like
  • an organic solvent such as methanol, ethanol, ether, or tetrahydrofuran, water, or a mixture thereof. It can be synthesized by reacting at room temperature or under heating in a solvent or without solvent.
  • Compound (IV) (wherein R, R 3 , R s , R 6 , R], and X are as described above) is compound (XII) (where R, R 3 , R s , R 6 and X are as described above) in the presence of an acid such as hydrochloric acid or hydrobromic acid in sodium nitrite or the like, in an organic solvent such as acetic acid, water or a mixed solvent thereof.
  • an acid such as hydrochloric acid or hydrobromic acid in sodium nitrite or the like
  • organic solvent such as acetic acid, water or a mixed solvent thereof.
  • CuR 4 wherein is the same as above
  • a halogen atom or a cyano group is particularly preferred).
  • the reaction can be carried out by reacting under cooling or heating in an organic solvent, water or a mixed solvent thereof, or no solvent.
  • the compound (V) is synthesized by the following method, Can be synthesized by the method of Steps 6 to 8.
  • Compound (XIV) (wherein R 13 ′ is a hydroxyl group or a mercapto group, and R 3 , R 4 , R s , R 6 and Z are as described above) are compound (XIII) (wherein R 3 , R 4 , R 6 , 13 ′ and Z are as described above) in the presence of an acid such as hydrochloric acid, hydrobromic acid or the like, with sodium nitrite or the like, an organic solvent such as acetic acid, water or a mixture thereof. After reacting in a solvent under cooling or heating, the reaction product is treated with CuR 5 (where R 5 is as described above) in the presence of hydrochloric acid, hydrobromic acid, sodium cyanide, or the like. In this case, a halogen atom or a cyano group is particularly preferred). It can be synthesized by reacting under cooling or heating in an organic solvent such as water, a mixed solvent thereof or no solvent.
  • Compound (XV I) (wherein R 3 , R 4 , R 5 , R 6 , R 13 ′ and Z are as described above) is a compound (XV) (where R 3 , R 4 , R s , R 6 , R 13 'and Z are as described above) in the presence of an acid such as hydrochloric acid or hydrobromic acid with sodium nitrite or the like, an organic solvent such as acetic acid, water or a mixture thereof. After reacting in a solvent under cooling or heating, the reaction product is cooled in the presence of sodium iodide or the like, in an organic solvent such as acetic acid, chloroform, water or a mixed solvent thereof or in a solvent-free state. Alternatively, it can be synthesized by reacting under heating.
  • Compound (XV II) may Ihigo compound (XV I) (wherein, R 3, R 4 , R s , R e , R 13 ′ and Z are as defined above) and compound Ru—Z, —R (where R, R 12 and Z t are as defined above) with potassium carbonate, In the presence of a base such as sodium carbonate or sodium hydrogen carbonate, the reaction is carried out under cooling or heating in an organic solvent such as dimethylformamide or acetone, or a mixed solvent thereof, or compound (XVI) and compound HO— A condensing agent obtained by combining Z, —R (wherein R and Z are as described above) with triphenylphosphine, trifluorobutylphosphine, etc., and diisopropyl azodicarboxylate, getyl azodicarboxylate, dicyclohexyl azodicarboxylate,
  • ether, te It can be synthesized by reacting in an organic solvent such as trahydrofuran, dioxane, dichloromethane, dichloromethane, benzene, toluene, dimethylformamide or the like, or a mixed solvent thereof under cooling to heating.
  • organic solvent such as trahydrofuran, dioxane, dichloromethane, dichloromethane, benzene, toluene, dimethylformamide or the like, or a mixed solvent thereof under cooling to heating.
  • Compound (XV III) (wherein, R, R 3, R 4 , R RN R 6 and X are as described above) is Ihigo compound (XV II) (wherein, R, R 3, R 4 , R 5 , R 6 and X are as described above), if necessary, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, and the like.
  • a catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, and the like.
  • the compound can be synthesized by reacting with copper cyanide or the like in an organic solvent such as dimethylformamide, pyridine or toluene, or a mixed solvent thereof at room temperature or under heating.
  • Compound (V) (wherein, R, R 3 , R 4 , R s , R 6 and X are as described above) is compound (XV III) (wherein, R, R 3 , R 4 , R s , R 6 and X are as described above) in the presence of a base such as sodium hydroxide or potassium hydroxide, in an organic solvent such as ethylene dali alcohol, ethanol, toluene, xylene or a mixed solvent thereof.
  • a base such as sodium hydroxide or potassium hydroxide
  • organic solvent such as ethylene dali alcohol, ethanol, toluene, xylene or a mixed solvent thereof.
  • Compound (I) can also be synthesized by the following method.
  • the compound (XIX) in which R 16 is a hydroxyl group, a mercapto group or —NHR 7 the compound can be synthesized by carrying out this step after protecting with a protecting group by a conventional method in advance.
  • these protective groups can be removed by a conventional method, if necessary, after performing Step 21 described below.
  • Compound (XXI) (wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 R 15 , R, 6 and Z are as described above) are compound (XX) (where R 3 , R 4 , R 5 , R 6 , R H , R, fi and Z are as described above) and the compound (VII) (wherein R, R 2 , R s and R] 5 are as described above), and pyridine, triethylamine, N— In the presence of a base such as methyl morpholine or N-methylbiperidine, an organic solvent such as dichloromethane, chloroform, tonoleene, ethere ⁇ , tetrahydrofuran, dioxane, diisopropinoleether, dimethoxetane, hexane, water or a mixture thereof. It can be synthesized by reacting under cooling or heating in a mixed solvent or without solvent.
  • a base such as
  • R 6 , R 8 , R, R 16 and Z are as described above) in the presence of a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide or sodium disulfide.
  • a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide or sodium disulfide.
  • the reaction is carried out in a medium, cooled or heated state, and then, if necessary, in the presence of an acid such as hydrochloric acid, acetic acid, p-toluene-nolefonic acid, or an organic solvent such as benzene, toluene, xylene, methanol, ethanol, or the like. It can be synthesized by reacting the mixture in a mixed solvent or a non-solvent with heating. This method is particularly effective when R 15 is a nitro group.
  • compound (XXI) when R 15 is a protected amino group or hydroxyl group, compound (XXI) can be prepared by reacting compound (XXI) with methanol, ethanol, toluene, benzene or benzene in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, and camphorsulfonic acid. It can also be synthesized by reacting in an organic solvent such as xylene or a mixed solvent thereof under heating.
  • Compound (I) (wherein, R, R !, R 2 , R 3 , R 4 , R s , R 6 , X and Y are as described above) is a compound (XXII) (where R 1 R 2 , R 3 , R 4 , R s , R 6 , R 13 , Y and Z are as described above) and compound R 12 — Zi—R (where R, R 12 and Z, are as described above) and potassium carbonate, sodium carbonate, carbonate
  • a base such as hydrogen sodium or sodium hydride
  • R 13 of compound (XX II) is a hydroxyl group
  • the compound R 12 - Z, - if R 12 in R is combinations are ® ⁇ atom is the presence of a base such as carbonate force Riumu, if necessary Add pyridine, etc., and use
  • compound (I) is compound (XXII) and compound HO—Z! —R (where R and are as described above).
  • It can also be synthesized by reacting under cooling or heating in an organic solvent such as chlorophonolem, benzene, tonolene or dimethylformamide or a mixed solvent thereof.
  • compound (I) is a compound (XXII) and compound OHC——R, wherein R and are as defined above.
  • compound (I) is a compound (XXII) and compound OHC——R, wherein R and are as defined above.
  • compound (I) is a compound (XXII) and compound OHC——R, wherein R and are as defined above.
  • dimethylformamide, dioxane, toluene, dimethylsulfoxide, methanol, ethanol or other organic solvent or a mixture thereof and then sodium borohydride, sodium cyanoborohydride, lithium borohydride, hydride
  • a reducing agent such as lithium aluminum, trimethylsilane or triethylsilane
  • organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropinoleanolone, dimethoxetane, or tonoleene, or a mixed
  • the salt addition compound of compound (I) or the hydrate or solvate of compound (I) obtained in step 22 can be synthesized by a conventional method after synthesizing compound (I). For example, they can be synthesized as follows.
  • compound (I) is prepared by treating compound (I) in the presence of hydrochloric acid, hydrogen chloride-ether, ethyl chloride-hydrogen monoxide, hydrogen chloride-dioxane, etc., in the presence of chloroform, dichloromethane, ethyl acetate, ethanol, methanol, acetone, toluene, tetrahydrochloride. It can be synthesized by reacting under cooling or heating in an organic solvent such as drofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or without solvent.
  • an organic solvent such as drofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or without solvent.
  • compound (I) can also be synthesized by synthesizing compound (VIII) by the following method and then performing step 8 described above.
  • Compound (XX ′) (wherein R ′′ R 4 , R 5 , R 6 , R 13 , R 14 and Z are as described above) is compound (XIX ′) (wherein R 3 , R 3 4 , R s , R 6 , R 13 and Z are as described above) in the presence of an acid halide such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc.
  • an acid halide such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc.
  • Form, dimethylformamid It can be synthesized by reacting under cooling or heating in an organic solvent such as solvent, dichloromethane, toluene, pyridine or the like or a mixed solvent thereof.
  • the compound (XX ′) can also be synthesized by, if necessary, protecting R 13 of the compound (XIX ′) with a protecting group by a conventional method and then performing this step. Further, after performing the following step 24, this protecting group can be removed by a conventional method as necessary.
  • the compound (XXI,) (wherein R 2 , R 3 , R 5 , R 6 , R 13 , R 15, and Z are as described above) is a compound (XX ′) (formula , R 3 , R 4 , R s , R fi , R 13 , R 14 and Z are as described above) and compound (VII) (where R !, R 2 , R 8 and R 1S are as described above).
  • a base such as pyridine, triethylamine, N-methylmorpholine, N-methylbiperidine, dichloromethane, chloroform, toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxetane, It can be synthesized by reacting under cooling or heating in an organic solvent such as xan, water or a mixed solvent thereof, or without solvent.
  • a base such as pyridine, triethylamine, N-methylmorpholine, N-methylbiperidine, dichloromethane, chloroform, toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxetane
  • compound (VIII) is compound (XXI ′) and compound HO—Z, —R (where R and Z, Are as described above) and ether, tetrahydrofuran in the presence of a condensing agent obtained by combining triphenylphosphine, tributylphosphine, etc. with diinpropyl azodicarboxylate, getyl azodicarboxylate, dicyclohexyl azodicarboxylate, etc. , Dioxane, dichloromethane, chlorophonolem, benzene, tonoleene, dimethylformamide, and the like, or a mixed solvent thereof, or by reacting the mixture under cooling or heating.
  • the compound (I) (wherein R, R, R 2 , R 3 , RR s , R 6 , X and Y are as described above) is the compound (XX III) (formula Wherein R, R 2 , R 3 , R 4 , R s , R e , R l2 , X and Y are as described above, and a compound R, B (OH) 2 (where R is With a catalyst such as tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium chloride, and a base such as sodium carbonate, triethylamine, sodium hydrogencarbonate or the like.
  • a catalyst such as tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium chloride
  • a base such as sodium carbonate, triethylamine, sodium hydrogencarbonate or the like.
  • the compound (I) in which the substituent at R is, for example, a carbamoyl group or a carbamoyl group substituted with a lower alkyl group is a corresponding compound wherein the substituent at R is a cyano group.
  • Compound (XX IV) (wherein, R, R 2 , R 3 , R 4 , R s , R 6 , X and Y are as described above) is compound (la) (where R !, R 2 , R 3 , R 4 , R s , R 6 , X and Y are the same as described above) in the presence of a base such as sodium hydroxide and potassium hydroxide, and an organic solvent such as ethylene glycol, ethanol and toluene. It can be synthesized by reacting in a solvent, water or a mixed solvent thereof under heating.
  • a base such as sodium hydroxide and potassium hydroxide
  • organic solvent such as ethylene glycol, ethanol and toluene
  • Compound (I) (where R, R or R 2 , R 3 , R or R s , R 6 , X and Y are as described above) is a compound (XX IV) (where R is in R 2, R 3, R 4 , R s, R 6, X ⁇ Pi Y are as described above) chloride
  • Anmoniumu or NHR 17 R 18 (wherein, R l7 and R 18 are identical or different A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, or a hydrogen atom) to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • Condensation agents such as xylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, etc., if necessary, can be used for 1-hydroxybenzotriazole, hydroxysuccinimide, N-hydroxy- Activator such as 5-norbornene 1,2,3-dicarbox
  • the compound (I) in which R s is, for example, a cyano group is obtained by synthesizing the corresponding compound (I) in which R s is a halogen atom by the aforementioned step 8 or step 22, It can also be synthesized by the following method.
  • Compound (I) (wherein, R, R, R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as described above) is a compound (I b) ( In the formula, R, R 1 3 ⁇ 4 R 2 , R 3 , R 4 , R e , R 12 , X and Y are the same as described above, and if necessary, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) ) In the presence of a catalyst such as palladium chloride, zinc cyanide, copper cyanide, etc., in an organic solvent such as dimethylformamide, pyridine, toluene or a mixed solvent thereof at room temperature or under heating.
  • a catalyst such as palladium chloride, zinc cyanide, copper cyanide, etc.
  • step 21 can also be performed on the corresponding compound (XXII) synthesized in step 21 described above.
  • compound (I) is obtained by converting the compound synthesized in this step into the above-described step. It can be synthesized by processing at 22.
  • the salt addition compound of the compound (I) obtained in the above step 26, 28 or 29 can be synthesized by a conventional method after synthesizing the compound (I) if necessary.
  • the compound (I) can be synthesized as follows.
  • compound (I) was prepared by treating compound (I) in the presence of hydrochloric acid, hydrogen chloride-ether, ethyl chloride-ethyl acetate, hydrogen chloride-dioxane, etc., in the presence of chloroform, dichloromethane, ethyl acetate, ethanolanol, methanolol, acetone, tonoren, It can be synthesized by reacting under cooling or heating in an organic solvent such as trahydrofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or no solvent.
  • an organic solvent such as trahydrofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or no solvent.
  • the substituents of the compounds used in the above steps 1 to 29 may be protected with a protecting group by a conventional method or may be subjected to each step after protecting with a protecting group, if necessary.
  • the protecting group may be removed by a conventional method as necessary, or may be removed by a conventional method in the final step.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.
  • Hydrobromic acid 100 ml was added to 4-amino-3-hydroxybenzoic acid (50.0 g), and the mixture was dissolved by heating at 55 ° C. Then, sodium nitrite (22 6 g) in water (50 ml) was added dropwise over 1 hour.
  • reaction solution was mixed with copper (I) bromide (25.8 g) and 48% hydrobromic acid.
  • 50 ml of suspension in black form 200 ml was added under stirring at 40 ° C. over 30 minutes, followed by stirring at 50 ° C. for 3.5 hours.
  • 1N hydrochloric acid 500 ml was added, and the mixture was extracted twice with ethyl acetate (500 ml), and washed sequentially with water (500 ml) and saturated saline (500 ml). After drying over sodium sulfate, the solvent was distilled off to obtain the title compound (64.8 g) as yellow crystals.
  • the obtained filtrate was added dropwise to a suspension of sodium borohydride (11.Og) in tetrahydrofuran (10 Om 1) over 15 minutes under ice-cooling with stirring over 1.5 minutes. Stirred. Further, after stirring at 4 O 4C for 4 hours, 6 ⁇ hydrochloric acid (30 ml) was added dropwise under ice cooling. After adding water (500 ml) and extracting twice with ethyl acetate (500 ml), the mixture is extracted twice with water (500 ml) and saturated aqueous sodium hydrogen carbonate (500 ml), and then with saturated saline (500 ml). Washed sequentially. After drying over sodium sulfate, the solvent was distilled off to give 4-fluoro-2- (trifluoromethyl) benzylanolenocore (49.4 g) as a yellow oil.
  • the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 82) to give 5-amino-2-methylbenzotrifluoride (9.53 g) as a colorless oil. Obtained.
  • the extract was washed twice with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated saline (100 ml) in that order, dried over sodium sulfate, and then the solvent was distilled off. The resulting residue was distilled (6. Om mHg, boiling point: 57) to give 5-bromo-2-methylbenzene as a colorless oil. Zotrifluoride (4.17 g) was obtained.
  • Step 7) N- (4-tert-butyl-l-2-nitrophenole) -14-bromo-13- [2- (trifluoromethyl) benzyloxy] benzamide (VIII) Obtained in Production Example 8 described above. 4 To a solution of 1-tert-butyl-2--2-troaniline (28.6 g) in pyridine (300 ml) was added the compound (55.1 g) obtained in the above step 6) at room temperature with stirring. Stirred for 13 hours. After evaporating the solvent, 3N hydrochloric acid (400 ml) was added, and the mixture was extracted twice with ethyl acetate (800 ml).
  • the organic layer was washed successively with 1 N hydrochloric acid (300 ml), saturated aqueous sodium hydrogen carbonate (300 ml) and saturated saline (300 ml), and dried over sodium sulfate. Further, the solvent was distilled off, and ethyl acetate (80 ml) and hexane (320 ml) were added, followed by stirring at room temperature for 1 hour. The precipitated crystals were collected to give the title compound (65.7 g) as yellow crystals.
  • step 2 To a solution of the compound (17.89 g) obtained in step 2) above in ethanol (75 ml) was added 4 N sodium hydroxide (25 ml), and the mixture was heated at 100 ° C for 1 hour. After refluxing, acetic acid (25 ml) was added. After allowing to cool, the mixture was further stirred for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (14.6 g) as white crystals.
  • Oxalyl chloride was added to a mixed solution of the compound (12.Og) obtained in the above step 5) in a mixture of chloroform (120 ml) and dimethylformamide (0.10 ml) at room temperature with stirring. (4.75 ml) was added dropwise, and the mixture was stirred for 4 hours, and the solvent was distilled off. Toluene (50 ml) was added to the obtained residue, the insolubles were removed by filtration, and the solvent was distilled off to obtain the title compound (12.6 g) as white crystals.
  • Step 7) N— (5-tert-butyl-2-hydroxyphenyl) 1-41-chloro mouth 1-3- [2- (trifluoromethyl) pendinoleoxy] benzamide (VIII)
  • pyridine 0.1 80 ml
  • the compound (0.698 g) obtained in the above step 6) was slowly added, and the mixture was stirred at room temperature overnight.
  • Step 5 using the compound obtained in the above step 3), the above-mentioned Example 1 or Example 2 was used.
  • Step 5) to Step 8> above to give the title compound 5-tert-butynole 2- [4-chloro-3- [2- (trifluoromethylinole) phenyloxymethyl] phenyl] benzimidazo Le hydrochloride hydrate was obtained.
  • Tetrakis (triphenylphosphine) palladium (0.139 g) was added to a solution of zinc powder (0.785 g) in dimethoxetane (20 ml), and the mixture was stirred at room temperature with stirring as described above.
  • the dimethoxetane of 4-chloro-3- (promomethyl) benzoyl benzoate (1.67 g) and 2- (trinoleolomethyl) benzinole bromide (1.44 g) obtained in Production Example 4 ( 10 ml)
  • reaction solution was extracted twice with ethanol acetate (40 ml), and the organic layer was extracted twice with water (40 ml), saturated aqueous sodium hydrogen carbonate (40 ml), and saturated saline (40 ml). It was washed successively and dried over sodium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate 9: 1) to give the title compound (1.44 g) as a yellow oil. Obtained.
  • Step: The compound (10.6 g) obtained in 13) was reduced (11.4 g) in a mixed solution of ethanol (100 ml), tetrahydrofuran (50 ml) and water (25 ml). ) And ammonium chloride (10.9 g), and heat at 100 for 1 hour under reflux. did. After cooling, insolubles were removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 2: 1) to give the title compound (6.53 g) as an orange solid.
  • Step 7) 1 ⁇ _ (2—1 6 1 "1: —Butoxycarburylamino 5—tert—Butylphenyl) -14-Chloro-N-Methylenol 3 -— [2- (Trifluoromethyl) benzyloxy) benzami De (VIII)
  • Step 8) 6-tert-butyl-2- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] -111-methylbenzimidazole hydrochloride monohydrate (I)
  • ethanol 6 ml
  • hydrochloric acid 13 ml
  • the mixture was heated under reflux at 100 ° C. for 1 hour.
  • water 6 ml
  • the mixture was allowed to cool and stirred for 1 hour.
  • the precipitated crystals were collected by filtration to give the title compound (0.980 g) as white crystals.
  • Step 7) to Step 8 of Example 3 described above were performed.
  • 6-tert-butynole-l 2- [4-chloro-3- [2- (trifnorelomethinole) benzyloxy] phenyl] benzoxazole
  • Example 1 Using the compound obtained in Step 6 of Example 3 and 4-tert-butyl-2-chloro-6-nitroaniline obtained in Production Example 14 described above, Example 1 or Example By reacting in the same manner as in Steps 7) to 8) of Step 2), the title compound, 6-tert-butynole-1,4-chloro-2- [4-chloro-3- [2- (triphenylenoleomethyl) benzyloxy] phenole, is obtained. A benzimidazo monohydrochloride hydrate was obtained.
  • Zinc cyanide (0.140 g) and tetrakis (tripheninolephosphine) were added to dimethylformamide (1 O ml) of the compound (1.0 g) obtained in Example 2 described above. Palladium (0.115 g) was added, and the mixture was heated under reflux at 160 under an argon atmosphere for 5 hours. After cooling, water (20 ml) was added, and the mixture was extracted twice with ethyl acetate (20 ml), and the solvent was distilled off.
  • Step 28 5-tert-Butyl-2-[[4-chloro-3- (2-force rubamoylbenzyloxy) phenyl] benzimidazole hydrochloride 'hydrate
  • the compound obtained in the above step 27) (0. 400 g) in a solution of dimethylformamide (5 ml) in 1-hydroxybenzotriazole (0.130 g), ammonium chloride (0.064 g), 1-ethyl-3- (3 —Dimethylaminopropinole)
  • Carbodiimide hydrochloride (0.168 g) and triethylamine (0.334 ml) were added, and the mixture was stirred at room temperature for 10 hours.
  • Step 8) 5-bromo-1- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazol (XX III)
  • tin (II) chloride dihydrate 18.6 g
  • Step 2 3-Acetoxy-l 4-cyclobenzoyl alkyd
  • XX ' The 3-acetoxy-4-l-chlorobenzoic acid (9.44 g) obtained in Production Example 5 above was obtained.
  • a dichloromethane (50 ml) solution was added a solution of oxalyl chloride (5.23 ml) in dimethylformamide (0.04 OmU), and the mixture was stirred at room temperature for 3 hours, and the solvent was distilled off. l) was added, and the insoluble material was filtered off. The solvent was distilled off to obtain the title compound (10.3 g) as white crystals.
  • Step 2 2) 5-tert-butyl-1-2- [4-chloro-1-3- (2- (trifnorolomethyl) benzylamino] phenyl] benzimidazole hydrochloride 'hydrate (I)
  • Step 2) 4-—Port 3— [5-Funoleo-methyl 2 (tri-Fnoroleolomethyl) benzoyloxy] Ethyl benzoate (IV)
  • a mixture of the compound (43.Og), acetic acid (450m) and reduced iron (16.Og) obtained in the above step 7) was heated under reflux at 13 for 3 hours. After allowing to cool, water (200 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). After the obtained organic layer was washed twice with water (500 ml), the solvent was distilled off.
  • the compound (64) obtained in the above-mentioned step 19) was added at room temperature to a solution of 4-tert-butyl-2-nitroaniline (42.7 g) obtained in Production Example 8 above in pyridine (400 ml). .0 g) was added and stirred for 2 hours. Further, water (800 ml) was added, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to obtain the title compound (73.9 g) as yellow crystals.
  • Test Example 1 LPL activating effect using 3T3-L1 cells
  • 3T3_L1 cells obtained from the Human Science Research Resource Bank were suspended in DMEM-low glucose medium containing 10% fetal bovine serum, and placed in a 96-well plate at 4 ⁇ 10 4 ce 11 s Zwell. (200 // 1 / well). After 2 S, this medium was removed and replaced with a DMEM-high glucose medium containing 10% fetal bovine serum containing or not containing a test compound prepared so that the final dimethylsulfoxide concentration was 0.1% (200 lZwe 11) . On the next day, remove the culture medium, and add phenolic-free DMEM containing low-glucose medium containing 100 ⁇ l of Zinc to a final concentration of 10 UZm and 0.1% bovine serum albumin, respectively.
  • Test example 2 Effect on serum parameters (TG, total cholesterol (TC) and HDL-cholesterol) of normal rats
  • the compound (I) according to the present invention has an excellent LPL activity enhancing action. Therefore, it is expected to be a new type of prophylactic or therapeutic drug for hyperlipidemia or arteriosclerotic disease, which can lower triglyceride in blood, as well as increase HDL-cholesterol.
  • This application is based on Japanese Patent Application No. 289 187 filed in Japan, Japanese Patent Application No. 351645, and Japanese Patent Application No. 2000-304587 filed in Japan. They are all included in the description.

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Abstract

L'invention se rapporte à des potentialisateurs de LPL contenant les composés représentés par la formule (I) en tant que principes actifs, des sels médicalement acceptables de ces composés ou des hydrates ou solvates de ces composés. Dans la formule (I), R est aryle éventuellement substitué; R1 est hydrogène, alkyle éventuellement substitué ou analogue; R2 est hydrogène, halogéno ou analogue; R3, R4, R5 et R6 sont chacun indépendamment hydrogène, halogéno ou analogue; X est alcylène, -Z-O-Z1- ou analogue; et Y est O- ou NR8- (où R8 est hydrogène, alkyle inférieur ou alkyle inférieur halogéné).
PCT/JP2000/007072 1999-10-12 2000-10-12 Potentialisateurs de lpl WO2001027088A1 (fr)

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Application Number Priority Date Filing Date Title
AU76845/00A AU7684500A (en) 1999-10-12 2000-10-12 Lpl potentiators

Applications Claiming Priority (6)

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JP28918799 1999-10-12
JP11/289187 1999-10-12
JP11/351645 1999-12-10
JP35164599 1999-12-10
JP2000304587A JP2001226358A (ja) 1999-10-12 2000-10-04 Ｌｐｌ活性増強剤
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060374A2 (fr) * 2001-01-29 2002-08-08 Insight Strategy And Marketing Ltd Derives de benz-1,3-azole et leurs utilisations en tant qu'inhibiteurs de l'heparanase
US7214695B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
WO2007138994A1 (fr) 2006-05-26 2007-12-06 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de la hsp90
WO2009139076A1 (fr) * 2008-05-14 2009-11-19 Otsuka Pharmaceutical Factory, Inc. Compositions activant la lipoprotéine lipase renfermant des dérivés benzéniques
WO2010090200A1 (fr) * 2009-02-04 2010-08-12 株式会社大塚製薬工場 Composés de phénylimidazole
US7868033B2 (en) 2004-05-20 2011-01-11 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US8362236B2 (en) 2007-03-01 2013-01-29 Chugai Seiyaku Kabushiki Kaisha Macrocyclic compound
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
CN106946710A (zh) * 2017-04-13 2017-07-14 安徽广信农化股份有限公司 一种噁草酮中间体硝基苯酚的合成工艺
CN107915570A (zh) * 2017-12-06 2018-04-17 金凯(辽宁)化工有限公司 一种4‑溴‑1‑甲基‑2‑（三氟甲基）苯的制备方法
CN110713441A (zh) * 2019-10-25 2020-01-21 湖南兴同化学科技有限公司 一种噁草酮中间体2,4-二氯-5-硝基苯酚的合成方法
CN112321513A (zh) * 2020-11-06 2021-02-05 中国药科大学 杂环类化合物及其制备方法和用途
WO2023006860A1 (fr) * 2021-07-29 2023-02-02 Merck Patent Gmbh Inhibiteurs de srpk

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2007069565A1 (ja) * 2005-12-12 2009-05-21 小野薬品工業株式会社 二環式複素環化合物

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US4714762A (en) * 1986-10-31 1987-12-22 Warner-Lambert Company Antiarteriosclerotic substituted benzimidazol-2-yl-and 3H-imidazo[4,5-b]pyridin-2-yl-phenoxy-alkanoic acids and salts and esters thereof
EP0402033A1 (fr) * 1989-05-30 1990-12-12 Otsuka Pharmaceutical Factory, Inc. Dérivés de carboxamides

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US4714762A (en) * 1986-10-31 1987-12-22 Warner-Lambert Company Antiarteriosclerotic substituted benzimidazol-2-yl-and 3H-imidazo[4,5-b]pyridin-2-yl-phenoxy-alkanoic acids and salts and esters thereof
EP0402033A1 (fr) * 1989-05-30 1990-12-12 Otsuka Pharmaceutical Factory, Inc. Dérivés de carboxamides

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060374A3 (fr) * 2001-01-29 2003-02-27 Insight Strategy And Marketing Derives de benz-1,3-azole et leurs utilisations en tant qu'inhibiteurs de l'heparanase
WO2002060374A2 (fr) * 2001-01-29 2002-08-08 Insight Strategy And Marketing Ltd Derives de benz-1,3-azole et leurs utilisations en tant qu'inhibiteurs de l'heparanase
US7214695B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7214696B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7560488B2 (en) 2002-12-19 2009-07-14 The Scripps Research Institute Methods for treating transthyretin amyloid diseases
US8653119B2 (en) 2002-12-19 2014-02-18 The Scripps Research Institute Methods for treating transthyretin amyloid diseases
US8168663B2 (en) 2002-12-19 2012-05-01 The Scripps Research Institute Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof
US8338459B2 (en) 2004-05-20 2012-12-25 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7868033B2 (en) 2004-05-20 2011-01-11 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US8193351B2 (en) 2006-05-26 2012-06-05 Chugai Seiyaku Kabushiki Kaisha HSP90 inhibitor
WO2007138994A1 (fr) 2006-05-26 2007-12-06 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de la hsp90
US8362236B2 (en) 2007-03-01 2013-01-29 Chugai Seiyaku Kabushiki Kaisha Macrocyclic compound
WO2009139076A1 (fr) * 2008-05-14 2009-11-19 Otsuka Pharmaceutical Factory, Inc. Compositions activant la lipoprotéine lipase renfermant des dérivés benzéniques
US8895599B2 (en) 2008-05-14 2014-11-25 Otsuka Pharmaceutical Factory, Inc. Lipoprotein lipase-activating compositions comprising benzene derivates
WO2010090200A1 (fr) * 2009-02-04 2010-08-12 株式会社大塚製薬工場 Composés de phénylimidazole
US8329739B2 (en) 2009-02-04 2012-12-11 Otsuka Pharmaceutical Factory, Inc. Phenylimidazole compounds
CN102307861A (zh) * 2009-02-04 2012-01-04 株式会社大塚制药工场 苯基咪唑化合物
CN102307861B (zh) * 2009-02-04 2014-10-29 株式会社大塚制药工场 苯基咪唑化合物
KR20110111300A (ko) * 2009-02-04 2011-10-10 가부시키가이샤 오츠까 세이야꾸 고죠 페닐이미다졸 화합물
KR101676889B1 (ko) 2009-02-04 2016-11-16 가부시키가이샤 오츠까 세이야꾸 고죠 페닐이미다졸 화합물
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
CN106946710A (zh) * 2017-04-13 2017-07-14 安徽广信农化股份有限公司 一种噁草酮中间体硝基苯酚的合成工艺
CN107915570A (zh) * 2017-12-06 2018-04-17 金凯(辽宁)化工有限公司 一种4‑溴‑1‑甲基‑2‑（三氟甲基）苯的制备方法
CN107915570B (zh) * 2017-12-06 2020-09-22 金凯(辽宁)化工有限公司 一种4-溴-1-甲基-2-(三氟甲基)苯的制备方法
CN110713441A (zh) * 2019-10-25 2020-01-21 湖南兴同化学科技有限公司 一种噁草酮中间体2,4-二氯-5-硝基苯酚的合成方法
CN110713441B (zh) * 2019-10-25 2023-03-10 湖南兴同化学科技有限公司 一种噁草酮中间体2,4-二氯-5-硝基苯酚的合成方法
CN112321513A (zh) * 2020-11-06 2021-02-05 中国药科大学 杂环类化合物及其制备方法和用途
WO2022095569A1 (fr) * 2020-11-06 2022-05-12 药康众拓(江苏)医药科技有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2023006860A1 (fr) * 2021-07-29 2023-02-02 Merck Patent Gmbh Inhibiteurs de srpk

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