WO2002032883A1 - Nouveau derive de 4-benzyloxyphenyle et utilisation de ce derive - Google Patents

Nouveau derive de 4-benzyloxyphenyle et utilisation de ce derive Download PDF

Info

Publication number
WO2002032883A1
WO2002032883A1 PCT/JP2001/009128 JP0109128W WO0232883A1 WO 2002032883 A1 WO2002032883 A1 WO 2002032883A1 JP 0109128 W JP0109128 W JP 0109128W WO 0232883 A1 WO0232883 A1 WO 0232883A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
group
hydrogen atom
disease
derivative
Prior art date
Application number
PCT/JP2001/009128
Other languages
English (en)
Japanese (ja)
Inventor
Kazumi Ogata
Kazuhiko Ito
Takahiro Sakaue
Yutaka Inoue
Original Assignee
Senju Pharmaceutical Co., Ltd.
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 Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Priority to AU2001295951A priority Critical patent/AU2001295951A1/en
Publication of WO2002032883A1 publication Critical patent/WO2002032883A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a novel 4-benzyloxyphenyl derivative or a pharmacologically acceptable salt thereof and use thereof.
  • the Na + / Ca 2+ exchange system (abbreviation: NCX) is one of the ion transport mechanisms to maintain the regulation of intracellular sodium ion concentration and potassium ion concentration.
  • C acts as a pathway (forward mode) for pumping intracellular Ca 2+ mobilized during stimulation to the outside of the cell (forward mode).
  • forward mode for pumping intracellular Ca 2+ mobilized during stimulation to the outside of the cell
  • Na 4 / H + exchange mechanism Activation and activation of Na + channels increase the intracellular Na + concentration and act as a pathway (reverse mode) for influx of extracellular Ca 2+ .
  • This Ca 2+ influx is excessive, it is known to cause myocardial cell damage becomes Ca 2+ overload.
  • NCX 1, NCX 2, NCX 3 three genes have been identified in NCX (NCX 1, NCX 2, NCX 3), NCX 1 is ubiquitously expressed mainly in various organs including myocardium, and NCX 2 is mainly expressed in brain, It is expressed in skeletal muscle, smooth muscle, kidney, etc., and NCX 3 is specifically expressed mainly in brain and skeletal muscle.
  • NCX has been found to be present in the cornea, retina, and lens.
  • NCX Compounds that selectively inhibit NCX include, for example, JP-A-7-41465 (quinazolidine derivatives), JP-A-9-167336 (isothioperia derivatives), and JP-A-10-218844 (2-phenoxyaniline derivatives).
  • JP-A-10-245336 (2- (4-benzyloxyphenoxy) aniline
  • JP-A-10-265460 phenoxypyridine derivative
  • 1,6-disubstituted isochroman for migraine treatment
  • the published international publication (W097 / 02259) states that 1,4- (4-benzyloxyphenyl) pidazine, which is considered to be closest to the compound of the present invention, synthesizes 1,6-disubstituted isochromans. (Example 9), but does not disclose any NCX inhibitory activity.
  • the present inventors have conducted various studies, and as a result, have created novel 41-benzyloxyphenyl derivatives and pharmacologically acceptable salts thereof, and these compounds have excellent NCX. They have found that they have an inhibitory effect, and have further studied to complete the present invention. That is, the present invention provides a novel 4-benzyloxyphenyl derivative having an NCX inhibitory action and its use. Disclosure of the invention
  • the present invention is a.
  • R and R 2 are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a cyano group or a lower alkyl group
  • R 3 represents any of the above structures
  • R 4 represents hydrogen
  • R 5 represents a hydrogen atom or a lower alkyl group
  • R 6 represents a hydrogen atom or a lower alkyl group
  • n represents 0 or a hydrogen atom or a lower alkyl group substituted with an atom, a hydroxyalkyl group, or an amino group.
  • m represents an integer of 0 or 1, provided that R 3 is piperazine A group containing a ring, when n is 0, and at least one of R 2 is a halogen atom, a nitro group, a cyano group or a lower alkyl group.
  • R 3 is piperazine A group containing a ring, when n is 0, and at least one of R 2 is a halogen atom, a nitro group, a cyano group or a lower alkyl group.
  • R 2 both represent the same halogen atom, or one of them represents a halogen atom, the other represents a hydrogen atom, and R 3 represents the above-mentioned piperazine ring.
  • R 4 represents a hydrogen atom, a hydroxyalkyl group, a phenyl group or an aminoalkyl group substituted with an amino group
  • R 5 represents a hydrogen atom or a lower alkyl group
  • n is an integer of 0 to 3.
  • R and R 2 both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R 3 represents a group containing the above thiazolidine ring.
  • R 6 represents a hydrogen atom or a lower alkyl group; m represents an integer of 0 or 1; the 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to the above (1) ,
  • R and R 2 both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R 3 represents the above-mentioned pyrazine ring.
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • n represents an integer of 0 to 3.
  • R 2 both represent a cyano group, one of them represents a cyano group, the other represents a hydrogen atom, and R 3 represents a group containing the above-mentioned pyrazine ring.
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • n represents an integer of 0 to 3.
  • R and R 2 each represent a lower alkyl group, or one of them represents a lower alkyl group, the other represents a hydrogen atom, and R 3 represents the above-mentioned piperazine
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • n represents an integer of 0 to 3
  • 4-benzylo according to the above (1) A xylenyl derivative or a pharmaceutically acceptable salt thereof,
  • a pharmaceutical composition comprising the 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), and a pharmaceutically acceptable carrier,
  • Intracellular administration comprising administering to a mammal an effective amount of the 4-benzyloxyphenyl derivative or a pharmaceutically acceptable salt thereof according to any of (1) to (7) above.
  • FIG. 1 shows the infrared absorption spectrum (IR) of the compound synthesized in Example 2.
  • FIG. 2 shows the infrared absorption spectrum (IR) of the compound synthesized in Example 6.
  • Examples of the halogen atom of and R 2 in the formula (I) of the compound of the present invention include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
  • the lower alkyl group for R, R 2 and R 5 means a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, pentyl group, isopentyl group, Neopentyl group, tert-pentyl group, 1-ethylpentyl pill group, 4-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,2-dimethylbutyl group, 2-ethylbutyl group, Examples thereof include a clopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an isoheptyl group,
  • it is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (methyl group, ethyl group, propyl group, isopropyl group).
  • the alkyl group in the hydroxyalkyl group for R 4 has the same meaning as the lower alkyl group for R 2 and R 5 described above.
  • Preferred hydroxyalkyl groups include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1-methylethyl group, Hydroxycyclopropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 1-hydroxybutyl Hydroxypentyl group,
  • hydroxyalkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and particularly preferably 2-hydroxyethyl.
  • the amino group may be located at any position of the phenyl group.
  • the alkyl group in the aminoalkyl group for R 4 has the same meaning as the lower alkyl group for R 2 and R 5 described above.
  • Preferred aminoalkyl groups include an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group, a 3-aminopropyl group, a 2-amino-1-methylethyl group, and an aminocyclo group.
  • aminoalkyl groups are an aminomethyl group, a monoaminoethyl group and a 2-aminoethyl group, particularly preferably a 2-aminoethyl group.
  • Pharmaceutically acceptable salts of this compound include acid addition salts such as salts with inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and salts with organic acids such as acetic acid, citric acid, and tartaric acid. Any of the pharmacologically acceptable salts can be appropriately used for the purpose of the present invention.
  • This compound can be appropriately synthesized, for example, by the following synthesis method or according to the method.
  • the method for producing this compound will be described in the following three cases.
  • R, R 2 , R 4 and R 5 are as defined above, and X is a halogen atom.
  • halogen atom for X include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.
  • the above reaction can be performed by using N-protected form.
  • the N-protected compound is dissolved in acetone or alcohol (methanol or ethanol), deprotected with an acid, and then recrystallized from, for example, methanol / acetone or methanol / ethyl acetate to form the acid addition salt of the target compound.
  • the acid for deprotection include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as acetic acid and trifluoroacetic acid.
  • R 4 of piperazine down derivative (VI II) is hydrogen, for example, was substituted with a protecting group of hydrogen, using a 1 one (3-butoxycarbonyl) R 5 substituted piperidines Rajin derivatives,, R 2 substituted Benzyloxyphenylalkylpiperazinyl N-protected.
  • This is dissolved in acetone or alcohol (methanol or ethanol), deprotected with an acid, and then recrystallized from methanol / acetone or methanol / ethyl acetate to obtain an acid addition salt of the target compound.
  • the acid for deprotection those described above can be used.
  • R 3 in the formula (I) is a group ( ⁇ , 1) containing a thiazolidine ring
  • the production method of the present compound is as follows.
  • aldehyde (IX) is dissolved in methylene chloride and oxidized with an oxidizing agent such as pyridinium chromate (PCC) or manganese dioxide to obtain an aldehyde (IX).
  • PCC pyridinium chromate
  • IX manganese dioxide
  • the aldehyde compound and cysteine alkyl ester hydrochloride or cysteine are added at room temperature for 2 to 15 hours in pyridine or the like. After stirring for a while, evaporate the solvent and extract with ethyl acetate. After evaporating the solvent, recrystallize from ethyl acetate / isopropyl ether / dimethylformamide / acetone to obtain the desired compound.
  • the compound thus obtained is a novel compound that has not been published in the literature, inhibits NCX and suppresses Ca 2+ overload, and is therefore useful in mammals (for example, horses, horses, dogs, horses, mice are useful rat, as a preventive and therapeutic agent for various diseases induced by Ca w excess load such as human Bok).
  • Specific diseases induced by Ca 2+ overload include ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction or ischemic renal disease, hypertension, heart failure, or circulatory system such as arrhythmia.
  • Disease glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, diabetic retinopathy, and the like. '
  • the present compound When the present compound is used as a pharmaceutical composition, one or more of the present compounds can be appropriately combined and contained according to the purpose and necessity.
  • the present compound is appropriately used orally or parenterally as a pharmaceutical composition for various diseases as described above.
  • the preparation can be prepared by any known method, for example, into solid preparations such as tablets, granules, powders and capsules or liquid preparations such as injections and eye drops. These preparations contain commonly used excipients, binders, thickeners, dispersants, resorption accelerators, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizing agents.
  • Various additives such as an agent and a pH adjuster may be appropriately used.
  • This compound has the characteristics, for example, of remarkably inhibiting NCX 1 and being soluble in water.
  • the compound of Example 6 described below is particularly excellent in NCX1 inhibitory activity
  • the compound of Example 4 is particularly excellent in water solubility (0. g / 0.5 mi or more).
  • the dosage of the compound when used as a pharmaceutical composition varies depending on the type of the compound used, the weight and age of the patient, the type and condition of the disease to be treated, the method of administration, and the like. For example, when applying to injections or cardiovascular diseases, for example, for injections, about lmg to about 30mg for adults once a day, for oral administration, for adults several times a day, about 1mg to about 100mg per dose Is good. Also> when applied to eye diseases, Adults Several times a day, 1 time drop> It is preferable to administer an eyedrop having a concentration of about 0.01 to 5 (w / v). Pharmaceutical compositions containing the present compound may be used unless they violate the purpose of the present invention. It may optionally contain other NCX inhibitors or other kinds of pharmaceutically active ingredients.
  • Example 3 [4- (4-Cyanobenzyloxy) phenyl] pidazine dihydrochloride 1- (tert-butyloxyl-propionyl) -1-4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 2.8 g, 2.2 g of 4-cyanophenylbenzylbutamide, 1.4 g of potassium carbonate, methyl The reaction and treatment were carried out in the same manner as in Example 1 using 30 ml of ethyl ketone, and the product was recrystallized from ethyl acetate-isopropyl ether to give 1- [4- (4-cyanobenzyloxy) having a melting point of 151 to 153 ° C.
  • Example 1 using 3.0 g of 4- (4-hydroxyphenyl) pidazine 1- (ethoxycarbonyl) piperazine, 4.8 g of 4-cyclopentyl benzyl chloride, 1.3 g of potassium carbonate, and 100 ml of methyl ethyl ketone.
  • the reaction and treatment were carried out in the same manner as described above to obtain 2.6 g of 4- [4- (4-methylbenzyloxy) phenyl] -41- (ethoxycarbonyl) pidazine.
  • This was dissolved in 2.6 g of ethanol (50 ml), a solution of lithium hydroxide (0.5 g) in water (10 ml) was added, and the mixture was heated under reflux for 15 hours.
  • the solvent was distilled off, 2N sodium hydroxide (20 ml) was added to the obtained residue, and the precipitated crystal was recrystallized from water to obtain 1.6 g of the target compound having a melting point of 94 to 97 ° C (decomposition).
  • Example 21 1- ⁇ 2- [4 -— (4-cyclobenzyloxy) phenyl] ethyl ⁇ -1,3-dimethylbiperazine dihydrochloride
  • the above is formed into tablets by a conventional method as a material for one tablet.
  • the above components are made into injections by a conventional method.
  • the above is prepared by an ordinary method to prepare eye drops.
  • the above is prepared by an ordinary method to prepare eye drops.
  • NCX1-expressing CCL-39 cells were cultured to confluence, and then replaced with a culture medium without fetal calf serum.
  • the Na + loading solution is removed, and the target concentration of test substance and Na-containing Ca 2+ uptake solution containing about 50 kilobecquerel (kBq) / ml of 45 Ca (lOtnMHEPES / Tris buffer, 146 mM aCl , 4 mM KC1, 2 mM MgCl 2 , 0.05 mM CaCl 2 , lmM perbain) or about 50 kBq / ml Na-free Ca 2+ uptake solution containing 45 Ca (10 ⁇ l MHEPES / Tris buffer, U6 mM choline chloride, 4 mM KC1, 2 mM MgCl 2 , 0.05 mM CaCl 2 , lmM perbain) were exchanged and incubated at 37 C for 30 seconds.
  • kBq kilobecquerel
  • the Na-containing Ca 2+ uptake solution or the Na-free Ca 2+ uptake solution was removed, and the cells were washed three times with ice-cold physiological saline containing 10 mM LaCl 3 .
  • the amount of 45 Ca in the solubilized cell solution was measured using a liquid scintillation counter.
  • DMS0 dimethylsulfoxide
  • Rats fasted for 2 hours were anesthetized by intraperitoneal administration of clonal hydrate. Evoked renal ischemia-reperfusion injury.
  • the right and left renal veins were closed with disposable clips (AM-1.60 g, BEAR) for 45 minutes, and the clips were removed for reperfusion.
  • AM-1.60 g, BEAR disposable clips
  • Blood was collected 24 hours after reperfusion, and urea nitrogen in serum was measured.
  • the test substance was administered intraperitoneally 30 minutes before ischemia (dose: 10 mg / 5 ml / kg). They fasted for 48 hours until blood collection.
  • the 4-benzyloxyphenyl derivative and the pharmacologically acceptable salt thereof of the present invention have NCX inhibitory activity, and are diseases induced by Ca 2+ overload, for example, ischemic heart such as myocardial infarction.
  • ischemic heart such as myocardial infarction.
  • ischemic brain disease such as cerebral infarction or ischemic renal disease
  • hypertension cardiovascular disease such as heart failure or arrhythmia, glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iris ciliary body It is useful as a prophylactic and therapeutic agent for inflammation, retinal artery occlusion, and diabetic retinopathy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un dérivé de 4-benzyloxyphényle ou à un sel pharmacologiquement acceptable de ce dérivé, lequel est représenté par la formule (I), où R1 et R2, qui sont identiques ou différents, représentent chacun hydrogène, halogéno, nitro, cyano ou alkyle inférieur, et R3 représente une structure représentée par (II) ou (III), (où R4 représente hydrogène, hydroxyalkyle, phényle substitué par amino, ou aminoalkyle; R5 représente hydrogène ou alkyle inférieur; R6 représente hydrogène ou alkyle inférieur; n est égal à un nombre entier compris entre 0 et 3; et m est égal au nombre entier 0 ou 1), à condition que, lorsque R3 représente un groupe contenant un cycle pipérazine et n est égal à 0, alors R1 et/ou R2 représentent halogéno, nitro, cyano ou alkyle inférieur. De tels dérivés sont utiles comme inhibiteur d"échange de Na+/Ca2+.
PCT/JP2001/009128 2000-10-18 2001-10-17 Nouveau derive de 4-benzyloxyphenyle et utilisation de ce derive WO2002032883A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001295951A AU2001295951A1 (en) 2000-10-18 2001-10-17 Novel 4-benzyloxyphenyl derivative and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000317807 2000-10-18
JP2000-317807 2000-12-06

Publications (1)

Publication Number Publication Date
WO2002032883A1 true WO2002032883A1 (fr) 2002-04-25

Family

ID=18796535

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/009128 WO2002032883A1 (fr) 2000-10-18 2001-10-17 Nouveau derive de 4-benzyloxyphenyle et utilisation de ce derive

Country Status (2)

Country Link
AU (1) AU2001295951A1 (fr)
WO (1) WO2002032883A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061700A1 (fr) * 2002-01-25 2003-07-31 Taisho Pharmaceutical Co.,Ltd. Medicaments servant au traitement de nephropathies chroniques
EP2567958A1 (fr) 2011-09-12 2013-03-13 Sanofi 2-(chromane-6-yloxy)-thiazoles substitués et leur utilisation comme médicaments
WO2013037388A1 (fr) 2011-09-12 2013-03-21 Sanofi Thiazoles à substitution 2-(chroman-6-yloxy) et leur utilisation comme produits pharmaceutiques
US8912224B2 (en) 2011-09-12 2014-12-16 Sanofi Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
US9440941B2 (en) 2013-03-08 2016-09-13 Sanofi Substituted chroman-6-yloxy-cycloalkanes and their use as pharmaceuticals

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10245336A (ja) * 1997-03-03 1998-09-14 Taisho Pharmaceut Co Ltd Ｎａ／Ｃａ交換系阻害剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10245336A (ja) * 1997-03-03 1998-09-14 Taisho Pharmaceut Co Ltd Ｎａ／Ｃａ交換系阻害剤

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061700A1 (fr) * 2002-01-25 2003-07-31 Taisho Pharmaceutical Co.,Ltd. Medicaments servant au traitement de nephropathies chroniques
EP2567958A1 (fr) 2011-09-12 2013-03-13 Sanofi 2-(chromane-6-yloxy)-thiazoles substitués et leur utilisation comme médicaments
WO2013037388A1 (fr) 2011-09-12 2013-03-21 Sanofi Thiazoles à substitution 2-(chroman-6-yloxy) et leur utilisation comme produits pharmaceutiques
WO2013037724A1 (fr) 2011-09-12 2013-03-21 Sanofi 2-(chroman-6-yloxy)-thiazoles substitués et leur utilisation en tant que produits pharmaceutiques
US8912224B2 (en) 2011-09-12 2014-12-16 Sanofi Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
US9440941B2 (en) 2013-03-08 2016-09-13 Sanofi Substituted chroman-6-yloxy-cycloalkanes and their use as pharmaceuticals

Also Published As

Publication number Publication date
AU2001295951A1 (en) 2002-04-29

Similar Documents

Publication Publication Date Title
ES2218552T3 (es) Derivado heterociclico y medicina.
CA3093851A1 (fr) Composes 1,1'-biphenyle substitues, analogues de ceux-ci, et procedes les utilisant
US20070219239A1 (en) Nitrogen-containing heterocycle derivatives, pharmaceutical compositions, and methods of use thereof as antiviral agents
US20120157497A1 (en) Compounds having analgesic and/or immunostimulant activity
CA2087604C (fr) Composes diamines et medicaments a base de ces composes pour la protection au niveau cerebral
KR20140006768A (ko) Lsd1의 아릴사이클로프로필아민 기반 디메틸라아제 억제제 및 이의 의학적 이용
MX2007002786A (es) Moduladores del canal de potasio kcnq st. laurent, quebec, h4s 1z94-arilespirocicloalquil-2-aminopirimidina carboxamida.
CZ33794A3 (en) Novel pyrazine derivatives, process of their preparation and pharmaceutical preparations in which they are comprised
IE55904B1 (en) Dihydropyridines
KR100234596B1 (ko) 3(2h)-피리다지논 유도체 및 그의 제조방법
JP2767321B2 (ja) ピペラジン誘導体及びこれを含有する医薬
KR20020016872A (ko) 신규한 피페라지닐알킬티오피리미딘 유도체, 그것을함유하는 약제 조성물, 및 활성성분의 제조방법
AU726239B2 (en) 2-phenoxyaniline derivatives
EP0221511B1 (fr) Amides ou esters d'acides 2-aminosulfonyl-6-nitrobenzoique, leur procédé de préparation et compositions pharmaceutiques les contenant
JPH02229148A (ja) 血糖低下活性アミジン化合物およびグアニジン化合物
WO2002032883A1 (fr) Nouveau derive de 4-benzyloxyphenyle et utilisation de ce derive
TW386988B (en) Arylbenzoylguanidines, the preparation and pharmaceutical compositions thereof
EP0738144A1 (fr) Hexanamides de phenylmethyle et leur utilisation
US10155722B2 (en) Antitumor compound targeting IDH2 mutation and method of use thereof
JP4316384B2 (ja) ヘテロアリール置換アミノシクロヘキサン誘導体
JP2003508381A (ja) 高脂血症の予防または治療用薬剤の製造のためのビススルホンアミドの使用
US20230303494A1 (en) Benzylamine derivative, preparation method therefor and use thereof
HUT58693A (en) Process for preparation of substances having pharmaceutical effectivity
SK143096A3 (en) Novel hydroximic acid derivatives, pharmaceutical compositions containing them and process for preparing same
CA2462390A1 (fr) Amides d'acide anthranilique et utilisations pharmaceutiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase