WO1997009306A1 - Nouveaux derives d'isothio-uree - Google Patents

Nouveaux derives d'isothio-uree Download PDF

Info

Publication number
WO1997009306A1
WO1997009306A1 PCT/JP1996/002491 JP9602491W WO9709306A1 WO 1997009306 A1 WO1997009306 A1 WO 1997009306A1 JP 9602491 W JP9602491 W JP 9602491W WO 9709306 A1 WO9709306 A1 WO 9709306A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
phenyl
group
compound
formula
Prior art date
Application number
PCT/JP1996/002491
Other languages
English (en)
Japanese (ja)
Inventor
Manabu Hori
Takeshi Yamamoto
Hiroshi Ohtaka
Fumio Nakajima
Kengo Harada
Tominori Morita
Original Assignee
Kanebo, Limited
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 Kanebo, Limited filed Critical Kanebo, Limited
Publication of WO1997009306A1 publication Critical patent/WO1997009306A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • 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
    • A61P9/06—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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to novel isothiourea derivatives. More specifically, the following formula (I) having an inhibitory effect on Na + / Ca 2+ exchange
  • R 1 , R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group, and R 4 and R 5 each independently represent , A hydrogen atom, a lower alkyl group or a substituted alkyl group, or R 4 and R "together represent a group represented by 1 (CH 2 ) -1;
  • CH. 0 (CH 2 ) 9 represents a group represented by 1.
  • n represents 2 or 3
  • m represents 1, 2 or 3.
  • the Na + / Ca 2+ exchange mechanism is one of the ion transport mechanisms responsible for regulating intracellular sodium and calcium ion concentrations. For example, once the myocardium enters ischemia, intracellular acidosis is induced, and excessive Na ions flow into the cells by activating the Na + ZH + exchange mechanism or activating the Na + channel. Then, the Na + Ca 2+ exchange mechanism is activated by reperfusion, and excess sodium ions are pumped out of the cells, and calcium ions flow into the cells instead.
  • amide mouth derivatives such as diclomouth benzamil represented by the following formula (II) [Proceedings of the National Academy of sciences of the United States of America, 181, 3238 -3242 (1984)].
  • Isothiourea derivatives having an inhibitory effect on the Na + ZCa 2+ exchange mechanism are not known.
  • the present inventors have made various studies for the purpose of providing a novel compound having a Na + ZCa2 + exchange mechanism inhibitory action.
  • the novel isothiourea derivative represented by the formula (I) and a pharmacologically acceptable salt thereof have an excellent Na + / Ca2 + exchanger inhibitory action. And completed the present invention.
  • the halogen atom of R 1 , R 2 and R 3 is, for example, a chlorine atom or a bromine atom
  • the lower alkyl group is, for example, a methyl group, an ethyl group, etc.
  • the group include a methoxy group and an ethoxy group.
  • the lower alkyl group or substituted alkyl group of R 4 and R 5 include a methyl group, an ethyl group, and a hydroxyethyl group.
  • the compound (I) of the present invention include N, ⁇ '-diethyl-S— [4- (4-cyclobenzyloxy) benzyl] isothiourea and S— [2-—4- (4-cyclobenzyloxy) phenyl ] Ethyl] isothioperia, 2- [2- [4- (4-chlorobenzyloxy) phenyl] ethyl] thio-4,5-dihydroimi Dazol, S— [2 -— [4- (4-cyclobenzyloxy) phenyl] ethyl] -1-N— (2-hydroxyxetyl) isothiourea, ⁇ , ⁇ '—Jetyl-S—
  • [2 -— [4 -— (4-Methoxybenzyloxy) phenyl] ethyl] isothiourea, 2- [2- [2-((4-chlorobenzyloxy) phenyl] ethyl] thiol 4,5-dihydroimidazole, 2 — [2 -— [3-((4-chlorobenzoyloxy) phenyl] ethyl] thio4,5-dihydroimidazole; and the pharmacologically acceptable salts of compound (I) of the present invention include: Examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid and nitric acid, and salts with organic acids such as methanesulfonic acid and p-toluenesulfonic acid.
  • the substituted benzyloquine group is at the 4-position, and R 1 , R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a methyl group or a nitro group.
  • R 4 and R “are both hydrogen atoms, or Is a group R 4 and R 5 are shown together in a connexion one (CH 2) 2 in one, Z gar 2 (CH.) - or a CH 2 0 2 (CH.) - a group represented by Certain isothiourea derivatives or pharmacologically acceptable salts thereof are mentioned as preferred compounds.
  • the preferred compounds of the present invention include S- [2- [4- (4-chlorobenzyloxy) phenyl] ethyl] isothioprea, 2- [2- [4- (4-cyclobenzylbenzyloxy) phenyl] ethyl] Thio 4,5-dihydroimidazole, S—
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof can be produced, for example, by the following method. , R 1 , R, 2, R, 3
  • Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group.
  • a pharmacologically acceptable salt of compound (I) can be produced by reacting compound (III) with compound (IV).
  • This reaction can be carried out by reacting the compound (III) with an equivalent amount of the compound (IV) in an inert organic solvent at room temperature to the boiling point of the solvent for 1 to 24 hours.
  • the inert organic solvent include methanol, ethanol, dioxane, acetate nitrile, and the like, or a mixed solvent obtained by appropriately mixing them.
  • the compound (I) of the present invention is prepared by reacting a pharmacologically acceptable salt of the compound (I) obtained by the above-mentioned production method with an aqueous solution of an inorganic base such as sodium hydrogencarbonate in a conventional manner. Can be manufactured.
  • the compound (I) of the present invention can also be produced by performing the above reaction in the presence of a base.
  • a pharmacologically acceptable salt of the compound (I) of the present invention can also be produced according to a conventional method using the compound (I) of the present invention and an organic or inorganic acid.
  • Compound (III) used as a raw material in the above production method can be produced by the following method.
  • the compound (III) is a compound produced by reacting a substituted benzyl halide 'with a hydroxyalkylphenol, etc., according to the method described in JP-A-50-148357.
  • (V) can be produced by halogenation, alkylsulfonyl esterification or arylsulfonyl esterification, or by performing a dehydration reaction with ethylene chlorohydrin.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent Na + / C a + exchange mechanism inhibitory action and are induced by excessive accumulation of calcium ions during myocardial ischemia.
  • Compound (I) and its pharmacologically acceptable salts of the present invention exhibits excellent N a + ZC a 2+ exchange mechanism inhibitory effect as shown in the following Test Examples, it is considered to be based on for the acting Fig. 4 shows a reperfusion arrhythmia suppressing effect and a reducing effect on myocardial infarction lesions. Therefore, the compound (I) of the present invention and a pharmacologically acceptable salt thereof are useful for treating disorders induced by excessive accumulation of calcium ions during myocardial ischemia, for example, for treating cardiac dysfunction, cardiomyocardial infarction and arrhythmia. Effective for prevention.
  • the inhibitory effect of the Na + ZCa2 + exchange mechanism was determined by the method of Reeves et al. [Journal of Biological Chemistry, 258, 3178-3182, using canine myocardial vesicle membranes prepared from fresh canine myocardium. 1983)].
  • the cells were incubated in a buffer solution [160 mM sodium chloride, 20 mM 3-N-morpholinopropanesulfonic acid (pH 7.4)] at 37 ° C for 30 minutes.
  • a buffer solution [160 mM sodium chloride, 20 mM 3-N-morpholinopropanesulfonic acid (pH 7.4)] at 37 ° C for 30 minutes.
  • the membrane sample was prepared using the reaction solution [16 OmM potassium chloride, 20 M 45 CaCl. , 0.4 mM vinomycin, 20 mM 3-N-morpholinopropanesulfonic acid (pH 7.4)] at 37 ° C for 2 seconds, followed by filtration using a glass filter.
  • radioactivity of 45 Ca in the vesicle membrane captured by the glass filter was measured [internal sodium ion concentration-dependent calcium ion inflow (A)]. Radioactivity was measured in the same manner by replacing potassium chloride in the reaction solution with sodium chloride [internal sodium ion concentration-independent calcium ion inflow (B)].
  • the ZC a 2+ exchange mechanism inhibition rate ⁇ %) was calculated by the following equation.
  • Inhibition rate (%) [1— (A-B) / (C-D)] X 100 Then, the concentration at which the test compound inhibits the Na + / Ca2 + exchange mechanism by 50% (ic 5 ( ) ) was determined from the regression equation.
  • mice Male Sprague-Dawley rats (body weight: 360-420 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 mg / kg). Under anesthesia, a force neuron was inserted into the trachea of the rat and connected to a ventilator. The electrocardiogram (Lead II) was guided from an electrode inserted into the limb and measured via a bioelectric amplifier. ° C was maintained. The rat was opened at the left intercostal space and the pericardium was incised to expose the heart.
  • test compound was dissolved in a mixed solvent of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol and 70% (v / v) physiological saline, and the solution was injected into the femoral vein.
  • a mixed solvent 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol and 70% (v / v) physiological saline, and the solution was injected into the femoral vein.
  • a mixed solvent 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol and 70% (v / v) physiological saline
  • the ventricle when only a mixed solvent of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol, and 70% (v / v) saline was administered.
  • the duration of fibrillation (s) was measured as above.
  • Test method Male Sprague-Dawley rats (body weight: 360-430 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 rag / kg). Under anesthesia, the body temperature was maintained at 37 ° C. after inserting a force neuron into the trachea of the rat and connecting it to a ventilator. The rat was opened at the left intercostal space and the pericardium was incised to expose the heart. Dissolve the test compound in a mixture of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol, 70% (v / v) was administered within. Ten minutes after drug administration, the origin of the left coronary artery was occluded.
  • TTC triphenyltetrazolium chloride
  • Methanesulfonic acid 2- [4- (4-chlorobenzyloxy) phenyl] ethyl ester (0.90 g)
  • thioprea (0.22 g)
  • ethanol 10 ml
  • the solvent was evaporated under reduced pressure, and the obtained crystals were washed with acetonitrile and recrystallized from methanol to give the title compound (0.50 g).
  • R 1 , R, and RO-substituted benzyloxy groups are 4 one (4 one black port Benjiruokishi) group, R 4 and R 5 together - (CH 2) 2 -, Z Gar (CH 2) 2 - methanesulfonate of compounds wherein:
  • Methanesulfonic acid 2- [4-((4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (2.20 g), a mixture of ethylenethiourea (0.60 g) and ethanol (20 ml) was refluxed for 1 ⁇ . The solvent was distilled off under reduced pressure, and dimethyl ether was added to the residue for crystallization. The resulting crystals were collected by filtration and recrystallized from ethyl acetate-nitrile acetate to give the title compound (0.70 g).
  • Methanesulfonic acid 2- [4- (4-cyclobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (1.19 g), N- (2-hydroxyethyl) thioperia (0.42 g), A mixture of ethanol (3.5 ml) was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding ethyl ether monoethyl acetate-ethanol. The resulting crystals were collected by filtration and recrystallized from acetonitrile to give the title compound (0.27 g).
  • Methanesulfonic acid 2- [4- (4-methylbenzyloxy) phenyl] ethyl ester (See Reference Example 4) (1.43 g), a mixture of thiopurea (0.34 g), and ethanol (4.4 ml) was refluxed for 1 ⁇ . The resulting crystals are collected by filtration, washed with ethyl ether, and recrystallized from ethyl acetate-methanol to give the title compound.
  • Methanesulfonic acid salt Methanesulfonic acid 2— [4— (3 , 4-Dichloro mouth benzyloxy) phenyl] ethyl ester (see Reference Example 5) (1.67 g), thioperea (0.34 g), and ethanol (4.4 ml) were refluxed for 1 hour. The residue was washed with dimethyl ether and recrystallized from ethyl acetate-methanol to obtain the title compound (1.10 g).
  • Methanesulfonic acid 2- [4- (4-nitrobenzyloxy) phenyl] ethyl ester (see Reference Example 6) (10.00 g), a mixture of thioperia (2.20 g), and ethanol (100 ml) was refluxed for 2 hours. The solvent was evaporated under reduced pressure, and the residue solid was recrystallized from ethanol to give the title compound (8.30 g).
  • R 1 , R 2 , R 3 substituted benzyloxy group is 4 one (3 two Toro benzyl O alkoxy) group, methanesulfonate of R 4, R 5 is a hydrogen atom, Z gar (CH 2) 2 one, compound:
  • Methanesulfonic acid 2- [4- (3- (2-nitrobenzyloxy) phenyl] ethyl ester (see Reference Example 7) (3.50 g), thioperia (0.76 g), ethanol A mixture of knol (10 ml) was refluxed for 7 hours. Ethyl acetate was added and the precipitated crystals were collected by filtration and recrystallized from isopropyl alcohol to give the title compound (2.69 g).
  • Methanesulfonic acid 2- [4- (2-chloro-4-212-trobenzyloxy) phenyl] ethyl ester (see Reference Example 8) (1.50 g), thioperia (0.30 g), ethanol (10 The mixture of m 1) was refluxed for 1 ⁇ . After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol-isopropyl alcohol to give the title compound.
  • Example 1 1 N-ethyl-S— “2-—4- (4-chlorobenzyloxy) phenyl: 1-ethyl-1-isothiourea methanesulfonate”
  • R 1 , R 2 , and R 3 -substituted benzyloxy groups Is a methanesulfonic acid salt of a compound in which is a 4- (4-cyclobenzyloxy) group, R 4 is an ethyl group, R 5 is a hydrogen atom, and Z is — _ (CH 2 ) 2 —.
  • Methanesulfonic acid 2- [4- (4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (1.00 g), a mixture of ethylthioperia (0.30 g), and ethanol (10 ml) was refluxed for 1 hour. did. The solvent was distilled off under reduced pressure, and the residue solid was recrystallized from acetonitrile to obtain the title compound (0.70 g).
  • Methanesulfonic acid 2- [4- (2,4-dichlorobenzyloxy) phenyl] ethyl ester (see Reference Example 9) (2.00 g), ethylene thiourea (0.65 g), ethanol (20 ml) The mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure, and acetonitrile was added to the residue for crystallization. The resulting crystals were collected by filtration and recrystallized from acetonitrile-ethanol to give the title compound (0.80 g).
  • Example 13 o 4,5-Dihydroimidazole "In the formula (I), R 1 , R 2 , R 3 -substituted benzyloxy group is a 4- (4-monobenzyloxy) group, and R 4 is Compound in which 1 (CH 2 ) 9 1 and Z are —CH 2 0 (CH ⁇ ) 2 1]: 2— [4- (4-chlorobenzyloxy) benzyloxy] ethyl chloride
  • Methanesulfonic acid 2- [4- (3,4-dichroic benzyloxy) phenyl] ethyl ester (see Reference Example 5) (4.33 g), a mixture of ethylenethioperia (1.12 g) and ethanol (40 ml) was refluxed for 21 hours. The solvent was distilled off under reduced pressure, and the crystals of the residue were recrystallized from acetonitrile to obtain the title compound (3.37 g).
  • R 1 , R 2 , and R 3 substituted benzyloxy groups are 4- (3,4-dichlorobenzene) groups, and R 4 and R 5 are Methanesulfonate of a compound that is an ethyl group, H (CH 2 ) 2 —
  • Methanesulfonic acid 2- [4- (3,4-dichlorobenzyloxy) phenyl] ethyl ester (see Reference Example 5) (6.38 g), N, N'-Jetylthiourea (1.92 g), ethanol ( (40 ml) was refluxed for 1 ⁇ . The solvent was distilled off under reduced pressure, dimethyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give the title compound (5.00 g).
  • Methanesulfonic acid 2- [4- (2,3,6-trichloromethylbenzyloxy) phenyl] ethyl ester (see Reference Example 12) (2.00 g), thioperia (0.37 g), and ethanol (10 ml) was refluxed for 1 ⁇ . The solvent is distilled off under reduced pressure Then, ethyl acetate was added to the residue for crystallization. The generated crystals were collected by filtration and recrystallized from ethanol to give the title compound (1.50 g).
  • Methanesulfonic acid 2- [4- (4-methoxybenzyloxy) phenyl] ethyl ester (see Reference Example 13) (1.50 g), a mixture of thioperia (0.34 g), and ethanol (5 ml) was refluxed for 1 ⁇ . The resulting crystals were collected by filtration, washed with getyl ether, and recrystallized from isopropyl alcohol to give the title compound (0.81 g).
  • 2-"2-" 2-(4-cyclobenzyloxy) phenyl] ethyl] thiol is also 5-dihydroimidazole methanesulfonate [-R 1 in formula (I).
  • R 2 , R 3 substituted benzyloxy group is a 2- (4-monobenzyloxy) group, R 4 and R 5 are joined together, — (CH 2 ) 2 —, Z is — (CH 2 ) 2
  • R 1 , R 2 , R 3 -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups, Z gar (CH 2) 2 one, compound Y is a methanesulfo Niruokishi group:
  • R 1 , R 2 , and R 3 -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups A compound wherein Z is — (CH 2 ) 1 and Y is a p-toluenesulfonyloxy group]:
  • R 1 , R 2 , and R ° -substituted benzyloxy groups are substituted with 4 -— (4-nitrobenzyloxy).
  • Methanesulfonic acid 2 “4- (3-Nitrobenzyloxy) phenyl 1-ethyl ester”
  • R 1 , R 2 , and R 3 -substituted benzyloquine groups are substituted by 4-(3-Nitrobenzyloxy) ) group, Z gar (CH 2) 2 one, compound Y is a methanesulfo Niruokin group:
  • ⁇ R 1 , _R 0 , _R 3 _ ⁇ Okishi group 4 one (2- chloro-4-nitrobenzyl O alkoxy) group
  • Z gar (CH 2 I) 2 one
  • compound Y is a methanesulfonyl O carboxymethyl group:
  • R 1 , R 3 -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups, and Z is —CH 20 0 (CH 2 ) 2 —, compound 1 in which Y is a chlorine atom 1:
  • Methanesulfonic acid 2- (4-benzyloxyphenyl) ethyl ester [In the formula (III), _R 2 , R 3 MJ Alkoxy group, Z gar (CH 2) 2 one, Y is methanesulfonyl O carboxymethyl compound L- benzylchloride line de is a group [Tokyo Kasei Co., Ltd.] and 2- (4-hydroxy phenylene) ethyl alcohol [ 2- (4-benzyloxyphenyl) ethyl alcohol (1.30 g), methanesulfonyl chloride (0.70) manufactured by Tokyo Chemical Industry Co., Ltd.] by a method according to Japanese Patent Application Laid-Open No. 50-148357.
  • R 1 , R 2 , and R 3 -substituted benzyloxy groups have 4—1 (2,3 , 6-trichloro port Benjiruokishi) group, Z gar (CH 2) 2 one, Y is methanesulfonyl O alkoxy group compounds:
  • R 1 , R 2 , and R 3 -substituted benzyloxy groups are substituted by 4- (4-methoxybenzyl).
  • Okishi) group, Z gar (CH 2) 2 one, two compounds Y is a methanesulfonic Ruhoniruokishi group:
  • — [4 -— (4-Methoxybenzyloxy) phenyl] ethyl alcohol (0.74 g), methanesulfonyl chloride (0.36 g), triethylamine (0.6 ml) and methylene chloride (10 ml) ) was stirred at 0 ° C for 30 minutes. Water was added and extracted with black-mouthed form.
  • R 1 , R 2 , R ° -substituted benzyloxy group is a 2- (4-cyclobenzyloxy) group
  • R 1 , R 2 , and R 3 -substituted benzyloxy groups are 31- (4-cyclobenzyloxy) groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dérivés d'isothio-urée représentés par la formule générale (I) ou sels pharmaceutiquement acceptables de ces dérivés. Dans ladite formule: R?1, R2, R3¿ représentent individuellement hydrogène, halogéno, nitro, alkyle inférieur ou alcoxy inférieur; R4 et R5 représentent individuellement hydrogène, alkyle inférieur ou alkyle substitué, ou bien R4 et R5 forment ensemble -(CH¿2?)n-; Z représente -(CH2)m- ou CH2O(CH2)2-; n correspond à 2 ou 3; et m correspond à 1,2 ou 3. Les composés (I) des sels pharmaceutiquement acceptables de ces dérivés présentent d'excellentes caractéristiques d'inhibition du mécanisme d'échange na?+/ca2+¿.
PCT/JP1996/002491 1995-09-04 1996-09-03 Nouveaux derives d'isothio-uree WO1997009306A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/251775 1995-09-04
JP7251775A JPH0967336A (ja) 1995-09-04 1995-09-04 新規なイソチオウレア誘導体

Publications (1)

Publication Number Publication Date
WO1997009306A1 true WO1997009306A1 (fr) 1997-03-13

Family

ID=17227743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/002491 WO1997009306A1 (fr) 1995-09-04 1996-09-03 Nouveaux derives d'isothio-uree

Country Status (2)

Country Link
JP (1) JPH0967336A (fr)
WO (1) WO1997009306A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7264935B2 (en) 2002-08-01 2007-09-04 Astellas Pharma Inc. Potassium-dependent sodium-calcium exchanger
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
WO2019175464A1 (fr) 2018-03-14 2019-09-19 Orion Corporation Composés utiles en tant qu'échangeur sodium-calcium (ncx)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI20011507A0 (fi) 2001-07-10 2001-07-10 Orion Corp Uusia yhdisteitä
FI20030030A0 (fi) 2003-01-09 2003-01-09 Orion Corp Uusia yhdisteitä
WO2012170037A1 (fr) * 2011-06-10 2012-12-13 Hitachi Chemical Co., Ltd. Dispositifs de capture de vésicule et leurs procédés d'utilisation
WO2014182330A1 (fr) 2013-05-06 2014-11-13 Hitachi Chemical Company Ltd Dispositifs et procédés de capture de molécules-cibles
US10266895B2 (en) 2014-11-05 2019-04-23 Hitachi Chemical Company Ltd. Exosomes and microvesicles in intestinal luminal fluids and stool and use of same for the assessment of inflammatory bowel disease
WO2016077537A1 (fr) 2014-11-12 2016-05-19 Hitachi Chemical Co., Ltd. Procédé et dispositif permettant de diagnostiquer une lésion touchant un organe
WO2017040520A1 (fr) 2015-08-31 2017-03-09 Hitachi Chemical Co., Ltd. Méthodes moléculaires pour évaluer une maladie urothéliale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0656744A (ja) * 1992-02-28 1994-03-01 Ono Pharmaceut Co Ltd フェノキシ酢酸誘導体および該誘導体を有効成分として含有する薬剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0656744A (ja) * 1992-02-28 1994-03-01 Ono Pharmaceut Co Ltd フェノキシ酢酸誘導体および該誘導体を有効成分として含有する薬剤

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7264935B2 (en) 2002-08-01 2007-09-04 Astellas Pharma Inc. Potassium-dependent sodium-calcium exchanger
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
WO2019175464A1 (fr) 2018-03-14 2019-09-19 Orion Corporation Composés utiles en tant qu'échangeur sodium-calcium (ncx)

Also Published As

Publication number Publication date
JPH0967336A (ja) 1997-03-11

Similar Documents

Publication Publication Date Title
RU2316537C2 (ru) Производные карбоновой кислоты, их фармацевтически приемлемые соли или сложные эфиры, лекарственное средство и фармацевтическая композиция на их основе, их применение и способы лечения и профилактики заболеваний
CN109438298B (zh) 作为有生理学价值的硝酰氧基供体的n-羟基磺酰胺衍生物
RU2372330C2 (ru) ЗАМЕЩЕННЫЕ ФЕНОКСИУКСУСНЫЕ КИСЛОТЫ, ОБЛАДАЮЩИЕ МОДУЛИРУЮЩЕЙ АКТИВНОСТЬЮ В ОТНОШЕНИИ РЕЦЕПТОРОВ CRTh2
KR100207145B1 (ko) (-)-((4-(1,4,5,6-테트라하이드로-4-메틸-6-옥소-3-피리다지닐)페닐히드라조노)프로판디니트릴
WO1997009306A1 (fr) Nouveaux derives d'isothio-uree
US11306102B2 (en) 1,3-di-substituted ketene compound and application thereof
FR2581993A1 (fr) Derives de (benzoyl-4 piperidino)-2 phenyl-1 alcanols, leur preparation et leur application en therapeutique
JPH04230681A (ja) １，４‐ベンゾチアゼピン誘導体
KR880000180B1 (ko) 디하이드로 피리딘의 제조방법
EP1951663A2 (fr) Dérivés (r)-arylalkylaminés et compositions pharmaceutiques contenant ceux-ci
US6288096B1 (en) Thiazolidinedione, oxazolidinedione and oxadiazolidinedione derivatives
BRPI0921369B1 (pt) Composto modulador do receptor de prostaciclina (pgi2), sua composição, sua composição farmacêutica, seus usos, bem como processos para a preparação das referidas composições
SK13752002A3 (sk) Difenyléterové zlúčeniny užitočné pri liečení
US4347371A (en) Disulfide compounds
US5225558A (en) 2-amino-5-cyano-1,4-dihydropyridines, and their use in medicaments
HUT64759A (en) Method for producing tetrazolyl-(phenoxy-and phenoxy-alkyl-)-pyridinyl-pyridazines
PT1720829E (pt) Derivados de heteroaril-alquilcarbamatos, sua preparação e sua aplicação como inibidores da enzima faah
US5332739A (en) Pyrimidinedione derivatives and antiarrhythmic agents containing same
WO2007143951A1 (fr) COMPOSÉS DOTÉS D'UNE ACTIVITÉ D'AGONISTE DU PPARγ ET LEUR APPLICATION
DE69531691T2 (de) Neues amin-derivat, verfahren zur herstellung und dessen verwendung als anti-arrhythmisches mittel
KR100293334B1 (ko) 알킬렌디아민유도체
PT874834E (pt) Processos e intermediarios para preparacao de 3-(1-piperazinil)-1,2-benzisotiazole
HU199813B (en) Process for producing new benzothiazinone derivatives and pharmaceutical compositions comprising such active ingredient
DE4041780A1 (de) Neue amine, verfahren zu ihrer herstellung, sowie diese verbindungen enthaltende arzneimittel
KR20030056481A (ko) 사이클로옥시게나제-2 의 저해제로서 선택성이 뛰어난디아릴 1,2,4-트리아졸 유도체

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase