WO1998013357A1 - Derives de benzo[1,4]thiazine et medicaments les contenant - Google Patents

Derives de benzo[1,4]thiazine et medicaments les contenant Download PDF

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Publication number
WO1998013357A1
WO1998013357A1 PCT/JP1997/003373 JP9703373W WO9813357A1 WO 1998013357 A1 WO1998013357 A1 WO 1998013357A1 JP 9703373 W JP9703373 W JP 9703373W WO 9813357 A1 WO9813357 A1 WO 9813357A1
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Prior art keywords
compound
benzo
thiazine
isopropyl
group
Prior art date
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PCT/JP1997/003373
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English (en)
Japanese (ja)
Inventor
Takeshi Yamamoto
Ikuo Watanabe
Kengo Harada
Shoji Ikeda
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Kanebo Limited
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Publication date
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Publication of WO1998013357A1 publication Critical patent/WO1998013357A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—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 a novel benzo [1,4] thiazine derivative or a pharmacologically acceptable salt and a medicament comprising the same. More specifically, the following formula (I) having an action of inhibiting the Na + / H + exchange mechanism
  • R 1 represents a hydrogen atom or a lower alkyl group
  • R 2 and R are the same or different and represent a hydrogen atom or a C 2 alkyl group
  • n represents 0 or 2.
  • guanidinocarbonyl The substitution position of the group is the 6-position or the 7.-position.
  • the present invention relates to a benzo [1,4] thiazine derivative represented by the formula or a pharmacologically acceptable salt thereof, and a drug comprising the same.
  • the Na + / H + exchange mechanism is responsible for regulating intracellular pH, sodium ion concentration and cell volume.
  • intracellular acidosis occurs due to ischemia or the like, that is, when the intracellular hydrogen ion concentration is increased, the action of this exchange mechanism is enhanced, and excessive incorporation of sodium ions into cells occurs.
  • water inflow occurs due to the osmotic pressure difference between the inside and outside of the cell, causing an increase in cell volume and edema [Biochimica et Biophysica Acta, 988, 73-97 (1989)].
  • sodium ions that are excessively accumulated due to the enhancement of the Na + / H2 + exchange mechanism are pumped out via the Na + / Ca2 + exchange mechanism, and are instead replaced by intracellular cells.
  • Calcium ions flow into the system. It has been reported that excessive accumulation of calcium ions causes cardiac dysfunction, myocardial necrosis and arrhythmias [Journal of Cardiovascular Pharmacology, 23, 72-78 (1994)].
  • compounds that inhibit the Na + / H + exchange mechanism may be useful for disorders induced by intracellular acidosis during myocardial ischemia, such as ischemia such as myocardial infarction and angina.
  • compounds that inhibit the Na + / H + exchange mechanism may be caused by ischemia, reperfusion injury, such as organ transplantation, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or thrombolytic therapy. It can be used as a medicine for the resulting disorders.
  • the enhancement of the Na + / H + exchange mechanism not only increases vascular smooth muscle cell proliferation but also increases fluid volume, and is considered to be involved in the development of essential hypertension [Diagnosis and treatment, 81, 2209-2213 ( 1993)]
  • compounds that inhibit the Na + / H + exchange mechanism may have therapeutic potential for essential hypertension.
  • amyloid rides represented by the following formula (II) and derivatives thereof, benzoylguanidine derivatives, indoloyluguanidine derivatives, and benzo [1,4 ⁇ Oxazine derivatives and the like are known.
  • the present inventors have made various studies for the purpose of providing a novel compound having a Na + / H + exchange mechanism inhibitory action and a medicament comprising the same.
  • examples of the lower alkyl group for R 1 include a methyl group, an ethyl group, a propyl group, and an isopropyl group, and an ethyl group and an isopropyl group are preferable.
  • R 2 and R 3 are different substituents, the 2-position of the benzo [1,4] thiazine skeleton becomes an asymmetric carbon, and the stereoisomer (optical activity ), But these stereoisomers, mixtures and hydrates thereof are also included in the compounds of the present invention.
  • the compound (I) of the present invention include N- (4-methyl-3-oxo-13,4-dihydro-2H-benzo [1,4] thiazine-16-carbonyl) guanidine and N— (4 —Ethyl-3—oxo-1,3 dihydro— 2 H—Venzo [1,4] thiazine—6—carbonyl) guanidine, N— (4-Isopropyl-3-oxo—3,4 dihydro 2H— benzo [1, 4] thiazine one 6-carbonyl) guanidine, N-(4-isopropyl-one 1, 1, 3-Toriokiso 1, 2, 3, 4 Tetorahi chondroitinase 1 scan 6 - base down zone [1, 4] Thiazine-1-6-carbonyl) guanidine, N- (3-oxo-3,4-dihydro 2H-benzo [1,4] thiazin-6-carbonyl) guanidine, N- (4
  • the pharmacologically acceptable salts of the compound (I) of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and carbonic acid, or acetic acid, lactic acid, citric acid, and tartaric acid. And salts with organic acids such as methanesulfonic acid and p-toluenesulfonic acid.
  • N- (4-ethyl-3-oxo-3,4-dihydro2H-benzo [1,4] thiazine-6-carbonyl) guanidine N- (4-isopropyl-1-oxo) 1,3,4-dihydro-2H-benzo [1.4] thiazine — 6-carbonyl) guanidine
  • N- (4-monoisopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine is mentioned as a particularly preferred compound.
  • Compound (I) of the present invention and a pharmacologically acceptable salt thereof can be produced, for example, according to the following Method A.
  • the compound (I) of the present invention is prepared by mixing a compound (III) and 1 to 20 equivalents of guanidine with respect to the compound (III) in an inert solvent from room temperature to the boiling point of the solvent for 1 to 24 times. It can be produced by reacting for hours.
  • inert solvent examples include dioxane, tetrahydrofuran, 1,2-dimethoxetane, dimethylformamide, dimethylsulfoxide, and the like, or a solvent obtained by appropriately mixing them.
  • a metal carbonate such as potassium carbonate
  • a metal hydride such as sodium hydride
  • a metal alkoxide such as sodium methoxide
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by reacting the above-mentioned inorganic acid or organic acid with the compound (I) obtained by the above production method according to a conventional method. it can.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be converted into a hydrate of the compound by recrystallization from a water-containing solvent such as a water-containing alcohol, if necessary.
  • the compound (III) [compound (I lia, II lb) where n is 0 and compound (III c) where n is 2] used as a raw material in the above Method A can be produced, for example, by the following method. it can.
  • R 1 ′ represents a lower alkyl group
  • X represents a halogen atom
  • substitution positions of the carboxyl group and the ethoxyquin carbonyl group are represented by the formula
  • a 2-octoronitrobenzene derivative (IV) is reacted with a thioglycolate ethylyl derivative such as thioglycolate ethyl ester in the presence of a base such as pyridine or potassium carbonate to form a thioether (V), which is then acid-catalyzed in ethanol.
  • Esters in the presence of to give compound (VI).
  • the compound (VI) is reduced in the presence of a catalyst such as PdZC in an alcohol in a hydrogen atmosphere, the ring-closure reaction also proceeds, and the compound (Ilia) is obtained. If the ring closure reaction is incomplete after the reduction reaction, the ring closure reaction is completed by heating in toluene to obtain (Ilia).
  • Compound (II lb) was added to compound (I lia) in an inert solvent such as dimethylformamide, tetrahydrofuran, or dimethoxetane, and potassium t-butoxide, It can be produced by reacting an alkyl halide (R 1 X) in the presence of a base such as 40% potassium fluoride-alumina.
  • an inert solvent such as dimethylformamide, tetrahydrofuran, or dimethoxetane, and potassium t-butoxide
  • the compound (IIIc) is obtained by adding the compound (IIIa) or (II lb) obtained by the above method to a benzoate such as potassium peroxomonosulfate or potassium peroxodisulfate, or m-chloroperbenzoic acid. It can be produced by oxidizing an organic peroxide.
  • a benzoate such as potassium peroxomonosulfate or potassium peroxodisulfate, or m-chloroperbenzoic acid. It can be produced by oxidizing an organic peroxide.
  • Compound (I) of the present invention can also be produced by the following Method B.
  • R 1 , R 2 , R 3 , and n are the same as described above.
  • the substitution position of the carbonyl group and the guanidino carbonyl group is the 6-position or the 7-position.
  • the compound (I) of the present invention is prepared by mixing the compound (VII) and 1 to 20 equivalents of guanidine with respect to the compound (VII) in an inert solvent at room temperature to the boiling point of the solvent for 1 to 24 times. It can be produced by reacting for hours.
  • guanidine can be used for the reaction after converting an acid addition salt of guanidine such as guanidine hydrochloride into guanidine with a base such as sodium methoxide or sodium hydride.
  • inert solvent examples include dioxane, tetrahydrofuran, 1,2-dimethoxetane, dimethylformamide, dimethylsulfoxide, and the like, or a solvent obtained by appropriately mixing them.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by reacting the above-mentioned inorganic acid or organic acid with the compound (I) obtained by the above production method according to a conventional method. it can.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be, if necessary, Recrystallization from a water-containing solvent such as a water-containing alcohol can lead to hydrates of these compounds.
  • Compound (VII) used as a raw material in the above-mentioned Method B can be produced by the following method.
  • R 1 , R 2 , R 3 , and n are the same as described above.
  • the substitution position of the carboxyl group or the carbonyl group is the 6-position or the 7-position.
  • compound (VII) can be produced by reacting compound (VIII) with a quenching agent such as thionyl chloride according to a conventional method.
  • the compound (VIII) used in the above-mentioned production method is prepared by first producing a compound (III) in the same manner as in the production method of the starting compound in the above-mentioned Method A. It can be produced by hydrolysis with a method such as
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent inhibitory effect on the Na + / H + exchange mechanism, and a disorder induced by intracellular acidosis at the time of myocardial ischemia. It can be used as a preventive and therapeutic agent for cardiac dysfunction, myocardial necrosis and arrhythmia seen in ischemic heart diseases such as infarction and angina. It can also be used as a medicament for ischemia and reperfusion injury, for example, for organ transplantation, CABG, PTCA and other disorders caused by surgery and thrombolytic therapy.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is administered orally or parenterally to a human.
  • Oral dosage forms include tablets, granules, powders, fine granules, hard capsules and the like.
  • Such preparations can be manufactured in a conventional manner, and may be tablets, granules, powders or fine granules.
  • hard capsules are prepared by appropriately filling the above-mentioned fine granules or powders into capsules.
  • Parenteral dosage forms include injections and the like.
  • preparations can be manufactured by a conventional method.
  • an injection is a compound of the present invention.
  • (I) or a pharmacologically acceptable salt thereof is dissolved or emulsified in purified water for injection, physiological saline or a fatty excipient, for example, vegetable oil, oily emulsion, glycol, or the like, and sterilized in a sample or vial. It is manufactured by encapsulating it. In addition, it can be obtained by dissolving in a stabilizer and purified water as appropriate as a freeze-dried preparation to be dissolved at the time of use, and freeze-drying by an ordinary method.
  • the dose of the compound of the present invention may vary depending on the patient's condition, administration route, age, body weight, etc., but generally ranges from 0.1 to 100 mg as the compound (I) of the present invention per adult. This is administered once or in two or three divided doses. It can also be increased as needed.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent inhibitory effect on Na + / H + exchange mechanism as shown in the following test examples, and myocardial ischemia which is considered to be based on this effect. It shows an action of suppressing reperfusion arrhythmia afterward. In addition, it is low toxic without any toxicity at the dose of the drug.
  • a drug comprising the compound U) of the present invention and a pharmacologically acceptable salt thereof is useful for a disorder induced by intracellular acidosis during myocardial ischemia, for example, ischemic diseases such as myocardial infarction and angina It is useful for preventing and treating cardiac dysfunction, myocardial necrosis and arrhythmias seen in heart disease. It is also useful for the prevention and treatment of ischemia / reperfusion injury, for example, damage caused by surgery or thrombolytic therapy such as organ transplantation, CABG, PTCA and the like.
  • Na + ZH + exchange mechanism inhibitory action The inhibitory effect of the Na + / H + exchange mechanism is based on the inhibitory effect of the test compound on sodium propionate-induced platelet swelling according to the method of Rosskoph et al. [Journal of Hypertension, 9, 23 238 (1991)]. We considered it as an index.
  • platelet-rich plasma was prepared according to the method of Mamen et al. [Diabetes Research and Clinical Practice, 9 (3), 265-272 (1990)]. That is, Wistar male rats (body weight: 230 to 300 g) were laparotomized under ether anesthesia, and blood was collected from the abdominal aorta. Add ACD solution (a mixture of 65 mM citric acid, 85 mM sodium citrate, and 11 mM dextrose) to suppress clotting, centrifuge (90 X g, 10 minutes), collect supernatant, and collect platelet-rich plasma was prepared.
  • ACD solution a mixture of 65 mM citric acid, 85 mM sodium citrate, and 11 mM dextrose
  • a test compound solution (dissolved in dimethyl sulfoxide) is added to a 14 OmM sodium propionate buffer solution, and then the platelet-rich plasma prepared above is added, and a platelet aggregometer (turbidimeter) and XY The decrease in optical density at 37 ° C was recorded over time with a recorder, and the decrease in optical density after mixing with platelet-rich plasma was determined.
  • the concentration (IC 5Q ) at which the inhibition rate became 50% by the test compound was calculated by the least square method.
  • Test compound Compound of Example 1 0.012 Compound of Example 2 0.0091 Compound of Example 3 ⁇ . ⁇ ⁇ Compound of Example 4 0.19 Compound of Example 5 0.051 Compound of Example 7 0.018 Compound of Example 8 U 0.053 Mouth Ride 13 ⁇ '
  • mice Male Sprague-Dawley rats (body weight: 310 to 50 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 mgZkg). Under anesthesia, a force neuron was inserted into the trachea of the rat and connected to a ventilator. The electrocardiogram (lead II) was induced from electrodes attached to the limbs and measured via a bioelectric amplifier. Body temperature was maintained at 37 ° C. The rat was opened in the left intercostal space and the pericardium was incised to expose the heart.
  • test compound is dissolved in a mixed solvent of polyethylene glycol 400, ethanol, and physiological saline (mixing ratio vZv, 3: 3: 14) and injected into the femoral vein.
  • a mixed solvent of polyethylene glycol 400, ethanol, and physiological saline mixtureing ratio vZv, 3: 3: 14
  • vZv physiological saline
  • Arrhythmias were determined according to the guidelines of The Lambeth Convention [Cai "diovascular Research, 22, 447-455 (1988):".
  • the duration (seconds) of ventricular fibrillation when only a mixed solvent of polyethylene glycol 400, ethanol, and saline (mixing ratio vZv, 3: 3: 14) was administered was set as described above. Measured.
  • R 1 is isopropyl Methanesulfonate of a compound (Example 1) in which the group, R 2 and R ° are hydrogen atoms, n is 0, and the substitution position of the guanidinocarbonyl group is 6-position]:
  • R 1 is a methyl group
  • R 2 A methanesulfonate of a compound in which R 3 is a hydrogen atom, n is 0, and the substitution position of the guanidinocarbonyl group is 6:
  • R 1 is an ethyl group, R , R 0 hydrogen atom, n force 0, guanidinocarbonyl group
  • substitution position of the methanesulfonate of the compound at position 6 ::
  • R 1 , R 2 , and R 3 represent a hydrogen atom, Methanesulfonic acid salt of a compound in which n is 0 and the substitution position of the guanidinocarbonyl group is 6-position]:
  • N- (4-Isopropyl-1-3-oxo-3,4-dihydro 2H-benzo [1,4] thiazine-6-carbonyl) guanidine methanesulfonate (implemented Dissolve 1 g in purified water for injection to make 10 Oml, filter aseptically with a membrane filter (0.2 / m), dispense 1 ml into ampoules, and seal. It is then sterilized at 120 ° C for 20 minutes.
  • Elemental analysis value (as C ⁇ HnNOe S): Calculated value (%) C, 46.31; H, 3.89; N, 4.91 Analytical value (%) C, 46.37; H, 3.95; N, 4.51
  • R 1 ' is a methyl group
  • R and R 3 are Compound 1 that is a hydrogen atom:
  • R 1 ′ is an ethyl group
  • R 2 R Compound 1 in which 3 is a hydrogen atom:
  • R 2 and R 3 are hydrogen atom, and the other is a methyl group.
  • R 1 ' is an isopropyl group, Compound in which one of 3 is a hydrogen atom and the other is a methyl group]:
  • R 1 is an isopropyl group
  • R 1 is an isopropyl group
  • R 2 Compound 1 in which R 3 is a methyl group and n is 0:

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

L'invention porte sur des dérivés de benzo[1,4]thiazine représentés par la formule générale (I) ou sur leurs sels pharmaceutiquement acceptables, formule dans laquelle R1 représente hydrogène ou alkyle inférieur; R2 et R3 sont identiques ou différents et représentent chacun hydrogène ou alkyle en C¿1-2?; n vaut 0 ou 2; le substituant guanidinocarbonyle étant lié à la position 6 ou 7. Ces composés présentent un excellent effet inhibiteur sur le système d'échange Na?+/H+¿. Les médicaments contenant ces composés sont donc utiles comme ingrédients actifs dans la prévention et les remèdes à des troubles induits par l'acidose intracellulaire au niveau de l'ischémie cardiaque, par exemple les maladies cardiaques, la nécrose myocardiaque et les arythmies observés dans les maladies cardiaques ischémiques telles que l'infarctus du myocarde et l'angine de poitrine.
PCT/JP1997/003373 1996-09-25 1997-09-22 Derives de benzo[1,4]thiazine et medicaments les contenant WO1998013357A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP8/275615 1996-09-25
JP27561596 1996-09-25
JP8358726A JPH10152481A (ja) 1996-09-25 1996-12-26 ベンゾ［１，４］チアジン誘導体およびそれからなる医薬
JP8/358726 1996-12-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045716A1 (fr) * 1999-12-20 2001-06-28 Gho'st Holding B.V. Composition pharmaceutique comprenant un compose, un sel ou un complexe de vanadium, acceptable au plan physiologique, et un inhibiteur d'echange na?+/h+¿

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200614995A (en) * 2004-11-10 2006-05-16 Nicholas Piramal India Ltd Tricyclic guanidine derivatives as sodium-proton exchange inhibitors
DE102006054005A1 (de) * 2006-11-16 2008-05-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Polymorphe von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester

Citations (4)

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Publication number Priority date Publication date Assignee Title
JPH04234860A (ja) * 1990-02-08 1992-08-24 Tanabe Seiyaku Co Ltd チアジン（又はオキサジン）誘導体、その製法及びその合成中間体
JPH07206823A (ja) * 1993-12-24 1995-08-08 Hoechst Ag 置換１−オキソ−１，２−ジヒドロイソキノリノイルグアニジン類及び１，１−ジオキソ−２ｈ−１，２−ベンゾチアジノイルグアニジン類
JPH0881442A (ja) * 1994-07-14 1996-03-26 Otsuka Pharmaceut Co Ltd 環状アミド誘導体
JPH08225513A (ja) * 1994-12-21 1996-09-03 Kanebo Ltd ナフトイルグアニジン誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04234860A (ja) * 1990-02-08 1992-08-24 Tanabe Seiyaku Co Ltd チアジン（又はオキサジン）誘導体、その製法及びその合成中間体
JPH07206823A (ja) * 1993-12-24 1995-08-08 Hoechst Ag 置換１−オキソ−１，２−ジヒドロイソキノリノイルグアニジン類及び１，１−ジオキソ−２ｈ−１，２−ベンゾチアジノイルグアニジン類
JPH0881442A (ja) * 1994-07-14 1996-03-26 Otsuka Pharmaceut Co Ltd 環状アミド誘導体
JPH08225513A (ja) * 1994-12-21 1996-09-03 Kanebo Ltd ナフトイルグアニジン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CIRCULATION, (1994), Vol. 89, No. 6, HENDRIKX M., MUBAGWA K., VERDONCK F., OVERLOOP K., HECKE P.V., VANSTAPEL F., LOMMEL A.V., VERBEKEN E., LAUWERYNS J., FLAMENG W., pages 2787-2789. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045716A1 (fr) * 1999-12-20 2001-06-28 Gho'st Holding B.V. Composition pharmaceutique comprenant un compose, un sel ou un complexe de vanadium, acceptable au plan physiologique, et un inhibiteur d'echange na?+/h+¿
WO2001045717A2 (fr) * 1999-12-20 2001-06-28 Gho'st Holding B.V. COMPOSITION PHARMACEUTIQUE COMPRENANT UN COMPOSE DE VANADIUM PHYSIOLOGIQUEMENT ACCEPTABLE, UN SEL OU UN COMPLEXE DE CE COMPOSE ET AU MOINS UN CONSTITUANT CHOISI PARMI DES INHIBITEURS D'ECHANGEUR DE Na+/H+, DES INHIBITEURS DE CYCLO-OXYGENASE ET DES INHIBITEURS DE CASPASE
WO2001045717A3 (fr) * 1999-12-20 2002-02-21 Gho St Holding B V COMPOSITION PHARMACEUTIQUE COMPRENANT UN COMPOSE DE VANADIUM PHYSIOLOGIQUEMENT ACCEPTABLE, UN SEL OU UN COMPLEXE DE CE COMPOSE ET AU MOINS UN CONSTITUANT CHOISI PARMI DES INHIBITEURS D'ECHANGEUR DE Na+/H+, DES INHIBITEURS DE CYCLO-OXYGENASE ET DES INHIBITEURS DE CASPASE

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