WO1996022086A1 - MEDICAMENT CONTENANT UN DERIVE DE β-OXO-β-BENZENEPROPANE-THIOAMIDE - Google Patents

MEDICAMENT CONTENANT UN DERIVE DE β-OXO-β-BENZENEPROPANE-THIOAMIDE Download PDF

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Publication number
WO1996022086A1
WO1996022086A1 PCT/JP1996/000046 JP9600046W WO9622086A1 WO 1996022086 A1 WO1996022086 A1 WO 1996022086A1 JP 9600046 W JP9600046 W JP 9600046W WO 9622086 A1 WO9622086 A1 WO 9622086A1
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Prior art keywords
group
imidazolyl
alkoxy
alkyl group
halogen atom
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PCT/JP1996/000046
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English (en)
Japanese (ja)
Inventor
Hideki Bessho
Youichi Abe
Toshiaki Tamaki
Shoji Kimura
Yasuharu Aki
Masayoshi MITSUKA
Mieko Nagae
Asami Seino
Akihiro Narimatsu
Yuji Abe
Original Assignee
Mitsubishi Chemical Corporation
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Priority claimed from JP494995A external-priority patent/JPH07244393A/ja
Application filed by Mitsubishi Chemical Corporation filed Critical Mitsubishi Chemical Corporation
Publication of WO1996022086A1 publication Critical patent/WO1996022086A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the present invention comprises a ⁇ -oxo- ⁇ -benzenepropane amide derivative as an active ingredient, and comprises a renal disease; a disease caused by proliferation of smooth muscle cells; and a heart disease such as angina pectoris, myocardial infarction and heart failure.
  • the present invention relates to a medicament useful for preventing and / or treating a disease.
  • Blood vessels have a layered structure composed of an intima composed of vascular endothelial cells, a media composed of vascular smooth muscle cells and fibroblasts, and an outer membrane.
  • intima composed of vascular endothelial cells
  • media composed of vascular smooth muscle cells and fibroblasts
  • an outer membrane In healthy adults, blood pressure is maintained by the contraction and relaxation functions of vascular smooth muscle cells, and the blood flow supplied to all organs such as the brain, heart, and digestive organs is regulated.
  • pathological conditions in the vascular wall have been shown to cause excessive proliferation of vascular smooth muscle cells in response to vascular damage (N. Engl. J. Med. 314, 488-500, 1986). This overgrowth narrows the lumen of the blood vessel and, in some cases, obstructs the blood vessel and interferes with the distribution of blood to the area under control.
  • Hyperproliferation of vascular smooth muscle cells can be based on internal damage or on external damage. When based on internal damage, for example, it progresses to atherosclerosis, renal hypertension, pulmonary hypertension, vasculitis and diabetic retinopathy.
  • drugs such as lipid-lowering agents and hypotensive agents have been conventionally used. However, these drugs merely reduce the risk factors for arteriosclerosis and do not affect the cause of the disease itself.
  • Hyperproliferation of vascular smooth muscle cells due to external injury can be due to wounding and surgery.
  • Surgery that may cause hyperproliferation of vascular smooth muscle cells includes, for example, percutaneous angioplasty using balloon or laser; percutaneous angioplasty using a stent; artectomy, rotaplator Percutaneous angioplasty using a technique called new device; vascular graft surgery including vascular bypass surgery and artificial vascular graft surgery Surgery; an invasive diagnostic method involving internal incision of a blood vessel such as an arterial catheter test; and organ transplantation of the kidney, liver, lung and heart.
  • restenosis occurs approximately 3 to 6 months after percutaneous coronary angioplasty for patients with coronary stenosis, and the incidence is 30 to 40% when using a balloon (J. Am. Coll. Cardiol., 12, pp. 616-623, 1988), 40% by laser (Am. J. Cardiol., 70, pp. 1533-1539, 1992; J. Interventional Cardiol., 5, 15-23, 1992), using a stent 20 to 303 ⁇ 4 (Circulation, 86, pp. 1836-1844, 1992), and 20 to 30 ⁇ ⁇ ⁇ (at International J. Cardiol., 35, pp. 143-146, 1992; J. Am. Coll. Cardiol., 21, p.
  • heparin is used to prevent stenosis or occlusion of thrombotic blood vessels during and after surgery (Circulation, 78, pp. 654-660, 1988).
  • heparin inhibits the proliferation of vascular smooth muscle cells in normal subjects, but has no effect on the proliferation of vascular smooth muscle cells in patients with restenosis (Lancet, 341, pp. 341-342, 1993).
  • heparin administration cannot prevent the proliferation of vascular smooth muscle cells that are clinically diagnosed as restenosis (Am. Heart J., 117, pp. 777-782). , 1989).
  • Antihypertensive drugs such as calcium antagonists
  • calcium antagonists mainly act in a relaxant manner on imported arteries to increase renal blood flow, but at the same time increase glomerular filtration rate Therefore, the glomerular pressure does not decrease (Naunyn-Schmiedeberg's Arch. Pharmacol., 336, 572, 1987). Therefore, there is a need for the development of a therapeutic agent for ⁇ disease, which has the effect of increasing renal blood flow and lowering glomerular pressure without increasing glomerular filtration rate.
  • Heart diseases such as angina, myocardial infarction, and heart failure are among the three major adult diseases along with stroke and cancer, and the number of patients is increasing year by year as the population ages.
  • drugs have been developed mainly for the purpose of improving symptoms.
  • nitrates, 3-blockers, calcium antagonists, etc. are used to treat angina
  • perokinase (UK), properokinase (proUK), and tissue plasminogen are used to treat myocardial infarction.
  • Activator-1 (t-PA) is used.
  • digitalis cardiac glycoside
  • diuretics angiotensin converting enzyme inhibitors
  • calcium antagonists calcium antagonists
  • ⁇ -blockers nitric acid and other vasodilators are used clinically. I have.
  • the calcium antagonist diltiazem (Di ltiazem: 3- (Acetyloxy) -5- [2-(, dimethylamino) -ethyl] -2,3-dihydro-2- ( 4-methoxyphenyl)-1, 5-benzothiazepin _4 (5H)-one) Ester) has an inhibitory effect on HK and cannot be applied to heart failure.
  • JP-A-5-246980 discloses that the following formula:
  • R 1 and R 2 each independently represent a hydrogen atom, or an alkyl group or a cycloalkyl group of C 3 -C 6 for ⁇ , or R 1 and R 2 together such connection - (- 6 of represents a Arukire emissions group.
  • R represents a hydrogen atom, an alkyl group or a cycloalkyl group of C 3 -C 6 for ⁇
  • R 4 represents an alkyl group or - a cycloalkyl group of C 6 a -
  • R 3 and R 4 together represent a C 2 to C r alkylene group
  • X 1 , X and X 3 each independently represent a hydrogen atom, a halogen atom, an alkyl group of ( ⁇ to ⁇ , c 3
  • An object of the present invention is to provide a medicament useful for treating and preventing or preventing renal disease. More specifically, it rapidly reduces intraglomerular pressure based on a new mechanism of action that is different from conventional therapeutic agents for renal disease, and reduces glomerulitis, diabetic nephropathy, renal sclerosis, and nephrotic syndrome.
  • An object of the present invention is to provide a medicament capable of preventing the occurrence of a disease beforehand or effectively treating a renal disease as described above. From another viewpoint, an object of the present invention is to provide a method for preventing renal disease, which can rapidly increase blood flow without increasing the amount of glomerular filtration, and can suppress the occurrence and progression of renal damage. Or to provide a therapeutic agent.
  • Another object of the present invention is to provide a medicament useful for treating and preventing or preventing arteriosclerosis and aortic aneurysm, and for preventing arterial stenosis after angioplasty. More specifically, it suppresses the excessive proliferation of vascular smooth muscle cells based on a new mechanism of action different from conventional drugs, and prevents the occurrence of arteriosclerosis, aortic aneurysm, etc., and cures them. It is an object of the present invention to provide a medicament which enables a therapeutic treatment or the prevention of arterial stenosis after angioplasty.
  • Still another object of the present invention is to provide a medicament which can treat and prevent or prevent heart diseases such as angina, myocardial infarction, and heart failure. More specifically, it has pharmacological actions such as coronary vasodilator action, coronary spasm remission action, ischemic myocardial protection action, inotropic action, angina pectoris, myocardial infarction (acute myocardial infarction, chronic myocardial infarction), heart failure, etc. It is an object of the present invention to provide a medicament capable of preventing the occurrence of heart diseases in advance or enabling treatment of these heart diseases. .
  • the present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a specific / 3_oxo_3-benzenebenzenepropane thioamide derivative known to have a potassium channel opening action has a blood flow rate Has the effect of increasing urinary volume and urinary excretion of urine by increasing urine output without increasing glomerular filtration rate. I found something.
  • the present inventors have concluded that the above-mentioned compound has an inhibitory action on the proliferation of vascular smooth muscle cells; It has a favorable pharmacological action on the heart, does not suppress cardiac function unlike conventional calcium antagonists, and has found that its action on coronary and ischemic myocardium is excellent in selectivity.
  • the present invention has been completed based on these findings.
  • R 1 and R 2 each independently represent a C ⁇ c 6 alkyl group, or are linked to each other to represent a C 2 to C 5 alkylene group
  • R 3 and R 4 each independently represent a hydrogen atom atom, a halogen atom,
  • ⁇ - ( ⁇ alkyl group; triflate Ruo Russia methyl Xia amino group; a nitro group; dialkyl ⁇ of ⁇ c 6 amino group; ⁇ alkoxy group or ⁇ alkyl group, to c 6
  • YS-oxo-3-benzenepropane amide derivative represented by the formula: Provide a preventive and therapeutic agent for diseases; a preventive and therapeutic agent for diseases caused by proliferation of smooth muscle cells; and a preventive and therapeutic agent for heart disease, comprising a salt, a hydrate or a solvate thereof as an active ingredient.
  • R 3 is ( ⁇ ⁇ (: 6 alkyl groups, ( ⁇ ⁇ (; 6 alkoxy Shi group and each prophylactic or therapeutic agent of the is one or more substituents which may I Midazo Lil group which may have a selected from a halogen atom; R 4 or the agent for preventing or treating the hydrogen atom; R Each of the above-mentioned prophylactic and therapeutic agents wherein 1 and R 2 are linked to form a trimethylene group; each of the above prophylactic and therapeutic agents wherein R 3 is bonded to the carbonyl group in a para-position to the carbonyl group; Each of the above prophylactic and therapeutic agents wherein R 3 is a 1-imidazolyl group.
  • a method comprising a step of administering an effective amount of each of the above-mentioned medicaments to a mammal (preferably a human), comprising renal disease, arteriosclerosis, and large cerebral aneurysm.
  • a renal protective agent As an active ingredient, a renal protective agent; a dilator of glomerular imported and exported arterioles; a vascular protective agent; Is selected from the group consisting of angina pectoris, myocardial infarction, and heart failure; the above-mentioned agents for preventing and treating heart disease; agents for increasing coronary blood flow; agents for protecting ischemic myocardium; An agent for increasing coronary blood flow without suppression of function; an agent for protecting ischemic myocardium; and an agent for improving local myocardial contraction insufficiency are provided.
  • use of the compound of the above formula (1) for the production of these medicaments is provided. Is provided. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a diagram showing that the medicament of the present invention suppresses a decrease in ATP content in reperfused myocardium.
  • the prophylactic / therapeutic agent of the present invention is represented by the formula (I): ⁇ -oxo- ⁇ -benze It is characterized in that an active ingredient is a propanepanamide derivative, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.
  • ( ⁇ -( ⁇ alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group, etc.
  • Examples of the C 2 -C 5 alkylene group include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, etc.
  • Examples of the halogen atom include a fluorine atom and a chlorine atom. , A bromine atom or an iodine atom may be used.
  • Examples of the alkoxy group of ⁇ to (: 6 include, for example, a methoxy group, an ethoxyquin group, an n-propoxy group, an isopropoxy group, an n-butoxy group, Examples thereof include an n-pentyloxy group, an n-hexyloxy group, etc.
  • Examples of the dialkylamino group of c 2 to c 6 include, for example, a dimethylamino group, a methylethylamino group, and a getyla group. Examples include a mino group and a dipropylamino group.
  • the imidazolyl group can be bonded to the phenyl group at any position.
  • an acid addition salt and the like can be used as a pharmaceutically acceptable salt of the compound represented by the formula (I).
  • mineral salts such as hydrochloride, sulfate and phosphate, and acetates
  • Organic acid salts such as malonate, fumarate, maleate, methanesulfonate, and paratoluenesulfonate can be used as acid addition salts.
  • Any hydrate or solvate thereof may be used as an active ingredient of the medicament of the present invention, in addition to a salt or a compound in a free form.
  • Solvents that can form solvates with the above compounds include, for example, methanol, ethanol, isopropanol, acetate, ethyl acetate, methylene chloride, and the like. It is preferable to use an ethanol solvate that is a solvate.
  • the compound represented by the formula (I) may have one or two or more asymmetric carbon atoms depending on the types of R 1 and R 2.
  • the isomers, arbitrary mixtures thereof, racemates which are equal mixtures of optical isomers, arbitrary distereoisomers based on two or more asymmetric centers, or arbitrary mixtures thereof, are all the pharmaceuticals of the present invention. It can be used as an effective component of
  • the compound included in the general formula (1) is a known compound disclosed in Japanese Patent Application Laid-Open No. 5-246980 (EP548680) itself, or is easily prepared by the method described in the same. And can be easily obtained by those skilled in the art. It is a compound that can be used.
  • a compound in which R 1 and R 2 are linked to form a trimethylene group R 3 is one or more selected from an alkyl group of, an alkoxy group of, and a halogen atom
  • R 3 is one or more selected from an alkyl group of, an alkoxy group of, and a halogen atom
  • a compound which is an imidazolyl group which may have a substituent or a 1-imidazolyl group a compound wherein R 3 is bonded to the carbonyl group in a para-position to the carbonyl group
  • R 4 is a hydrogen atom
  • the medicament of the present invention relaxes both the imported and exported arterioles before and after the glomeruli of the kidney. This has the effect of rapidly increasing the blood flow of the kidney without increasing the glomerular filtration rate. Therefore, the medicament of the present invention has a protective effect on the kidney, and is useful for the prevention and treatment of renal diseases such as glomerulonephritis, diabetic nephropathy, renal sclerosis, and nephrotic syndrome.
  • the medicament of the present invention is not limited to these diseases, and can be used for the prevention and / or treatment of any disease that requires kidney protection.
  • the medicament of the present invention is useful for various diseases caused by proliferation of smooth muscle cells, for example, arteriosclerosis such as coronary arteriosclerosis, cerebral arteriosclerosis, arteriosclerosis, arteriosclerosis obliterans, aortic aneurysm, and more. It is useful as a prophylactic and / or therapeutic agent for the prevention and disease of vascular hypertrophy or stenosis which occurs after percutaneous angioplasty, vascular transplantation, internal arterial incision, organ transplantation and the like.
  • arteriosclerosis such as coronary arteriosclerosis, cerebral arteriosclerosis, arteriosclerosis, arteriosclerosis obliterans, aortic aneurysm, and more. It is useful as a prophylactic and / or therapeutic agent for the prevention and disease of vascular hypertrophy or stenosis which occurs after percutaneous angioplasty, vascular transplantation, internal arterial incision, organ transplantation and the like.
  • the medicament of the present invention has a protective effect on blood vessels, and prevents or develops arteriosclerosis, aortic aneurysm, or arterial stenosis after angioplasty. It also has the effect of reducing or completely relieving these diseases.
  • the medicament of the present invention requires prevention and treatment of arteriosclerosis as one disease, and protection of blood vessels such as hypertension, diabetes, and hyperlipidemia, which may be accompanied by arteriosclerosis. It may be used to prevent or treat any kind of disease.
  • the above-mentioned oxo- ⁇ -benzenepropane amide derivative has an effect of increasing coronary blood flow and relieving coronary spasm, and thus is useful for the prevention and treatment of angina pectoris, and has a protective effect on ischemic myocardium. It is useful in the prevention and treatment of myocardial infarction such as acute myocardial infarction and chronic myocardial infarction. It is also useful for prevention and treatment.
  • the medicament of the present invention has the above-mentioned pharmacological action on the heart, and is characterized by being applicable to the prevention and treatment of a wide range of heart diseases such as angina pectoris, myocardial infarction, and heart failure.
  • the medicament of the present invention does not decrease cardiac contractility, and has a feature of high selectivity to coronary vessels. Therefore, the medicament of the present invention is not limited to the above-mentioned heart diseases such as angina pectoris, myocardial infarction, and heart failure, and prevents heart diseases requiring protection of cardiac tissues, coronary vessels, and cardiac functions. And can be used for treatment.
  • heart diseases such as angina pectoris, myocardial infarction, and heart failure
  • Japanese Patent Application Laid-Open No. 5-246980 discloses that the compound, which is an active ingredient of the present invention, has a potassium channel opening action and has a vasodilatory action, a bronchodilatory action, a gastrointestinal tract smooth muscle relaxation action, and the like. It has been shown that pharmacological effects can be expected.However, it has been specifically described that it has a protective effect on the kidney, has a vascular smooth muscle cell proliferation inhibitory effect, and has an effect on coronary blood vessels and cardiac function. Not. Also, as shown in the following examples, the action of the medicament of the present invention on the heart is not based solely on the force channel opening action.
  • the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, which is an active ingredient of the medicament of the present invention may be administered to a patient as a medicament itself. It is preferable that a pharmaceutical composition containing one or more of these active ingredients is produced and administered to a patient.
  • a pharmaceutical composition include tablets, capsules, pongee granules, powders, pills, troches, sublinguals, and liquid preparations for oral administration, or injections, suppositories, ointments, and patches. Preparations for parenteral administration such as Can be exemplified.
  • Tablets or capsules for oral administration are usually presented as unit dosages, such as binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding a usual pharmaceutical carrier. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrroli. A disintegrating agent such as don, starch derivative, or sodium starch glycolate; a lubricant such as magnesium stearate; a wetting agent such as sodium lauryl sulfate may be used.
  • enteric coating for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrroli.
  • a disintegrating agent such as don, starch derivative, or sodium starch glycolate; a lubricant such as magnesium stea
  • Liquid preparations for oral administration include, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs, as well as dry preparations which can be re-dissolved in water or a suitable vehicle before use.
  • Such solutions may contain conventional additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyxethyl cellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat.
  • emulsifiers such as lecithin, sorbitan monoolate, gum arabic, armando oil, rectified coconut oil, oily esters (eg glycerin esters), propylene glycol, ethyl alcohol (including edible oils
  • Non-aqueous media, preservatives such as methyl, ethyl or propyl esters of P-hydroxybenzoic acid, or sorbic acid, and, if necessary, conventional flavoring or coloring agents. it can.
  • Preparations for oral administration can be manufactured by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation.
  • Formulations for parenteral administration are generally provided as liquid unit dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solutions for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtrating and filling suitable vials or ampoules and sealing. To enhance stability, the composition may be filled into vials after freezing and the water removed under vacuum.
  • Parenteral suspensions are manufactured in substantially the same manner as parenteral solutions, but the active ingredient must be suspended in a vehicle and sterilized with etylene oxide. Can be more suitably produced. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.
  • the dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the patient's symptoms, weight, age, sex, etc. In this case, about 0.01 mg to l, 000 mg can be administered orally per day per adult. It is advisable to administer such a dosage in one or several divided doses per day.
  • the renal artery was exposed by laparotomy and denervation was performed.
  • the renal blood flow was measured using an electromagnetic blood flow meter, and the glomerular filtration rate was measured by the creatinine clearance method.
  • Systemic blood pressure was measured from the femoral artery via a catheter inserted into the aorta.
  • Urine was collected from a catheter inserted into the ureter.
  • the active ingredient of the medicament of the present invention the compounds of No.
  • Rat aortic smooth muscle cells prepared by the enzyme dispersion method (Berk, BC, et al., Hypertension, 13, 305-314, 1989) were inoculated into a 96-well culture plate in the presence of 103 ⁇ 4 FCS / DMEM ( 2.5 xlO 3 100 ⁇ l 'ell).
  • the medium was replaced with 2% FCS DMEM containing various portability drugs, and the cells were further cultured for 3 days.
  • the drug of the present invention (0.64-400 mg) inhibited the proliferation of cultured smooth muscle cells by serum in a dose-dependent manner.
  • Table 4 shows the effect of each drug on vascular smooth muscle proliferation.
  • Table 4 Reagent concentration ( ⁇ M) Number of cells (3 ⁇ 4) Drug of the present invention 0.64 103
  • Lemakalim (-) _ 6-Cyano-3,4-dihydro-2,2 1: 3- -dimethyl-trans-4- (2-oxo-l-pyrrolidyl) -2H-benzo [b] pyran-3-ol
  • a potent drug antagonist clinically used in the treatment of hypertension and angina pectoris
  • the used two Fujipin was used.
  • the male and female mongrel dogs were thoracotomized under pentobarbital anesthesia, the left circumflex branch of the left coronary artery was removed, and the coronary blood flow was measured using an electromagnetic flowmeter.
  • the test drug was administered intravenously.
  • the medicament of the present invention (0.01 to 1 mg kg) increased coronary blood flow in a concentration-dependent manner by intravenous administration.
  • the medicament of the present invention (ED C () : 210 g / kg) is different from nicorandil (ED 5Q : 420 kg) used as a control. It was twice as powerful.
  • glibenclamide N- [4-( ⁇ -(2-raethoxy-5-chlorobenzamide) ethyl) benzosulfonyl] -N'-cyclohexylurea
  • the heart of a male rat (Sprague-Dawley strain) was excised and a force aura was introduced into the aorta.
  • the blood was perfused with Crepes-Henseleit solution in a Langendorff manner at a constant pressure of 60 bandg Hg, and the coronary blood flow was measured using an electromagnetic blood flow meter.
  • Coronary spasm was induced by administering 30 pmole of Endothelin-1 from the aortic power neura. Five minutes after the administration of Endothelin-1, when the decrease in coronary perfusion was stabilized, the test drug was administered from the aortic force neuron. The degree of recovery of coronary perfusion was calculated and defined as the effect of relieving spasm.
  • the drug of the present invention restored the coronary blood flow decreased by endothelin-1 in a concentration-dependent manner by intracoronary injection. Perfusion rate was restored to the level prior to endothelin-1 administration (relieving coronary spasm) by the concentration of the drug (ED 1 Q () ).
  • the drug of the present invention ED1 () () : 180 nmole
  • ED1QQ ED1QQ : 480 nmole
  • the heart of a male rat (Sprague-Dawley strain) was excised and a force aura was inserted into the aorta.
  • Perfusion was performed at constant pressure of 60 mmHg in the Langensdorf method using Cleps-Henseleit solution, and the double product (LVDP x HR) was calculated from the left ventricular pressure (LVDP) and heart rate (HR).
  • LVDP x HR the double product
  • HR heart rate
  • the aortic force neura was blocked 5 minutes later and a 20-minute ischemia was induced. Thereafter, reperfusion was performed for 30 minutes using a perfusion solution containing no test drug. The degree of recovery of the double product after reperfusion was calculated assuming that the double product before the test drug treatment was 100%.
  • the male and female hybrid dogs were opened under pentobarbital anesthesia and the left anterior descending coronary artery (LAD) was removed.
  • a pair of ultrasonic crystal probes were inserted into the endocardial layer in the LAD region to measure segment shortening and used as an index of local contraction function.
  • the LAD was occluded for minutes and then reperfused for 120 minutes.
  • Test drug is 15 minutes before ischemia It was continuously infused intravenously until the end of the experiment or administered 30 minutes after reperfusion.
  • the medicament of the present invention (1 to 10 g kg min) recovered the segment 'shorting after reperfusion in a dose-dependent manner with little effect on blood pressure.
  • the dose (ED 5Q ) to restore 50% of local wall motion «SS) was 0.9 kg min.
  • Remacarim (0.1, 0.3 / ig kg min), which was used as a positive control, also restored the segmentation's shot after reperfusion in a dose-dependent manner, but at the same time significantly reduced blood pressure.
  • Nifedipine (l / g kg min) reduced blood pressure, but had a weaker effect on segment 'shots (ineffective at l / g kg min).
  • Table 6 shows the results. Table 6 Reagents and concentrations Segments Mean blood pressure change
  • the medicament of the present invention (1 to 10 g / kg min) dose-dependently restored the reduced segment shortening even when administered 30 minutes after reperfusion.
  • Table 7 shows the results. From these results, it is clear that the medicament of the present invention has an action of improving myocardial stunning (local contraction failure).
  • Table 7 Pharmaceutical segmentation and seating of the present invention (3 ⁇ 4)
  • Papillary muscles isolated from the right ventricle of the male guinea pig were suspended on a Magnus device, and the tension was measured using an FD big-box.
  • the specimen was driven by 1 Hz electrical stimulation, and after the tension was stabilized, the test drug was cumulatively added to the nutrient solution.
  • the medicament (0.01 to 100 M) of the present invention showed a positive inotropic effect in a concentration-dependent manner, and enhanced the myocardial contractile force.
  • remacalime did not show a positive inotropic effect, and showed a negative inotropic effect at high concentrations. Table 8 shows the results.
  • the medicament of the present invention reduces glomerular pressure without increasing glomerular filtration rate while increasing renal blood flow, and thus is useful for prevention and / or treatment of various renal diseases.
  • it since it suppresses excessive proliferation of vascular smooth muscle cells, it is also useful for preventing and / or treating arteriosclerosis, cerebral aneurysm, and arterial stenosis after angioplasty.
  • the medicament of the present invention has an effect of increasing coronary blood flow, an effect of relieving coronary spasm, an effect of protecting ischemic myocardium, an effect of improving myocardial stunning (local systolic insufficiency), and an effect of cardiotonia, and suppresses cardiac function It has high selectivity for coronary blood vessels, and is useful for the prevention and treatment of heart diseases such as angina pectoris, myocardial infarction and heart failure.

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Abstract

Cette invention concerne un médicament contenant un dérivé de β-oxo-β-benzènepropane-thioamide en tant qu'ingrédient actif, utilisé dans le traitement et la prévention des maladies des reins, des maladies dues à la prolifération de fibres musculaires lisses et des maladies cardiaques, lequel dérivé peut être représenté par la formule suivante (I), où: soit R1 et R2 représentent chacun indépendamment un alkyle C¿1-6?, soit R?1 et R2¿ se lient l'un à l'autre pour former un alkylène C¿2-5?; R?3 et R4¿ représentent chacun indépendamment les éléments suivants: hydrogène, halogéno, alkyle C¿1-6?, alkoxy C1-6, trifluorométhyle, cyano, nitro, dialkylamino C2-6, ou un imidazolyle ayant éventuellement un ou plusieurs substituants choisis parmi: alkyle C1-6, alkoxy C1-6 ou halogéno.
PCT/JP1996/000046 1995-01-17 1996-01-16 MEDICAMENT CONTENANT UN DERIVE DE β-OXO-β-BENZENEPROPANE-THIOAMIDE WO1996022086A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP7/4949 1995-01-17
JP494995A JPH07244393A (ja) 1994-01-17 1995-01-17 負帯電型印刷用感光性樹脂組成物
JP474795 1995-01-17
JP474895 1995-01-17
JP7/4747 1995-01-17
JP7/4748 1995-01-17

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* Cited by examiner, † Cited by third party
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WO2023099406A1 (fr) 2021-11-30 2023-06-08 Farmerscent GmbH Granulés en croûte à base de fibres brutes, aliments pour animaux contenant lesdits granulés, et procédés et utilisations correspondants

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246980A (ja) * 1991-12-26 1993-09-24 Mitsubishi Kasei Corp β−オキソ−β−ベンゼンプロパンチオアミド誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246980A (ja) * 1991-12-26 1993-09-24 Mitsubishi Kasei Corp β−オキソ−β−ベンゼンプロパンチオアミド誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FARMACO, Vol. 48, No. 7, (1993), BRUNO ORGA et al., "N-Substituted 4, 5(3)-Diphenyl-3(5)-Pyrazoleamines with Antipyretic, Antiarrhythmic, Hypotensive and Other Activities", p. 967-77. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023099406A1 (fr) 2021-11-30 2023-06-08 Farmerscent GmbH Granulés en croûte à base de fibres brutes, aliments pour animaux contenant lesdits granulés, et procédés et utilisations correspondants

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