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WO2003033471A1 - Nouveau derive de pyridone et agent therapeutique pour les maladies du systeme circulatoire les contenant - Google Patents

Nouveau derive de pyridone et agent therapeutique pour les maladies du systeme circulatoire les contenant Download PDF

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Publication number
WO2003033471A1
WO2003033471A1 PCT/JP2001/009121 JP0109121W WO03033471A1 WO 2003033471 A1 WO2003033471 A1 WO 2003033471A1 JP 0109121 W JP0109121 W JP 0109121W WO 03033471 A1 WO03033471 A1 WO 03033471A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyridone
nitro
ethylcarbamoyl
pharmaceutical composition
nitrooxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2001/009121
Other languages
English (en)
Japanese (ja)
Inventor
Yasumi Uchida
Masashi Ogawa
Norihiro Iibuchi
Tadashi Morita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CARDIOVASCULAR INSTITUTE LTD
Tobishi Pharmaceutical Co Ltd
CARDIOVASCULAR Inst Ltd
Original Assignee
CARDIOVASCULAR INSTITUTE LTD
Tobishi Pharmaceutical Co Ltd
CARDIOVASCULAR Inst 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 CARDIOVASCULAR INSTITUTE LTD, Tobishi Pharmaceutical Co Ltd, CARDIOVASCULAR Inst Ltd filed Critical CARDIOVASCULAR INSTITUTE LTD
Priority to PCT/JP2001/009121 priority Critical patent/WO2003033471A1/fr
Publication of WO2003033471A1 publication Critical patent/WO2003033471A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P9/08—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
    • 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

Definitions

  • the present invention relates to a novel pyridone derivative having a selective calcium-sensitizing lithium channel opening action.
  • Vasodilators are mainly used as drug treatments for ischemic heart disease such as hypertension, angina pectoris, myocardial infarction, cerebrovascular disease, and obstructive peripheral arteriosclerosis. Many of them exert their effects by acting on receptors and channels in the cell membrane of vascular smooth muscle to relax vascular smooth muscle.
  • Typical clinically used ones are those that block calcium channel nernole, those that block the nervous system, those that block the sympathetic alpha receptor, those that block the sympathetic beta receptor, and those that block the angiotensin receptor.
  • the present invention relaxes the blood vessels by selectively opening the calcium-sensitive realm channel, and prevents vasospasm associated with a part of angina pectoris and cerebral ischemia.
  • New pyridone derivative It is intended to provide.
  • the present inventors have made various studies to solve the above-mentioned problems, and as a result, the novel pyridone derivative having a nitrate group selectively opens the calcium-sensitive rheumatic channel, thereby improving the blood vessel.
  • the present inventors have found that they exhibit a diastolic effect, a hypotensive effect, an effect of increasing coronary blood flow, and an effect of preventing vasospasm arrest, and thus completed the present invention.
  • (1 ⁇ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group substituted by one or two lower alkyl groups, or a benzyl group, and the benzyl group is unsubstituted or optionally substituted. Substituted by one to three selected lower alkoxy, halogen, cyano, trifluoromethyl, methylenedioxy or cyclopropylmethyloxy;
  • R 2 is a hydrogen atom or a diethoxy lower alkyl group
  • R 3 is a hydrogen atom or a ditoxoxy lower alkyl group) or a salt thereof.
  • the present invention also provides a pharmaceutical composition comprising a compound as described above.
  • This pharmaceutical composition is useful as a therapeutic agent for cardiovascular disease, and examples of the cardiovascular disease include ischemic heart disease, hypertension, peripheral circulatory insufficiency, vasospasm, and ischemic brain disease.
  • the pharmaceutical composition is also useful as a potassium-sensitive potassium channel opener.
  • FIG. 1 shows the effect of Compound 1 on blood pressure and coronary blood flow in anesthetized beagle dogs.
  • ECG indicates electrocardiogram
  • HR indicates heart rate
  • SBP indicates body pressure
  • CBF indicates coronary artery blood flow.
  • FIG. 2 shows the effect of Compound 1 (1) on the model of coronary spasm.
  • the upper part indicates the periodicity spasm suppression in the case of 10- 5 M administering the compound 1, and the lower, pro spasm suppression when Compound 1 was administered 10- 5 M is at I Berio toxin (IBTX) Indicates that it is locked.
  • IBTX I Berio toxin
  • FIG. 3 shows the effect (2) of compound 1 on the model of coronary spasm.
  • the upper row shows that Compound 1's anti-convulsant activity is not affected by dalipene clamide (GC), and the lower row shows that Compound 1's anti-convulsive action is not blocked by methylene blue (MB) .
  • GC dalipene clamide
  • MB methylene blue
  • the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as a methyl group, an ethyl group, and a -Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, linear or branched heptyl group, linear or branched hexyl group, and the like.
  • the halogen is fluorine, chlorine, bromine, or the like, and is preferably chlorine.
  • R 2 and R 3 least for the even is a representative compound that is preferred.
  • the present invention is a two-preparative Rookishi lower alkyl group, for example, the following Compounds. 1- (3,4-Dimethoxybenzyl) -3- ⁇ 2- (nitroxoxy) ethylcarpamoinole] -5-nitro-2-pyridone;
  • the compounds of the present invention further include salts of the above compounds, especially pharmaceutically acceptable salts.
  • the salt include acid addition salts, for example, acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as acetic acid.
  • the compound represented by the general formula (I) of the present invention can be produced by utilizing any known reaction.
  • the compound represented by the general formula (II) as a starting material may be used. It is manufactured from the roucotic acid derivative through the following three steps.
  • a nicotinic acid derivative (II), an alcohol represented by the general formula RiOH, and triphenylphosphine (Ph 3 P) are dissolved in a solvent such as dimethylformamide, tetrahydrofuran, and dioxane.
  • a solvent such as dimethylformamide, tetrahydrofuran, and dioxane.
  • a solution of diisopropylpropylazocarboxylate (DIAD) is added dropwise to this solution over about 5 minutes to 1 hour under ice-cooling stirring, and the mixture is further stirred at about 5 to 50 ° C for about 0.5 to 36 hours.
  • the reaction product is extracted and purified by silica gel chromatography or the like to obtain an N-substituted pyridone derivative (III).
  • a solvent such as Ami de, mono- or di-substitution Arukanoruami down nitrate ester
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • the compounds of the present invention are shown in the experimental examples described below.
  • it selectively opens the calcium-sensitive potassium channel, so that it can be generally used as a calcium-sensitive potassium channel opener, specifically, vasodilatory, hypotensive, coronary blood flow It exerts an increasing action, a vasospasm stopping action, etc., and is therefore an active ingredient of a preventive or therapeutic agent for cardiovascular diseases, for example, ischemic heart disease, hypertension, peripheral circulatory failure, vasospasm, ischemic brain disease It can be used as
  • the pharmaceutical composition of the present invention is administered orally or parenterally.
  • parenteral administration include intravenous administration, intramuscular administration, subcutaneous administration, and intraperitoneal administration.
  • the dosage varies depending on the condition of the patient, the type of disease to be treated or prevented, the mode of administration, and the like, but it should be 0.01 mg to 100 mg / kg.
  • carriers used together with the active ingredient include generally known extenders, excipients, stabilizers, and the like, and extenders.
  • extenders for example, sodium bisulfite, para-hydroxybenzoic acid ethyl ester / tocopherol, etc. Is mentioned.
  • the extract was then washed with a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride.
  • the organic layer was washed sequentially with an aqueous solution of lime, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography to obtain the desired product as pale yellow amorphous. Hexane was added to this to form a powder, and 201 mg (80% yield) was obtained as a pale yellow powder.
  • Example 2 l- (3,4-Dimethoxybenzyl) -3- [bis (2- (2-hydroxyl) ethyl) carpamoyl] -5-nitro-2-pyridone (Compound 2) 150 mg of 1- (3,4-dimethoxybenzyl) -3-carboxy-5-nitro-2-pyridone obtained in Example 1 (2), 103 mg of 1-hydroxybenzotriazole-hydrate, and 113 mg of triethylamine are dissolved in 3 mL of dichloromethane, and 174 mg of N, N-bisethanolamine nitrate nitrate and 129 m of 3- (3-dimethylaminopropyl)-1-ethylcarposimid hydrochloride are added.
  • 3-hydroxy-2-hydroxy-2-pentapyridine 200 mg, 1-hydroxy 200 mg of xybenzotriazole monohydrate, 220 mg of monoethanolamine nitrate nitrate, and 250 mg of 3- (3-dimethylaminopropyl) -11-ethylcarposimid hydrochloride were suspended in 2 mL of dichloromethane.
  • a solution obtained by adding 2 mL of dichloromethane to 220 mg of lyethylamine was added, and the mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to this mixture, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography.
  • the product was obtained as pale yellow powder (72 mg, yield 24%).
  • the coronary artery blood flow was measured at the 4th intercostal space, the left circumflex coronary artery was detached from the surrounding tissue, a non-invasive electromagnetic blood flow meter probe was attached to the origin, and measured with an electromagnetic blood flow meter.
  • the aortic blood flow meter was fitted with a non-invasive electromagnetic blood flow meter probe at the start of the aortic arch, and measured with an electromagnetic blood flow meter, which was defined as the cardiac output.
  • the left ventricular pressure was measured by a retrograde catheter inserted from the left carotid artery and a pressure-inhibited amplifier. Furthermore, the left ventricular pressure was differentiated, and the rise rate (max dP / dt) of the left ventricular systolic pressure was obtained.
  • the electrocardiogram recorded the standard limb lead III. Each parameter was recorded simultaneously on a recorder.
  • the test drug was rapidly intravenously administered from a polyethylene tube inserted into the left femoral vein. The dose of the drug was 100 ii g / kg.
  • the solvent used was 100% dimethyl sulfoxide (DMS0) as a rule, and the water-soluble compounds were dissolved in physiological saline by reducing the amount of DMS0 appropriately if it was soluble in water.
  • the maximum dose volume was 0.1 ml / kg . % Was calculated by subtracting the effect of DMS0. The results were as shown in Table 4 below. Table 4
  • the compounds of the present invention can selectively open calcium-sensitive potassium channels to provide therapeutic agents for cardiovascular diseases, especially ischemic heart disease such as angina, ischemic brain disease, hypertension, peripheral circulatory insufficiency, and vascular disease. It is useful for treatment of spasm and the like.
  • cardiovascular diseases especially ischemic heart disease such as angina, ischemic brain disease, hypertension, peripheral circulatory insufficiency, and vascular disease. It is useful for treatment of spasm and the like.

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

Abstract

L'invention se rapporte à un composé représenté par le formule (I) ou à un sel de ce dernier. Ce composé permet d'ouvrir les canaux potassium sensibles au calcium et est utile dans le traitement des maladies cardiaques ischémiques, de l'hypertension, etc. (Dans la formule (I), R1 est hydrogène, alkyle inférieur, aminoalkyle inférieur substitué par un ou deux alkyles inférieurs, ou benzyle qui n'a pas été substitué ou a été substitué indifféremment par un à trois substituants choisis parmi alkoxys inférieurs, halogènes, cyano, trifluorométhyle, méthylènedioxy, et cyclopropylméthyloxy ; R2 est hydrogène ou un groupe nitrooxyalkyle inférieur ; et R3 est hydrogène ou un groupe nitrooxyalkyle inférieur. )
PCT/JP2001/009121 2001-10-17 2001-10-17 Nouveau derive de pyridone et agent therapeutique pour les maladies du systeme circulatoire les contenant Ceased WO2003033471A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2001/009121 WO2003033471A1 (fr) 2001-10-17 2001-10-17 Nouveau derive de pyridone et agent therapeutique pour les maladies du systeme circulatoire les contenant

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2001/009121 WO2003033471A1 (fr) 2001-10-17 2001-10-17 Nouveau derive de pyridone et agent therapeutique pour les maladies du systeme circulatoire les contenant

Publications (1)

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WO2003033471A1 true WO2003033471A1 (fr) 2003-04-24

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015608A1 (fr) * 1991-02-27 1992-09-17 Lacer S.A. AGENTS ANTI-HYPERTENSIFS A BASE DE DIPEPTIDES N-($G(a)-SUBSTITUE-PYRIDINYLE)CARBONYLE
US5716971A (en) * 1993-04-28 1998-02-10 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
EP0882716A1 (fr) * 1996-11-19 1998-12-09 Nisshin Flour Milling Co., Ltd. Derives de pyridinecarboxamide
JP2000256358A (ja) * 1999-03-10 2000-09-19 Yamanouchi Pharmaceut Co Ltd ピラゾール誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015608A1 (fr) * 1991-02-27 1992-09-17 Lacer S.A. AGENTS ANTI-HYPERTENSIFS A BASE DE DIPEPTIDES N-($G(a)-SUBSTITUE-PYRIDINYLE)CARBONYLE
US5716971A (en) * 1993-04-28 1998-02-10 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
EP0882716A1 (fr) * 1996-11-19 1998-12-09 Nisshin Flour Milling Co., Ltd. Derives de pyridinecarboxamide
JP2000256358A (ja) * 1999-03-10 2000-09-19 Yamanouchi Pharmaceut Co Ltd ピラゾール誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BANTICK J.R. ET AL.: "New non-peptide angiotensin II receptor antagonists. 1: Structure-activity relationships of a series of 2(1H)-pyridinones", BIOORG. MED. CHEM. LETT., vol. 4, no. 1, 1994, pages 121 - 126, XP002907771 *

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