Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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 1,4-dihydroxypyridine-1,3,5-dicarboxylic ester derivative, and more particularly, to a compound represented by the general formula:
• R represents an imidazolyl group or a pyridyl group
• R represents a hydrogen atom, a halogen atom, a nitro group or a trimethyl group
• R represents a lower methyl group.
• An alkyl group, X is CH or N
• A is a lower alkylene group, ⁇ > ⁇ ⁇ — ⁇ is a lower alkylene group or ⁇ — a lower alkylene group),
• n 1 or 2
• 1,4-dihydroxypyridine-1,3-dicarboxylic derivative has a pharmacological action such as vasodilatory action.
• Various compounds have been synthesized and their pharmacological effects are being studied. O For example, diphenyldipine [pattern, double.
• the compound I) of the present invention has a vasodilatory effect, a blood flow increasing effect, a platelet aggregation inhibitory effect, and a tromboxan.
• the compounds of the present invention have both an effect of increasing coronary blood flow and an effect of inhibiting the production of tromboxan A 2, and thus have an effect on arterial It is particularly advantageous as a therapeutic agent for sclerosis.
• the compound U) of the present invention has an increased Features such as long duration of action and weak heart rate increase o
• the compound (J) of the present invention can be produced, for example, by any of the following methods A to D. o Method A:
• A-1 is a hansipyridine synthesis method
• A-2 to A-7 is a modified method thereof.
• the reaction of A-1 to A-7 can be performed by heating at 30 to 180 C, preferably 50 to 130 C, in a solvent or without solvent for 2 to 24 hours.
• Solvents to be used include lower alcohols such as ethanol, butanol, isobutanol and n-butanol, and chlorinated alcohols.
• Halogenated carbohydrates such as mouth chlorochlorethane and trichlorethane, benzene, pyridine, etc. can be used o
• DBU sodium alcoholate
• Imidazole * Alkali metal clay can also be used.
• the inert solvent tetrahydrofuran, dilute xan, black Mouth film, methylene chloride-chloride, ⁇ , ⁇ -dimethyl methyl chloride, dimethyl sulfoxide, etc.
• the mixture proceeds by stirring for 1 to 24 hours under heating to give compound U.
• compound (DO is introduced into a halide according to a conventional method, and compound QO is added thereto.
• U Compound Uj can be obtained by reacting o
• the compound UX which is a starting material, is a known compound (Chemical and Pharmaceutical Blechin). 2 7, 1 4 2 6 tl 9 7 9))), which can be manufactured by various methods o
• the compound u of the present invention is produced.
• This reaction can be carried out, for example, in an inert solvent using dicyclohexylcarbodiimide DCC ) O
• the reaction accelerator use may be made of 4-dimethylamino pyridine, 4-bi-amino pyridine, or the like. ⁇ or the compound
• the starting compound [XIJ is produced according to the above-mentioned A-1 to A-17: 5 method or compound UX] and the compound of the formula HO—cCH 2 ) m OH Produced by reacting in the same manner as in Method C above.
• the compound U) of the present invention is produced.
• imidazole is used as an alkali metal salt
• the pyridine is, for example, n-butyllithium in bromidine.
• pyridyl lithium obtained by reacting It is preferable to use it as a rigid alkyl lithium.
• the reaction is favored by performing the reaction in an inert solvent such as ether or tetrahydrofuran at a temperature of 180-130 ° C for a few minutes or 1 hour. Proceed to o
• the starting compound XI) of this method D can be obtained by (1) complying with the method of A-1 to A-7 described above, or (2) compound UX by the formula
• a compound, a compound, or an N-protected compound of the compound OS is used, and after performing these reactions, the protecting group is released.
• the compound (U) of the present invention is also obtained.
• the N-protecting group for example, a methoxymethyl group, an ethoxymethyl group or the like can be used. These can be easily removed by hydrolysis after completion of the reaction.
• the compound of formula I thus obtained can be prepared according to a conventional method using hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid, citric acid, maleic acid and the like. And inorganic or organic acid salts such as tartaric acid, etc.o It is possible to show the pharmacological effects of the representative compounds of the present invention.o Weight 35 to 40? Using a male ddY mouse of the present invention, the compound of the present invention is orally administered, and one hour later, blood is collected from citric acid. And the aggregation by addition of collagen 12.5 ⁇ ? ⁇ was observed by an aggregometer, and after 5 minutes, the peak in the anti-IE solution was observed.
• boxane B 2 C (a stable metabolite of oxoxane A 2 ) was measured by the KIA method. The results are shown in Table 1 with the Tronhoxane B 2 TXB 2 J production suppression rate 0
• the compounds of the present invention was o or having a strong preparative port emissions Bokisa emissions A 2 generated inhibitory action extremely, the present invention compounds chromatic also blood flow increasing action of the coronary and vertebral arteries However, it has a characteristic that its holding time is long.o In addition, it has a characteristic that its heart rate increasing effect is weak despite the increase in coronary blood flow.o
• a liquid or solid carrier or diluent may be used. These carriers may be used in the production of a pharmaceutical composition.
• Examples of carriers or diluents include varnish starch, wheat starch, corn Starches such as starch and rice starch; sugars such as lactose, sucrose, glucose, manitol and sorbitol Crystal cell mouth, carboxyl mouth, scalpium, and hydroxypropyl propylcell mouth with little substitution; Inorganic substances such as lime, calcium sulfate, calcium carbonate, and talc; gelatin, gelatin, rubber Cellulose, Cellulose Methyl Cellulose Natrium, Polibuly Lip, Hydroxypropyl Cellulose Binders such as fatty acid monoglyceride, fatty acid ester of nurbitan, shell mouth and polyglycerol fatty acid ester, etc.
• compositions can be in any dosage form known in pharmaceutics such as suppositories, powders, granules, tablets, sublingual tablets, solutions, injections, suspensions and the like.
• composition of the compound of the present invention may be administered orally or parenterally such as intravenously, sublingually or rectally. However, for long-term administration, oral administration is preferred.
• the dose may be varied as necessary.
• the compound [I] of the present invention may have a dose of about 1 to 500
• the compound of the present invention has an acute toxicity value LD so of about 300 / g when administered orally. ) In the case of intravenous administration, it is extremely low toxicity in the range of 30 to 500 kf [rat].
• Example 2 3-3-2 1-Mouth Benzylidene Acetate Vinegar 3 obtained in (2) 3-[4-1 [2-(1-imidazo (Ril) ethoxy) Benzoyl (prototype) 3 8 2 Isobutanol 4 ⁇ Acetate ester in solution Te le 0.1 and ⁇ a down mode two a water 0.0 6 / ⁇ a Chi was added, 3 8 0 C. 5 h, after o cooling was ⁇ , anti ⁇ mixture in vacuo ⁇ The obtained residue was purified using silica gel chromatograph to give the compound of Example 6 with a yellow powder as a yellow powder. Got ⁇
• Example 23 The set vinegar obtained in 3 (1) 3-1 [4-C2-1-imidazolyl) ethoxy] benzoyl acetate] Isobutanol 2 of Luester 1 86 »3 12 benzenes aldehyde '76 and 3-amino crotonate in solution The mixture was stirred and returned for 4.5 hours with 0,0 7 3 ⁇ Cooled, and then the reaction mixture was decompressed and concentrated to obtain a residue. The compound was prepared using ram chromatograph to give the compound 2661 of Example 6 (yield 85%) as a yellow powder.
• Example 2 3 Acetacetovinegar obtained in (1) 3— [4-1- (2-Midazolyloxy)] Benzoyl (Kizo)] Bropir Estel 3 09 / 3 ⁇ 4? In ethanol 3 solution of 3-Nitroben's aldehyde 1 39 % acetoacetate vinegar ethyl ester 0.12 and concentrated ammonia A) Add 0.075 m of water, stir and reflux at 80 C for 5 hours. Ammonia water (0.53 ⁇ ) was added, and the mixture was further stirred and refluxed for 1 hour. After cooling, the reaction mixture was decompressed and the resulting residue was purified using silica gel chromatography to obtain Example 6 as a yellow powder. Compound 2 92 2 ⁇ (yield 57) was obtained ⁇

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

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Citations (8)

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• 1984
  • 1984-08-14 JP JP59169588A patent/JPS6147477A/ja active Granted
• 1985
  • 1985-08-12 WO PCT/JP1985/000449 patent/WO1986001206A1/ja not_active Ceased
  • 1985-08-12 KR KR860700209A patent/KR860700252A/ko not_active Withdrawn
  • 1985-08-12 AU AU47217/85A patent/AU577152B2/en not_active Ceased
  • 1985-08-12 US US06/851,134 patent/US4737506A/en not_active Expired - Fee Related
  • 1985-08-12 HU HU853611A patent/HU195500B/hu not_active IP Right Cessation
  • 1985-08-12 EP EP19850904021 patent/EP0190364A4/en not_active Withdrawn
  • 1985-08-14 ES ES546136A patent/ES8707185A1/es not_active Expired
• 1986
  • 1986-04-11 NO NO861422A patent/NO861422L/no unknown
  • 1986-04-11 DK DK165686A patent/DK165686A/da not_active IP Right Cessation
• 1987
  • 1987-02-09 ES ES557372A patent/ES8801206A1/es not_active Expired
  • 1987-02-09 ES ES557371A patent/ES8802512A1/es not_active Expired

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