Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/14—Oxygen atoms

Definitions

• the present invention is useful as a cardiotonic agent]), a novel pyridazinone derivative or a salt thereof having a vasodilatory effect and an antihypertensive effect.
• Cardiotonic drugs have the effect of directly acting on the heart to increase its contractile force, and various drugs have conventionally been used to treat heart failure.
• cardiotonic drugs have the disadvantage that the safety margin is extremely narrow and arrhythmia is caused by i9 or its cardiotonic effect is transient and unsuitable for oral administration There are many things.
• the present inventors have conducted a search for a compound having high activity as a cardiotonic agent and capable of sufficiently exhibiting the sustainability of the effect, and have reached the present invention. Disclosure of the invention
• the gist of the present invention is the following general formula (I):
• R 2 and R 3 represent a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of less than or equal to (methoxy, ethoxy, propoxy, butyl) ⁇ , ⁇ , and ⁇ and ⁇ ⁇ together represent 1 0— GH 2 — 0— or 1 0—CE.
• R 4 represents an alkyl group (preferably an alkyl group having not more than carbon atoms), and n represents 0 to 2 -CH 2 -0-. Represents an integer, and the dotted line represents a single bond or a double bond.)
• pyridazinone derivative or a salt thereof In the pyridazinone derivative or a salt thereof.
• the pyridazinone derivative in the method of the present invention can be synthesized, for example, by the following route.
• the compound of the above general formula (I) can be produced by the usual amide bond formation reaction between carboxylic acid (E) or a derivative thereof and amide ( ⁇ 1). .
• the mixed acid-hydrate method that is, the reaction of carboxylic acid ( ⁇ ) with alkyl carboxylic acid to give a mixed acid anhydride, m)
• the (carbo) carbodimid method that is, carboxylic acid ( ⁇ ) and amide (m) are introduced into the mouth
• a method of condensation in the presence of a imide such as a 7k complex ij, a carboxylic acid halide method, an active ester method, etc. may be mentioned, but the mixed anhydride method is preferred.
• Mixed acid anhydrides include basic compounds (triethylamine. Pyridin, diazabicyclo decene (DB-II)), organic bases, and potassium carbonate. In the presence of sodium carbonate or any inorganic base), carboxylic acid ( ⁇ ) and alkylhalocarboxylic acid can be treated with tetrahydrofuran and dioxan. , Toluene, chlorophosolem, gfe acidhole, dimethylene noiromit,,,
• the reaction temperature ranges from about 1 to about 2 ° C, and the reaction time ranges from about 1 minute to about 1 minute.
• the resulting mixed acid anhydride can be reacted with the amide ( ⁇ 1) without isolation.
• the reaction with amimin is one. 2 ⁇ ⁇ . At C, it is performed for about i minutes to hours.
• Carbonic acid (E) can be obtained from the Journal of Medicinal Chemistry (J. Med. Chem.) / Volume 7, 2 ⁇ / — 2 ⁇ page (/? 7). Year).
• Amin (1) is a well-known piperazine derivative.
• Examples of the pyridazinone derivative of the present invention obtained by the above-mentioned method include the following compounds.
• the compounds of the present invention include those in which the substituent R 4 is a methyl group.
• Compounds such as R 4 ethyl, propinole-butynole, and pentinole groups are also included in the compounds of the present invention. Be done
• salts of the above compounds are included in the scope of the present invention.
• the salts include salts of mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, and nitric acid, and salts of organic acids such as lactic acid, acetic acid, and oxalic acid. All of these compounds are useful as cardiotonic agents, and also have vasodilatory and barolytic effects.
• the compound according to the present invention when used as a cardiotonic agent, the compound can be administered orally or parenterally. ⁇
• the form provided may be for oral administration, such as powders, granules, tablets, dragees, pills, capsules, solutions, etc., for non-oral administration.
• oral administration such as powders, granules, tablets, dragees, pills, capsules, solutions, etc.
• the amount of the compound of the present invention to be administered as a cardiotonic drug depends on age, gender, body weight, sensitivity difference, administration method, time of administration, interval, degree of medical condition, physical condition, properties of pharmaceutical preparation, preparation, kind, kind of active ingredient: ⁇ Consider a doctor and ask your doctor! ) It is determined.
• a dose of about 0.1 to about 10% of body weight / day / day is selected, but it is needless to say that the dose is limited to this.
• New paper Hereafter, according to the examples! ) The present invention will be described in more detail, but the present invention is not limited to the following examples as long as the gist is not exceeded.
• the silica gel to which the obtained target substance was adsorbed was placed on a column filled with a 30 f silica gel, and a chloroform / methanol solvent was used. (Up to 1/0 //).
• the fraction containing the target substance is evaporated, and the obtained target substance is N, N-dimethylformamide? ⁇ ⁇ ⁇ ⁇ I 0 0 0 N N N N N N N N N N N N / N
• add 50 mi of xanthine ether and w-n-hexane add 50 mi of xane, precipitate the precipitate B, filter it, dry it, and dry it to obtain the desired product.
• 1/1 / Pilazinolone force / Nil] Feninole] 1 ⁇ , J "-Ji-Hydr-J-Metinor-J ( 2H) 1 pyridazinone hydrochloride
• the obtained gel with the target substance adsorbed thereon is placed on a column filled with 40 ⁇ of the gel with a gel, and a black hole solvent / metano mono-solvent is used. (Cross mouth home alone / up to 0 //:
• New paper was used for column chromatography purification.
• the fraction containing the target substance is evaporated, and the obtained target substance is N, LT-dimethylmethylformamide? ⁇ And ethanol
• the pharmacology test method is described below.
• CO cardiac output
• the catheter destination Ma Roh menu COMPUTER to the left ventricle, to measure the left ventricular pressure, it'll change rate of the electrically left ventricular pressure the (d P Z) required
• New paper I did. A strain gauge on the right ventricle wall! ) The right ventricular muscle contraction force (Cont) was measured. Systemic blood pressure was measured from the left femoral artery. Heart rate is ECG (Lead I)]? The compound dissolved in the solvent was intravenously administered to the left femoral vein.
• the pyridazinone derivative or a salt thereof of the present invention is useful as a cardiotonic agent, and has a vasodilatory effect and a hypotensive effect.

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

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• 1984
  • 1984-08-10 JP JP59167336A patent/JPS6144873A/ja active Granted
• 1986
  • 1986-02-21 HU HU861996A patent/HU197897B/hu not_active IP Right Cessation
  • 1986-02-21 EP EP86901500A patent/EP0258435B1/en not_active Expired - Lifetime
  • 1986-02-21 AT AT86901500T patent/ATE71089T1/de not_active IP Right Cessation
  • 1986-02-21 DE DE8686901500Q patent/DE3683295D1/de not_active Expired - Lifetime
  • 1986-02-21 WO PCT/JP1986/000083 patent/WO1987005016A1/ja not_active Ceased
  • 1986-02-21 US US07/026,758 patent/US4822797A/en not_active Expired - Fee Related

Patent Citations (1)

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