WO1991018893A1 - Nouveau derive de 1,4-thiazine et cardiotonique contenant ce compose comme ingredient actif - Google Patents

Nouveau derive de 1,4-thiazine et cardiotonique contenant ce compose comme ingredient actif Download PDF

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Publication number
WO1991018893A1
WO1991018893A1 PCT/JP1991/000732 JP9100732W WO9118893A1 WO 1991018893 A1 WO1991018893 A1 WO 1991018893A1 JP 9100732 W JP9100732 W JP 9100732W WO 9118893 A1 WO9118893 A1 WO 9118893A1
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WO
WIPO (PCT)
Prior art keywords
methyl
thiazine
tetrahydropyrid
hydroxy
brs
Prior art date
Application number
PCT/JP1991/000732
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English (en)
Japanese (ja)
Inventor
Muneaki Takase
Kimitomo Yoshioka
Hiroaki Yamazaki
Original Assignee
Zenyaku Kogyo Kabushiki Kaisha
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 Zenyaku Kogyo Kabushiki Kaisha filed Critical Zenyaku Kogyo Kabushiki Kaisha
Publication of WO1991018893A1 publication Critical patent/WO1991018893A1/fr

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Classifications

    • 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
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings

Definitions

  • the present invention has the general formula I
  • the present invention relates to a novel 1,4-thiazine derivative or a pharmaceutically acceptable acid addition salt thereof represented by the formula:
  • the present inventors have succeeded in synthesizing a novel 1,4-thiazine derivative as a cardiotonic agent that has an excellent positive inotropic effect, which is superior to conventional compounds, and that suppresses an increase in heart rate
  • the present invention relates to a 1,4-thiazine derivative having a substituted tetrahydropyridyl group or a substituted piperazinylmethyl group at the 6-position represented by the general formula I, or a pharmaceutically acceptable acid addition thereof.
  • the present invention relates to salts and cardiotonic agents containing them as active ingredients.
  • lower means a group having 1 to 6 carbon atoms, if not limited.
  • the “lower alkyl group” includes straight-chain or branched alkyl such as methyl, ethyl, n-propyl, iso-vinyl, n-butynole, tert-butynole, n-pentynole, and n-hexyl. Groups.
  • the “lower alkoxy group” includes straight-chain or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy and n-pentoxy Is mentioned.
  • alkoxy groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy and n-pentoxy Is mentioned.
  • the compound of the present invention has an asymmetric carbon atom in the molecule
  • the compound includes isomers derived from the asymmetric carbon atom and mixtures thereof.
  • the compound of the present invention represented by the general formula I can be produced, for example, by the following method.
  • a 1,4-thia having a substituted tetrahydropyridyl group at the 6-position an unsubstituted or substituted phenacyl ester having a molarity equal to or greater than that of a 1,4-thiazine derivative (general formula ⁇ ⁇ ) disclosed in Japanese Patent Publication No. 1-21830 or JP-A-61-85386.
  • Reaction of the amide or alkyl ester in a lower alcohol for example, methanol, ethanol or iso-propanol, at room temperature for 1 day or under reflux with heating for 1 to 8 hours to remove the substituent of the quaternary amine salt.
  • the 1.4-thiazine derivative (hereinafter referred to as Intermediate 1) at the position is precipitated as yellow crystals.
  • This intermediate 1 is a novel compound.
  • Precipitated Intermediate 1 is of high purity that does not require further purification, but can be obtained by general purification methods, such as recrystallization with methanol, ethanol, anhydrous ethanol, etc., or column chromatography. May be purified.
  • This intermediate 1 is dissolved in a lower alcohol such as methanol, ethanol, iso-blovanol or the like, and an equimolar to 10-fold molar reducing agent, for example, sodium borohydride, is gradually added under cooling, and By stirring for 24 hours, a 1,4-thiazine derivative having a substituted tetrahydropyridyl group at the 6-position, which is a compound of the present invention, can be produced (reaction formula 1).
  • a lower alcohol such as methanol, ethanol, iso-blovanol or the like
  • an equimolar to 10-fold molar reducing agent for example, sodium borohydride
  • This intermediate 2 was reacted with a 1,4-thiazine derivative (general formula ⁇ ) in the presence of formalin in a solvent at 60 to under reflux for 3 to 5 hours, followed by post-treatment by a conventional method. Purification by column chromatography or recrystallization can produce a 1,4-thiazine derivative having a substituted biperazinylmethyl group at the 6-position, which is the compound of the present invention.
  • the solvent used in this case include lower alcohols such as methanol, ethanol, and iso-propanol; lower carboxylic acids such as formic acid, acetic acid, propionic acid, and butyric acid; and dimethyl sulfoxide. Use side or mixed solvent of them and water (Reaction formula 3)
  • the compound of general formula I can be converted into a pharmaceutically acceptable acid addition salt with a suitable acid.
  • suitable acid for inorganic acids, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.
  • organic acids for example, acetic acid, propionic acid, glycolic acid, lactic acid, birubic acid, malonic acid, succinic acid, maleic acid, fumaric acid Acids, lingic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, salicylic acid and the like are used.
  • the cervix was dissected and sacrificed by phlebotomy.
  • the heart was excised, the left atrium and the right atrium were isolated and used as left and right atrial specimens, respectively. Both samples were suspended in a 15 ml Magnus bath with a load of lg, contraction during electrical stimulation (1 Hz, 5 msec, 1.5X threshold voltage) from the left atrial sample, spontaneous contraction from the right atrial sample. Recordings were made on a polygraph system via a transducer (Orientec, T7-8-240).
  • ICR mice In acute toxicity studies, ICR mice (5 weeks old, body weight 25 ⁇ 2 g) are intraperitoneally administered with a test compound prepared in saline containing 1.0% hydroxypropyl cellulose (HPC) and observed for 14 days.
  • the LD 50 was determined by the Litchfield-Wilcoxon method.
  • the compounds of the present invention selectively increase myocardial contractile force without causing an increase in heart rate, and have low acute toxicity, so that they are useful for treatment and prevention of heart disease. is there.
  • oral administration In administering the compound of the present invention to the human body, oral administration, injection (subcutaneous, muscle, intravenous) and other methods are used.
  • oral administration when used as a solid preparation, it can be made into tablets, granules, powders, capsules, etc., binders such as sugars and cellulose preparations commonly used in pharmaceutical preparations, bulking agents, disintegration An additive such as an agent may be included.
  • binders such as sugars and cellulose preparations commonly used in pharmaceutical preparations, bulking agents, disintegration
  • An additive such as an agent may be included.
  • oral liquid preparation When used, they may be in the form of an internal solution, suspension, emulsion, syrup or the like, or may be in the form of a dry product which is redissolved before use.
  • aqueous solution for injection, it may be in the form of an aqueous solution, suspension, oily or water-soluble emulsion, but is usually adjusted by dissolving or suspending in a solvent such as sterile water or physiological saline. If necessary, commonly used solubilizers, stabilizers, preservatives, tonicity agents and the like may be added.
  • LO rag preferably 0.6 to 6 mg divided into 1 to 3 divided doses. Can be administered.
  • Example 1- (2,4-Dimethoxyphenylcarbonylmethyl) -4- (5-methyl-2H-1.4-thiazine-3 (4H) -one-6-yl) pyridinium bromide The same treatment as in 1) was performed to obtain the title compound.
  • IlUKBi cm— 1 3330, 3220, 3105, 1675, 1630
  • IRCKBrJcm- 1 3210, 3090, 1680, 1650, 1630
  • IRCKBricm- 1 3200, 3100, 1700, 1655
  • the myocardial contractile force can be selectively increased without increasing the heart rate, and Because of its low toxicity, it is useful as a cardiotonic in the treatment and prevention of heart disease.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à un nouveau dérivé de 1,4-thiazine représenté par la formule générale (I) et à un sel d'addition d'acide pharmaceutiquement acceptable de ce composé, utile comme cardiotonique. Dans la formule (I), R1 et R2 représentent chacun un hydrogène ou un alkyle inférieur; et R3 représente -E-(CR'R')n-z où E représente (α) ou (β), R représente un hydrogène ou un alkyle inférieur, n représente un nombre entier compris entre 0 et 2, R' et R' représentent chacun un hydrogène ou un alkyle inférieur, Z représente un hydrogène, un phényle éventuellement trifluorométhylé, un pyridyle ou (γ), où A représente -CO- ou -CHOH-, et X et Y représentent chacun séparément un hydrogène, un alkyle inférieur, un alcoxy inférieur, un trifluorométhyle, un halogène, un nitro, un cyano, un amino ou un phényle, ou dans une variante, X et Y sont combinés entre eux pour former un méthylènedioxy.
PCT/JP1991/000732 1990-06-01 1991-05-31 Nouveau derive de 1,4-thiazine et cardiotonique contenant ce compose comme ingredient actif WO1991018893A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP14362890 1990-06-01
JP2/143628 1990-06-01

Publications (1)

Publication Number Publication Date
WO1991018893A1 true WO1991018893A1 (fr) 1991-12-12

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ID=15343177

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000732 WO1991018893A1 (fr) 1990-06-01 1991-05-31 Nouveau derive de 1,4-thiazine et cardiotonique contenant ce compose comme ingredient actif

Country Status (1)

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WO (1) WO1991018893A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138058A1 (fr) * 1983-09-16 1985-04-24 Zenyaku Kogyo Kabushiki Kaisha Dérivés de 1,4-thiazine
JPS61225174A (ja) * 1985-03-28 1986-10-06 Zenyaku Kogyo Kk 新規１．４−チアジン誘導体
EP0199968A1 (fr) * 1985-03-27 1986-11-05 Zenyaku Kogyo Kabushiki Kaisha Dérivés de thiazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138058A1 (fr) * 1983-09-16 1985-04-24 Zenyaku Kogyo Kabushiki Kaisha Dérivés de 1,4-thiazine
EP0199968A1 (fr) * 1985-03-27 1986-11-05 Zenyaku Kogyo Kabushiki Kaisha Dérivés de thiazole
JPS61225174A (ja) * 1985-03-28 1986-10-06 Zenyaku Kogyo Kk 新規１．４−チアジン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Abstract No. 108(17): 150397x ; & CHEM. PHARM. BULL., 35(6), 2243-2253, (1987). *

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