WO1989000566A1 - Composes de pyridine et leurs utilisations en medecine - Google Patents

Composes de pyridine et leurs utilisations en medecine Download PDF

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Publication number
WO1989000566A1
WO1989000566A1 PCT/JP1988/000716 JP8800716W WO8900566A1 WO 1989000566 A1 WO1989000566 A1 WO 1989000566A1 JP 8800716 W JP8800716 W JP 8800716W WO 8900566 A1 WO8900566 A1 WO 8900566A1
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WO
WIPO (PCT)
Prior art keywords
methyl
ethoxy
alkyl
aralkyl
pyridyl
Prior art date
Application number
PCT/JP1988/000716
Other languages
English (en)
Japanese (ja)
Inventor
Takeshi Kawakita
Mitsuharu Sano
Yuji Ono
Keiichiro Haga
Original Assignee
Yoshitomi Pharmaceutical Industries, 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
Priority to KR1019900700587A priority Critical patent/KR940006717B1/ko
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Publication of WO1989000566A1 publication Critical patent/WO1989000566A1/fr

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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

Definitions

  • the present invention relates to a novel pyridine compound having an anti-ulcer action, a gastric acid secretion inhibitory action, a gastrointestinal cell protective action, an anti-diarrheal action, etc., a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof.
  • Japanese Patent Publication No. 59-181277 discloses that the 4-position of viridyl is substituted with an alkyl substituent on the amino nitrogen; Compounds having two carbon atoms and substituted by dialkylaminoalkoxy containing 1 to 4 carbon atoms in the alkoxy group are included.
  • the disclosure of this publication is very extensive, and only 2— (N, N—dimethylamino) ethoxy is described as an example of the substituent. It does not contain any data to specifically grasp the effects and effects. -
  • the present inventors have conducted intensive studies with the aim of developing a prophylactic / therapeutic agent for gastrointestinal diseases, and as a result, have found that
  • R 1 is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or haloalkyl
  • R 3 are the same or different and represent hydrogen, halogen or alkyl
  • R 4 and R 5 represents hydrogen.
  • the other represents hydrogen, alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, or acyl
  • one of R 4 and R 5 represents When referring to alkyl. Phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, etc .: 3 ⁇ 4 "indicates phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, or R And 4 and R 5 are bonded together with an adjacent nitrogen atom to form a heterocyclic ring which may be condensed.) Or a formula:
  • R 6 is hydrogen, alkyl or acyl
  • Z is methylene, oxygen or sulfur
  • 1 and m are the same or different and each represents 0 or an integer of 1-3.
  • n 0 or an integer of 1 to 8.
  • halogen refers to chlorine, bromine, fluorine, and iodine
  • alkyl refers to methyl, ethyl, propyl, isopropyl, butino, isobutyl, tertiary butyl, pentyl, hexyl, Alkyl having 1 to 20 carbon atoms such as octyl, decyl, dodecyl, octadecyl, eicosyl, etc.
  • alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, isobutoxy, tertiary.
  • Alkoxy having 1 to 20 carbon atoms such as butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, eicosiloxy, etc.
  • alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, propoxy.
  • a phenyl-substituted alkyl group having 1 to 8 carbon atoms such as rubutyl, & phenylhexyl, and 8-phenyloctyl
  • acetyl is acetyl, buocyl pionyl, isopropionyl, butylyl, pinodylol, and nodelli.
  • Alkenyl or benzoyl having 1 to 5 carbon atoms, such as phenyl, is substituted with 1 to 3 halogens, alkyl, alkoxy, A-alkyl, hydroxyl, hydroxy, or substituted phenyl or substituted aralkyl.
  • An optionally condensed heterocyclic ring formed from a group selected from toro and amino with an adjacent nitrogen atom includes 1-pyrrolidine, biperidine, and 1-bipe Radinzole, 4-Alkyl-1-biperazinyl, 4-Aralkyl-1-piperazinyl, 4-Substituted alanolexicle-1-Biperazul, 4-Alzolequinole 1
  • L is of the formula: R 4
  • R is alkyl
  • R 5 is aralkyl or substituted aralkyl, or R 4 and R 5 are bonded together with the adjacent nitrogen atom to form a condensed group.
  • It is a compound of the general formula (I) showing a group forming a good heterocyclic ring.
  • L is N-benzyl N-methylamino and has from 1 to 3 halogen atoms, alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms as substituents.
  • It is a compound of the general formula (I) which may be 1,2,3,4-tetrahydroquinoline-1-yl.
  • the compound of the general formula (I) of the present invention may have various isomers.
  • the invention contemplates one of these isomers or a mixture of these isomers.
  • salts of the pyridine compounds of the general formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, and citrate.
  • Acid addition salts such as salts, maleates, fumarates, malonates, lingates, tartrates, succinates, methansulfonates and the general formula
  • sodium salts, calcium salts: and magnesium salts are particularly preferred.
  • the compounds of the present invention also exist as hydrates (hemihydrate, monohydrate, sesquihydrate, etc.) and solvates, and these are also included in the present invention.
  • the compound of the general formula (I) of the present invention has the general formula
  • ⁇ represents a reactive atom or group (halogen or methane) Sulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and other sulfonyloxy groups), and other symbols are as defined above.
  • the reaction between compound (III) and compound (H) is usually carried out in a solvent inert to the reaction (eg, water or methanol, ethanol, dimethylformamino, or a mixed solvent thereof, preferably aqueous ethanol).
  • a solvent inert eg, water or methanol, ethanol, dimethylformamino, or a mixed solvent thereof, preferably aqueous ethanol.
  • Medium bases sodium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, carbonate
  • Temperature from about 0'C to the boiling point of the solvent used, preferably 20% in the presence of sodium, carbonated carbonate, metallic sodium, triethylamine, pyridine, etc. It takes about 10 minutes to 24 hours, preferably 30 minutes to 3 hours.
  • the oxidizing agents used in the oxidation reaction include perbenzoic acid, peracetic acid, peracetic acid, perfluoroacetic acid, permaleic acid, sodium hypobromite, and sodium hypochlorite. Emissions include tritium and hydrogen peroxide.
  • the reaction is usually carried out in an inert solvent (water or Organic acids (formic acid, acetic acid, propionic acid, butyric acid, maleic acid, fumaric acid, malonic acid, etc.) in rometan, chloroform, tedrohydrofuran, dioxane, dimethylformamide or mixtures thereof.
  • the compound ( ⁇ ) thus produced can be isolated and purified by conventional means such as recrystallization, column chromatography and the like.
  • the optical isomer of the compound (I) of the present invention can be produced by subjecting the reaction product to fractional crystallization or the like, or by performing the above-mentioned reaction using a raw material compound that has been optically resolved in advance.
  • the compound represented by the general formula (II) of the present invention includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, malonic acid, and lingo.
  • the above-mentioned acid addition salt can be obtained by treating with an acid, tartaric acid, succinic acid, methanesulfonic acid or the like in a conventional manner.
  • the salt compound of the general formula (I ′) can be obtained by reacting a compound of the general formula (I) with a corresponding base.
  • the compound of the present invention has an anti-ulcer effect, an inhibitory effect on gastric acid secretion, a protective effect on gastrointestinal cells, an anti-diarrheal effect, and prevents digestive system diseases (gastric ulcer, duodenal ulcer, gastritis, diarrhea, colitis, etc.).
  • digestive system diseases gastric ulcer, duodenal ulcer, gastritis, diarrhea, colitis, etc.
  • ⁇ Useful as a therapeutic It is.
  • it has low toxicity, is stable against acids and the like, and has characteristics such as a small increase in blood gastrin level.
  • a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof may be added to a pharmaceutically acceptable excipient, carrier, diluent, solubilizing agent, or the like. It can be administered in the form of capsules, tablets (including sugar-coated tablets and film-coated tablets), granules, injections, and infusions by mixing with additives.
  • the dose is about 0.01 to 30 nig / kgs per adult per day, preferably 0.1 to 3 mZkg, but may vary depending on the patient's condition, age, drug resistance, etc. Needless to say.
  • ⁇ ( PP m) 1.10 (t, 3H), 2.14 (s, 3 ⁇ ), 2.68 (q, 2 ⁇ ), 2.92 (t, 2 ⁇ ), 3.70 (s, 2 ⁇ ), 4.04 (t, 2 ⁇ ), 4.36 (s, 2 ⁇ ), 6, 62 and 8.30 (d, 2H, respectively), 7.00 to 7.64 (m, 9H, respectively)
  • Tablets Active ingredient 5 m The tablets have the following composition.
  • Capsule A capsule containing 3 mg of the active ingredient is prepared according to the following composition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés de pyridine représentés par la formule générale (I) où R1 représente hydrogène, halogène, alkyle, alkoxy, alkoxycarbonyle ou haloalkyle, R2 et R3, qui peuvent être identiques ou différents, représentent chacun hydrogène, halogène ou alkyle, L représente un groupe représenté par la formule (II) (à condition que lorsque l'un des membres R4 et R5 représente hydrogène, l'autre membre représente hydrogène, alkyle, phényle, phényle substitué, aralkyle, aralkyle substitué ou acyle, et que lorsque l'un des membres R4 et R5 représente alkyle, phényle, phényle substitué, aralkyle, aralkyle substitué ou acyle, l'autre membre représente phényle, phényle substitué, aralkyle, aralkyle substitué ou acyle, ou alors R4 et R5 pris ensemble avec l'atome d'azote adjacent représentent un groupe formant un anneau hétérocyclique éventuellement fusionné), ou un groupe représenté par la formule (III) (où R6 représente hydrogène, alkyle ou acyle, Z représente méthylène, oxygène ou soufre, et l et m, qui peuvent être identiques ou différents, représentent chacun 0 ou un nombre entier compris entre 1 et 3), et n représente 0 ou un nombre entier compris entre 1 et 8. On décrit également des sels de ces composés acceptables en pharmacologie, ainsi que leurs applications en médecine. Ces composés représentent des effets antiulcéreux et antidiarrhéiques, réduisent la sécrétion des sucs gastriques et protègent les cellules gastro-intestinales, ce qui permet de les utiliser en tant que médicaments pour la prévention et le traitement des maladies de l'appareil digestif.
PCT/JP1988/000716 1987-07-21 1988-07-18 Composes de pyridine et leurs utilisations en medecine WO1989000566A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019900700587A KR940006717B1 (ko) 1988-07-18 1988-07-17 리클라이닝(reclining)장치

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP18259087 1987-07-21
JP62/182590 1987-07-21
JP33607387 1987-12-29
JP62/336073 1987-12-29

Publications (1)

Publication Number Publication Date
WO1989000566A1 true WO1989000566A1 (fr) 1989-01-26

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Application Number Title Priority Date Filing Date
PCT/JP1988/000716 WO1989000566A1 (fr) 1987-07-21 1988-07-18 Composes de pyridine et leurs utilisations en medecine

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WO (1) WO1989000566A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632823B1 (en) * 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59181277A (ja) * 1983-02-11 1984-10-15 アクチエボラゲツト・ヘツスレ 新規な薬理学的に活性な化合物
JPS6122079A (ja) * 1984-06-16 1986-01-30 ビク・グルデン・ロムベルク・ヘミツシエ・フアブリク・ゲゼルシヤフト・ミト・ベシユレンクテル・ハフツング ジアルコキシピリジン及びそれを含有する薬剤
JPS6124589A (ja) * 1984-07-05 1986-02-03 ビーチヤム・グループ・ピーエルシー 新規化合物，その製造方法及びそれを含む医薬組成物
JPS6150979A (ja) * 1984-08-16 1986-03-13 Takeda Chem Ind Ltd ピリジン誘導体およびその製造法
JPS61215388A (ja) * 1985-03-15 1986-09-25 ヘキスト・アクチエンゲゼルシヤフト 置換ベンズイミダゾール誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59181277A (ja) * 1983-02-11 1984-10-15 アクチエボラゲツト・ヘツスレ 新規な薬理学的に活性な化合物
JPS6122079A (ja) * 1984-06-16 1986-01-30 ビク・グルデン・ロムベルク・ヘミツシエ・フアブリク・ゲゼルシヤフト・ミト・ベシユレンクテル・ハフツング ジアルコキシピリジン及びそれを含有する薬剤
JPS6124589A (ja) * 1984-07-05 1986-02-03 ビーチヤム・グループ・ピーエルシー 新規化合物，その製造方法及びそれを含む医薬組成物
JPS6150979A (ja) * 1984-08-16 1986-03-13 Takeda Chem Ind Ltd ピリジン誘導体およびその製造法
JPS61215388A (ja) * 1985-03-15 1986-09-25 ヘキスト・アクチエンゲゼルシヤフト 置換ベンズイミダゾール誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6632823B1 (en) * 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

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