WO1993024485A1 - Derives d'oxazole et leur utilisation en tant qu'agents antiulcereux et antagonistes du recepteur h2 - Google Patents

Derives d'oxazole et leur utilisation en tant qu'agents antiulcereux et antagonistes du recepteur h2 Download PDF

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Publication number
WO1993024485A1
WO1993024485A1 PCT/JP1993/000687 JP9300687W WO9324485A1 WO 1993024485 A1 WO1993024485 A1 WO 1993024485A1 JP 9300687 W JP9300687 W JP 9300687W WO 9324485 A1 WO9324485 A1 WO 9324485A1
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Prior art keywords
compound
salt
amino
formula
hydrogen
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PCT/JP1993/000687
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English (en)
Inventor
Hisashi Takasugi
Yousuke Katsura
Yoshikazu Inoue
Tetsuo Tomishi
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP6500390A priority Critical patent/JPH07507296A/ja
Publication of WO1993024485A1 publication Critical patent/WO1993024485A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • This invention relates to new compounds and pharmaceutically acceptable salts thereof.
  • oxazole derivatives and pharmaceutically acceptable salts thereof which have antiulcer activity and H ⁇ -receptor antagonism, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of ulcer in human being or animals.
  • One object of this invention is to provide new oxazole derivatives and pharmaceutically acceptable salts thereof which possess antiulcer activity and H 2 -receptor antagonism.
  • Another object of this invention is to provide processes for the preparation of said oxazole derivatives and salt thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said oxazole derivatives or pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide a therapeutical method for the treatment of ulcer in human being or animals.
  • the oxazole derivatives of this invention are new and can be represented by the following general formula ( I )
  • R 1 is amino which may have suitable substituent(s)
  • R 2 and R 3 are each hydrogen or aliphatic hydrocarbon group which may have suitable subst i tuent(s)
  • A is lower alkylene
  • Y is pyridinediyl or furandiyl.
  • the object compound (I) or a salt thereof can be prepared by processes as illustrated in the following reaction schemes.
  • R-.R-'.R 3 , A and Y are each as defined above, R*a is acylamino,
  • R * b is acylamino having protected hydroxy
  • R * c is acylamino having hydroxy
  • R" is hydrogen,cyano, nitro, or acyl
  • R 5 is hydrogen, alkylthio, protected hydroxy or amino which may have suitable substituent(s)
  • R 5 a is amino which may have suitable substituent(s)
  • R ⁇ is lower alkyl or aryl
  • R 7 is amino-protecting group
  • R 8 , R 11 , R 13 and R 1 are each lower alkyl
  • R 9 is protected hydroxy
  • R 10 is hydrogen or lower alkyl
  • R 1 •* is heterocyclic group
  • R 1S is acyl
  • X I is S or 0,
  • Z 1 is halogen or acyloxy
  • Z 2 , Z 3 and Z 4 are each acid residue.
  • lower is intended to mean a group having 1 to 6 carbon atom(s) preferably 1 to 4 carbon atom(s), unless otherwise provided.
  • Aliphatic hydrocarbon group means a saturated or unsaturated, straight or branched aliphatic hydrocarbon group having 1 to 10, preferably 1 to 6, more preferably 1 to 4 carbon atom(s).
  • Suitable "aliphatic hydrocarbon group” may include alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, neopentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
  • alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, neopentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
  • alkenyl e.g., vinyl, 1-propenyl, allyl, 1-methylal lyl , 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.
  • alkynyl e.g., ethynyl, 1-propynyl, propargyl, 1- methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4- pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.
  • Suitable "substituent” in the term “aliphatic hydrocarbon group which may have suitable substituent(s)” may include lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.
  • lower alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.
  • (C3-C7 )-cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • mono or di or trihalo( lower)alkyl e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloro ethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2- chloroethyl, 1, 1-difluoroethyl , 2, 2-difluoroethyl, etc.
  • halogen e.g., chlorine, bromine, fluorine, iodine
  • carboxy protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc. ) which may have suitable substituent(s) (e.g., lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, etc,), nitro, amino, protected amino, di (lower)alkylamino (e.g., dimethylamino, diethylamino, di isopropylamino, ethylmethylamino, isopropylmethyla ino, ethylpropylamino, etc.
  • acyl e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.
  • lower alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.
  • imido heterocyclic group, and the like.
  • Suitable “lower alkyl” may be a straight or branched C. -C 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl or the like, in which the preferable one is C1-C4 alkyl.
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
  • Suitable "lower alkylthio” may include ethylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, and the like.
  • Suitable “acid residue” may include halogen such as chloro, bromo, fluoro and iodo.
  • Suitable "halogen” may be chloro, bromo, fluoro and iodo.
  • Suitable “lower alkylene” may be straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylnene, and the like, in which the preferable one is C1-C4 alkylene and the most preferable one is methylene and ethylene.
  • Suitable "amino which may have suitable substi tuent(s)" is coventional one used in a pharamaceutical field and may include amino, mono or di ( lower)alkylamino (e.g. methylamino, dimethylamino, ethyla ino, butylamino, etc. ), lower alkenyla ino (e.g. vinylamino, propenyla ino, etc. ), lower alkynylamino (e.g. ethynylamino, propynylamino, etc. ), hydroxy( lower)alkylamino (e.g.
  • R* is hydrogen, cyano, nitro, or acyl
  • R 5 is hydrogen, alkylthio, protected hydroxy or amino which may have suitable substituent(s), each of which is as mentioned above or below, and the like.
  • acyl and the acyl group in the term “acylamino” may include carbamoyl, thiocarbamoyl, sulfamoyl, an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carbamic, sulfonic, carboxylic or carbonic acid and their thio acids.
  • the aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl , pivaloyl, hexanoyl, etc. ), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g.
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl , pivaloyl, hexanoyl, etc.
  • lower alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.
  • lower alkenoyl e.g. acryloyl
  • the aromatic acyl may include aroyl (e.g. benzoyl, ni torobenzoyl, toluoyl, xyloyl, etc. ), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc. ), and the like.
  • aroyl e.g. benzoyl, ni torobenzoyl, toluoyl, xyloyl, etc.
  • arenesulfonyl e.g. benzenesulfonyl, tosyl, etc.
  • the heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, 1-oxonicotinoyl , isonicotinoyl , thiazolylcarbonyl, thiadiazolylcarbonyl , tetrazolylcarbonyl, tetrahydrofurylcarbonyl, piperidylcarbonyl, orphol inocarbonyl , etc. ), and the like.
  • heterocyclic carbonyl e.g. furoyl, thenoyl, nicotinoyl, 1-oxonicotinoyl , isonicotinoyl , thiazolylcarbonyl, thiadiazolylcarbonyl , tetrazolylcarbonyl, tetrahydrofurylcarbonyl, piperidylcarbonyl, orphol inocarbonyl , etc.
  • the aliphatic acyl substituted with aromatic group(s) may include phenyl ( lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl ( lower)- alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc. ), phenoxy( lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl , etc. ), and the like.
  • phenyl ( lower)alkanoyl e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.
  • phenyl ( lower)- alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • the aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl , thiadiazolylpropionyl, and the like.
  • acyl groups may be further substituted with suitable substituent(s) such as hydroxy, amino, guanidino, carboxy, oxo, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), (C 3 -C. )-cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower alkenyl (e.g. vinyl, al ly1, etc. ), halogen (e.g.
  • suitable substituent(s) such as hydroxy, amino, guanidino, carboxy, oxo, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), (C 3 -C.
  • lower alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.
  • lower alkoxycarbonyl lower alkoxycarbonyl ( lower)alkoxy (e.g. methoxycarbonylmethoxy, etc. )
  • lower alkylthio e.g.methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.
  • heterocyclic group as mentioned below, heterocycl ic( lower)alkylthio (e.g.
  • acyloxy for example, lower alkanoyloxy (e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, etc. ), lower alkylamino (e.g. methylamino, dimethylamino, ethylamino, etc. ), amino-protective group as after entioned, and the like, and the preferable acyl having such substi tuent(s) may be lower alkoxy( lower)alkanoyl (e.g.
  • lower alkylamino(lower)alkanoyl e.g. dimethylaminoacetyl , etc.
  • lower alkylthio(lower)alkanoyl e.g. ethylthioacetyl, etc.
  • lower alkoxycarbonyl lower)alkoxy( lower)alkanoyl (e.g. methoxycarbonyl ethoxyacetyl, etc. )
  • N-lower alkoxycarbo ylamino( lower)alkanoyl e.g. N-t-butoxycarbonyl- a inoacetyl, etc.
  • lower alkyl C 3 -C?
  • Suitable "heterocyclic group” and heterocyclic moiety in the terms “heterocyclic amino” and “heterocyclic thio” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-ato such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be 5 or 6-membered aromatic hetero onocycl ic group (e.g. pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl , etc. ), 5- or 6-membered aliphatic heteromonocycl ic group (e.g. morpholinyl, pyrrol idinyl , imidazol idinyl, pyrazol idinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc.
  • aromatic hetero onocycl ic group e.g. pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyri
  • heterocyclic moiety may have suitable substituent(s) such as amino, oxo, halogen as chloro, lower alkyl as defined above, and the like.
  • substituent(s) such as amino, oxo, halogen as chloro, lower alkyl as defined above, and the like.
  • such groups are triazolyl having amino and lower alkyl (e.g.
  • triazolyl having amino e.g. 3-amino-lH-triazolyl-5-yl, etc.
  • benzoisothiazolyl having oxo e.g. 1, 1-dioxobenzoisothiazolyl , etc.
  • Suitable “imido” may include succinimido, phthalimido, and the like.
  • Suitable amino-protective group in the term “protected amino” may include aryl ( lower)alkyl such as benzyl, benzhydryl, phenethyl and the like, and acyl as mentioned above.
  • Suitable hydroxy-protective group in the term "protected hydroxy” may include aforesaid acyl, aryl( lower)alkyl (e.g. benzyl, trityl, etc. ) lower alkoxy( lower)alkyl (e.g. methoxymethyl, 1-methyl-l-methoxyethyl, methoxypropyl, etc.), tetrahydropyranyl, aryl (e.g. phenyl, etc. ), lower alkyl (e.g. methyl, ethyl, etc.), and the like.
  • aryl( lower)alkyl e.g. benzyl, trityl, etc.
  • lower alkoxy( lower)alkyl e.g. methoxymethyl, 1-methyl-l-methoxyethyl, methoxypropyl, etc.
  • tetrahydropyranyl aryl (e.g. phenyl, etc.
  • acylamino having protected hydroxy may include acylamino as mentioned above which is substituted by a protected hydroxy as exemplified above, for example, protected hydroxy( lower)alkanoylamino such as lower alkanoyloxy( lower)- alkanoylamino (e.g. acetoxyacetylamino, etc. ), and the like.
  • acylamino having hydroxy may include acylamino as mentioned above which is substituted by hydroxy, for example, hydroxy( lower)alkanoylamino (e.g. hydroxyacetyla ino, etc.), and the like.
  • acylamino having protected amino may include acylamino as mentioned above which is substituted by a protected amino as exemplified above, for example, protected amino( lowerJalkanoylamino such as lower alkoxycarbonylamino- ( lower)alkanoylamino (e.g. t-butoxycarbonylaminoacetylamino, etc. ), and the 1 ike.
  • acylamino having amino may include acylamino as mentioned above which is substituted by amino, for example, amino( lower)alkanoylamino (e.g. aminoacetylamino, etc. ), and the like.
  • Suitable "(C3-C7 )-cycloalkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Suitable "lower alkenyl” may include vinyl, 1-propenyl, ally, 1-methylal lyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4- pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, and the like.
  • Suitable “lower alkynyl” may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl , 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, and the like.
  • Suitable "aryl” may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like, in which the preferred one is C ⁇ -C.o aryl.
  • Suitable "acyloxy” may include an aliphatic acyloxy and an aromatic acyloxy.
  • the aliphatic acyloxy may include lower alkanoyloxy (e.g. acetyloxy, propionyloxy, etc. ), lower alkylsulfonyloxy (e.g. mesyloxy, ethansulfonyloxy, etc. ), and the like.
  • the aromatic acyloxy may include aroyloxy (e.g. benzoyloxy, toluoyloxy, etc. ), arenesulfonyloxy (e.g. benzensulfonyloxy, tosyloxy, etc. ), and the like.
  • Pyridinediyl means bivalent pyridine such as pyridine-2, 6- diyl.
  • Fluandiyl means bivalent furan such as furan-2, 5-diyl .
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, ethanesulfonate, benzenesulfonate, toluenesufonate, etc. ], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc. ], a salt with an acidic amino acid [e.g. aspartic acid salt, glutamic acid salt, etc. ], and the like.
  • organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, ethanesulfonate, benzenesulfonate, toluenesufonate, etc.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphat
  • R 1 , R 2 , R 3 and A are as fol lows.
  • R 1 is amino ; acylamino such as lower alkanoylamino (e.g. acetylamino, etc. ), lower alkoxycarbonylamino (e.g. ethoxycarbonylamino, etc. ), lower alkanoyloxy( lower )- alkanoylamino (e.g. acetoxyacetylamino, etc. ), ureido and lower alkylureido (e.g. 3-methylureido, etc. ) ; or guanidino (e.g. 2-cyano-3-methylguanidino etc. ); R 2 is hydrogen ; alkyl (e.g.
  • n-butyl isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, etc.
  • lower alkenyl e.g. vinyl, etc.
  • lower alkynyl e.g. propargyl, etc.
  • lower alkoxy( lower)alkyl e.g. ethoxyethyl , etc.
  • mono or di or trihalo( lower )alkyl e.g. 2,2,2- trif luoroethyl, etc.
  • (C3-C7 )-cycloalkyl ( lower)alkyl e.g. cyclopropyl- ethyl, etc. ) ; lower alkylthio( lower)alkyl (methyl thioethyl, etc. ) aryl ( lower)alkyl (e.g. 2-phenylethyl, etc. )
  • R 3 is hydrogen;
  • A is lower alkylene (e.g. methylene, etc.).
  • the processes for preparing the object compounds (I) of the present invention are explained in detail in the following.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III).
  • This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc. ], acetic acid, formic acid, etc. or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc. ], acetic acid, formic acid, etc. or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually conducted under cooling to heating.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (IV).
  • This reaction is preferably carried out in the presence of a base or an acid.
  • Suitable base and acid are to be reffered to those as explained in Process 2.
  • the reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc.], acetic acid, formic acid, etc. or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc.], acetic acid, formic acid, etc. or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually conducted under cooling to heating.
  • the object compound (1-2) or a salt thereof can be prepared by subjecting the compound (1-1) or a salt thereof to deacylation.
  • Suitable method for this deacylation reaction may include conventional one such as hydrolysis, reduction or the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc. ), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc. ), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc. ), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc. ), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc. ), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.
  • an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc. ), al
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • an organic base such as tri ( lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N- methylpyrrol idine, N-methylmorphol ine, 1, 5-diazabicyclo- [4.3.0]non-5-one, 1, 4-diazabicyclo[2.2.2]-octane, 1,5- diazabicyclo[5.4.0]undecene-5 or the like.
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc. ).
  • organic acid e.g. formic acid, acetic acid, propionic acid, etc.
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-1) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with an acylating agent.
  • the compound (1-2) may be used in the form of its conventional reactive derivative at the amino group.
  • the acylating agent can be represented by the compound of the formula :
  • R l ⁇ is acyl as defined above and its conventional reactive derivative at the hydroxy group.
  • the suitable example may be an acid halide (e.g. acid chloride, etc. ), an acid anhydride, an activated amide, an activated ester, and the like.
  • an acid halide e.g. acid chloride, etc.
  • an acid anhydride e.g. an acid anhydride
  • an activated amide e.g. an activated ester, and the like.
  • the acylating agent is usually used in the form of cyanate or isocyanate.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc. ], acetone, dioxane, acetoni tri le, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, N.N-dimethylacetamide, pyridine, acetic acid or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc. ], acetone, dioxane, acetoni tri le, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, N.N-dimethylacetamide, pyridine, acetic acid or any other organic solvent which does not adversely influence the reaction.
  • These conventional solvents may also be
  • reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri ( lower)alkylamine, pyridine, N-(lower)alkylmorphol ine, N,N- di ( lower)alkylbenzylamine, or the like.
  • the object compound (1-3) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (V).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N- dimethylformamide N,N- dimethylformamide
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-4) or a salt thereof can be prepared by reacting the compound (1-3) or a salt thereof with the compound (VI).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N- dimethylformamide N,N- dimethylformamide
  • the compound (VI) is liquid, it can be also used as a solvent.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-6) or a salt thereof can be prepared by subjecting the compound (1-5) or a salt thereof to hydrolysis reaction.
  • This reaction is usually carried out in a conventional manner for transforming nitrile to amide.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol [e.g. methanol, ethanol, propanol, etc. ], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, alcohol [e.g. methanol, ethanol, propanol, etc. ], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-8) or a salt thereof can be prepared by subjecting the compound (1-7) or a salt thereof to elimination reaction of the amino-protective group.
  • This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc. ] of this reaction are to be referred to those as explained in Process 2.
  • the object compound (1-9) or a salt thereof can be prepared by reacting the compound (1-8) or a salt thereof with the compound (VII).
  • This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc. ] of this reaction are to be referred to those as explained in Process 1.
  • reaction mode and reaction conditions e.g. solvent, reaction temperature, etc.
  • the object compound ( I-10) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (VIII ).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N- dimethylformamide N,N- dimethylformamide
  • reaction temperature is not critical, and the reaction i s usual ly carr i ed out at ambi ent temperature or under warmi ng or heat ing.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound (X) or a salt thereof.
  • This reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc. ] of this reaction are to be referred to those as explained in Process 5.
  • reaction mode and reaction conditions e.g. solvent, reaction temperature, etc.
  • the object compound (1-12) or a salt thereof can be prepared by reacting the compound (1-11) or a salt thereof with the compound (XI).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc. ], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran e.g. methanol, ethanol, propanol, etc.
  • dioxane dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N- dimethylformamide N,N- dimethylformamide
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-13) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (XII) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetoni trile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N- dimethylacetamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetoni trile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N- dimethylacetamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetoni trile, chloroform, dichloromethane, ethylene chloride, tetrahydrofur
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri ( lower)alkylamine (e.g. triethylamine, etc. ), pyridine, N- ( lower)alkylmorphol ine, N,N-di (lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri ( lower)alkylamine (e.g. triethylamine, etc. ), pyridine, N- ( lower)alkylmorphol ine, N,N-di (lower)alkylbenzylamine, or the like.
  • the compound (XIV) or a salt thereof can be prepared by reacting the compound (1-8) or a salt thereof with the compound (XIII) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N- dimethylformamide N,N- dimethylformamide
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-14) or a salt thereof can be prepared by reacting the compound (XIV) or a salt thereof with the compound (XV) or a salt thereof.
  • This reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc. ] of this reaction are to be referred to those as explained in Process 5.
  • reaction mode and reaction conditions e.g. solvent, reaction temperature, etc.
  • the object compound (1-16) or a salt thereof can be prepared by subjecting the compound (1-15) or a salt thereof to elimination reaction of the hydroxy-protective group.
  • the object compound (1-17) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (XVI) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- di ethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran e.g. methanol, ethanol, propanol, etc.
  • dioxane dimethyl sulfoxide
  • N,N- di ethylformamide a mixture thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as tri ( lower)alkylamine (e.g. triethylamine, etc.), or the like.
  • an inorganic or organic base such as tri ( lower)alkylamine (e.g. triethylamine, etc.), or the like.
  • the compound (II) can be prepared by the following steps. CH , _ CN
  • a 1 is lower alkylene
  • R * a is acylamino
  • Z-a is halogen
  • Z l b is acyloxy.
  • each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
  • the new oxazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity and H 2 - receptor antagonism, and are useful for a therapeutic treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zoll inger-El1ison syndrome, reflux esophagitis, upper gastrointestinal bleeding, and the like.
  • the compound (I) and pharmaceutically acceptable salts thereof of the present invention possess high antimicrobial activity against pathogenic microorganisms such as helicobacter pyloridis, and the like, which is a gram- negative bacillus that has recently been found beneath the mucus gel of the human stomach.
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 g/body and about 1,000 mg/body may be administered per day.
  • Test A H 2 -receptor antagonism in isolated guinea-pig atrium
  • the atrial strip isolated from guinea-pig was suspended under an initial tension 0.3 to 0.6 g in an organ bath containing Tyrode solution at 30°C, aerated 95% 0 2 - 5% C0 2 gas.
  • the beating rate and amplitude of contraction of the atrium were recorded by ⁇ ans of a transducer and a polygraph. Histamine (1 x 10 _ ⁇ g/ml) was added to the bathing fluid and the increase in beating rate after dosing was measured. Addition of test compounds (1 x 10- ⁇ g/ml) was made 30 minutes after washing out histamine. Inhibitory effect of test compound was calculated by comparing histamine-induced increases in beating rate before and 30 minutes after dosing with the test compounds.
  • Test B Gastric secretion from lumen perfused stomach in anesthetized rats
  • the animals were anesthetized with 1.25 g/kg urethane intraperi toneally.
  • the abdomen was opened and the gastric lumen was perfured with saline throughout the experiment.
  • the perfusate was titrated by an autotitrator with
  • test compound (1 mg/kg) was given intravenously. Drug effect was expressed as maximal inhibition by acid output.
  • Test C Inhibition of HCl-aspirin ulcer:
  • test compounds 32 mg/kg suspended in 0.1% methylcel lulose solution was administered orally 30 minutes before aspirin administration.
  • Aspirin suspended in 0.1% methylcel lulose solution containing 0.2N HCl, was administered orally at a dose of 200 mg/kg/10 ml.
  • Test D Anti-microbial activity
  • In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in Brucella broth Agar with 3% horse serum and 2% starch at 37°C for 4 days, and 10 s cfu/ml were inoculated with a multipoint replicater onto Brucella agar plus 7% horse blood plate containing serial 2-fold dilutions of each drug and incubated at 37°C for 3 days. Incubation was carried out in an atmosphere of 10% C0 2 . MIC was read after incubation as the lowest drug concentration that inhibited macroscopic colonial growth. Data showed below meaned MIC against clinical isolates.
  • the solvent was removed by concentration in vacuo.
  • the separated organic layer was washed with brine and dried over magnesium sulfate.
  • the extract layer was dried over magnesium sulfate and the solvent was removed by concentration in vacuo.
  • Ethyl chloroformate (1.0 ml) was added to a mixture of 4- (6-aminomethylpyridin-2-yl )-2-[ (amino) (methylamino)- methyleneamino]oxazole trihydrochloride (3.0 g) and triethylamine (4.9 ml) in dichloromethane (60 ml) under ice- cooling and the mixture was stirred for 4.5 hours at ambient temperature.
  • the solvent was removed by concentration and a residue was added to a mixture of tetrahydrofuran, ethyl acetate amd water.
  • the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the separated organic layer was washed with brine and dried over magnesium sulfate.
  • the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the mixture was extracted with the mixture of ethyl acetate and tetrahydrofuran.
  • Methyl isocyanate (0.2 ml) was added to a mixture of 4-(6- aminomethylpyridin-2-yl )-2-[ (amino) (n-butylamino)- methyleneamino]oxazole trihydrochloride (1.1 g) and triethylamine (1.2 ml) in a mixture of tetrahydrofuran (22 ml) and methanol (5 ml) and the mixture was stirred for 2 hours at ambient temperature.
  • 4N-Dioxanoic hydrogen chloride (0.73 ml) was added to a solution of 4-(6-acetylaminomethylpyridin-2-yl )-2-[ (amino) (2- phenylethylamino)methyleneamino]oxazole (500 mg) in methanol (20 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. Di isopropyl ether (80 ml) was added and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration.

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Abstract

L'invention concerne un composé répondant à la formule (I) dans laquelle R1 représente amino pouvant avoir un ou des substituants appropriés, R2 et R3 représentent chacun hydrogène ou un groupe hydrocarboné aliphatique qui peut avoir un ou des substituants appropriés, A représente alkylène inférieur et Y représente pyridinediyle ou furandiyle. L'invention concerne également un sel pharmaceutiquement acceptable dudit composé. Ce composé a un effet antiulcéreux, constitue un antagoniste du récepteur H¿2?, et est utile dans le traitement des gastrites, des ulcères (par exemple l'ulcère gastrique, l'ulcère duodénale, l'ulcère peptique, etc), du syndrome de Zollinger-Ellison, de l'÷sophagite peptique, des hémorragies digestives hautes, et d'autres affections semblables.
PCT/JP1993/000687 1992-05-26 1993-05-24 Derives d'oxazole et leur utilisation en tant qu'agents antiulcereux et antagonistes du recepteur h2 WO1993024485A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP6500390A JPH07507296A (ja) 1992-05-26 1993-05-24 オキサゾール誘導体およびその抗潰瘍剤およびｈ２−受容体拮抗剤としての用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9211163.2 1992-05-26
GB929211163A GB9211163D0 (en) 1992-05-26 1992-05-26 New oxazole derivatives

Publications (1)

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WO1993024485A1 true WO1993024485A1 (fr) 1993-12-09

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JP (1) JPH07507296A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2366392A1 (fr) 2004-02-19 2011-09-21 Abbott GmbH & Co. KG Composés de guanidine et leur utilisation comme partenaire de liaison pour récepteurs 5-HT5

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003640A2 (fr) * 1978-01-18 1979-08-22 Imperial Chemical Industries Plc Dérivés de guanidine à activité antisécrétive de l'acide gastrique, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0089730A2 (fr) * 1982-03-24 1983-09-28 ISTITUTO DE ANGELI S.p.A. Guanidino phénylamidines hétérocycliques, procédé pour les préparer et leur utilisation pharmaceutique
EP0355612A2 (fr) * 1988-08-15 1990-02-28 Fujisawa Pharmaceutical Co., Ltd. Dérivés de furylthiazole, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0417751A2 (fr) * 1989-09-15 1991-03-20 Fujisawa Pharmaceutical Co., Ltd. Thiazoles, procédés de préparation et compositions pharmaceutiques les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003640A2 (fr) * 1978-01-18 1979-08-22 Imperial Chemical Industries Plc Dérivés de guanidine à activité antisécrétive de l'acide gastrique, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0089730A2 (fr) * 1982-03-24 1983-09-28 ISTITUTO DE ANGELI S.p.A. Guanidino phénylamidines hétérocycliques, procédé pour les préparer et leur utilisation pharmaceutique
EP0355612A2 (fr) * 1988-08-15 1990-02-28 Fujisawa Pharmaceutical Co., Ltd. Dérivés de furylthiazole, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0417751A2 (fr) * 1989-09-15 1991-03-20 Fujisawa Pharmaceutical Co., Ltd. Thiazoles, procédés de préparation et compositions pharmaceutiques les contenant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2366392A1 (fr) 2004-02-19 2011-09-21 Abbott GmbH & Co. KG Composés de guanidine et leur utilisation comme partenaire de liaison pour récepteurs 5-HT5
EP2366697A1 (fr) 2004-02-19 2011-09-21 Abbott GmbH & Co. KG Composés de guanidine et leur utilisation comme partenaire de liaison pour récepteurs 5-HT5

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GB9211163D0 (en) 1992-07-08
JPH07507296A (ja) 1995-08-10

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