WO1992016526A1 - Derives de thiazole - Google Patents

Derives de thiazole Download PDF

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Publication number
WO1992016526A1
WO1992016526A1 PCT/JP1992/000279 JP9200279W WO9216526A1 WO 1992016526 A1 WO1992016526 A1 WO 1992016526A1 JP 9200279 W JP9200279 W JP 9200279W WO 9216526 A1 WO9216526 A1 WO 9216526A1
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WIPO (PCT)
Prior art keywords
alkyl
amino
compound
formula
hydrogen
Prior art date
Application number
PCT/JP1992/000279
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English (en)
Inventor
Hisashi Takasugi
Yousuke Katsura
Yoshikazu Inoue
Tetsuo Tomishi
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP4505609A priority Critical patent/JPH06505724A/ja
Publication of WO1992016526A1 publication Critical patent/WO1992016526A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to new thiazole derivatives and pharmaceutically acceptable salts thereof.
  • thiazole derivatives and pharmaceutically acceptable salts thereof which have antiulcer activity and H 2 -receptor antagonism, to 10 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 thiazole derivatives and pharmaceutically 15 acceptable salts thereof which possess antiulcer activity and H_-receptor antagonism.
  • Another object of this invention is to provide processes for the preparation of said thiazole derivatives and salt thereof. 20
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiazole derivatives or pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide 25 a therapeutical method for the treatment of ulcer in human being or animals.
  • the thiazole derivatives of this invention are new and can be represented by the following general formula (I) :
  • R is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula :
  • R is hydrogen, cyano or acyl, """ R is amino or lower alkoxy, and
  • R 2 is N or CH
  • R 3 and R8 are each hydrogen, acyl, lower alkyl which may have suitable substituent(s)
  • R 2 and R3 when one of R 2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, 4 R is hydrogen and g
  • R is hydrogen, then the other of R 2 and R3 is
  • the object compound (I) or a salt thereof can be prepared by processes as illustrated in the following reaction schemes.
  • R , R , R , R , Y and A are each as defined above,
  • R is protected amino, R, 1 i.s acylammo,
  • R is acylamino having protected hydroxy
  • R 1- is acylamino having hydroxy
  • R is acylamino having protected amino.
  • R f is acylamino having amino.
  • R 9 is lower alkylthio or protected hydroxy,
  • R is hydrogen, cyano, nitro or acyl
  • R is lower alkyl
  • R 12 is lower alkyl
  • R 13 is am o which may have suitable substituent(s) ,
  • X is aicciidd rreessi.due, and is N or CH.
  • lower is intended to mean a group having 1 to 6 carbon atom(s) preferably 1 to 4 carbon atom(s), unless otherwise provided.
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • Suitable "lower alkylthio” may include methylthio, 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 "lower alkylene” and lower alkylene moiety formed by linkage of R 2 and R3 may be straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like, in which the preferable one is C--C. alkylene and the most preferable one is methylene and ethylene.
  • Suitable "amino which may have suitable substituent(s)” is conventional one used in a pharmaceutical field and may include amino, mono or di(lower)alkylamino (e.g. methylamino, dimethylamino, ethylamino, butylamino, etc.), lower alkenylamino (e.g.
  • lower alkynylamino e.g. ethynylamino, propynylamino, etc.
  • hydroxy(lower)- alkylamino e.g. hydroxymethylamino, hydroxyethylamino, hydroxypropylammo, etc.
  • lower alkoxy(lower)alkylamino e.g. methoxymethylamino, etc.
  • mono or di(lower)- alkylamino(lower)alkylamino e.g.
  • acylamino in which acyl is as mentioned below
  • heterocyclic amino in which heterocyclic group is as mentioned below
  • cyclo(lower)alkenylamino which may have one or more, preferably one to three suitable substituent(s) such as amino and oxo [e.g.
  • R Si is hydrogen, lower alkylthio, protected hydroxy or amino which may have suitable substituent(s) , each of which is as mentioned above or below, and the like.
  • Suitable “lower alkyl” may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or the like, in which the preferable one is C--C. alkyl and the more preferable one is methyl or ethyl.
  • 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.
  • (C.,-C 7 )-cycloalkanecarbonyl e.g. cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.
  • lower alkoxalyl e.g. methoxalyl, ethoxalyl, etc.
  • lower alkanoylcarbonyl e.g. pyruvoyl, etc.
  • the aromatic acyl may include aroyl (e.g. benzoyl, nitrobenzoyl, toluoyl, xyloyl, etc. ) , arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.
  • the heterocyclic acyl may include heterocyclic carbonyl (e.g.
  • furoyl thenoyl, nicotinoyl, 1-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, tetrahydrofurylcarbonyl, pyperidylcarbonyl, morpholinocarbonyl, etc. ) , and the like.
  • the aliphatic acyl substituted with aromatic group(s) may include phenyKlower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)- alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethylo.xycarbonyl, etc. ), phenoxy(lower)alkanoy1 (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like.
  • phenyKlower alkanoyl e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.
  • phenyl(lower)- alkoxycarbonyl e.g. benzyloxycarbonyl, phenethylo.xycarbonyl, etc.
  • the aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolyl- propionyl, 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,-C 7 )- cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower alkenyl (e.g. vinyl, allyl, 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,-C 7 )-
  • lower alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.
  • 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, heterocyclic(lower)alkylthio (e.g.
  • furylmethylthio, thiazolylmethy1thio, etc. heterocyclic(lower)alkylsulfinyl (e.g. furylmethylsulfinyl, thiazolylmethylsulfinyl, etc.), nitro, heterocyclic(lower)alkylaryloxy(lower)alkyl (e.g. pyrrolidinylmethylphenoxypropyl, etc.), acyl as mentioned above, protected amino in which the amino protective moiety may be the same as those herein, aryl (e.g. phenyl, etc.), aroyl (e.g.
  • aryloxy e.g., phenoxy, tolyloxy, etc.
  • protected hydroxy such as acyloxy, for example, lower alkanoyl ⁇ xy (e.g. for yloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexan ⁇ yloxy, etc.), lower alkylamino (e.g. methylamino, dimethylamino, ethylamino, etc.
  • amino-protective group as aftermentioned, and the like, and the preferable acyl having such substituent(s) may be lower alkoxy(lowerJalkanoyl (e.g., methoxyacetyl, ethoxyacetyl, etc.), lower alkoxycarbonyl (e.g. tert-butoxycarbonyl, etc.), lower alkanoyloxy(lower)alkanoyl (e.g., acetoxyacetyl, acet ⁇ xypropionyl, etc.), N-lower alkylcarbamoyl (e.g.
  • lower alkoxy(lowerJalkanoyl e.g., methoxyacetyl, ethoxyacetyl, etc.
  • lower alkoxycarbonyl e.g. tert-butoxycarbonyl, etc.
  • lower alkanoyloxy(lower)alkanoyl e.g., acetoxyace
  • hydroxy(lower)alkanoyl e.g. hydroxyacetyl, etc.
  • amino(lower)alkanoyl e.g. aminoacetyl, etc.
  • lower alkylamino(lower)alkanoyl e.g. dimethylaminoacetyl, etc.
  • lower alkylthio(lower)alkanoyl e.g. methylthioacetyl, etc.
  • lower alkoxycarbonyl(lower)alkoxy(lower)alkanoyl e.g.
  • N-lower alkoxycarbonylamino(lower)alkanoyl e.g. N-t-butoxycarbonylaminoacetyl, etc.
  • lower alkyl(C 3 ⁇ C 7 )- cycloalkanecarbonyl e.g. methylcyclopropanecarbonyl, etc.
  • N-aminocarbamoyl N-guanidinocarbamoyl
  • N-lower alkylsulfamoyl e.g. N-methylsulfamoyl, etc.
  • 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-atom such as an oxygen, sulfur nitrogen atom and the like. Especially preferably heterocyclic group may be 5 or 6-membered aromatic heteromonocyclic group (e.g.
  • furyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyri idinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc. ), unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s) (e.g.
  • 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.
  • 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.
  • triazolyl having amino and lower alkyl e.g. 3-amino-l-methyl-lH-triazol-5-yl, etc.
  • triazolyl having amino e.g.
  • protected amino may include ar(lower)alkyl such as benzyl, benzhydryl, phenethyl and the like, and acyl as mentioned above.
  • Suitable hydros-protective group in the term "protected hydroxy" may include aforesaid acyl, ar(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.
  • ar(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
  • Suitable "halogen” may be chloro, bromo, fluoro and iodo.
  • Suitable "lower alkyl which may have suitable substituent(s)” is conventional one used in a pharmaceutical field and may include lower alkyl as mentioned above, mono or di or trihalo(lower)alkyl such as trifluoro(lower)alkyl (e.g. trifluoromethyl, trifluoroethyl, etc.), lower alkoxy(lower)alkyl (e.g. methoxymethyl, methoxyethyl, methoxypropyl, etc. ) , di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethy1, etc.) , hydroxy(lower)alkyl (e.g.
  • acylamino(lower)alkyl such as lower alkanoylamino(lower)alkyl (e.g. acetylaminomethyl, acetylaminoethyl, etc.) , ar(lower)alkyl, in which the aryl moiety may be substituted by lower alkoxy, such as di(lower)alkoxyphenyl(lower)alkyl (e.g. dimethoxyphenethyl, etc. ) , lower alkylthio(lower)alkyl which may have suitable substituent(s) such as lower alkylthio(lower)alkyl (e.g.
  • methylthiomethyl. methylthioethyl, etc.) and di(lower)alkylamino(lower)- alkylfuryl(lower)alkylthio(lower)alkyl e.g. dimethylaminomethylfurfurylthioethyl, etc.
  • heterocyclic(lower)alkyl in which heterocyclic moiety is as mentioned above, such as furyl(lower)alkyl (e.g. furfuryl, furylethyl, etc.), pyridyKlower)alkyl (e.g.
  • Suitable "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.
  • Suitable "acylamino having hydroxy” may include acylamino as mentioned above which is substituted by hydroxy, for example, hydroxy(lower)alkanoylamino (e.g. hydroxyacetylamino, etc.) , and the like.
  • Suitable "acylamino having protected amino” may include acylamino as mentioned above which is substituted by a protected amino as exemplified above, for example, protected amino(lower)alkanoylamino such as lower alkoxycarbonylamino(lower)alkanoylamino (e.g. t-butoxycarbonylaminoacetylamino, etc.), and the like.
  • Suitable "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 "lower alkylthioureido” may include 3-lower alkylthioureido (e.g. 3-methylthioureido, etc.), and the like.
  • Suitable "(C 3 -C 7 )-cycloalk ⁇ l” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Suitable "lower alkenyl” may include vinyl, 1-propenyl, allyl, 2-butenyl, 2-methylallyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms.
  • Suitable “lower alkynyl” may include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like, preferably one having 2 to 4 carbon atoms.
  • 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, methanesulfonate, benzenesulfonate, toluenesulfonate, 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, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • R 1, R2, R 3, R4, R8, Y and A are as follows.
  • R is amino, acylamino, for example, ureido, lower alkanoylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, etc.), lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, etc.), hydroxy(lower)alkanoylamino (e.g.
  • lower alkanoylamino e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, etc.
  • lower alkoxycarbonylamino e.g. methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonyla
  • hydroxyacetylamino, etc. protected hydroxy(lower)alkanoylamino such as lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, acetoxypropi ⁇ nylamino, etc. ), lower alkylureido such as 3-lower alkylureido (e.g.
  • (c,-C 7 )-eyeloalkanecarbonylamino e.g. eyelopropanecarbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexanecarbonylamino, cycloheptanecarbonylamino, etc.
  • heterocycliccarbonylamino such as 5- or 6-membered heteromonocycliccarbonylamino (e.g. furoylamino, nicotinoylamino, tetrahydrofurylcarbonylamino, pyperidylcarbonylamino, etc. ), heterocyclic(lower)alkanoylamino such as 5- or
  • 6-membered heteromonocyclic(lower)alkanoylamino e.g. dithiacyclopentylvalerylamino, etc.
  • heterocyclic(lower)alkylaryloxy(lower)alkylureido such as 5- or 6-membered heteromonocyclic(lower)- alkylaryloxy(lower)alkylureido (e.g. pyrrolidinylmethylphenoxypropylureido, etc. )
  • acyl such as (C 3 -C 7 )-cycloalkylcarbamoyl (e.g.
  • lower alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, etc.
  • lower alkoxy(lower)alkyl e.g. methoxyefehyl, methoxypropyl, etc.
  • (C 3 ⁇ C 7 )-cycloalkyl e.g. cyclohexyl, cyclopropyl, cyclopentyl, etc.
  • lower alkenyl e.g. allyl, etc.
  • mono or di or trihalo(lower)alkyl e.g. trifluoroethyl, etc.
  • lower alkynyl e.g. 2-propyn ⁇ l, etc.
  • hydroxy(lower)alkyl e.g. hydroxyethyl, etc.
  • acylamino(lower)alkyl such as lower alkanoylamino- (lower)alkyl, (e.g.
  • acetylaminoethyl, etc. ) ar(lower)alkyl, in which the aryl moiety may be substituted by lower alkoxy, such as di(lower)alkoxyphenyl(lower)alkyl (e.g. dimethoxyphenethyl, etc.), lower alkylthio(lower)alkyl (e.g. methylthioethyl, etc. ) , di(lower)alkylamino(lower)alkyIfuryl(lower)alkylthio- (lower)alkyl (e.g.
  • heterocyclic(lower)alkyl such as furyl(lower)alkyl (e.g. furfuryl, etc.), pyridyl(lower)alkyl (e.g. pyridylethyl, etc.) and indolyl(lower)alkyl (e.g. indolylpropyl, etc.) ; 3 .
  • R is hydrogen; or lower alkyl (e.g. methyl, etc. ) ; and R is hydrogen; or lower alkyl (e.g. methyl, etc. ) ; or A and R are linked together to form lower alkylene (e.g. ethylene, etc. ) ; and
  • R is hydrogen; or R 2 and R8 are linked together to form lower alkylene optionally interrupted by oxygen (e.g. pentamethylene, 3-oxapentamethylene, etc.); and
  • R is hydrogen; or lower alkyl (e.g. methyl, etc.);
  • A is bond; or lower alkylene (e.g. methylene, etc.).
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone, 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 methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone, 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 elimination reaction of the amino protective group.
  • Suitable method for this elimination 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.
  • alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
  • alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • ammonia or the like
  • organic base such as tri(lower)alkylamine
  • 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 (1-3) 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 :
  • 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.
  • reaction when the compound (VIII) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, and the like.
  • a conventional condensing agent such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, 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, acetonitrile, 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, acetonitrile, 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.
  • alcohol e.g. methanol
  • reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lowerJalkylamine, pyridine,
  • N-(lower)alkylmorphorine N,N-di(lower)alkylbenzylamine, or the like. This present reaction includes, within its scope, the
  • the object compound (1-4) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (IV).
  • 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.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (1-5) or a salt thereof can be prepared by reacting the compound (V) 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 e.g. methanol, ethanol, propanol, etc.
  • dioxane 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 (1-7) or a salt thereof can be prepared by reacting the compound (1-6) or a salt thereof with the compound (VII) .
  • This reaction is usually carried out in a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile. chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile. chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound (1-9) or a salt thereof can be prepared by subjecting the compound (1-8) or a salt thereof to elimination reaction of the hydroxy-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.
  • reaction mode and reaction conditions e.g. solvent, reaction temperature, etc.
  • the object compound (1-11) or a salt thereof can be prepared by subjecting the compound (1-10) 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.
  • reaction mode and reaction conditions e.g. solvent, reaction temperature, etc.
  • 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 thiazole 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.), Zollinger-Ellison 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 Campylobacter pyloridis,
  • Helicobacter pyloridis and the like, which are 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, inadmixture 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 mg/body and about 1,000 mg/body may be administered per day.
  • Test compounds (a) 2-[(Allylamino) (amino)methyleneamino]-4-(6- ureidomethylpyridin-2-yl)thiazole dihydrochloride
  • Test A Gastric secretion from lumen perfused stomach in anesthetized rats
  • Rats Male Sprague-Dawley rats weighing about 250 g were used. Rats were deprived of food but allowed free access to water for 24 hours. The animals were anesthetized with 1.25 g/kg urethane intraperitoneally. The abdomen was opened and the gastric lumen was perfured with saline throughout the experiment. The perfusate was titrated by an antotitrator with 25 mM sodium hydroxide as a titrant. Gastric secretion was stimulated by intravenous infusion with histamine (3 mg/kg/hr) . After reaching plateau, test compound (1 mg/kg) was given intravenously. Drug effect was expressed as maximal inhibition by acid output.
  • Test B Anti-microbial activity
  • Test C Inhibition of HCl-aspirin ulcer
  • test compounds 32 mg/kg suspended in 0.1% methylcellulose solution was administered orally 30 minutes before aspirin administration.
  • the animals were sacrificed and their stomachs were removed. The stomach was then fixed with 2% formalin. The length of ulcers was measured for each animal, and percentage of inhibition was calculated by comparing the mean length of ulcers (mm) in the test animals with that in the control animals.
  • Acetic anhydride (1.29 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.10 g) in pyridine (21 ml). The solution was stirred for four hours at ambient temperature and evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-(acetylaminomethyl)-2-pyridinecarbonitrile (1.72 g). mp : 91-92°C
  • Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminometyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50°C for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate.
  • Propionic anhydride (76.3 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (84.1 g) in water (800 ml) under keeping pH 7 ⁇ 8 with 40% aqueous potassium carbonate at ambient temperature and the mixture was stirred at the same temperature for 30 minutes.
  • the aqueous mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give
  • Methanesulfonic acid (18.6 g) was added to a solution of 2-acetyl-6-(propionylaminomethyl)pyridine (40.0g) in dioxane (800 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes. Bromine (34.1 g) was added slowly to the mixture at room temperature. The mixture was heated at 50°C for 3 hours. To the mixture sodium hydrogencarbonate (65.2 g) , thiourea (17.7 g) and methanol (800 ml) was added. The mixture was heated at 50°C for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (700 ml).
  • Diammomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethylene- amino)thiazole (430 mg) . mp 255-256°C IR (DMSO-dg, ⁇ ) : 1.91 (3H, s), 4.54 (2H, d,
  • reaction mixture was added a mixture of ethyl acetate tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate.
  • the separated organic layer was washed with brine and dried over magnesium sulfate.
  • the solvent was removed by concentration and the residue was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-(6-cyclobutanecarbonyl- aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole
  • Example 5 A mixture of 2-(diaminomethyleneamino)-4-[6-(1-tert- butoxycarbonylpiperidin-3-y1)carbonylaminomethylpyridin-2- yl]thiazole (1.9 g) and 4N-methanolic hydrogen chloride (40 ml) was stirred for 7 hours at ambient temperature. To the reaction mixture was added a tetrahydrofuran (40 ml) and the isolated precipitate was collected by filtration. The precipitate was added to water and adjusted to pH 13 with 5N-sodium hydroxide. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran.
  • Example 18 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 20 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 22 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 39 A mixture of 2-acetylaminomethyl-6- bromoacetylpyridine (3.0 g) and (amino) [ (2-propynyl)- amino]methylenethiourea (2.1 g) in ethanol (20.0 ml) was stirred for 2 hours at 50°C and ethyl acetate (20 ml) was added to the reaction mixture at ambient temperature under stirring. The isolated precipitate was collected by filtration and the precipitate was added to a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the separated organic layer was dried over magnesium sulfate.
  • Example 44 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 51 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 55 The following compound was obtained according to a similar manner to that of Example 11.
  • Example 59 Methyl isocyanate (0.4 ml) was added to a mixture of 2-[ (allylamino) (amino)methyleneamino]-4-(6-aminomethyl- pyridin-2-yl)thiazole trihydrochloride (2.0 g) and triethylamine (2.1 ml) in a mixture of tetrahydrofuran (30.0 ml) and methanol (10.0 ml) and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate.
  • Example 61 The following compound was obtained according to a similar manner to that of Example 59.
  • Example 62 The following compound was obtained according to a similar manner to that of Example 60.
  • Propionic anhydride (0.7 ml) was added to a mixture of 2-[(amino) [(2-methoxyethyl)amino]methyleneamino]-4- (6-methylaminopyridin-2-yl)thiazole trihydrochloride (2.0 g) and triethylamine (2.8 ml) in tetrahydrofuran (40.0 ml) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. The mixture was added a mixture of ethyl acetate, tetrahydrofuran and water and the separated organic layer was dried over magnesium sulfate.
  • Example 65 The following compound was obtained according to a similar manner to that of Example 65.
  • Example 72 The following compound was obtained according to a similar manner to that of Example 71.
  • Example 74 A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [ (allylamino) (amino)methyleneamino]thiazole (8.0 g) and cone, hydrochloric acid (20.2 ml) in ethanol (80 ml) was heated under reflux for 15 hours. The solvent was removed by concentration and the residue was triturated with isopropyl alcohol. The precipitate was collected by filtration to give 2-[(allylamino)(amino)methyleneamino]- 4-(6-aminomethylpyridin-2-yl)thiazole trihydrochloride (8.94 g). mp : 164-166°C IR (Nujol) : 3320, 1680, 1630 cm "1
  • Example 76 The following compound was obtained according to a similar manner to that of Example 74.
  • Example 78 4N-Dioxanic hydrogen chloride (0.82 ml) was added a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2- [ (amino) (methylamino)methyleneamino]thiazole (1.0 g) in methanol (5.0 ml) and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added a diisopropyl ether (5 ml) and the isolated precipitate was collected by filtration.
  • Example 79 The following compound was obtained according to a similar manner to that of Example 78.
  • Methanesulfonic acid (0.21 ml) was added a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2-[ (amino)- (methylamino)methyleneamino]thiazole (1.0 g) in methanol (5.0 ml) and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added a diisopropyl ether (5.0 ml) and the isolated precipitate was collected by filtration.
  • Example 80 The following compound was obtained according to a similar manner to that of Example 80.

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Abstract

L'invention se rapporte à des dérivés de thiazole représentés par la formule (I), ou à un sel de ces dérivés, qui sont utiles comme agent antiulcéreux, comme antagoniste des récepteurs de H2 ou comme agent antimicrobien.
PCT/JP1992/000279 1991-03-13 1992-03-09 Derives de thiazole WO1992016526A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027606A1 (fr) * 1993-05-28 1994-12-08 Unisearch Limited Procede de traitement de l'infection provoquee par helicobacter pylori
WO1994029304A1 (fr) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Derives de thienylthiazole
WO2000049015A1 (fr) * 1999-02-17 2000-08-24 Fujisawa Pharmaceutical Co., Ltd. Composes pyridine et leur utilisation pharmaceutique
WO2005082871A3 (fr) * 2004-02-19 2005-11-10 Abbott Gmbh & Co Kg Composes de guanidine et leur utilisation comme elements de liaison pour les recepteurs 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
EP0050458A2 (fr) * 1980-10-14 1982-04-28 Pfizer Inc. Guanidino-2-hétéroarylthiazoles-4 et produits pharmaceutiques qui les contiennent
EP0161841A1 (fr) * 1984-04-30 1985-11-21 Pfizer Inc. 2-(Guanidino-N-substitué)-4-hétéroarylthiazoles comme agents anti-ulcères
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
EP0050458A2 (fr) * 1980-10-14 1982-04-28 Pfizer Inc. Guanidino-2-hétéroarylthiazoles-4 et produits pharmaceutiques qui les contiennent
EP0161841A1 (fr) * 1984-04-30 1985-11-21 Pfizer Inc. 2-(Guanidino-N-substitué)-4-hétéroarylthiazoles comme agents anti-ulcères
EP0417751A2 (fr) * 1989-09-15 1991-03-20 Fujisawa Pharmaceutical Co., Ltd. Thiazoles, procédés de préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 101, no. 1, 2 July 1984, (Columbus, Ohio, US), see pages 611-612, abstract no. 7147r, & JP,A,5936674 (YAMANOUCHI PHARMACEUTICAL CO., LTD) 28 February 1984 *
Chemical Abstracts, vol. 103, no. 3, 22 July 1985, (Columbus, Ohio, US), see page 577, abstract no. 22581n, & JP,A,59225186 (YAMANOUCHI PHARMACEUTICAL CO., LTD) 18 December 1984 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027606A1 (fr) * 1993-05-28 1994-12-08 Unisearch Limited Procede de traitement de l'infection provoquee par helicobacter pylori
WO1994029304A1 (fr) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Derives de thienylthiazole
WO2000049015A1 (fr) * 1999-02-17 2000-08-24 Fujisawa Pharmaceutical Co., Ltd. Composes pyridine et leur utilisation pharmaceutique
US6521643B1 (en) 1999-02-17 2003-02-18 Fujisawa Pharmaceutical Co., Ltd. Pyridine compounds and their pharmaceutical use
WO2005082871A3 (fr) * 2004-02-19 2005-11-10 Abbott Gmbh & Co Kg Composes de guanidine et leur utilisation comme elements de liaison pour les recepteurs 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
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
EP2380885A1 (fr) * 2004-02-19 2011-10-26 Abbott GmbH & Co. KG Composés de guanidine et leur utilisation comme partenaire de liaison pour récepteurs 5-HT5
US8431604B2 (en) 2004-02-19 2013-04-30 Abbott Gmbh & Co. Kg Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors
US8481576B2 (en) 2004-02-19 2013-07-09 Abbott Gmbh & Co. Kg Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors
US9475782B2 (en) 2004-02-19 2016-10-25 AbbVie Deutschland GmbH & Co. KG Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors

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