WO1996017850A1 - Composes de cepheme et leur utilisation pharmaceutique - Google Patents

Composes de cepheme et leur utilisation pharmaceutique Download PDF

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Publication number
WO1996017850A1
WO1996017850A1 PCT/JP1995/002505 JP9502505W WO9617850A1 WO 1996017850 A1 WO1996017850 A1 WO 1996017850A1 JP 9502505 W JP9502505 W JP 9502505W WO 9617850 A1 WO9617850 A1 WO 9617850A1
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Prior art keywords
alkyl
cephem
suitable substituent
thiadiazol
amino
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PCT/JP1995/002505
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English (en)
Inventor
Yoshiki Yoshida
Hiroshi Sasaki
Keiji Matsuda
Hisashi Takasugi
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Fujisawa Pharmaceutical Co., Ltd.
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Publication date
Priority claimed from GBGB9424865.5A external-priority patent/GB9424865D0/en
Priority claimed from GBGB9520714.8A external-priority patent/GB9520714D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP8517485A priority Critical patent/JPH10510258A/ja
Priority to AU41233/96A priority patent/AU4123396A/en
Priority to EP95939389A priority patent/EP0796263A1/fr
Publication of WO1996017850A1 publication Critical patent/WO1996017850A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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

Definitions

  • This invention relates to new use of cephem compounds and pharmaceutically acceptable salts thereof.
  • cephem compounds and pharmaceutically acceptable salts thereof which have antimicrobial activity against He l icobac t er pylori
  • a pharmaceutical composition comprising said cephem compound or a pharmaceutically acceptable salt thereof and to a method for the prophylaxis and/or treatment of ulcer and the prophylaxis of stomach cancer in human being and animals.
  • acid secretion inhibitors such as H 2 -blocker and proton pump inhibitor, and mucosalprotective factor enhancers
  • H 2 -blocker and proton pump inhibitor have been mainly used for the treatment of peptic ulcers such as gastric ulcer and duodenal ulcer.
  • mucosalprotective factor enhancers have been mainly used for the treatment of peptic ulcers such as gastric ulcer and duodenal ulcer. While the use of H.-blocker and proton pump inhibitor shortens treatment period, the problem of possible recurrence of the disease still remains to be solved.
  • Hel i cobac ter py lori is a Gram negative bacterium found in the mucous layer on the gastric epithelium of humans, and infection with H. py lori has been found to induce gastrointestinal diseases, such as chronic gastritis and peptic ulcer (e.g., gastric ulcer and duodenal ulcer).
  • chronic gastritis and peptic ulcer e.g., gastric ulcer and duodenal ulcer.
  • the drug having an antimicrobial action on H. pylori is useful for the treatment and/or prevention of gastritis and ulcer, and a new drug having such pharmacological action is desired.
  • One object of this invention is to provide new use of cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activity against He l i cobact er pylori .
  • cephem compounds and pharmaceutically acceptable salts thereof are useful as anti-tfei icobacter py lori agents, anti- gastritis agents, antiulcer agents and anticancer agents.
  • the cephem compounds and pharmaceutically acceptable salts thereof may be used as ant ⁇ -He I icobacter pylori agents, anti-gastritis agents, antiulcer agents and anticancer agents in combination with an acid secretion inhibitor such as an H 2 -blocker and a proton pump inhibitor.
  • a further object of this invention is to provide a pharmaceutical composition for the prophylactic and/or therapeutic treatment of diseases caused by Hel i cobacter pylori infection in human being or animals, comprising, as an active ingredient, said cephem compound or a pharmaceutically acceptable salt thereof.
  • a further object of this invention is to provide a therapeutical method for the prophylaxis and/or treatment of the diseases caused by Hel icobacter pylori infection such as gastritis, ulcer [e.g. peptic ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer etc.) etc.], MALT lymphoma, non-ulcer dyspepsia, and stomach cancer in human being and animals.
  • the diseases caused by Hel icobacter pylori infection such as gastritis, ulcer [e.g. peptic ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer etc.) etc.], MALT lymphoma, non-ulcer dyspepsia, and stomach cancer in human being and animals.
  • cephem compounds used in the present invention can be represented by the following general formula (I) :
  • R 1 is aryl (lower)alkyl which may have one or more suitable substituent(s) , arylthio(lower)alkyl , lower alkenylthio(lower)alkyl which may have one or more suitable substituent(s) , or a group of the formula: R 4 -A- or R*-S-A- in which R* is heterocyclic group which may have one or more suitable substituent(s) , and A is lower alkylene which may have one or more suitable substituent(s) or lower alkenylene, R 2 is heterocyclic group which may have one or more suitable substituent(s) , or heterocyclic(lower)- alkyl, and R 3 is carboxy or protected carboxy.
  • the cephem compound (I) and a salt thereof can be prepared by processes as illustrated in the following reaction schemes. Process 1
  • R 1 and R 2 are as defined above, R 5 is protected hydroxy, and R 6 is protected carboxy.
  • lower is intended to mean a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl” moiety in "aryl(lower)alkyl", “arylthio(lower)alkyl”, “lower alkenylthio(lower)alkyl”, “lower alkylthio”, “phenyl (lower) alkyl”, “phenylthio(lower)alkyl”, etc. include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert-butyl , pentyl, isopentyl and hexyl, preferable ones having 1 to 4 carbon atoms.
  • Suitable "aryl” and “aryl” moiety in “aryl (lower)alkyl”, “arylthio(lower)alkyl” and “arylthio” include Cs-Ci. aryl, such as phenyl, naphthyl, tolyl, xylyl, mesityl and cumenyl, in which more preferred one is phenyl.
  • Suitable "aryl (lower)alkyl” includes benzyl, phenethyl, a -methylbenzyl and naphthylmethyl , in which more preferred one is phenyl (lower)alkyl and the most preferred one is benzyl.
  • the aryl (lower)alkyl mentioned above may have one or more, preferably 1 to 3 suitable substituent(s) on the aromatic ring, such as lower alkyl, lower alkoxy, halogen, halo(lower)- alkyl, hydroxy, amino, lower alkyla ino, acylamino, cyano, nitro, carboxy, acyl and lower alkylthio, in which more preferred ones are halogen, nitro, hydroxy, amino and lower alkyl.
  • suitable substituent(s) on the aromatic ring such as lower alkyl, lower alkoxy, halogen, halo(lower)- alkyl, hydroxy, amino, lower alkyla ino, acylamino, cyano, nitro, carboxy, acyl and lower alkylthio, in which more preferred ones are halogen, nitro, hydroxy, amino and lower alkyl.
  • Suitable "lower alkyl” moiety in "aryl(lower)alkyl which may have one or more suitable substituent(s)” may have one or more suitable substituent(s) , such as hydroxy, amino and the like.
  • Suitable "arylthio(lower)alkyl” includes phenylthio ethyl, phenylthioethyl , phenylthiopropyl and phenylthiobutyl , in which more preferred one is phenylthio(lower)alkyl and the most preferred one is phenylthiomethyl.
  • Suitable "lower alkenyl” moiety in “lower alkenylthio(lower)alkyl” and “lower alkenylthio” includes straight or branched alkenyl having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl , 1-pentenyl and 2-pentenyl, preferable ones having 2 to 4 carbon atoms.
  • Suitable "lower alkenylthio(lower)alkyl” includes vinylthiomethyl, vinylthioethyl , vinylthiopropyl , 1- propenylthiomethyl , 1-propenylthioethyl , allylthiomethyl and allylthioethyl , in which more preferred one is (C ⁇ -C.)- alkenylthio(C ⁇ -C ⁇ )alkyl.
  • the lower alkenylthio(lower)alkyl mentioned above may have one or more, preferably 1 to 3 suitable substituent(s) such as cyano and carbamoyl.
  • Suitable "lower alkoxy” includes straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxyl, preferable ones having 1 to 4 carbon atoms.
  • Suitable "halogen” includes chloro, bro o, fluoro and iodo.
  • halo(lower)alkyl includes chloromethyl, fluoromethyl, bromomethyl, difluoromethyl , dichloromethyl, trifluoro ethyl , trichloro ethyl and 2-fluoroethyl .
  • Suitable "lower alkylamino” includes mono- or di(lower)- alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, dimethyla ino, diethylamino, dipropylamino, dibutylamino, diisopropylamino, dipentylamino, dihexylamino and N-methyl-N-ethylamino.
  • acyl and “acyl” moiety in “acylamino” include carbamoyl, thiocarbamoyl , sulfamoyl, an aliphatic acyl and an aromatic acyl derived from carbamic, sulfonic, caboxylic acids or their thio acids.
  • the aliphatic acyl includes saturated or unsaturated, acyclic or cyclic ones, such as lower alkanoyl (e.g. for yl, acetyl , propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl ) , lower alkanesulfonyl (e.g. methanesulfonyl , ethanesulfonyl , propanesulfonyl ) , lower alkoxycarbonyl (e.g.
  • lower alkanoyl e.g. for yl, acetyl , propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl
  • lower alkanesulfonyl e.g. methanesulfonyl , ethanesulfonyl
  • lower alkenoyl e.g. acryloyl, methacryloyl, crotonoyl
  • C3-C7cycloalkanecarbonyl e
  • the aromatic acyl includes aroyl (e.g. benzoyl, nitorobenzoyl, toluoyl, xyloyl) and arenesulfonyl (e.g. benzenesulfonyl, tosyl).
  • aroyl e.g. benzoyl, nitorobenzoyl, toluoyl, xyloyl
  • arenesulfonyl e.g. benzenesulfonyl, tosyl
  • Suitable "lower alkylthio” includes ethylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert- butylthio, pentylthio, isopentylthio and hexylthio, in which more preferred one is (C1-C4 )alkylthio.
  • Suitable "lower alkenylthio” includes vinylthio, 1- propenylthio, allylthio, isopropenylthio, 1-butenylthio, 2- butenylthio, 1-pentenylthio and 2-pentenylthio, in which more preferred one is (C2-C4 )alkenylthio.
  • Suitable "arylthio” includes phenylthio, naphthylthio, tolylthio, xylylthio, mesitylthio and cumenylthio, in which more preferred one is phenylthio.
  • heterocyclic moiety in “heterocyclic group which may have one or more suitable substituent(s)” or “heterocyclic(lower)alkyl” includes heterocyclic groups such as: unsaturated 3 to 8-membered (more preferably 5 or 6- me bered) hetero onocyclic group containing 1 to 4 nit ' rogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.
  • unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl , etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • the heterocyclic group mentioned above may have one or more, preferably 1 to 3 suitable substituent(s) such as lower alkyl, amino, acylamino, lower alkylthio, arylthio, lower alkenylthio lower alkylamino, di (lower)alkylamino, pyrrolidinyl and morpholinyl.
  • suitable substituent(s) such as lower alkyl, amino, acylamino, lower alkylthio, arylthio, lower alkenylthio lower alkylamino, di (lower)alkylamino, pyrrolidinyl and morpholinyl.
  • heterocyclic(lower)alkyl for R 2 include lower alkyl having unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), more preferred one is (C ⁇ -Cs)alkyl having pyrazolyl, and the most preferred one is pyrazolylmethyl.
  • heterocyclic group for R* include unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), and unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s), and more preferred ones are thiazolyl, thiadiazolyl (e.g. 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl ), tetrazolyl, pyridyl and thienyl.
  • thiazolyl thiadiazolyl (e.g. 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl ), tetrazolyl, pyridyl and thienyl.
  • Suitable "lower alkylene” in “lower alkylene which may have one or more suitable substituent(s)” includes straight or branched ones such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene and hexamethylene, in which more preferred one is C1-C4 alkylene, and the most preferred ones are methylene and ethylene.
  • suitable substituent(s) in “lower alkylene which may have one or more suitable substituent(s)” include lower alkoxyi ino, in which more preferred one is methoxyimino.
  • Suitable "lower alkenylene” includes straight or branched one having 2 to 6 carbon atom(s) such as vinylene, propenylene, l-(or 2-)butenylene, l-(or 2- or 3-)pentenylene, l-(or 2- or 3-)hexenylene, methylvinylene, ethylvinylene, l-(or 2- or 3-) methylpropenylene, l-(or 2- or 3-)ethylpropenylene, l-(or 2- or 3- or 4-)methyl-l-(or 2-)butenylene, and the like, in which more preferred one is (C 2 -C 4 )alkenylene, and the most preferred one is vinylene.
  • Suitable "protected carboxy” includes carboxy group protected by conventional protective group such as substituted or unsubstituted lower alkoxycarbonyl (e.g. ethoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, butoxycarbonyl, tert- butoxycarbonyl , pentyloxycarbonyl , hexyloxycarbonyl, 2- (dimethylamino)ethoxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl) , substituted or unsubstituted aryloxycarbony1 (e.g.
  • aryl (lower)alkoxycarbonyl for example, mono or di or triphenyl (lower)alkoxycarbonyl which may be substituted with nitro (e.g. benzyloxycarbonyl , phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl) .
  • Suitable "protected hydroxy” includes hydroxy protected by conventional protective group, for example, a substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g. methoxy ethoxy) , lower alkoxy(lower)alkoxy(lower)alkoxy (e.g. methoxyethoxy- methoxy), a substituted or unsubstituted aryl (lower)alkoxy (e.g. benzyloxy, nitrobenzyloxy) ; acyloxy such as lower alkanoyloxy (e.g. acetoxy, propionyloxy, pivaloyloxy) , aroyloxy (e.g.
  • alkanesulfonyloxy e.g. methanesulfonyloxy, ethanesulfonyloxy
  • tri(lower)alkylsilyloxy e.g. trimethylsilyloxy
  • Suitable salts of the object compound (I) are pharmaceutically acceptable salts such as conventional non- toxic salts and include an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, aleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate) , an inorganic acid addition salt (e.g ⁇ hydrochloride, hydrobromide, sulfate, phosphate), an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt).
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, aleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate
  • an inorganic acid addition salt e.g ⁇ hydrochloride, hydrobromide, sulfate,
  • the preferred examples of the compound (I) used in the present invention are as follows: 1) the compound of the formula (I) wherein
  • R 1 is arylthio(lower)alkyl
  • R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s); more preferred one is that wherein
  • R 1 is phenylthio(lower)alkyl , and R 2 is triazolyl ; and the most preferred one is that wherein R 1 is phenylthiomethyl, and R 2 is l,2,4-triazol-3-yl.
  • R 1 is arylthio(lower)alkyl
  • R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) ; more preferred one is that wherein R 1 is phenylthio(lower)alkyl, and R 2 is thiadiazolyl ; and the most preferred one is that wherein R 1 is phenylthiomethyl, and R 2 is l,3,4-thiadiazol-2-yl or l,2,3-thiadiazol-5-yl.
  • R 1 is lower alkenylthio(lower)alkyl having cyano
  • R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s); more preferred one is that wherein
  • R 1 is (C 2 -C 6 )alkenylthio(C ⁇ -C 6 )alkyl having cyano
  • R 2 is triazolyl ; and the most preferred one is that wherein
  • R 1 is ethenylthiomethyl having cyano
  • R 2 is l,2,4-triazol-3-yl.
  • R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) or unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have a suitable substituent; more preferred one is that wherein R 1 is phenyl (lower)alkyl, and
  • R 2 is triazolyl, thiadiazolyl or thiadiazolyl having lower alkyl; and the most preferred one is that wherein R 1 is benzyl, and R 2 is l,2,3-triazol-5-yl, l,2,4-triazol-3-yl, l,2,3-thiadiazol-5-yl, l,3,4-thiadiazol-2-yl or 5-methyl-l,3,4-thiadiazol-2-yl.
  • R 1 is a group of the formula: R*-A- or R*-S-A- in which R 4 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have a suitable substituent, and A is lower alkylene, and R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s); more preferred one is that wherein R 1 is thiazolylmethyl having a suitable substituent, thiadiazolylmethyl which may have a suitable substituent or thiadiazolylthiomethyl having a suitable substituent, and R 2 is triazolyl; and the most preferred one is that wherein R 1 is (l,2,5-thiadiazol-3-yl)methyl, (2-amino-thiazol-4-yl) methyl, (2-formylamino-thiazol-4-yl )methyl or (5-
  • R 1 is arylthio(lower)alkyl
  • R 2 is unsaturated 3 to 8-membered heteromonocycli group containing 1 to 4 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) ; more preferred one is that wherein
  • R 1 is phenylthio(lower)alkyl
  • R 2 is triazolyl which may have lower alkyl; and the most preferred one is that wherein
  • R 1 is phenylthiomethyl
  • R 2 is l,2,4-triazol-3-yl or l-methyl-l,3,4-triazol-2-yl .
  • R 1 is arylthio(lower)alkyl
  • R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) ; more preferred one is that wherein R 1 is phenylthio(lower)alkyl, and R 2 is thiadiazolyl which may have lower alkyl; and the most preferred one is that wherein R 1 is phenylthiomethyl, and
  • R 2 is l,3,4-thiadiazol-2-yl, l,2,3-thiadiazol-5-yl or 5-methyl-l,3,4-thiadiazol-2-yl . 3) the compound of the formula (I) wherein
  • R 1 is lower alkenylthio(lower)alkyl having cyano
  • R 2 is a) lower alkyl having unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), b) unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), or c) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) ; more preferred one is that wherein R 1 is lower alkenylthio(lower)alkyl having cyano, and R 2 is triazolyl, pyrazolyl (lower)alkyl or thiadiazolyl; and the most preferred one is that wherein R 1 is ethenylthiomethyl having cyano, and R 2 is l,2,4-triazol-3-yl, l,2,3-triazol-5-yl, (pyrazol
  • R 1 is aryl (lower)alkyl which may have 1 to 3 suitable substituent(s)
  • R 2 is a) unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) , or b) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have a suitable substituent; more preferred one is that wherein
  • R 1 is phenyl (lower)alkyl which may have a halogen
  • R 2 is triazolyl, thiadiazolyl, thiadiazolyl having lower alkyl, thiadiazolyl having amino, triazolyl having lower alkyl, thiazolyl or pyridyl; and the most preferred one is that wherein R 1 is benzyl, chlorobenzyl or fluorobenzyl, and R 2 is l,2,3-triazol-5-yl, l,2,4-triazol-3-yl, l,2,3-thiadiazol-5-yl , l,3,4-thiadiazol-2-yl , 5-methyl-l,3,4-thiadiazol-2-yl, 5-methyl-l,3,4- triazol-2-yl , 5-amino-l,3,4-thiadiazol-2-yl , 2-thiazolyl or 2-pyridyl.
  • R 1 is a group of the formula: R 4 -A- or R*-S-A- in which R 4 is a) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have a suitable substituent, or b) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s), and A is lower alkylene or lower alkenylene, and R 2 is a) unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) , or b) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) ; more preferred one is that wherein
  • R i is thiazolylmethyl having a suitable substituent, thiadiazolylmethyl which may have a suitable substituent, thiadiazolylthiomethyl having a suitable substituent, or thienyl ethyl
  • R 2 is triazolyl, thiadiazolyl, thiadiazolyl having methyl or thiadiazolyl having amino; and the most preferred one is that wherein R i is (l,2,5-thiadiazol-3-yl)methyl, (2-amino-thiazol-4-yl )- methyl, (2-formylamino-thiazol-4-yl)methyl, (5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl, 2-thienylmethyl or 3-thienylmethyl, and R 2 is l,2,4-triazol-3-yl, l,3,4-thiadiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl or 5-amino-l,3,4
  • R i is phenyl (lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of halogen, nitro, hydroxy and amino; phenylthio(lower)alkyl; lower alkenylthio(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of cyano and acyl; or a group of the formula:
  • R «-A- or R 4 -S-A- in which R 4 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) ; unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) selected from the group consisting of amino, acylamino and lower alkyl; or unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) ; A is lower alkylene which may have 1 to 3 lower alkoxy- imino; or lower alkenylene; and R 2 is unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl and amino; unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur
  • R 2 is a) unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) , or b) unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have 1 to 3 suitable substituent(s) , and R 3 is carboxy; more preferred one is that wherein R is phenylthio(lower)alkyl, R 2 is triazolyl which may have lower alkyl or thiadiazolyl which may have lower alkyl, and R 3 is carboxy; and the most preferred one is that wherein R i is phenylthiomethyl,
  • R 2 is l,2,4-triazol-3-yl, l-methyl-l,3,4-triazol-2-yl , l,3,4-thiadiazol-2-yl, l,2,3-thiadiazol-5-yl or 5-methyl-l,3,4-thiadiazol-2-yl, and R 3 is carboxy.
  • R is ethenylthio ethyl having cyano
  • R 2 is l,2,4-triazol-3-yl, l,2,3-triazol-5-yl,
  • R 1 is benzyl which may have a halogen
  • R 2 is triazolyl, thiadiazolyl, thiadiazolyl having lower alkyl, thiadiazolyl having amino, thiadiazolyl having lower alkylamino, triazolyl having lower alkyl, thiazolyl or pyridyl, and R 3 is carboxy; more preferred one is that wherein R is benzyl, chlorobenzyl or fluorobenzyl, R 2 is l,2,3-triazol-5-yl, l,2,4-triazol-3-yl, l,2,3-thiadiazol-5-yl, l,3,4-thiadiazol-2-yl ,
  • R 3 is carboxy; and the most preferred one is that wherein R i is benzyl, R 2 is 5-methyl-l,3,4-thiadiazol-2-yl or
  • R 3 is carboxy.
  • R 2 is l,2,4-triazol-3-yl, l,3,4-thiadiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-amino-l,3,4-thiadiazol-2-yl or 5-methylamino-l,3,4-thiadiazolyl-2-yl , and
  • R 3 is carboxy
  • the compound (III) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to elimination of for yl group in the presence of an acid.
  • Suitable acid includes an organic acid (e.g. formic acid, acetic acid, propionic acid) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid).
  • organic acid e.g. formic acid, acetic acid, propionic acid
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid
  • the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, chloroform, tetrachloro ethane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, chloroform, tetrachloro ethane, tetrahydrofuran, a mixture thereof or any other 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 compound (V) or a salt thereof can be prepared by reacting the compound (III) or its reactive derivative at the amino group or a salt thereof with the compound (IV) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the carboxy group of the compound (IV) includes an acid halide, an acid anhydride, an activated amide and an activated ester.
  • Suitable exmaples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g.
  • acetic acid propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), or aromatic carboxylic acid (e.g. benzoic acid); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g.
  • Suitable salts of the compound (IV) and its reactive derivative include a base salt such as an alkali metal salt (e.g. sodium salt, potassium salt), an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt and an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt).
  • a base salt such as an alkali metal salt (e.g. sodium salt, potassium salt), an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt and an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt).
  • Suitable reactive derivative at the amino group of the compound (III) includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde or ketone; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl )- aceta ide, mono(trimethylsilyl)acetamide or bis(tri ethylsilyl)- urea; and a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene.
  • a carbonyl compound such as aldehyde or ketone
  • silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl )- aceta ide, mono(trimethylsilyl)acetamide or bis(tri ethylsilyl)- urea
  • the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride,
  • the reaction when the compound (IV) 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 N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethyl- carbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)- carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropyl- carbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-(2-methylimidazole) ; pentamethyleneketene-N- cyclohexyli ine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-
  • ethyl chloroformate isopropyl chloroformate
  • triphenylphosphine 2-ethyl-7-hydroxybenz- isoxazolium salt
  • l-(p-chlorobenzenesulfonyloxy)-6-chloro- lH-benzotriazole or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal hydrogencarbonate, tri (lower)alkylamine, pyridide, N-(lower)- alkylmorpholine or N,N-di (lower)alkylbenzylamine.
  • an inorganic or organic base such as an alkali metal hydrogencarbonate, tri (lower)alkylamine, pyridide, N-(lower)- alkylmorpholine or N,N-di (lower)alkylbenzylamine.
  • the compound (lb) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof with the compound (VI) or a salt thereof.
  • Suitable salts of the compound (VI) include alkali metal salts (e.g. sodium salt, potassium salt).
  • the reaction is usually carried out in the presence of a base.
  • a base include organic bases such as triethylamine, trimethylamine, N,N-diisopropylethylamine, dimethylamine, N-methylmorpholine and pyridine, and inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), and alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate) .
  • alkali metal hydroxides e.g. sodium hydroxide, potassium hydroxide
  • alkali metal carbonates e.g. sodium carbonate, potassium carbonate
  • alkali metal hydrogencarbonates e.g. sodium hydrogencarbonate, potassium hydrogencarbonate
  • the reaction is usually carried out in a solvent such as water, acetone, acetonitrile, dioxane, tetrahydrofuran, N,N- dimethylformamide, dimethyl sulfoxide, 1,2-dimethoxyethane, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, acetone, acetonitrile, dioxane, tetrahydrofuran, N,N- dimethylformamide, dimethyl sulfoxide, 1,2-dimethoxyethane, a mixture thereof or any other 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 (la) or a salt thereof can be prepared by subjecting the compound (lb) or a salt thereof to an elimination reaction of the carboxy-protective group.
  • Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate), alkali metal acetates (e.g. sodium acetate, potassium acetate), alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate), and alkali metal hydrogen phosphates (e.g.
  • inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate),
  • disodium hydrogen phosphate dipotassium hydrogen phosphate
  • organic bases such as trialkylamines (e.g. trimethylamine, triethyla ine) , picoline, N-methylpyrrolidine, N-methylmorpholine, and 1,5- diazabicy lo[4.3.0]non-5-one, l,4-diazabicyclo[2.2.2]octane, and l,5-diazabicyclo[5.4.0]undecene-5.
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid) and inorgnic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid).
  • organic acids e.g. formic acid, acetic acid, propionic acid
  • inorgnic acids e.g. hydrochloric acid, hydrobromic acid, sulfuric acid.
  • the present hydrolysis is usually carried out in water or an organic solvent or a mixed solvent thereof.
  • the reaction temperature is not critical, and it may be selected suitably in accordance with the kind of carboxy protective group and elimination method.
  • the elimination using a Lewis acid is preferable for eliminating a substituted or unsubstituted aryl (lower)alkyl ester, and carried out by reacting the compound (lb) or a salt thereof with a Lewis acid.
  • the Lewis acid are boron trihalides (e.g. boron trichloride, boron trifluoride) , titanium tetrahalides (e.g. titanium tetrachloride, titanium tetrabro ide), tin tetrahalides (e.g. tin tetrachloride, tin tetrabromide) , aluminium halides (e.g.
  • This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane), alkylene halide (e.g. methylene chloride, ethylene chloride), diethyl ether, carbon disulfide or any other solvent which does not adversely influence the reaction.
  • cation trapping agents e.g. anisole, phenol
  • alkylene halide e.g. methylene chloride, ethylene chloride
  • diethyl ether diethyl ether
  • carbon disulfide e.g. methylene chloride, ethylene chloride
  • any other solvent which does not adversely influence the reaction.
  • the reduction elimination can be preferably conducted for eliminating a protective group such as halo(lower)alkyl (e.g 2- iodoethyl, 2,2,2-trichloroethyl) ester, and aryl (lower)alkyl (e.g. benzyl) ester.
  • a protective group such as halo(lower)alkyl (e.g 2- iodoethyl, 2,2,2-trichloroethyl) ester, and aryl (lower)alkyl (e.g. benzyl) ester.
  • the reduction applicable for the elimination reaction includes the reduction using a combination of a metal (e.g. zinc, zinc amalgam) or a salt of chromium compound (e.g. chromous chloride, chromous acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel) .
  • a metal e.g. zinc, zinc amalgam
  • a salt of chromium compound e.g. chromous chloride, chromous acetate
  • an organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid
  • a conventional metallic catalyst e.g. palladium carbon, Raney nickel
  • reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the compound (VII) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (VI) or a salt thereof.
  • reaction can be carried out in substantially the same manner as in Process 3, and therefore the reaction mode and reaction conditions (e.g. bases, solvent, reaction temperature) of this reaction are to be referred to those as explained in Process 3.
  • reaction mode and reaction conditions e.g. bases, solvent, reaction temperature
  • the compound (VIII) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to elimination of formyl group in the presence of an acid.
  • the compound (lb) or a salt thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (IV) or its reactive derivative at the carobxy group or a salt thereof.
  • reaction can be carried out in substantially the same manner as in Process 2, and therefore the reaction mode and reaction conditions (e.g. reactive derivatives, condensing agents, solvent, reaction temperature) of this reaction are to be referred to those as explained in Process 2.
  • reaction mode and reaction conditions e.g. reactive derivatives, condensing agents, solvent, reaction temperature
  • the compound (IX) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to an elimination reaction of the carboxy-protective group.
  • reaction can be carried out in substantially the same manner as in Process 4, and therefore the reaction mode and reaction conditions (e.g. bases, acids, catalysts, solvent, reaction temperature) of this reaction are to be referred to those as explained in Process 4.
  • reaction mode and reaction conditions e.g. bases, acids, catalysts, solvent, reaction temperature
  • the compound (la) or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound (VI) or a salt thereof.
  • the compound (X) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to an elimination reaction of the carboxy-protective group.
  • reaction can be carried out in substantially the same manner as in Process 4, and therefore the reaction mode and reaction conditions (e.g. bases, acids, catalysts, solvent, reaction temperature) of this reaction are to be referred to those as explained in Process 4.
  • reaction mode and reaction conditions e.g. bases, acids, catalysts, solvent, reaction temperature
  • the compound (la) or a salt thereof can be prepared by reacting the compound (X) or its reactive derivative at the amino group or a salt thereof with the compound (IV) or a salt thereof.
  • reaction can be carried out in substantially the same manner as in Process 2, and therefore the reaction mode and reaction conditions (e.g. reactive derivatives, condensing agents, solvent, reaction temperature) of this reaction are to be referred to those as explained in Process 2.
  • reaction mode and reaction conditions e.g. reactive derivatives, condensing agents, solvent, reaction temperature
  • the starting compound (II) can be prepared by the known method such as disclosed in Japanese Patent Publication No. 52- 83492.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography or reprecipitation.
  • each of the object compound (I) may include one or more steroisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) or double bond(s) and all such isomers and mixtures thereof are included within the scope of this invention.
  • cephem compound (I) and a pharmaceutically acceptable salt thereof include a solvate [e.g., enclosure compound (e.g., hydrate, etc.)].
  • cephem compound (I) and a pharmaceutically acceptable salt thereof include both their crystal form and non-crystal form.
  • cephem compound (I) and pharmaceutically acceptable salts thereof are stable even in a strong acid such as gastric juice.
  • cephem compound (I) and pharmaceutically acceptable salts thereof possess antimicrobial activity against H. pylori , and are useful for the prophylaxis and/or treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer), MALT lymphoma and non-ulcer dyspepsia and the prophylaxis of stomach cancer.
  • the cephem compound (I) and pharmaceutically acceptable salts thereof may be administered in combination with an acid secretion inhibitor such as an H 2 - blocker (e.g. cimetidine, ranitidine, famotidine, etc.) or a proton pump inhibitor (e.g.
  • omeprazole for the prophylaxis and/or treatment of chronic gastritis, peptic ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer), MALT lymphoma and non-ulcer dyspepsia and the prophylaxis of stomach cancer.
  • cephem compound (I) and pharmaceutically acceptable salts thereof are particularly effective for the prophylaxis and/or treatment of the diseases caused by Hel icobacter pylori infection such as gastritis, ulcer [e.g. peptic ulcer (e.g. gastric ulcer, duodenal ulcer, anomatic ulcer, etc.) etc.], MALT lymphoma, non-ulcer-dyspepsia and stomach cancer when administered with an acid secretion inhibitor such as an H 2 - blocker (e.g. cimetidine, ranitidine, famotidine, etc.) or a proton pump inhibitor (e.g. omeprazole, lansoprazole, etc.).
  • an H 2 - blocker e.g. cimetidine, ranitidine, famotidine, etc.
  • a proton pump inhibitor e.g. omeprazole, lansoprazole, etc.
  • the cephem compound (I) and pharmaceutically acceptable salts thereof possess selective antimicrobial activity against H. pylori , they can act selectively on H. pylori without exerting adverse influence on other useful enterobacteria. Accordingly, the cephem compound (I) and pharmaceutically acceptable salts thereof serve well for the eradication of H. pylori and are useful for the treatment of ulcers and/or prevention of recurrence of ulcers.
  • the cephem compound (I) and pharmaceutically acceptable salts thereof may be administered in combination with an acid secretion inhibitor such as an H_-blocker (e.g. cimetidine, ranitidine, famotidine, etc.) or a proton pump inhibitor (e.g. omeprazole, lansoprazole, etc.) for the treatment of ulcers and/or prevention of recurrence of ulcers.
  • an H_-blocker e.g. cimetidine, ranitidine, famotidine, etc
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used as they are, or in the form of pharmaceutical preparations 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 or emulsion.
  • auxiliary substances stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives such as lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol.
  • 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, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 mg/body and about 2,000 mg/body may be administered per day.
  • a product comprising the cephem compound (I) or a pharmaceutically acceptable salt thereof.and an acid secretion inhibitor as a combined preparation for simultaneous, separate or sequential use for the prevention and/or treatment of the diseases caused by Hel i cobact er pylori infection.
  • cephem compound (I) or a pharmaceutically acceptable salt thereof and an acid secretion inhibitor for the manufacture of medicament for simultaneous, separate or sequential use for the prevention and/or treatment of the diseases caused by Hel icobacter pylori infection.
  • a product comprising the cephem compound (I) and an acid secretion inhibitor for simultaneous, separate or sequential use as a medicament.
  • a pharmaceutical composition comprising the cephem compound (I) and an acid secretion inhibitor and optionally pharmaceutically acceptable carriers or excipients.
  • composition characterized in that the composition is adapted for only oral administration and comprises, as an active ingredient, the cephem compound (I) or a pharmaceutically acceptable salt thereof and an acid secretion inhibitor.
  • a product comprising: a) the cephem compound (I) or a pharmaceutically acceptable salt thereof, and, b) an acid secretion inhibitor in a ratio by weight of: a) to b) of from 0.01/1 to 100/1.
  • a method for treatment or inhibition of the diseases caused by Hel icobact er py lori infection which comprises administering an effective amount of the cephem compound (I) to a patient in need of said treatment or inhibition.
  • a method for the veterinary treatment of an animal infected with Hel icobacter py lori which comprises administering an effective amount of the cephem compound (I) to an animal in need of said treatment.
  • Test 1 Anti- bacterial activity against He l i cobact er py lori .
  • Hel i cobac t er py lori was cultured on a Brucella agar plate containing 3% horse serum and 2% starch at 37 ⁇ C for 3 days under 10% C0 2 , and suspended in a Brucella broth to a turbidity of McFarland No. 1. This suspension was inoculated on Brucella agar supplemented with 7% horse blood containing graded concentrations of the test compound, and the minimum inhibitory concentration (MIC) was expressed in terms of ⁇ g/ml after incubation at 37 * C for 3 days under 10% C0 2 .
  • MIC minimum inhibitory concentration
  • test compound suspended in 0.5% methylcellulose was orally administered to male rats at a dose of 100 or 32 mg/kg/day for 2 weeks.
  • Benzhydryl 3-(5-amino-l,3,4-thiadiazol-2-yl)thio-7 ⁇ - formamido-3-cephem-4-carboxylate was prepared according to a method similar to that of Preparation 3 from benzhydryl 7 ⁇ - formamido-3-methanesulfonyloxy-3-cephem-4-carboxylate and 5- amino-2-mercapto-l,3,4-thiadiazole.
  • Benzhydryl 7 ⁇ -amino-3-(5-amino-l,3,4-thiadiazol-2-yl )- thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Preparation 1 from benzhydryl 3-(5-amino- l ,3, 4-thiadiazol-2-yl ) thio-7 ⁇ -formamido-3-cephem-4- carboxylate.
  • Benzhydryl 7 ⁇ -amino-3-(l,3,4-thiadiazol-2-yl)thio-3- cephem-4-carboxylate hydrochloride was prepared according to a method similar to that of Preparation 19, from benzhydryl 7 ⁇ -
  • Benzhydryl 7B-formamido-3-(l,2,3-triazol-5-yl )thio-3- cephem-4-carboxylate was prepared according to a method similar to that of Preparation 27.
  • Benzhydryl 7 ⁇ -amino-3-(benzothiazol-2-yl)thio-3-cephem-4- carboxylate was prepared according to a method similar to that of Preparation 1.
  • Benzhydryl 7 ⁇ -amino-3-(thiazol-2-yl)thio-3-cephem-4- carboxylate was prepared according to a method similar to that of Preparation 1.
  • reaction mixture was poured into a mixture of ethyl acetate and water, and the mixture was adjusted to pH 5.0 with IN hydrochloric acid.
  • the separated organic layer was washed with a saturated aqueous sodium chloride solution three times, dried over magnesium sulfate and evaporated under reduced pressure.
  • the separated aqueous layer was adjusted to pH 4.5 with IN hydrochloric acid and subjected to column chromatography on non- ionic adsorption resin, Diaion HP-20 (Trade mark, made by Mitsubishi Chemical Industries) (eluent; 10% aqueous acetonitrile).
  • Diaion HP-20 Trade mark, made by Mitsubishi Chemical Industries
  • the fractions containing the desired compound were collected, concentrated under reduced pressure and freeze- dried to give 7B-[2-(phenylthio)acetamido]-3-(l,2,4-triazol-3- yl)thio-3-cephem-4-carboxylic acid (0.3 g).
  • the precipitate was dissolved in a mixture of tetrahydrofuran (20 ml), ethyl acetate (20 ml) and an aqueous sodium hydrogencarbonate solution (96 mg/40 ml).
  • the separated aqueous layer was added to ethyl acetate (40 ml), and the mixture was adjusted to pH 2 with IN hydrochloric acid.
  • the separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added ether.
  • IR (KBr) 3300, 1790, 1710, 1650, 1560, 1540, 1520, 1440,
  • the precipitate was dissolved in a mixture of a saturated aqueous sodium hydrogencarbonate solution (10 ml), water (20 ml), tetrahydrofuran (10 ml) and ethyl acetate (10 ml).
  • the aqueous layer was washed with a mixture of ethyl acetate (10 ml) and tetrahydrofuran (10 ml).
  • Ethyl acetate (20 ml) and tetrahydrofuran (10 ml) were added to the aqueous layer and the mixture was adjusted to pH 2.0 with IN hydrochloric acid with stirring.
  • the precipitate was dissolved in a mixture of a saturated aqueous sodium hydrogencarbonate solution (12 ml), water (12 ml), tetrahydrofuran (12 ml) and ethyl acetate (12 ml).
  • the aqueous layer was washed twice with a mixture of ethyl acetate (8 ml) and tetrahydrofuran (8 ml).
  • Ethyl acetate (30 ml) was added to the aqueous layer and the mixture was adjusted to pH 2.0 with IN hydrochloric acid.
  • the organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give a solid.
  • the precipitate was dissolved in a mixture of a saturated aqueous sodium hydrogencarbonate solution (10 ml), water (50 ml), tetrahydrofuran (30 ml) and ethyl acetate (30 ml).
  • the aqueous layer was washed with a mixture of ethyl acetate (20 ml) and tetrahydrofuran (20 ml), adjusted to pH 5.0 with IN hydrochloric acid with stirring and evaporated under reduced pressure to remove the organic solvent.
  • the resulting residue was adjusted to pH 5.0 with IN hydrochloric acid and was subjected to column chromatography on non-ionic adsorption resin, Diaion HP-20, sequentially eluting with water (100 ml) and 10% isopropyl alcohol in water (300 ml). The fractions containing the desired compound were collected and evaporated under reduced pressure to remove the organic solvent.
  • the resulting residue was adjusted to pH 2.0 with IN hydrochloric acid and extracted twice with a mixture of tetrahydrofuran (100 ml) and ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a solid.
  • Benzhydryl 7B-[2-(2-formamido-thiazol-4-yl)acetamido]-3-(5- methyl-l,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(5-methyl-l,3,4-thiadiazol-2-yl)thio- 3-cephem-4-carboxylate and (2-formamido-thiazol-4-yl)acetic acid.
  • NMR (DMS0-d 6 , ⁇ ) 2.67 (3H, s), 3.60 (2H, s),
  • Benzhydryl 7 ⁇ -[2-(2-amino-thiazol-4-yl)acetamido]-3-(5- methyl-l,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 28 from benzhydryl 7 ⁇ -[2-(2-formamido-thiazol-4-yl )acetamido]-3- (5-methyl-l,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate.
  • NMR (DMS0-d 6 , ⁇ ) 2.68 (3H, s), 3.38 (2H, s),
  • Benzhydryl 7 ⁇ -[2-(2-formamido-thiazol-4-yl)acetamido]-3- (l,2,3-triazol-5-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(l,2,3-triazol-5-yl)thio-3-cephem-4- carboxylate and (2-formamido-thiazol-4-yl)acetic acid.
  • Benzhydryl 73-[2-(2-amino-thiazol-4-yl)acetamido]-3-(1,2,3- triazol-5-yl )thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 28 from benzhydryl 7B-[2-(2-formamido-thiazol-4-yl)acetamido]-3-(1,2,3-triazol-5- yl )thio-3-cephem-4-carboxylate.
  • Benzhydryl 7B-[2-(phenylthio)acetamido]-3-(1,2,3-triazol 5-yl )thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 5 from benzhydryl 7 ⁇ -[2- (phenylthio)acetamido]-3-methanesuIfonyloxy-3-cephem-4- carboxylate and 5-mercapto-l,2,3-triazole sodium salt.
  • Example 43 7 ⁇ -[2-(Phenylthio)acetamido]-3-(l,2,3-triazol-5-yl)thio- 3-cephem-4-carboxylic acid was prepared according to a method similar to that of Example 2 from benzhydryl 7 ⁇ -[2- (phenylthio)acetamido]-3-(1,2,3-triazol-5-yl)thio-3-cephem-4- carboxylate.
  • Benzhydryl 7B-[2-(phenylthio)acetamido]-3-(5-methyl- l,3,4-triazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ -[2-(phenylthio)acetamido]-3-methanesulfonyloxy- 3-cephem-4-carboxylate and 5-methyl-l,3,4-triazole-2-thiol .
  • NMR (CDCl3, ⁇ ) 2.43 (3H, s),
  • Benzhydryl 7 ⁇ -[2-(phenylthio)acetamido]-3-(1-methyl- l,3,4-triazol-2-yl )thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ -[2-(phenylthio)acetamido]-3-methanesulfonyloxy- 3-cephem-4-carboxylate and l-methyl-l,3,4-triazole-2-thiol .
  • Benzhydryl 7B-[2-(phenylthio)acetamido]-3-(5-methyl- l,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7B-[2-(phenylthio)acetamido]-3-methanesulfonyloxy- 3-cephem-4-carboxylate and 5-methyl-l,3,4-thiadiazole-2-thiol.
  • NMR (CDCl3, ⁇ ) 2.75 (3H, s),
  • Benzhydryl 7B-[2-(phenylthio)acetamido]-3-(1-methyl- tetrazol-5-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 5 from benzhydryl 7 ⁇ -[2-(phenylthio)acetamido]-3-methanesulfonyloxy- 3-cephem-4-carboxylate and 5-mercapto-l-methyltetrazole sodium salt.
  • Benzhydryl 7B-(2-phenylacetamido)-3-(5-methyl-1,3,4- triazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ - (2-phenylacetamido)-3-methanesulfonyloxy-3-cephem-4-carboxylate and 5-methyl-1,3,4-triazole-2-thiol.
  • NMR (DMS0-d 6 , ⁇ ) 2.38 (3H, s),
  • Benzhydryl 7 ⁇ -(2- ⁇ henylacetamido)-3-(1-methyl-1,3,4- triazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ - (2-phenylacetamido)-3-methanesulfonyloxy-3-cephem-4-carboxylate and l-methyl-l,3,4-triazole-2-thiol.
  • Benzhydryl 7 ⁇ -(2-phenylacetamido)-3-(1-methyl-tetrazol-5- yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 5 from benzhydryl 7 ⁇ -(2- phenylacetamido)-3-methanesulfonyloxy-3-cephem-4-carboxylate and 5-mercapto-l-methyltetrazole sodium salt.
  • Benzhydryl 7B-(2-phenylacetamido)-3-(thiazol-2-yl)thio-3- cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ -(2-phenylacetamido)- 3-methanesulfonyloxy-3-cephem-4-carboxylate and 2- mercaptothiazole.
  • Benzhydryl 7 ⁇ -(2-phenylacetamido)-3-(5-amino-l,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ -(2-pheny1acetamido)-3-methanesu1fony1oxy-3- cephem-4-carboxylate and 5-amino-2-mercapto-l,3,4-thiadiazole.
  • Benzhydryl 7 ⁇ -(2-phenylacetamido)-3-(pyridin-2-yl)thio-3- cephem-4-carboxylate was prepared according to a method similar to that of Example 11 from benzhydryl 7 ⁇ -(2-phenylacetamido)- 3-methanesulfonyloxy-3-cephem-4-carboxylate and 2- mercaptopyridine.
  • Benzhydryl 7B-(3-nitrophenyl)acetamido-3-(1,3,4-triazol- 2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7B-amino- 3-(l,3,4-triazol-2-yl)thio-3-cephem-4-carboxylate and 3- nitrophenylacetic acid.
  • Benzhydryl 7 ⁇ -(2-thienyl)acetamido-3-(l,3,4-triazol-2-yl )- thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3- (l,3,4-triazol-2-yl )thio-3-cephem-4-carboxylate and 2- thienylacetic acid.
  • Benzhydryl 7 ⁇ -(3-thienyl )acetamido-3-(l,3,4-thiadiazol-2- yl )thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ - amino-3-(l,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate and 3-thienylacetic acid.
  • Benzhydryl 7 ⁇ -(2-thienyl)acetamido-3-(l,3,4-thiadiazol-2- yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ - amino-3-(l,3,4-thiadiazol-2-yl )thio-3-cephem-4-carboxylate and 2-thienylacetic acid.
  • Benzhydryl 7B-(3-f1uoropheny1)acetamido-3-(1,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(l,3,4-thiadiazol-2-yl)thio-3-cephem-4- carboxylate and 3-fluorophenylacetic acid.
  • Benzhydryl 7 ⁇ -(4-fluorophenyl )acetamido-3-(l,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-(1,3,4-thiadiazol-2-yl)thio-3-cephem-4- carboxylate and 4-fluorophenylacetic acid.
  • Benzhydryl 7 ⁇ -(3-chlorophenyl )acetamido-3-(1,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(l,3,4-thiadiazol-2-yl )thio-3-cephem-4- carboxylate and 3-chlorophenylacetic acid.
  • Benzhydryl 7 ⁇ -[3-(3-thienyl)acryloylamino]-3-(l,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(l,3,4-thiadiazol-2-yl )thio-3-cephem-4- carboxylate and 3-(3-thienyl)acrylic acid.
  • Benzhydryl 7 ⁇ -[2-(phenylthio)acetamido]-3-(pyrazol-4-yl )- methylthio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino- 3-(pyrazol-4-yl)methylthio-3-cephem-4-carboxylate and phenylthioacetic acid.
  • Benzhydryl 7 ⁇ -[2-(3-thienyl)acetamido]-3-(5-amino-l,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 27 from benzhydryl 7 ⁇ -amino-3-(5-amino-l,3,4-thiadiazol-2-yl )thio-3- cephem-4-carboxylate and 3-thienylacetic acid.
  • NMR (DMSO-de, ⁇ ) 3.55 (2H, s),
  • Example 87 7 ⁇ -[2-(3-Thienyl)acetamido]-3-(5-amino-l,3,4-thiadiazol-2- yl)thio-3-cephem-4-carboxylic acid was prepared according to a method similar to that of Example 2 from benzhydryl 7B-[2- (3-thienyl)acetamido]-3-(5-amino-l,3,4-thiadiazol-2-yl)thio-3- cephem-4-carboxylate.
  • Phosphorus oxychloride (268 ⁇ l ) was added dropwise to a mixture of N,N-dimethylformamide (220 ⁇ l ) and ethyl acetate (0.7 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added tetrahydrofuran (10 ml). The suspension was stirred at the same temperature for 30 minutes. To the suspension was added 3- chlorophenylacetic acid (403 mg) . The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution.
  • the resulting precipitate was collected by filtration, dissolved in a mixture of ethyl acetate (30 ml), tetrahydrofuran (15 ml) and an aqueous sodium hydrogencarbonate solution (30 ml).
  • the separated aqueous layer was adjusted to pH 5.0 with IN- hydrochloric acid and subjected to column chromatography on non- ionic adsorption resin "Diaion HP-20" (20 ml) (eluent; 5 - 10% aqueous diisopropyl alcohol).
  • Benzhydryl 7B-[2-(4-pyridylthio)acetamido]-3-(l,3,4- triazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Preparation 2.
  • the mixture was stirred at the same temperature for an hour.
  • reaction mixture was poured into diisopropyl ether (50 ml).
  • Example 94 The following compound was prepared according to a method similar to that of Preparation 2.
  • the precipitate was dissolved in a mixture of an aqueous sodium hydrogencarbonate solution (20 ml), tetrahydrofuran (10 ml) and ethyl acetate (30 ml). To the separated aqueous layer were added ethyl acetate (30 ml) and tetrahydrofuran (10 ml). The mixture was adjusted to pH 1.5 with IN-hydrochloric acid. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give crude product (121 mg) .
  • the crude product (95 mg) was dissolved in a mixture of tetrahydrofuran (10 ml) and an aqueous sodium hydrogencarbonate solution (20 ml). The solution was washed with ethyl acetate (20 ml) and evaporated in vacuo to remove the organic solvent. The resulting residue was adjusted to pH 6.5 with IN- hydrochloric acid, purified by high pressure liquid chromatography (R-0DS-C-15, YMC-pack) eluting with 0 - 15% acetonitrile-phosphate buffer (pH 6.0). The fractions containing the desired compound were collected and concentrated in vacuo.
  • Example 104 73-[D-2-Amino-2-(4-hydroxypheny1)acetamido]-3-(1,3,4- thiadiazol-2-yl)thio-3-ce ⁇ hem-4-carboxylic acid was prepared according to a method similar to that of Example 2.
  • Benzhydryl 73-(L-2-hydroxy-2-phenylacetamido)-3-(1,3,4- thiadiazol-2-yl)thio-3-cephem-4-carboxylate was prepared according to a method similar to that of Example 107 using L- mandelic acid instead of D-mandelic acid.
  • Example 111 The compounds of Example 111 to Example 115 were prepared according to a method similar to that of Preparation 3.
  • Example 111
  • Example 116 The compounds of Example 116 to Example 120 were prepared according to a method similar to that of Example 2.
  • Example 116 The compounds of Example 116 to Example 120 were prepared according to a method similar to that of Example 2.
  • the precipitate was dissolved in a mixture of an aqueous sodium hydrogencarbonate solution (30 ml) and tetrahydrofuran (10 ml). The solution was washed twice with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 2 with IN-hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to give 7 ⁇ -(2-phenylacetamido)-3-(5- amino-l,3,4-triazol-2-yl)thio-3-cephem-4-carboxylic acid (198 mg).
  • 73-(2-Phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxlic acid was prepared according to a method similar to that of Preparation 3 from 73-(2- phenylacetamido)-3-methanesu1fonyloxy-3-cephem-4-carboxlic and 2-mercapto-5-methyl-l,3,4-thiadiazole.
  • Phosphorus oxychloride (82 ⁇ l ) was added dropwise to a mixture of N,N-dimethylformamide (67.3 ⁇ l ) and ethyl acetate (0.2 ml) under ice-cooling. After being stirred at the same temperature for 10 minutes, the mixture was cooled until a precipitate appeared. To the suspension was added tetrahydrofuran (3 ml). The suspension was stirred at the same temperature for 30 minutes. To the suspension was added 4- fluorophenylacetic acid (103 mg) . The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution.
  • the aqueous layer was washed with ethyl acetate (200 L) .
  • An aqueous solution of hydrochloric acid was added dropwise in order to adjust the pH of the aqueous layer to 2.5.
  • the resultant crystals were collected by centrifugation and washed with water (200 L).
  • Example 129 The compounds of Example 129 to Example 131 were prepared according to a method similar to that of Preparation 3.
  • Example 129
  • the mixture was stirred at the same temperature for 70 minutes.
  • the reaction mixture was poured into diisopropyl ether (60 ml).
  • the precipitate was collected by filtration and dried in vacuo.
  • the precipitate was dissolved in a mixture of an aqueous sodium hydrogencarbonate solution (30 ml) and tetrahydrofuran (10 ml).
  • the solution was washed with ethyl acetate (20 ml).
  • To the aqueous layer was added a mixture of tetrahydrofuran (10 ml) and ethyl acetate (30 ml), and the mixture was adjusted to pH 2.5 with IN-hydrochloric acid.
  • the mixture was stirred under ice-cooling for 30 minutes.
  • Example 137 The compounds of Example 137 to Example 143 were prepared according to a method similar to that of Preparation 3.
  • Example 137
  • Example 144 The compounds of Example 144 to Example 148 were prepared according to a method similar to that of Example 2.
  • Example 144
  • Example 151 The compounds of Example 151 to Example 153 were prepared according to a method similar to that of Preparation 2.
  • Example 151
  • Example 154 The compounds of Example 154 to Example 156 were prepared according to a method similar to that of Preparation 1.
  • Example 154
  • Example 157 The compounds of Example 157 to Example 159 were prepared according to a method similar to that of Example 2.
  • Example 157
  • the active ingredient, lactose and corn starch were thoroughly blended and, then, wetted with 20% polyvinyl ⁇ pyrrolidone in ethanol.
  • the composition was dried at 45"C .
  • the granules thus obtained were mixed with magnesium stearate and the mixture was compressed into tablets.

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Abstract

La présente invention concerne une nouvelle utilisation d'un composé de céphème de formule (I) dans laquelle R1 est aryle alkyle(inférieur) pouvant posséder un ou plusieurs substituants appropriés, arylthio alkyle (inférieur), alcénylthio inférieur alkyle (inférieur) pouvant posséder un ou plusieurs substituants appropriés, ou bien un groupe de la formule R4-A- ou R4-S-A- dans laquelle R4 est un groupe hétérocyclique pouvant posséder un ou plusieurs substituants appropriés, et A est alkylène inférieur pouvant posséder un ou plusieurs substituants appropriés ou bien alcénylène inférieur, R2 est un groupe hétérocyclique pouvant posséder un ou plusieurs substituants appropriés, ou bien alkyle (inférieur) hétérocyclique et R3 est carboxy ou carboxy protégé, et son sel pharmaceutiquement acceptable, qui présentent une activité antimicrobienne contre Helicobacter pylori, et sont utiles comme agents anti-Helicobacter pylori, agents anti-gastrite, agents antiulcéreux et agents anticancéreux.
PCT/JP1995/002505 1994-12-09 1995-12-06 Composes de cepheme et leur utilisation pharmaceutique WO1996017850A1 (fr)

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JP8517485A JPH10510258A (ja) 1994-12-09 1995-12-06 セフェム化合物およびその医薬用途
AU41233/96A AU4123396A (en) 1994-12-09 1995-12-06 Cephem compounds and pharmaceutical use thereof
EP95939389A EP0796263A1 (fr) 1994-12-09 1995-12-06 Composes de cepheme et leur utilisation pharmaceutique

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GBGB9424865.5A GB9424865D0 (en) 1994-12-09 1994-12-09 Cephem compounds and pharmaceutical use thereof
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GBGB9520714.8A GB9520714D0 (en) 1995-10-10 1995-10-10 Cephem compounds and pharmaceutical use thereoof
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Publication number Priority date Publication date Assignee Title
WO1997029111A1 (fr) * 1996-02-12 1997-08-14 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes de cephem et leur utilisation pharmaceutique
JPH11279180A (ja) * 1998-01-23 1999-10-12 Toyama Chem Co Ltd 新規なセファロスポリン誘導体またはその塩並びにそれらを含有する抗菌剤
US6214852B1 (en) 1998-10-21 2001-04-10 Bristol-Myers Squibb Company N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US6262096B1 (en) 1997-11-12 2001-07-17 Bristol-Myers Squibb Company Aminothiazole inhibitors of cyclin dependent kinases
WO2001083491A1 (fr) * 2000-04-28 2001-11-08 Biochemie Gesellschaft M B H Intermediaires de la cephalosporine
WO2002017854A2 (fr) * 2000-08-29 2002-03-07 Essential Therapeutics, Inc. Antibiotiques cephalosporine et leurs promedicaments
US6392053B2 (en) 1999-12-15 2002-05-21 Bristol-Myers Squibb Company Process for preparing arylacetylaminothiazoles
US6414156B2 (en) 1998-10-21 2002-07-02 Bristol-Myers Squibb Company Process for preparing azacycloalkanoylaminothiazoles
US6515004B1 (en) 1999-12-15 2003-02-04 Bristol-Myers Squibb Company N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
EP1576092A2 (fr) * 2002-03-27 2005-09-21 Smithkline Beecham Corporation Composes et procedes

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FR2282895A1 (fr) * 1974-08-30 1976-03-26 Ciba Geigy Ag Derives d'acides thio-cephem-carboxyliques utiles comme medicaments et leur procede de preparation
FR2293935A1 (fr) * 1974-12-13 1976-07-09 Lilly Co Eli 3-(thio substitue) cephalosporines antibiotiques
FR2318642A1 (fr) * 1975-07-22 1977-02-18 Shionogi & Co Procede de cyclisation pour l'obtention de noyaux de cephem et nouveaux produits ainsi obtenus, a activite antibacterienne
US4123528A (en) * 1975-11-21 1978-10-31 Merck & Co., Inc. 3-(Substituted thio) cephalosporins, derivatives and nuclear analogues thereof
EP0009008A2 (fr) * 1978-09-08 1980-03-19 Ciba-Geigy Ag Dérivés de céphalosporine, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0504404A1 (fr) * 1989-12-07 1992-09-23 Meiji Seika Kaisha Ltd. Procede de production d'un compose thio-3-cephem substitue en 3
US5162521A (en) * 1991-06-06 1992-11-10 Bristol-Myers Squibb Company Processes for making cephems from allenylazetidinone derivatives
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FR2293935A1 (fr) * 1974-12-13 1976-07-09 Lilly Co Eli 3-(thio substitue) cephalosporines antibiotiques
FR2318642A1 (fr) * 1975-07-22 1977-02-18 Shionogi & Co Procede de cyclisation pour l'obtention de noyaux de cephem et nouveaux produits ainsi obtenus, a activite antibacterienne
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EP0504404A1 (fr) * 1989-12-07 1992-09-23 Meiji Seika Kaisha Ltd. Procede de production d'un compose thio-3-cephem substitue en 3
US5162521A (en) * 1991-06-06 1992-11-10 Bristol-Myers Squibb Company Processes for making cephems from allenylazetidinone derivatives
WO1995026966A1 (fr) * 1994-04-01 1995-10-12 Microcide Pharmaceuticals, Inc. Cephalosporines antibiotiques

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150351A (en) * 1996-02-12 2000-11-21 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and pharmaceutical use thereof
WO1997029111A1 (fr) * 1996-02-12 1997-08-14 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes de cephem et leur utilisation pharmaceutique
US6262096B1 (en) 1997-11-12 2001-07-17 Bristol-Myers Squibb Company Aminothiazole inhibitors of cyclin dependent kinases
JPH11279180A (ja) * 1998-01-23 1999-10-12 Toyama Chem Co Ltd 新規なセファロスポリン誘導体またはその塩並びにそれらを含有する抗菌剤
US6414156B2 (en) 1998-10-21 2002-07-02 Bristol-Myers Squibb Company Process for preparing azacycloalkanoylaminothiazoles
US6214852B1 (en) 1998-10-21 2001-04-10 Bristol-Myers Squibb Company N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US6613911B2 (en) 1999-12-15 2003-09-02 Bristol-Myers Squibb Company Process for preparing arylacetylaminothiazoles
US6392053B2 (en) 1999-12-15 2002-05-21 Bristol-Myers Squibb Company Process for preparing arylacetylaminothiazoles
US6515004B1 (en) 1999-12-15 2003-02-04 Bristol-Myers Squibb Company N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US6521759B2 (en) 1999-12-15 2003-02-18 Bristol-Myers Squibb Company Aminothiazole inhibitors of cyclin dependent kinases
US6639074B2 (en) 1999-12-15 2003-10-28 Bristol Myers Squibb Company Process for preparing azacycloalkanoylaminothiazoles
WO2001083491A1 (fr) * 2000-04-28 2001-11-08 Biochemie Gesellschaft M B H Intermediaires de la cephalosporine
US6787649B2 (en) 2000-04-28 2004-09-07 Sandoz Gmbh Cephalosporin intermediates
KR100789156B1 (ko) * 2000-04-28 2007-12-28 산도즈 게엠베하 세팔로스포린 중간체
WO2002017854A3 (fr) * 2000-08-29 2002-06-13 Tomasz W Glinka Antibiotiques cephalosporine et leurs promedicaments
WO2002017854A2 (fr) * 2000-08-29 2002-03-07 Essential Therapeutics, Inc. Antibiotiques cephalosporine et leurs promedicaments
EP1576092A2 (fr) * 2002-03-27 2005-09-21 Smithkline Beecham Corporation Composes et procedes
EP1576092A4 (fr) * 2002-03-27 2009-11-04 Smithkline Beecham Corp Composes et procedes

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EP0796263A1 (fr) 1997-09-24

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