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WO1997040039A1 - Composes pyridiniques et utilisations medicales de ceux-ci - Google Patents

Composes pyridiniques et utilisations medicales de ceux-ci Download PDF

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Publication number
WO1997040039A1
WO1997040039A1 PCT/JP1997/001365 JP9701365W WO9740039A1 WO 1997040039 A1 WO1997040039 A1 WO 1997040039A1 JP 9701365 W JP9701365 W JP 9701365W WO 9740039 A1 WO9740039 A1 WO 9740039A1
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Prior art keywords
methyl
ethoxy
ethylsulfanyl
alkyl
haloalkyl
Prior art date
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PCT/JP1997/001365
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English (en)
Japanese (ja)
Inventor
Mitsuharu Sano
Nobuhiro Sakurai
Yoshifumi Ikeda
Takeshi Kawakita
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU25768/97A priority Critical patent/AU2576897A/en
Publication of WO1997040039A1 publication Critical patent/WO1997040039A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel pyridine compound or a pharmaceutically acceptable salt thereof having an antibacterial action against Helicobacter pylori, a gastric acid secretion inhibitory action, an anti-ulcer action, a gastrointestinal cell protective action, an ulcer relapse prevention action, and the like.
  • the present invention provides a pharmaceutical composition comprising the pyridine compound and a pharmaceutically acceptable carrier, a pharmaceutical composition comprising the pyridine compound or a pharmaceutically acceptable salt thereof and an anti-ulcer drug
  • the present invention relates to a pharmaceutical composition comprising the pyridine compound or a pharmaceutically acceptable salt thereof, an anti-ulcer drug, and an antibiotic or antiprotozoal.
  • a method for preventing or treating a gastrointestinal disease by administering the pyridine compound or a pharmaceutically acceptable salt thereof, and a gastrointestinal disease by administering the pyridine compound or a pharmaceutically acceptable salt thereof and an anti-ulcer drug.
  • a method for preventing and treating digestive diseases by administering the pyridine compound or a pharmaceutically acceptable salt thereof, an antitumor drug, an antibiotic or an antiprotozoal drug.
  • H. pylori is a gram-negative bacterium isolated from the gastric mucosa of patients with active chronic gastritis (Warren, JR & Marshall, BJ Lanceti: 1273). -1275, 1983). The bacterium is isolated at a higher rate than gastroduodenal ulcer patients and shows evidence of active gastritis apparently from infection experiments with human volunteers (Morris, A. & Nicholoson, G. Am. J. Gastroenterology, 82 : 192-199, 1987), and experimental animals infected with H. Pylori also show symptoms of gastritis similar to humans. Thus, the association with upper gastrointestinal diseases has become quite clear. Recently, it has been noted as one of the important risk factors for gastric cancer (Parsonnet, J. et al. N. Eng. J. Med. 325: 1127-1131, 1991).
  • Antibacterial activity against H. Pylori is particularly good among the antibacterial drugs, amoxicillin and clarithromycin.
  • the weak while also antibacterial activity in Purotonbo pump inhibitors such as Omeburazoru is seen, cimetidine, not found in H 2 receptor antagonists such as famotidine.
  • drugs with such antibacterial activity have only a weak clinical effect when administered alone.
  • the present inventors have conducted various studies. As a result, they have not only selectively excellent antibacterial activity against H. Pylori, but also have an inhibitory effect on gastric acid secretion and anti-inflammatory activity. A compound that also has an ulcer action, a gastrointestinal cell protective action, and an action to prevent relapse of ulcers has been found.Furthermore, the compound of the present invention reflects the antibacterial action in vitro against H. Pylor i. The present inventors have found that Pyl ori has an excellent bactericidal effect, and have completed the present invention.
  • the present invention as seen in two-agent and new three-agent combination therapy, by using a compound represented by the general formula (I) of the present invention in combination with an anti-ulcer drug, preferably a proton pump inhibitor, Alternatively, by using the compound represented by the general formula (I) in combination with an anti-ulcer drug and an antibiotic or an antiprotozoal drug, a clearly superior eradication effect, The present inventors have found that an ulcer effect, an ulcer relapse, and a recurrence prevention effect can be obtained, and the present invention has been completed.
  • an anti-ulcer drug preferably a proton pump inhibitor
  • the present invention provides a compound represented by the general formula (I):
  • R is one (CH 2 -CH 2 -0) k -D
  • D 2 represents haloalkyl
  • m represents an integer of 1 to 10
  • n represents an integer of 0 to 10
  • a and B may be the same or different and each have a substituent.
  • Good alkylene having 2 to 10 carbon atoms provided that when n represents 0, A represents alkylene having 3 to 10 carbon atoms, and when n represents an integer of 1 to 10, A and B At least one of them represents an alkylene having 3 to 10 carbon atoms.
  • R 1 represents hydrogen, amino, logen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.
  • R 2 and R 3 are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.
  • R 4 is hydrogen or one CO OR 5
  • R 5 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl-rubumoylalkyl, dialkyl-rubumoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent.
  • Z and Y are the same or different and represent CH or N, respectively.
  • P and q are the same or different and each represents 0, 1 or 2.
  • the halogen denotes chlorine, fluorine, bromine, iodine.
  • Alkyl refers to alkyl having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl, decyl, dodecyl, octadecyl, and icosyl, and is preferable.
  • Alcoquin is defined as having 1 to 20 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy and eicosiloxy.
  • Alkoxycarbonyl refers to methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxycarbonyl, isobutynecarbonyl, tertiary butkincarbonyl, pentyloxycarbonyl, hexoxycarbonyl, octyloxycarbonyl.
  • alkoxycarbonyl having 2 to 20 carbon atoms such as deoxycarbonyl, dodecyloxycarbonyl, octadecyloxycarbonyl and eicosyloxycarbonyl.
  • Haloalkyl is trifluoromethyl, 2-fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,3,3-trifluorotrifluoropropyl, 1,2,2 —Tetrafluoroethyl, pentafluoroethyl, 3,3,3—Trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3 —Pentafluoropropyl, hepta Fluoropropyl, hexafluoroisopropyl, 2,2,3,3,4,4,4-heptafluorobutyl, 2-chloroethyl, 3-chloropropyl pill, 2-bromoethyl, 3-bromopropyl And haloalkyl having 1 to 10 carbon atoms, preferably haloalkyl having 1 to 5 carbon atoms, particularly haloalkyl having
  • R 1 is preferably hydrogen.
  • examples of the halogen, alkyl and alkoxy are the same as those described for R ′.
  • R 2 is preferably alkyl having 1 to 4 carbon atoms, and particularly preferably methyl.
  • R 3 is preferably hydrogen.
  • Examples of the alkyl and haloalkyl in R 5 of COOR 5 of R 4 are the same as those in R 1 .
  • Hydroxyalkyl means hydroxymethyl, 1-hydroxyl, 2-hydroxyl, 3-hydroxypropyl, 2,3-dihydroquinpropyl, 4-hydroxylbutyl, etc. Indicates droxyalkyl.
  • Acyloxyalkyl means acetyloxymethyl, propionyloxymethyl, 2-acetyloxyshethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, benzoyloxymethyl, 2-benzo Select from halogen, alkyl, alkoxy, haloalkyl, hydroquine, nitro, and amino for iloxhetyl and phenyl! And benzoyloxymethyl having 2 to 3 substituents, 21-benzoyloxyshethyl and the like.
  • the acrylalkyl is selected from acetylmethyl, propylionylmethyl, 2-acetylethyl, 3-acetylpropyl, 4-acetylbutyl, benzoylmethyl, 2-benzoylethyl, halogen, alkenyl, alkoxy, haloalkyl, hydroxy, nitro, and amino for the phenyl group.
  • C- carboxyalkyl representing benzoylmethyl having 1 to 3 substituents, 2-benzoylethyl and the like is carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and the like having 2 to 5 carbon atoms. Represents carboxyalkyl.
  • Alkoxycarbonylalkyl means methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylethyl, isopropoxycarbonylethyl, butoxycarbonylmethyl, isobutoxycarbonylethyl, tertiary butoxycarbonylmethyl, pentyloxycarbonylmethyl, Xyloxy force Rubonylmethyl, octyloxycarbonylmethyl, decyloxycarbonylmethyl, etc. It shows that an alkoxycarbonyl of 0 is bonded to an alkyl having 1 to 4 carbon atoms.
  • Alkoxyalkyl is defined as methoxymethyl, 2-methoxyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyquinethyl, In particular, 3-ethoxyquinbutyl, etc., in which alkoxy having 1 to 10 carbon atoms is bonded to alkyl having 1 to 10 carbon atoms.
  • Lumbamoylalkyl refers to those in which lumbamoyl is bonded to an alkyl having 1 to 10 carbon atoms, such as lumbamoylmethyl, 2-lbumbylethyl, 3-lbumbylpropyl, and 4-lbumbylbutyl.
  • Examples of the substituent of phenyl which may have a substituent and aralkyl which may have a substituent include 1 to 3 groups selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, nitro and amino. can give.
  • Aralkyl of aralkyl which may have a substituent means aralkyl of benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 8-phenyloctyl, etc. Represents an alkyl of 8.
  • alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, dirubamoylalkyl, monoalkylcarbamoylalkyl, dialkyldirubamoylalkyl are preferable, and particularly alkyl, non-alkyl, alkoxy.
  • Alkyl, rubamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl are preferred.
  • Examples of the haloalkyl for D 1, and D 2 are the same as those described for R 1 .
  • Z and Y are both CH.
  • the alkylene having 2 to 10 carbon atoms in A and B means ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, etc., and has an appropriate branched chain. It may be.
  • substituents such as alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, and hydroxyalkyl.
  • alkylene having 3 to 10 carbon atoms means propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, etc., and may have a branched chain as appropriate. Good.
  • alkylenes having 2 to 4 carbon atoms such as ethylene, trimethylene and tetramethylene are preferable.
  • p is preferably 0 or 1.
  • q is preferably 0.
  • k is preferably 2 to 4.
  • m is preferably from 3 to 3.
  • n is preferably from 0 to 3.
  • R ′ represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.
  • R 2 and R 3 are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.
  • R 4 is hydrogen or one CO OR 5
  • R 5 is alkyl, haloalkyl, hydroxyalkyl, alkoxyal Kill, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyllrubamoylalkyl, dialkyllrubamoylalkyl, alkoxycarbonylalkyl, fuynyl which may have a substituent, may have a substituent Indicates an aral kill.
  • D represents haloalkyl
  • Z and Y are the same or different and represent CH or N, respectively.
  • P and Q are the same or different and each represents 0, 1 or 2.
  • k represents an integer of 1 to 10;
  • R ′ is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroquine or haloalkyl having 1 to 5 carbons,
  • R 2 and R 3 are the same or different and are each hydrogen or an alkyl having 1 to 5 carbon atoms, and the others are the same as described above, and a pyridine compound or a pharmaceutically acceptable salt thereof is more preferable.
  • R represents hydrogen, halogen, alkyl having 1 to 3 carbons, alkoxy, hydroxy, or haloalkyl having 1 to 3 carbons.
  • R 4 is hydrogen or COOR 5
  • R 5 is alkyl, haloalkyl, hydroquinine alkyl, alkoxyal Kill, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyllrubamoylalkyl, dialkyllrubamoylalkyl, alkoxycarbonylalkyl, phenyl which may have a substituent, may have a substituent Indicates an aral kill.
  • D represents haloalkyl
  • P 0, 1 or 2.
  • k represents an integer of 1 to 10;
  • R la of the general formula (IIa) the same halogen as R 1 is exemplified.
  • the alkyl having 1 to 3 carbon atoms, the alkoxy having 1 to 3 carbon atoms and the haloalkyl having 1 to 3 carbon atoms include those having 1 to 3 carbon atoms among those exemplified for R 1 .
  • R ′ represents hydrogen, halogen, alkyl, alkyne, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.
  • R 2 and R 3 are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.
  • R 4 is hydrogen or COOR 5
  • R 5 is alkyl, haloalkyl, hydroquinine alkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboquinalkyl carbamo Examples thereof include ylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, phenyl which may have a substituent, and aralkyl which may have a substituent. )
  • D 2 represents haloalkyl
  • Z and Y are the same or different and represent CH or N, respectively.
  • P and q are the same or different and each represents 0, 1 or 2.
  • n an integer of 1 to 10.
  • n an integer of 0 to 10.
  • a and B are the same or different and each may have a substituent. It represents alkylene of 0.
  • A represents alkylene having 3 to 10 carbon atoms
  • n represents an integer of 10 to M
  • at least one of A and B is an alkylene having 3 to 10 carbon atoms.
  • R 1 is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroxy or haloalkyl having 1 to 5 carbons,
  • R 2 and R 3 are the same or different, each is hydrogen or alkyl having 1 to 5 carbon atoms, and the other is the same as described above, more preferably a pyridine compound or a pharmaceutically acceptable salt thereof.
  • R la represents hydrogen, halogen, alkyl having 1 to 3 carbons, alkoxy, hydroxy or haloalkyl having 1 to 3 carbons.
  • R 4 is hydrogen or — COOR 5
  • R 5 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent.
  • D 2 represents haloalkyl
  • P 0, 1 or 2.
  • n an integer of 1 to 10.
  • n an integer of 0 to 10.
  • A represents an alkylene having 3 to 10 carbon atoms
  • n represents 1 and an integer of 10 or more
  • at least one of A and B has 3 to 0 carbon atoms.
  • a pharmaceutically acceptable salt thereof are particularly preferred.
  • optical isomers When the compound of the general formula (I) has an asymmetric atom, at least two types of optical isomers exist. These optical isomers and their racemates are included in the present invention. In addition, cis isomers, trans isomers, and mixtures thereof are also included.
  • Pharmaceutically acceptable salts of the compounds of general formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, phosphate, citrate, maleate Acid addition salts such as acid salts, fumarate, malonate, malate, tartrate, succinate, methanesulfonate, benzenesulfonate, alkali metal salts such as sodium salt, potassium salt, calcium And alkaline earth metal salts such as magnesium salts.
  • the compounds of the present invention also exist as hydrates (hemihydrate, monohydrate, sesquihydrate and the like) and solvates, and these are also included in the present invention.
  • W represents a reactive atom or group (sulfonyloxy group such as halogen or methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and other symbols are as defined above. is there. ]
  • the reaction between the compound of the general formula (IV) and the compound of the general formula (V) is usually inert.
  • a solvent water or methanol, ethanol, dimethylformamide, or a mixed solvent thereof, preferably aqueous ethanol
  • a base sodium hydroxide, hydroxide hydroxide, sodium hydride, hydrogenation catalyst
  • Temperature from about 0 ° C to the boiling point of the solvent used, preferably 20 ° C to 80 ° C, in the presence of lium, sodium methoxide, sodium carbonate, potassium carbonate, metallic sodium, triethylamine, pyridine and the like. in ° C, about 1 0 minutes to 2 4 hours, preferably c also proceeds at 3 0 minutes to 7 hours, the acid addition salts of the compounds of general formula (V), hydrochloride salt, hydrobromic acid salt mentioned Can be
  • the compound of the general formula (I) in which is 1 or 2 is produced by subjecting the compound of the general formula (I-1) in which p is 0 to an oxidation reaction.
  • oxidizing agent used in the oxidation reaction examples include metabenzo-perbenzoic acid, peracetic acid, trifluoroperacetic acid, permalic acid, potassium superoxide, sodium hypobromite, sodium hypobromite, and hydrogen peroxide.
  • reaction is usually carried out in a solvent inert to the reaction (water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixture thereof) in an organic acid (formic acid, acetic acid, propionic acid, butyric acid, Temperature from 170 ° C to the boiling point of the solvent used in the presence of maleic acid, fumaric acid, malonic acid, succinic acid, benzoic acid, metachlorobenzoic acid, P-nitrobenzoic acid, phthalic acid, etc.
  • solvent inert water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixture thereof
  • organic acid formic acid, acetic acid, propionic acid, butyric acid, Temperature from 170 ° C to the boiling point of the solvent used in the presence of maleic acid, fumaric acid, malonic acid, succinic acid, benzoic acid, metach
  • a temperature of 50 ° C to room temperature Preferably at a temperature of 50 ° C to room temperature, more preferably at a temperature of 20 ° C to 0 ° C for about 5 minutes to 24 hours, preferably about 5 minutes to 20 hours, or water or ethanol
  • an alcoholic solvent such as methanol or propanol
  • a base alkali hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide
  • the temperature is reduced to 170 ° C.
  • Temperature up to the boiling point of the solvent used usually from 150 ° C to room temperature, preferably from 120 ° C to 10 ° C, for about 5 minutes to 24 hours, preferably from 1 hour to 10 hours. Do.
  • Examples of the deoxidizing agent include sodium hydride, sodium hydroxide, potassium hydroxide, sodium methylate, potassium carbonate, and metallic sodium.
  • the reaction is usually carried out in an inert solvent (N, N-dimethylformamide, ethanol, methanol, methanol, dichloromethane, water, etc.) at a temperature of less than 20 ° C.
  • an inert solvent N, N-dimethylformamide, ethanol, methanol, methanol, dichloromethane, water, etc.
  • the compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method.
  • a conventional method such as a recrystallization method and a column chromatography method.
  • the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier.
  • Individual diastereomers can be separated by such means as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like.
  • Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.
  • the compound of the general formula (I) of the present invention includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, malonic acid, malic acid, tartaric acid,
  • the above-mentioned acid addition salt can be obtained by treating with succinic acid, methanesulfonic acid, benzenesulfonic acid or the like in a conventional manner.
  • the corresponding metal salt can be obtained by reacting with sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like.
  • a hydrate or a solvate can be obtained by treating the compound of the present invention with water, an aqueous solvent or another solvent.
  • the compound of the general formula (V) can be produced, for example, according to the following reaction route.
  • the compound of the general formula (IX) is heated with acetic anhydride, and the obtained compound of the general formula (X) is hydrolyzed using sodium hydroxide or the like to obtain a compound of the general formula (XI). Then, by treating this with a halogenating agent such as thionyl chloride or a sulfonylating agent such as methanesulfonyl chloride, a compound of the general formula (V) is obtained.
  • a halogenating agent such as thionyl chloride or a sulfonylating agent such as methanesulfonyl chloride
  • w 2 represents chlorine, bromine, iodine or nitro, and other symbols are as defined above.
  • the reaction is usually carried out in a solvent that is inert to the reaction (water or alcohols such as methanol or ethanol, chloroform, dichloromethane, benzene, toluene, dimethylformamide, or a mixture thereof).
  • a solvent that is inert to the reaction
  • water or alcohols such as methanol or ethanol, chloroform, dichloromethane, benzene, toluene, dimethylformamide, or a mixture thereof.
  • a base sodium hydroxide, hydroxide hydroxide, sodium hydride, sodium methoxide, sodium methoxide, sodium carbonate, potassium carbonate, metal sodium, triethylamine, pyridine, etc.
  • It proceeds at a temperature up to the boiling point of the solvent, preferably 20 to 80, for about 10 minutes to 24 hours, preferably 30 minutes to 7 hours.
  • the compound of the general formula (IX) in which q is 1 or 2 can be produced by subjecting the compound of the general formula (IX) in which Q is 0 to an oxidation reaction.
  • Oxidizing agents used in the oxidation reaction include metabenzo-perbenzoic acid, peracetic acid, trifluoroperacetic acid, permalic acid, superoxide, sodium hypobromite, sodium hypobromite, hydrogen peroxide, etc. Is raised.
  • the reaction is usually carried out in a solvent inert to the reaction (water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixture thereof) and an organic acid (formic acid, acetic acid, propionic acid, maleic acid).
  • W 3 represents a reactive atom or group (sulfonyloxy group such as halogen or methanesulfonyloxy, benzenesulfonyloxy, ⁇ -toluenesulfonyloquine, etc.), and E represents one (CH 2 CH 2 0) k—or—
  • the compound of the general formula (XVI) is reacted with an alcohol corresponding to the haloalkyl in D in the presence of a deoxidizing agent such as sodium hydride and sodium metal, and the obtained compound of the general formula (XVII) is treated with thionyl chloride.
  • a deoxidizing agent such as sodium hydride and sodium metal
  • thionyl chloride By treating with a halogenating agent such as chloride or treating with a sulfonylating agent such as methanesulfonyl chloride, a compound of the general formula (XIII) can be obtained.
  • the compound of the general formula (XV) can be obtained by reacting with thiourea and then thiolating by hydrolysis using sodium hydroxide or the like.
  • a compound having a removable alcohol protecting group may be used instead of the compound of the general formula (XVI), and the compound may be reacted with an alcohol to remove the protecting group. ) Can be produced.
  • the eliminable alcohol protecting group is a general protecting group, for example, acetyl, tetrahydroviranyl, etc., and the elimination method includes acid or alcohol hydrolysis.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof are represented by Pylori. Selective antibacterial activity against Helicobacter bacteria, and also shows good eradication activity in H. Pylori-infected animal models, indicating that various infectious diseases such as gastritis and gastric ulcer caused by Helicobacter bacteria. It is effective for prevention and treatment of Namely, the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter genus and preventing recurrence of ulcers in mammals including humans. It is used to prevent vomiting, prevent and treat non-ulcer dyspepsia, and prevent and treat tumors (such as gastric cancer).
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a gastric acid secretion inhibitory action, an anti-hampering action, a gastrointestinal cell protecting action, an anti-diarrheal action, and the like. It is useful for the prevention and treatment of duodenal ulcer, gastritis, diarrhea, colitis, etc.). Furthermore, it has low toxicity, is stable against acids, etc., and has characteristics such as a small increase in blood gastrin level.
  • the present invention relates to the use of a compound represented by the general formula (I) of the present invention in combination with an anti-ulcer drug, preferably a proton pump inhibitor, as seen in two-drug and new-drug combination therapy.
  • an anti-ulcer drug preferably a proton pump inhibitor
  • an anti-ulcer drug preferably a proton pump inhibitor
  • an anti-ulcer drug and an antibiotic or antiprotozoal a clearly superior eradication effect can be obtained with each drug alone. , Anti-hamlet effect, ulcer relapse and recurrence prevention effect.
  • the antiulcer drugs to be used in the present invention together with the above compound (I), pro Tonbon flop inhibitors, histamine H 2 antagonists, and the like protective factor enhancer.
  • the proton pump inhibitor include omebrazole, lansoprazole, pantoprazole, parabrazole and the like.
  • Specific examples of the protective factor enhancer include cetraxate hydrochloride, sucralfate, ecabapide, prostaglandin derivatives (misoprostol, ornoprosteel, etc.).
  • the medicament of the present invention includes an antibiotic or an antibiotic together with the compound (I) and the anti-ulcer drug.
  • antibiotics include, in particular, antibacterial antibiotics such as amoxicillin, clarithromycin, ampicillin or its prodrug.
  • antiprotozoal drugs include metronidazole, tinidazole and the like. These drugs can preferably use a commercially available preparation.
  • Compound (I) is appropriately selected depending on the type and symptoms of gastritis and peptic ulcer.
  • Compound (I) having an anti-H. Pylori action is 0.1 to 50 mg / kg ZB, preferably 0.3 to 0.3.
  • 11 OmgZkg days can be administered.
  • the antiulcer drug to be used in combination is administered at 0.01 to 1 OmgZkg / day, preferably at 0.1 to 1.0 mgZkg day.
  • H 2 antagonists 0. 1 ⁇ 1 0 Omg / k gZ day, preferably administered 1 ⁇ 1 OmgZk gZ date.
  • the dose is 1.0 to 10 OmgZkgZ days, preferably 10 to 50 mg / kg / day.
  • antibiotics to be used in combination are 0.1 to 10 Omg / kg day, preferably 5 to 3 OmgZkg days, and antiprotozoal drugs are 0.1 to 1 OmgZk gZ days, preferably 1 to 10 OmgZk gZ days. Is administered.
  • Compound (I) is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.) to form a pharmaceutical composition
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.
  • parenteral formulation as a preparation such as an ointment or an ointment.
  • carriers include, for example, sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans, pectins, Tran gum, gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sonorebitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyquinpropylmethylcellulose, Glycerin, polyethylene glycol, sodium bicarbonate, magnesium stearate, Luk or the like is used.
  • the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.
  • animal and vegetable oils oil, corn oil, castor oil, etc.
  • mineral oils vaseline, white petrolatum, solid paraffin, etc.
  • waxes jojoba
  • these commercially available products include Witepsol (manufactured by Dynamid Nobel), Pharmasol (manufactured by NOF Corporation), and the like.
  • examples of the carrier include sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, and ethyl alcohol.
  • a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used.
  • a suitable suspending agent such as sodium carboxymethyl cellulose, a nonionic surfactant, a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination.
  • the above pharmaceutical composition may further contain an anti-ulcer drug, or may contain an anti-ulcer drug and an antibacterial substance or an antiprotozoal drug.
  • the raw material preparation was carried out by using 2- (2-trifluoromethyloxy) ethyl chloride instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy chloride) ethyl chloride.
  • 2- (2-trifluoromethyloxy) ethyl chloride instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy chloride) ethyl chloride.
  • 2,3-dimethyl-1-4- (2- (2-trifluoromethyloxetoxy) ethylsulfanyl) pyridine-1-N-oxide is obtained.
  • Preparation A of Raw Material Preparation of Raw Material A was prepared by using 4-mercapto-1,2,3,5—trimethylpyridine-1-N-oxide instead of 2,3-dimethyl-4-mercaptopyridine-N-oxide. In the same manner as described above, 4- (2- (2- (2,2,2-trifluorotrifluoroethoxy) ethoxy) ethylsulfanyl) -1,2,3,5-trimethylpyridine-1-N-oxide is obtained.
  • Raw material preparation example 2 3-dimethyl-4-1 (2- (2- (2,2-difluoroethoxy) ethoxy) ethylsulfanyl) obtained in G. Same as raw material preparation example AA using pyridine-1N-oxide. By the method, 3-methyl-4- (2- (2- (2,2 difluoroethoxy) ethoxyquin) ethylsulfanyl) pyridine-1- 2-methano
  • Raw material preparation example 2 3-Dimethyl-4 _ (2- (2- (2-fluoroethoxy) ethkin) ethylsulfanyl) pyridine-N-year-old oxide obtained by H Method similar to raw material preparation example AA This gives 3-methyl-4-1 (2- (2- (2-fluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol.
  • Raw material preparation example 2 3-Dimethyl-4-1 (2- (2- (2-chloroethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide
  • Example of raw material preparation Example of raw material preparation using 2,3-dimethyl-4-1 (3- (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) pyridine-N-oxide obtained in L In the same manner as in AA, 3_methyl-41- (3- (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) pyridine-12-methanol is obtained.
  • Raw material preparation example Raw material preparation using 2,3-dimethyl-4-1 (4-1 (4- (2,2,2-trifluoroethoxy) butoxy) butylsulfanyl) pyridine-1-N-oxide obtained in M
  • 4--1 4--1 (4,2,2,2-trifluoroethoxy) butyne) butylsulfanyl) pyridine-12-methanol is obtained.
  • Raw material preparation example Raw material preparation using 2,3-dimethyl-4_ (3- (2- (2,2,2-trifluoroethyl) ethoxyquin) propylsulfanyl) pyridine-N-oxo obtained in N Example In the same manner as in AA, 3-methyl-4-1 (3- (2- (2,2,2-trifluoroethoxy) ethoxy) propylsulfanyl) pyridin-1-2-methanol is obtained.
  • Raw material preparation example PP Example of raw material preparation Example of raw material preparation using 2,3-dimethyl-4-1 (4- (2- (2,2,2-trifluoroethoxy) ethoxy) butylsulfanyl) pyridine-1N-oxide obtained in P In the same manner as for AA, 3-methyl_4- (4- (2- (2,2,2-trifluoroethoxy) ethoxy) butylsulfanyl) pyridine-12-methanol is obtained.
  • Raw material preparation example 2 Metal—4— (2— (2— (2,2,2—trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine obtained from U Same as raw material preparation example ⁇ using ⁇ -oxide To obtain 4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol.
  • Raw material preparation example YY Raw material preparation example 3-Methyl mouth 2-methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine monooxide obtained from Y In the same manner as in Raw Material Preparation Example ⁇ , 3-chloro-41- (2- (21- (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) pyridin-12-methanol is obtained.
  • Example 1 H 2 CF ;
  • Raw material preparation example 3-Methyl-4_ (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) obtained from AA O2 ml, and under ice-cooling, 2.2 ml of thionyl chloride was added dropwise, and the mixture was stirred at 40 to 5 (TC for 3.5 hours.
  • the reaction solution was poured into ice water, and carbonic acid was added thereto.
  • Example 3 H 2 - 0- CH 2 CF 3
  • Example of raw material preparation 2.5 g of 3-methyl-4- (4- (2,2,2-trifluoroethoxy) butylsulfanyl) pyridine-2-methanol obtained by CC is dissolved in 60 ml of chloroform. Under ice-cooling, 1.5 ml of thionyl chloride was added dropwise, and the mixture was stirred at 40 to 50 ° C for 2.5 hours. The reaction solution was poured into ice water, supersaturated with potassium carbonate, and extracted with chloroform.
  • the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily 2-clomethyl-3-methyl-4-1- (4- (2,2,2-trifluoroethyl) butylsulfanyl. ) 2.1 g of pyridine were obtained.
  • This was added to 30 ml of ethanol containing 1.0 g of 2-mercaptobenzoimidazole and 0.5 g of sodium hydroxide dissolved in 5 ml of water, followed by stirring at room temperature for 4.5 hours. The insoluble material was removed by filtration, the ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform.
  • Raw material preparation example Dissolve 9.1 g of 4- (2- (2-chloroethyne) ethylsulfanyl) -13-methylpyridine-12-methanol obtained in DD in 200 ml of chloroform. Under ice cooling, 4 ml of thionyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, supersaturated with carbonated lime, and extracted with black-mouthed form.
  • the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 9.0 g of 4- (2- (2-chloroethoxy) ethylsulfanyl) -12-chloromethyl_3-methylpyridine. Obtained. This was added to ethanol (200 ml) containing 3.93 g of 2-mercaptobenzoimidazole and 2.08 g of sodium hydroxide dissolved in 25 ml of water, and was added at room temperature for 2 hours. Stirred. Ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The black-mouthed form layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the medicament of the present invention can be formulated according to the following formulation examples.
  • a tablet containing compound (I) 2 Omg is prepared according to the following composition.
  • Example 1 The compound of Example 1 (1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, filtered to remove pyrogens, and the filtrate was aseptically transferred to an ampoule, sterilized, and then sealed by melting. The active ingredient is obtained as an injection containing O mg.
  • the medicament of the present invention can also be used in a combination therapy of two drugs and a new triple drug, in which case compound (I) and an anti-ulcer drug, or compound (I) and an anti-ulcer drug and an antibiotic or an antibiotic or It is sufficient that the antiprotozoal drug coexist in the living body, and it may be combined with one drug or may be separately formulated and administered to a patient simultaneously or separately.
  • the pyridine combination drug of the present invention is formulated, for example, as follows.
  • Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))
  • compositions (1) and (2) can be administered to a patient simultaneously or separately.
  • Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))
  • Amoxicillin capsules available as amolin capsules (trade name, manufactured by Takeda Pharmaceutical Company Limited)
  • the preparations (1), (2) and (3) can be administered to a patient simultaneously or separately.
  • Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))
  • Oral tablets of metronidazole available as Oral tablets of Frasil (trade name, manufactured by Shionogi & Co., Ltd.)
  • the preparations (1), (2) and (3) can be administered to a patient simultaneously or separately.
  • the pharmacological action of the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be confirmed by the following method.
  • a clinical isolate (18 strains) cultured for 72 hours at 37 ° C in microaerobic conditions using 5% horse serum was diluted with Brucella broth to obtain a bacterial population of about 10 6 cells / m1.
  • a liquid was prepared.
  • the diluted bacterial solution was spot-inoculated on agar plates containing test compounds in 2-fold dilution series using a microplanter, and cultured at 37 ° C under 8% carbon dioxide for 3 to 4 days.
  • the minimum inhibitory concentration (MIC) was determined. MIC 5 based on that value. Values (minimum concentration that inhibits growth by 50%) and MIC 9 . Values (minimum concentration that inhibits 90% growth) were calculated.
  • MIC 5 of the compound of the present invention Value is 0. 0 1 2 5 ⁇ 0.
  • test solution containing the test compound is administered intravenously 5 minutes before the administration of histamine hydrochloride.
  • the acidity of the stomach is titrated to pH 7.0 using an automatic infusion device, and the rate of inhibition of gastric acid secretion by the test compound is measured.
  • Comparative compound 1 10 ml / kg, b.i.d. 14 days 5 0 0.0 1 2
  • Comparative compound 2 10 ml / kg, b.i.d. 14 days 5 0 0.0 2 5
  • the eradication rate of Comparative Compound 1 and Comparative Compound 2 was 50%, while the eradication rate of the compound of Example 1 was 100%, and the compound of Example 1 was clearly in vivo. Excellent eradication effect.
  • a 7-week-old male gerbil which has been fasted for about 20 hours, is gavaged with a culture of a standard strain of H. Pylori (ATC C4354) for about 24 hours. After administration of the culture solution, the animals are fasted for about 4 hours and maintained in a water-free state, and then fed with normal solid food and drinking water to create a gerbil model infected with H. Pylori.
  • the drug is orally administered twice a day for 2 weeks from 6 weeks after infection.
  • the compound of Example 1 and a proton pump inhibitor In a combination experiment with the compound of Example 1 or a combination of the compound of Example 1 with a proton pump inhibitor and an antibiotic or an antiprotozoal drug, administration of the proton pump inhibitor first
  • the compound of Example 1, or the compound of Example 1, and an antibiotic or antiprotozoal are orally administered.
  • the stomach is crushed with a homogenizer in 1 Om1 of phosphate buffered saline. Dilute the disrupted solution appropriately with the same buffer, and inoculate 1 ml of the solution into the selective medium for H. Pyl or i bacteria. This is cultured in the presence of carbon dioxide to check for the presence of H. Pyl or i.
  • Example 1 shows an excellent eradication effect even when administered alone, the compound of Example 1 is administered in combination with a proton pump inhibitor, or the compound of Example 1 is administered with a proton pump inhibitor and an antibiotic or an antibiotic. Coadministration with the antiprotozoal drug clearly enhanced the eradication effect, and promoted gross and histopathological repair of inflammatory symptoms. No inflammatory symptoms recurred in the complete eradication group by the combined administration.
  • Example 5
  • a single oral dose of the compound of Example 1 was administered to a 5-week-old male ICR mouse (Charles River Japan, Japan) that had been fasted for about 24 hours, and the subsequent death was observed.
  • a single intravenous administration of the compound of Example 1 was performed to a 5-week-old ICR male mouse (Charles River Japan), and the survival and death 3 days later were observed.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof selectively show antibacterial activity against bacteria of Helicopter ⁇ represented by H. Pylori. It shows good eradication activity in infected animal models, and is effective in preventing and treating various diseases such as gastritis and gastric ulcer caused by Helicobacter bacteria. That is, the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter genus and preventing recurrence of ulcers in mammals including humans. It is used to control vomiting, prevent and treat non-ulcer dyspepsia, and prevent and treat tumors (such as gastric cancer).
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a gastric acid secretion inhibitory action, an anti-ulcer action, a gastrointestinal cell protective action, an anti-diarrheal action, and the like. , Diarrhea, colitis, etc.). Furthermore, it has low toxicity, is stable against acids, etc., and has characteristics such as a small increase in blood gastrin level.
  • the eradication effect is enhanced by the combined administration of compound (I) and an anti-ulcer agent or the combined administration of compound (I) and an anti-ulcer agent with an antibiotic or antiprotozoal.
  • the effect of promoting ulcer healing is obtained.
  • the dose can be reduced as compared with single administration, side effects and improvement in patient compliance can be expected.

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Abstract

L'invention concerne des composés pyridiniques représentés par la formule générale (I) ou des sels de ceux-ci, acceptables sur le plan pharmaceutique. Les symboles de cette formule sont définis dans la description. L'invention concerne également des compositions médicales contenant ces composés et des vecteurs acceptables sur le plan pharmaceutique; des compositions médicinales contenant les composés ci-dessus et des médicaments anti-ulcéreux, éventuellement en association avec des antibiotiques ou des médicaments anti-protozoaires; une méthode pour prévenir ou traiter des maladies digestives, consistant à administrer les médicaments ci-dessus; et une méthode pour prévenir ou traiter des maladies digestives consistant à administrer les composés ci-dessus et des médicaments anti-ulcéreux éventuellement en association avec des antibiotiques ou des médicaments anti-protozoaires. Les composés en question sont utilisables sur les mammifères et l'homme pour prévenir et soigner différentes maladies causées par des souches d'Helicobacter, pour empêcher la réapparition d'ulcères, empêcher les vomissements et prévenir ou soigner la dyspepsie non ulcéreuse et les tumeurs du type cancer gastrique. En outre, ces composés ont des effets inhibiteurs sur la sécrétion de l'acide chlorhydrique gastrique, des effets anti-ulcéreux, des effets protecteurs par rapport aux cellules gastro-intestinales, des effets anti-diarrhéiques, etc. Ces composés sont donc utiles en tant qu'agents préventifs et curatifs contre des maladies digestives telles que les ulcères gastriques, les ulcères du duodénum, la gastrite et l'inflammation du côlon.
PCT/JP1997/001365 1996-04-23 1997-04-18 Composes pyridiniques et utilisations medicales de ceux-ci WO1997040039A1 (fr)

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JP10074796 1996-04-23
JP10543796 1996-04-25
JP08/105437 1996-04-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005077365A3 (fr) * 2004-02-12 2005-12-01 Inst Superiore Di Sanita Utilisations d'inhibiteurs de pompe a protons

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06500547A (ja) * 1990-09-14 1994-01-20 ビイク　グルデン　ロンベルク　ヒエーミツシエ　フアブリーク　ゲゼルシヤフト　ミツト　ベシユレンクテル　ハフツング ピリジルメチルスルフィニル―１ｈ―ベンゾイミダゾール誘導体のヘリコバクターにより起こされる病気の治療のための使用
WO1995011897A1 (fr) * 1993-10-29 1995-05-04 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyridine et son utilisation en tant que remede
JPH07278141A (ja) * 1994-01-12 1995-10-24 Eisai Co Ltd 光学活性ベンズイミダゾール誘導体の製造法および中間体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06500547A (ja) * 1990-09-14 1994-01-20 ビイク　グルデン　ロンベルク　ヒエーミツシエ　フアブリーク　ゲゼルシヤフト　ミツト　ベシユレンクテル　ハフツング ピリジルメチルスルフィニル―１ｈ―ベンゾイミダゾール誘導体のヘリコバクターにより起こされる病気の治療のための使用
WO1995011897A1 (fr) * 1993-10-29 1995-05-04 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyridine et son utilisation en tant que remede
JPH07278141A (ja) * 1994-01-12 1995-10-24 Eisai Co Ltd 光学活性ベンズイミダゾール誘導体の製造法および中間体

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005077365A3 (fr) * 2004-02-12 2005-12-01 Inst Superiore Di Sanita Utilisations d'inhibiteurs de pompe a protons
CN1953750A (zh) * 2004-02-12 2007-04-25 国家高等卫生院 质子泵抑制剂的新应用

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