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WO1998026769A1 - Inhibiteur d'adp-ribosyltransferase - Google Patents

Inhibiteur d'adp-ribosyltransferase Download PDF

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Publication number
WO1998026769A1
WO1998026769A1 PCT/JP1997/004579 JP9704579W WO9826769A1 WO 1998026769 A1 WO1998026769 A1 WO 1998026769A1 JP 9704579 W JP9704579 W JP 9704579W WO 9826769 A1 WO9826769 A1 WO 9826769A1
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salt
infectious disease
curing
disease caused
quinolon
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Ceased
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PCT/JP1997/004579
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English (en)
Inventor
Masatoshi Noda
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority claimed from JP9030140A external-priority patent/JPH10231247A/ja
Priority claimed from JP9030139A external-priority patent/JPH10231246A/ja
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to AU54109/98A priority Critical patent/AU5410998A/en
Publication of WO1998026769A1 publication Critical patent/WO1998026769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to an ADP-ribosyltransferase inhibitor which comprising, as the effective ingredient, a carbostyril derivative represented by the general formula ( I ) ,
  • R is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom); the side-chain of the formula,
  • the invention relates to an agent for curing infectious diseases caused by Helicobacter pylori and an agent for curing infectious diseases caused by vivoendotoxin type bacteria, on the basis of the activity for inhibiting ADP-ribosylation according to the present invention.
  • ADP-ribosylation is one of the reactions of protein modification, thus, ADP-ribose moiety is cut out from coenzyme NAD by the action of toxins, then ADP- ribose moiety translocates to the target protein.
  • NAD which is usable for ADP-ribosylation, has the paticular molecular structure wherein ADP-ribose moiety is bonded to nicotinamide, and the reaction for translocating ADP-ribose moiety to the target protein is called as ADP-ribosylation. This reaction was discovered in 1968 as the reaction in which diphtheria toxin acts as the catalyst.
  • EF-2 a peptide chain elongation factor in case of eukaryotic cell, while it is called as EF-TU in case of procryotic cell.
  • EF-2 a peptide chain elongation factor in case of eukaryotic cell
  • EF-TU a peptide chain elongation factor in case of procryotic cell
  • cholera toxin or heat-labile enterotoxin of enterotoxigenic Escherichia coli continuously activates adenylate cyclase by ADP-ribisylating Gs ⁇ , which is one of the GTP binding proteins, and increases the concentration of cAMP in the enteroepitherial cell, which promotes secretion of a large quantity of water and electrolytes, and induces hydragogue.
  • vacuolating cytotoxin which is a toxin capable to induce the vacuolated degeneration as well as the cell deaths of HeLa cells and Vero cells, is secreted in the supernatant fluid of culturing
  • the gene (i.e., vac A gene) of the above- mentioned vacuolating cytotoxin which is noticed mostly as the pathogenic factor of Helicobacter pylori , is coding the precursor protein having the molecular weight of 139 kDa, containing a signal sequence consisting of 33 of amino acids, 87 of cytotoxin and bacterial adventitial protein having the molecular weight of 50 kDa, [Phadnis, S. H., et al . : Infect. Immunol., 62,
  • intestinal infectious diseases so-called "travellers' diarrhea", which are frequency of overt infectious diseases caused by the pathogens involving entero- toxigenic Escherichia coli , genus Salmonella , pathogenic genus Vibrio (e.g. , Vibrio cholera. Vibrio para- hae olyticus ) , genus Shiqella, genus Campylobacter and the like.
  • entero- toxigenic Escherichia coli genus Salmonella
  • pathogenic genus Vibrio e.g. , Vibrio cholera. Vibrio para- hae olyticus
  • genus Shiqella genus Campylobacter and the like.
  • cholera is very serious disease of high mortality rate caused by infection of Vibrio cholera , with very severe hydragogue as the main symptoms.
  • the pathogenetic mechanism of hydragogue is understood as follows: (1) orally taken Vibrio cholera is adhered and fixed on the small intestine mucosa;
  • CT activates adenylate cyclase in the enteroepitherial cells
  • hydragogue which is the main symptom of cholera, is occurred through the action of cAMP- dependent Cl-channel (CFTR).
  • cholera toxin and Bordetella pertusis toxin are toxins which inhibit the transmission of biological information in down stream by ADP-ribosylating G-protein.
  • IIDA Tetsuya, YOAKE Jun, HONDA Takeshi: BYOUTAI-SEIRI (Pathophysiology), 14., (3), 181-186, (1995)].
  • Cell response phenomena caused by a toxin are shown in the number of receptors in the system wherein the receptor stimulation is varied for increasing or inhibiting the activity of adenylate cyclase through GTP-binding protein having accelerative (Gs) and inhibitory (Gi) properties. From this system, the concentration of cyclic AMP (cAMP) in the cell is increased or decreased, then the activity of cAMP-dependent protein phophorylated enzyme (A-kinase) changes, and a functional protein is introduced by phosphorylation.
  • cAMP cyclic AMP
  • Cholera toxin is a typical A-B type toxin which is consisting of A-subunit having the activity, and B-subunit relating to the bonding to a receptor.
  • A-subunit is consisting of Al peptide having the molecular weight of 21.8 kDa and A2 peptide having the molecular weight of 5.4 kDa, both of which are connected to each other by S-S bonding.
  • B-subunit having the molecular weight of 11.6 kDa and 5 of B-subunits are connected to one A-subunit.
  • the activity of cholera toxin exhibited by Al peptide, and the S-S bonding between Al peptide and A2 peptide should necessarily be reduced.
  • B-subunit combines with the cell through GM1 ganglioside on the cell membrane as the receptor, then CT (cholera toxin) connecting to GM1 is taken into the cell by the action of endocytosis through B-subunit.
  • CT cholera toxin
  • Al peptide of cholera toxin makes ADP-ribosylation of ⁇ -subunit in the trimer of G protein (Gs), then this
  • ADP-ribosylated ⁇ -subunit activates adenylate cyclase of the effector.
  • Cholera toxin makes ADP- ribosylation of ⁇ -subunit of Gs (i.e., Al peptide possesses the activity of ADP-ribosyltransferase which can be cut out ADP-ribose group from NAD, and ADP-ribose translocates to the target protein), according to this ADP-ribosylation of Gs ⁇ by CT, adenylate cyclase is maintained in an activated state, because the activity of GTPase of Gs ⁇ is controlled. As the result, the concentration of cAMP in the cell is continuously increased.
  • ADP-ribosylating reaction concerns various pathologic symptoms, particularly it relates to the actions of exotoxins . Therefore, various infectious diseases induced by said ADP- ribosylation can be cured by inhibiting said ADP- ribosylating reaction.
  • RG tannin which was separated and refined from the extract of Rhei Rhizoma was the only known as an agent for inhibiting ADP-ribosylation, so that development of safty and effective agent for inhibiting ADP-ribosylation is expected .
  • the present inventors have made an extensive research work to find an effective agent having the activity for inhibiting ADP-ribosyltransferase .
  • a carbostyril derivative represented by the general formula ( I ) especially 2- ( 4-chlorobenzoylamino ) -3- ( 2-quinolon-4- yl)propionic acid or salt thereof shows an excellent activity for inhibiting ADP-ribosyltransferase and is useful for curing infectious diseases caused by
  • the present invention provides an agent for inhibiting ADP-ribosyltransferase, agent for curing infectious diseases caused by Helicobacter pylori and agent for curing infectious diseases caused by vivoendotoxin type bacteria containing, as the effective ingredient, a carbostyril derivative represented by the general formula ( I ) ,
  • R is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom) ; the side-chain of the formula.
  • the carbostyril derivative of the present invention inhibits the activity of ADP-ribosyl- transferase and is capable to improve various pathological symptoms caused by ADP-ribosylation of proteins .
  • the carbostyril derivative of the present invention is useful as an agent for curing infectious diseases caused by Helicobacter pylori , because said derivative is capable to control the activation of vacuolating cytotoxin by inhibiting the activity of ADP-ribosyltransferase. Concretely, the carbostyril derivative improves various pathological syndromes, for example, ulcer caused by Helicobacter pylori .
  • the carbostyril derivative of the present invention improves various infectious diseases caused by vivoendotoxin type bacteria represented by enterotoxigenic Escherichia coli, genus Salmonella, pathogenic genus Vibrio (e.g., Vibrio cholera and Vibrio parahaemolyticus ) , genus Shiqella, genus Campylobacter and the like. That is, the carbostyril derivative of the present invention is useful as agents for curing infectious diseases caused by vivoendotoxin type bacteria, because the carbostyril derivative inhibits the activity of ADP-ribosyltransferase. For example, in case of infectious disease caused by Vibrio cholera, the carbostyril derivative inhibits ADP-ribosylation of cholera toxin and controls the activity of adenylate cyclase.
  • enterotoxigenic Escherichia coli genus Salmonella
  • pathogenic genus Vibrio e
  • the ADP-ribosyltransferase inhibitor of the present invention can be prepared in the form of combined drugs by formulating the carbostyril derivative represented by the general formula ( I ) or salt thereof with antibiotics .
  • a carbostyril derivative of the general formula (I) or salt thereof can be used in the form of a combined drug jointly with antibiotics for example, Clarithromycin, Metronidazole, Tinidazole, Amoxicilline and the like.
  • antibiotics for example, Clarithromycin, Metronidazole, Tinidazole, Amoxicilline and the like.
  • 2- ( 4-chlorobenzoylamino ) -3- ( 2-quinolon-4- yl)propionic acid or salt thereof can be used jointly in combination with Clarithromycin and Metronidazole; in combination with Clarithromycin and Tinidazole; in a combination with Clarithromycin and Amoxicillin; and the like .
  • the carbostyril derivative of the general formula (I) or salt thereof can be used in the form of a combined drug jointly with antibiotics, for example newer quinoline type antibiotics such as Nafloxacin, Enoxacin, Ofloxacin, Ciproxacin, Lomefloxacin, Tosufloxacin, Sparfloxacin, Levofloxacin and the like; and tetracycline type antibiotics such as Tetracycline, Tetracycline hydrochloride, Tetracycline metaphosphite, Oxytetracycline hydrochloride and the like.
  • antibiotics for example newer quinoline type antibiotics such as Nafloxacin, Enoxacin, Ofloxacin, Ciproxacin, Lomefloxacin, Tosufloxacin, Sparfloxacin, Levofloxacin and the like; and tetracycline type antibiotics such as Tetracycline, Tetracycline hydrochloride, Tetracycline metaphosphite,
  • a compound having acidic group can form a salt with pharmaceutically acceptable basic compound.
  • metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like; carbonates or bicarbonates of alkali metals such as sodium carbonate, sodium hydrogencarbonate and the like; alkali metal alcoholates such as sodium methylate, potassium ethylate and the like can be exemplified.
  • a compound having bsic group can form a salt with common pharmaceutically acceptable acid.
  • inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid and the like
  • organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid and the like
  • salts can also be used, similar to compounds represented by the general formula (I) in free form, as compounds of effective ingredient in the present invention.
  • compounds represented by the general formula ( I ) involve inevitably their stereoisomers and optical isomers, and these isomers can also be used as compounds of effective ingredients.
  • an ADP-ribosyltrans- ferase inhibitor an agent for curing infectious diseases caused by Helicobacter pylori and an agent for curing infectious diseases caused by vivoendotoxin type bacteria are prepared in the form of general types of pharmaceutical preparations by formulating a carbostyril derivative of the general formula (I) or a salt thereof, and if necessary it can be used in combination with the above-mentioned antibiotics .
  • These pharmaceutical preparations of the present invention can be prepared into various forms of common pharmaceutical preparations by formulating with commonly employed diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants and the like.
  • the pharmaceutical preparations can be shaped into various forms depending upon the curing purposes, thus, typical examples of the forms are tablets, pills, powders, liquid medicines, suspensions, emulsions. granules, capsules, suppositories, injection preparations (liquid, emulsion, suspension and the like), and syrup preparations. Further, sustained release preparations can also be prepared by formulating with suitable resins.
  • any known carriers which are used widely in this field can be applied, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl- cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrators such as dry starch, sodium alginate, agar powder, laminalia powder, sodium hydrogencarbonate , calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oils and the like; absorption accelerators such as quaternary am
  • the tablets can be prepared in the form of common coated tablets, for example, sugar-coated tablets, gelatin film-coated tablets, enteric film-coated tablets, film-coated tablets, or in the form of double-layers tablets, multiple-layers tablets and the like .
  • any known carriers which are widely used in this field can be applied, for example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as arabic gum powder, tragacanth gum powder, gelatin, ethanol and the like; and disintegrators such as laminaria, agar-agar and the like can be exemplified.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like
  • binders such as arabic gum powder, tragacanth gum powder, gelatin, ethanol and the like
  • disintegrators such as laminaria, agar-agar and the like can be exemplified.
  • any known carriers which are widely used in this field can be applied, for example, polyethylene glycols, cacao butter, higher alcohols, esters of higher alcohol, gelatin, semi-synthesized glycerides and the like can be exemplified.
  • injection preparations For the purpose of shaping into the form of injection preparations, they can be prepared to solutions, emulsions or suspensions. Generally they are sterilized and preferably made isotonic to the blood.
  • any known diluents which are widely used in this field can be applied. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan and the like can be exemplified.
  • sufficient amount of sodium chloride, glucose or glycerin may be contained therein.
  • a dissolving adjuvant a buffer solution, an analgesic agent and the like which are commonly used may be contained therein.
  • a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent and other medicines may be contained therein .
  • Preparations for external use are prepared in the form of common pharmaceutical preparations for external use.
  • common pharmaceutical preparations for external use are including, for example, a liquid medicine, a medicinal oil, a lotion, a liniment, an oleaginous ointment, an emulsion type ointment, such as 0/W type hydrophilic ointment and W/O type water- absorbing ointment, a water-soluble ointment, a pasta, a plaster, a patch, a cream, an emulsion and the like, and these forms of pharmaceutical preparations for external use are not restricted within the scope of these examples .
  • Each one of these forms of pharmaceutical preparations for external use can be prepared by common methods . In shaping of these preparations for external use, various base materials which are widely used in this field can also be applied.
  • At least one oleaginous base can be used singly, or mixture of two or more of them can be used widely; or at least one water-soluble ointment base can be used singly, or mixture of two or more of them can be used widely.
  • these ointment base are fats and oils such as peanut oil, sesame oil, soybean oil, safflower oil, avogado oil, sunflower oil, corn oil, rapeseed oil, cotton seed oil, castor oil, camellia oil, coconut oil, olieve oil, poppy seed oil, cacao butter, beef tallow, lard, wool fat and the like; modified bases obtained by subjecting these fats and oils to chemical changes such as hydrogenation; mineral oils such as petrolatum, paraffin, silicone oil, squalane and the like; higher fatty acid esters such as isopropyl myristate, n.-butyl myristate, isopropyl linoleate, acetyl ricin
  • Aerosol type preparations can be prepared generally by formulating a sterilized solution or suspension of the carbostyril derivative of the general formula ( I ) with a propellant .
  • any one of known diluents which are commonly used in this field can also be used, thus the diluents which are exemplified in formulating the injection preparations can be used.
  • the propellant any one of the propellants which are commonly used in this field can also be used, thus, chlorofluorocarbons such as Fron-12 or Fron-123; compressed gas propellants such as nitrogen gas and carbon dioxide and the like can be exemplified.
  • the aerosol type preparations may further contain a common solubi- lizing adjuvant, a buffering agent, and the like, and if necessary, a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent may be added thereto.
  • a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent may be added thereto.
  • the amount of the carbostyril derivative of the general formula ( I ) or salt thereof to be contained in the agent for inhibiting ADP-ribosyltrasferase of the present invention is not particularly restricted and can be selected from a wide range, and the amount may be generally selected within the range of 1-70% by weight, preferably 5-50 % by weight.
  • Method for administering ADP-ribosyltrans- ferase of the present invention is not particularly restricted, except that in the case to be selected specifically for the particular treating purpose.
  • the method is decided depend upon the form of preparation, the age of patient, the distinction of sex and other relating conditions, the degree of disease condition of the patient and others.
  • tablets, pills, a liquid medicine, a suspension, an emulsion, granules, a syrup and capsules are administered orally.
  • An injection preparation is administered intravenously singly or in combination with common auxiliary solutions such as glucose solution and/or amino acid solution. In case of necessity, it is singly administered intramuscularly, intradermally, subcutaneously or intraperitoneally.
  • a suppository is administered intrarectally.
  • a prepara- tion for external use is coated on the diseased part of the body.
  • Dosage of the ADP-ribosyltransferase inhibitor of the present invention may be suitably selected depend upon the age of patient, the distinction of sex and other conditions, the degree of disease condition of the patient as well as other related factors, and generally the amount of carbostyril derivative of the general formula (I) or a salt thereof may be administered about 0.6 to 50 mg per 1 kg of the body weight per day.
  • the desirable content of the effective ingredient in each unit of the administration form may be 10 to 1,000 mg.
  • Citric acid 1.0 g Lactose 33.5 g
  • Pluronic F-68 30.0 g Sodium lauryl sulfate 15,.0 g Polyvinylpyrrolidone 15. .0 g
  • Polyethylene glycol (Carbowax 1500) 4, .5 g Polyethylene glycol (Carbowax 6000) 45. .0 g Corn starch 30. ,0 g
  • Test Example 1 Inhibition test of ADP-ribosyltrans- ferase (Determination of ADP- ribosylation of P70 protein and Agmatine ) Main toxicological action of cholera toxin
  • Test compound 2-(4-chloro- benzoylamino) -3- (2-quinolon-4-yl)propionic acid
  • reaction liquid consisting of 1 ⁇ M of [ ⁇ - 32 P]NAD (2 ⁇ Ci), 10 mM of thymidine, 1 mM of EDTA, 5 mM of dithiothreitol (DTT) and 50 mM of potassium phosphate buffer solution (pH 7.5), was added 100 ⁇ g of P70 protein or Agmatine, 2.5 ⁇ g of cholera toxin A (CTA) and 1 mM of "Test compound". Then the whole mixture was reacted at 37°C for 1 hour. Trichloroacetic acid was added to the reaction mixture to obtain precipitate, then conducted an SDS-polyacryl- amide gel electrophorasis . Radioactivity of the gel was determined by use of BlO-Imageing Analyser. In conducting the control test, reaction was conducted similarly, except that "Test compound" was not used.
  • Test Example 2 Inhibition test of ADP-ribosylation of 70 kDa protein of Helicobacter pylori
  • Helicobacter pylori was cultivated on an agar culture of Brucella agar (5% fetal calf serum was added) for 2 days. Cultivated cell bodies of bacteria on the agar plate was taken by scratching with sterilized swab and was suspended in 90 ml (placed in a flask of 500 ml capacity) of a Brucella broth (5% fetal calf serum was added), then the suspension was subjected to shaking culture under a slightly aerobic condition for 24 hours. Then cultivated cell bodies of bacteria in the culture fluid were collected by filtration and were suspended in 10 nM tris-HCl solution (pH 7.5), then the suspension was shaken for 30 minutes. The cell bodies of bacteria were removed by centrifugal separation and filtration by use of a filter (pore diameter: 0.2 ⁇ m) and obtained a crude extract of cell bodies of Helicobacter pylori . (2) ADP-ribosylation
  • the heat-treated sample fluid was subjected to an electrophoresis by using 10% SDS-polyacrylamide gel, then the intake of radioactivity into the colored protein in the gel was quantitatively analyzed by use of Bioimage Analyzer (manufactured by Fuji Photo Film Co., Ltd.).
  • the position of 70 kDa protein on the gel was determined in terms of the position of molecular weight marker on the electrophoresis conducted at the same time [Cf., Morinaga, N. I., Noda, M. and Kato, I., FEBS Letters, 271, 211, (1990)].
  • the carbostyril derivative of the present invention clearly inhibits the ADP- ribosylation of the protein 70 kDa of Helicobacter pylori , thus the carbostyril derivative of the present invention possesses activity for inhibiting ADP- ribosyltransferase .
  • Table 1
  • Agmatine assay was conducted according to the method reported by Noda, et al . , [Kato I., Noda M. : ADP- ribosylation of cell membrane proteins by Staphylococcal ⁇ -toxin and leukocidin in rabbit erythrocytes and poly- morphonuclear leukocytes; FEBS Letter, 281, 185-190 (1989)].
  • potassium phosphate buffer solution [containing 5 mM of MgCl 2 , 100 ⁇ M of guano ⁇ ine triphosphate (GTP), 100 ⁇ M of [adenine- C] NAD (60000 cpm) , 20 mM of dithiothreitole (DTT), 20 mM of agmatine and egg white albumin (0.1 mg/ml)] was mixed with 1 ⁇ g of A-subunit of cholera toxin (CTA) and test compound (300 ⁇ l in total volume), and reacted at 30°C for 3 hours.
  • GTP guano ⁇ ine triphosphate
  • DTT dithiothreitole
  • CTA A-subunit of cholera toxin
  • test compound 300 ⁇ l in total volume
  • the activity for inhibiting ADP-ribosyltransferase performed by the test compound was shown as the relative activity in terms of that the value of control test was defined as 100%.
  • the results are shown in Table 2.
  • the carbostyril derivative of the present invention clearly inhibits the ADP-ribosylation of agmatine, thus the carbostyril derivative of the present invention possesses activity for inhibiting ADP-ribosyltrasferase.

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Abstract

Nouvel inhibiteur d'ADP-ribosyltransférase contenant en tant que principe actif un dérivé de carbostyryle représenté par la formule générale (I) (dans laquelle R est un atome d'halogène) ou un sel ce dernier.
PCT/JP1997/004579 1996-12-16 1997-12-12 Inhibiteur d'adp-ribosyltransferase Ceased WO1998026769A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54109/98A AU5410998A (en) 1996-12-16 1997-12-12 Adp-ribosyltransferase inhibitor

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP33546296 1996-12-16
JP8/335462 1996-12-16
JP9030140A JPH10231247A (ja) 1996-12-16 1997-02-14 生体内毒素型細菌性感染症治療剤
JP9/30139 1997-02-14
JP9/30140 1997-02-14
JP9030139A JPH10231246A (ja) 1996-12-16 1997-02-14 Ａｄｐ−リボシル化阻害剤

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

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Publication number Priority date Publication date Assignee Title
WO1994012182A1 (fr) * 1992-11-26 1994-06-09 Otsuka Pharmaceutical Co., Ltd. Agent de prevention et de traitement de troubles de la muqueuse de l'intestin
WO1995012579A1 (fr) * 1993-11-05 1995-05-11 Otsuka Pharmaceutical Company, Limited Sel de bismuth de derives de carbostyrile destines au traitement des ulceres gastro-duodenaux
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

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