WO1995028929A1 - COMPOSES ANTIMICROBIENS A BASE D'AMINOLINE-N-OXYDE UTILISES CONTRE LES INFECTIONS A $i(H. PYLORI) - Google Patents

COMPOSES ANTIMICROBIENS A BASE D'AMINOLINE-N-OXYDE UTILISES CONTRE LES INFECTIONS A $i(H. PYLORI) Download PDF

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Publication number
WO1995028929A1
WO1995028929A1 PCT/GB1995/000886 GB9500886W WO9528929A1 WO 1995028929 A1 WO1995028929 A1 WO 1995028929A1 GB 9500886 W GB9500886 W GB 9500886W WO 9528929 A1 WO9528929 A1 WO 9528929A1
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compound
formulation
infection
pylori
treating
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PCT/GB1995/000886
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English (en)
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Graham Walter Taylor
Sandra Lynn Lacey
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Rpms Technology Limited
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Priority to AU22621/95A priority Critical patent/AU2262195A/en
Publication of WO1995028929A1 publication Critical patent/WO1995028929A1/fr

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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

Definitions

  • the present invention relates to compounds that are effective in reducing or preventing infection by Helicobacter pylori or other microaerophiles.
  • it relates to compounds that are useful in treating patients with gastric Helicobacter pylori infections and who suffer from gastric ulceration.
  • H. pylori (previously known as Campylobacter pylori) is recognised as the major cause of chrome gastritis in man. It is a Gram- negative microaerophile, that is to say it requires a low oxygen tension for growth (but cannot grow in the absence of oxygen) and a raised carbon dioxide level. Thus, typically, an oxygen concentration of about 3-15% and a C0 2 concentration of about 3-5% are required.
  • the presence of H. pylori in the pyloric antrum has been associated with duodenal ulcers and the organism has been linked to gastric ulcers and gastric carcinoma.
  • H. pylori Eradication of the H. pylori is often difficult because the bacterium is intrinsically resistant to a number of antibiotics, including vancomycin, trimethoprim and the sulphonamides, and becomes resistant to other antibiotics that have been used against it, such as metronidazole and the macrolides.
  • 2-Heptyl-4-hydroxyquinoline N-oxide is a lipoxygenase inhibitor and has been proposed for use in treating bronchial asthma, allergic disorders, circulatory disorders and inflammations (EP 0 128 374).
  • SUBSTITUTE SHEET (RULE 2 ⁇ N-oxide, produced by Pseudomonas aeruginosa, has also been shown to inhibit the growth of the Gram-positive bacteria Staphylococcus aureus, Bacillus sphaericus, Bacillus subtilis and Listeria monocytogenes (Machan et al (1992) J. Antimicrobial Chemother. 30, 615-623). This report concluded that alkyl hydroxyquinoline N-oxides are only active against Gram-positive organisms; Gram-negative bacteria were found to be unaffected by these compounds.
  • the present invention aims to provide new uses for, and formulations of, 2-alkyl-4-hydroxyquinolines and their N-oxides and new methods of treating or preventing infection by microaerophiles, especially Helicobacter pylori.
  • a first aspect of the invention provides the use of a compound with the structural formula:
  • R is H or lower alkyl and R 2 is C 1-20 alkyl or C 2-20 alkenyl with one or two unsaturated bonds or a pharmaceutically acceptable salt, ester or salt of such ester or amide of such compounds, in the manufacture of a medicament for treating or preventing infection by Gram negative microaerophilic bacteria, especially Helicobacter pylori .
  • lower alkyl we mean -CH 3 , -C 2 H 5 , -C 3 H 7 and -C 4 H 9 . It is preferred if R, is H. It is preferred if R 2 is a straight chain alkyl group or mono or di-unsaturated derivatives thereof. It is more preferred if R 2 is C 5 -, 2 alkyl or C 5 -, 2 alkenyl. It is still more preferred if R 2 is w-heptyl or /i-nonyl or n-nonenyl.
  • R is H
  • a pharmaceutically acceptable ester or salt may be prepared as follows. Suitable esters can be made using acids or acid chlorides, for example, R 3 COOH or R 3 COCl wherein R 3 is an alkyl group which may contain an acidic or basic group. Preferably R 3 is -CH 3 , -C 2 H 5 , -C 3 H 7 or a carboxylic acid- or amino-derivative thereof.
  • Salts which may be conveniently used in therapy include physiologically acceptable base salts, for example, derived from an appropriate base, such as an alkali metal (eg sodium), alkaline earth metal (eg magnesium) salts, ammonium and ⁇ X 4 + (wherein X is C,- 4 alkyl) salts.
  • physiologically acceptable acid salts include hydrochloride, sulphate, mesylate, besylate, phosphate and glutamate.
  • Salts according to the invention may be prepared in conventional manner, for example by reaction of the parent compound with an appropriate base to form the corresponding base salt, or with an appropriate acid to form the corresponding acid salt.
  • the compound is a 2-alkyl-4-hydroxyquinoline or its N-oxide. It is most preferred if the compound is 2-heptyl-4-hydroxy- quinoline, 2-nonyl-4-hydroxyquinoline, 2-nonenyl-4-hydroxyquinoline or their N-oxides. The reduced compound is preferable to the N-oxide.
  • Helicobacter pylori infection we mean any infection of man in which H. pylori can be isolated.
  • Diseases of man that are associated with or caused by H. pylori infection include peptic ulcers, duodenal ulcers, gastric ulceration, mucosal-associated B-cell lymphomas and gastric carcinoma.
  • H. pylori is increasingly recognised as an important underlying cause of peptic ulcers.
  • up to 95 % of patients with duodenal ulcer have H jy/o ⁇ ' -associated gastritis;
  • H. /ry/ ⁇ ri-negative patients with duodenal ulcers usually have some different aetiological factor, such as use of non- steroidal anti-inflammatory agents or pancreatitis.
  • H. pylori mucosal-associated lymphoid tissue
  • H. pylori is present in 90% of gastric MALT lymphomas. Given its close association with gastric MALT lymphoma, H. pylori might evoke immune responses and, in so doing, stimulate tumour growth. Thus, eradication of H. pylori should inhibit the growth of low-grade gastric lymphoma, and anti-H. pylori treatment should be given for this lymphoma as first line of treatment.
  • gastric carcinoma is not a homogeneous entity and considerable differences in the aetiological forces involved have been identified for the several types so far recognised. Only some forms of gastric cancer appear to be associated with H. pylori.
  • H. pylori The most common form linked to H. pylori arises in multifocal chronic atrophic gastritis (MAG).
  • MAG multifocal chronic atrophic gastritis
  • Epithelial cell damage is associated with H. pylori colonisation, in which a marked decrease of cytoplasmic ucin is seen where colonization is severe.
  • Cell damage is followed by cell repair, in which the presence of the bacteria is associated with decrease in size and number of nuclei as well as their displacement to upper portions of the cytoplasm.
  • MAG correlates very closely with the risk of gastric cancer; its prevalence is higher in populations at high cancer risk. In populations of low gastric cancer risk, MAG is very rare.
  • the medicament is used for treating gastric ulceration, mucosal-associated B-cell lymphomas, gastric carcinoma, peptic ulcers or duodenal ulcers.
  • the physician will readily diagnose the above diseases and others with which H. pylori infection is associated.
  • H. pylori infection can be established using standard medical microbiological techniques.
  • the medicaments of the invention may also be useful in treating non-ulcer dyspepsia which is believed to involve H. pylori infection.
  • a second aspect of the invention provides a formulation comprising a compound with the structural formula:
  • R is H or lower alkyl and R 2 is C,- ⁇ alkyl or C 2 - 20 alkenyl with one or two unsaturated bonds, or a pharmaceutically acceptable salt, ester or salt of such ester or amide of such compounds and a pharmaceutically acceptable carrier, wherein the formulation is adapted for oral administration such that the compound is released in the stomach.
  • Preferred compounds of the formulation are the same as preferred compounds of the first aspect of the invention.
  • formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient compound of the invention
  • carrier which constitutes one or more accessory ingredients.
  • SUBSTITUTE SHEET (RULE 261 are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the formulation provides preferential action in the stomach.
  • a gavage using polyethylene glycol as the carrier may be suitable.
  • the compounds of the invention appear to be acid stable.
  • the preferential action in the stomach may be achieved by providing for preferential release in the stomach or by providing for preferential retention in the stomach, for example by formulating the compound(s) in or on microspheres having adhesins specific for stomach mucus (eg sulphated groups) or stomach villi, or a moiety specific for H. pylori, for example an antibody against an H. pylori adhesin.
  • the K12 adhesin of E. coli may be used.
  • the formulation contains a further compound effective at combating H. pylori infection such as tripotassium dicitratobismuthate or metronidazole.
  • the formulation contains a compound effective at treating or preventing gastric or duodenal ulcers.
  • Suitable compounds include H 2 -receptor antagonists such as cimetidine, famotidine, nizatidine and ranitidine; selective anti-muscarinics such as pirenzepine; chelates and complexes such as bismuth chelate and sucralfate; prostaglandin analogues such as misoprostol; proton-pump inhibitors such as omeprazole; and other ulcer-healing drugs such as carbenoxolone sodium.
  • the formulation and dosage regime may provide for a local concentration in the site of action, for example the stomach, of above about 0.01 ⁇ g/ml, for example above about 0.5 ⁇ g/ml. Administration over a period of between 1 day and 10 weeks, for example about 3 weeks, should be sufficient to eradicate the bacteria.
  • a third aspect of the invention provides a method of treating a patient with an actual or suspected infection with a Gram negative microaerophilic bacterium, such as Helicobacter pylori, or to prevent such an infection comprising administering to the patient an effective amount of a compound with the structural formula:
  • R is H or lower alkyl and R 2 is C, -20 alkyl or C 2-20 alkenyl with one or two unsaturated bonds, or a pharmaceutically acceptable salt, ester or salt of such ester or amide of such compounds and a pharmaceutically acceptable carrier.
  • Preferred compounds of the method of treatment are the same as the preferred compounds of the first aspect of the invention.
  • Further methods of treatment using the compounds of the invention include administering the compounds concomitantly with another compound effective at combating the infection (such as those described above) or a compound effective at treating or preventing gastric duodenal ulcers (such as those described above) or a combination thereof.
  • another compound effective at combating the infection such as those described above
  • a compound effective at treating or preventing gastric duodenal ulcers such as those described above
  • the compounds of the invention may be administered to the patient on one day and the compound effective against ulcers may be administered to the patient on the next day.
  • the compounds may be made by either of the two general methods disclosed in EP 128 374, namely the method of Cornforth et al (1956 Biochem. J. 63, 124) or the method of Hirobe et al (1982 Jap. Pharm. Soc. Lecture Summaries, page 206), incorporated herein by reference.
  • Figure 1 shows the HPLC profile of the Pseudomonas anti-Helicobacter activity showing (a) A- ⁇ UV absorbance and (b) anti-bacterial activity expressed as the size of inhibition in the well plate assay. Activity elutes in fractions 25-40, and is well separated from pyocyanin and hydroxyphenazine (fractions 13 and 19, respectively). Fractions were collected after 4 minutes. Fraction 29 + 30 was in error doubly diluted.
  • Figure 2(a) shows the UV spectra taken in methanol of fraction 30 and Figure 2(b) that of fraction 25 both following HPLC purification.
  • Figure 3(a) and (b) shows fast atom bombardment mass spectra of fractions 30 and 31, respectively. Both spectra show intense protonated molecular ions (M+H + ) at m/z 272 and 270 together with smaller amounts of ions at m/z 240,242. Note the ratio of m/z 272/270 increases from fraction 30 to fraction 31 consistent with partial separation of these two related materials by HPLC.
  • H. pylori Strains of H. pylori were obtained from gastric biopsies of patients attending the gastrointestinal clinic at the Hammersmith Hospital, London. The biopsies were transported to the laboratory in a simple transport medium consisting of brain heart infusion broth ((BHI) broth, Sigma, Poole, Dorset) and 5% (v/v) foetal calf serum (Gibco). The biopsies were plated on both selective (blood agar containing Skirrows supplement (Oxoid, Basingstoke, Hants, UK)) and non-selective (blood agar containing 2 ⁇ g/ml amphotericin (Oxoid)) media in the laboratory.
  • BHI brain heart infusion broth
  • Sigma Sigma, Poole, Dorset
  • the biopsies were plated on both selective (blood agar containing Skirrows supplement (Oxoid, Basingstoke
  • the plates were incubated at 37°C on blood agar medium containing amphotericin for approximately 3 days in Gas Pak anaerobic jars (Trademark, Oxoid) in the presence of a Campypak microaerophilic gas generating envelope (Trademark, Oxoid) and a palladium catalyst (Oxoid). Further subcultures were performed on blood agar plates containing amphotericin. (Also strains of H. pylori could be preserved in BHI broth containing 10% glycerol under liquid nitrogen.) The identity of isolates was confirmed using Gram stain, oxidase urease and catalase. Each strain was tested for metronidazole sensitivity using a 5 ⁇ g metronidazole disc (Oxoid). H. pylori was also grown in broth culture in BHI broth plus 10% horse serum (Gibco).
  • Pseudomonas aeruginosa A clinical isolate of -P. aeruginosa was grown on blood agar plates and incubated at 37 °C overnight. The bacteria were removed by scraping and resuspended in BHI. A heavy suspension was then used to inoculate 400 ml of BHI and incubated at 37°C overnight. Assays for anti-Helicobacter activity
  • Well plate assay Antibacterial activity post HPLC was detected using the well plate assay.
  • a sterile swab was used to spread a three day old broth culture of test strains of H. pylori over the surface of blood/amphotericin plates (see above).
  • Four wells (7 mm diameter) were cut in each plate with a sterile metal punch and filled with 100 ⁇ l of suitable samples (eg post HPLC) dissolved in methanol. A methanol control was also used. Plates were incubated as above (section 2.1) and the zone of inhibition caused by test samples measured after 3 days.
  • ⁇ -oxide 4-heptyl-2-hydroxyquinoline N-oxide
  • a series of sterile universal bottles were labelled; 32 ⁇ g, 16 ⁇ g, 8 ⁇ g, 4 ⁇ g, 2 ⁇ g, 1 ⁇ g and 0.5 ⁇ g.
  • the P. aeruginosa culture was divided into universal bottles and centrifuged at 3000 revolutions per minute for 15 min. 200 ml of culture supernatant was poured into a separating funnel and extracted twice with 400 ml of chloroform. Excess chloroform was removed by rotary evaporation at ⁇ 30°C. The product was transferred to a universal bottle with 2 x 1 ml of methanol; solvent was removed under nitrogen.
  • HPLC HPLC was carried out on a Waters dual pump instrument (Millipore, UK,
  • UV spectroscopy was carried out in methanol on a Perkin Elmer 555 instrument. Scans were undertaken between 450-220 nm at 60 nm/min. A holmium filter was used to confirm wavelength assignments.
  • Mass spectrometry was carried on a Finnigan 4500 instrument in either the fast atom bombardment and desorption electron impact modes or by gas chromatography-electron impact modes.
  • FAB-MS Fast Atom Bombardment Mass spectrometry: FAB-MS was carried out using an M-Scan ion gun and xenon (10 kilo volts) as the ionising species. Samples were dissolved in 25 ⁇ l of methanol and 2 ⁇ l loaded onto the glycerol matrix for analysis.
  • Desorption electron impact MS Samples were loaded onto a rhenium filament and desorbed at 10 amps per second.
  • Gas chromatography-electron impact MS GC was carried out on a DB5 capillary column (Jones Chromatography, Hengoed, Wales) using helium as a carrier gas. After 1 min at 200°C the column temperature was raised by 20°C from 200°C to 300°C. Samples were injected in octane using a Grob injector in the spitless mode set at 250°C. The gas chromatography column was routed into the mass spectrometer operated in the electron impact mode (70 eV electron energy).
  • a crude chloroform extract of P. aeruginosa was dissolved in 1 ml of methanol and 1 ml of 1.9 Molar titanium trichloride in 2 Molar hydrochloric acid (Sigma) was added. This was left at room temperature for 2 h with regular gentle shaking. The reduced product was extracted with 2 x 5 ml of chloroform; the chloroform layer was washed with 10 ml of water to remove any water soluble impurities. Solvent was removed under nitrogen. Authentic 2-heptyl-4-hydroxyquinoline N-oxide (Sigma) was reduced in a similar manner.
  • Trimethylsilylation was carried out with 100 ⁇ l of bistrifluoromethyl- trifluoroacetamide and left at room temperature for 18 hr. Excess reagent was removed under nitrogen.
  • Example 2 Isolation and identification of compounds effective against H. pylori
  • Pseudomonas strain PY05 was used. The strain was cultured in BHI broth and activity extracted into chloroform. The conditions used to obtain the best separation in a single step were a linear gradient of acetonitrile:water:FBA (20:80:0.04-04-70:30:0.04).
  • Figure 1 shows the HPLC UV and bioactivity profile of a Pseudomonas chloroform extract. Although 50 x 1 ml fractions were collected, they were bulked into 25 x 2 ml fractions to determine bioactivity. Activity was associated mainly with a UV absorbing peak in fraction 31 +32 although bioactivity was observed in neighbouring fractions ( Figure 1, Table 1). A large scale preparation of P. aeruginosa was obtained from 1.2 1 of culture filtrate, and, after chloroform extraction, chromatographed on HPLC. Although the resolution was somewhat diminished, activity was again found to be associated with fractions 31 +32.
  • Table 1 The zones of inhibition in the well plate assay against sensitive and resistant strains of H. pylori for the HPLC fractions of the Pseudomonas factor.
  • the primary ionising beam was a cold-cathode discharge source producing argon ions with an energy between 8 and 10 KeV.
  • argon ions with an energy between 8 and 10 KeV.
  • resonant charge-transfer takes place between the argon ions and the sample in its glycerol matrix.
  • the atom beam takes the place of the electron beam in a classical electron-impact ionization source.
  • Samples of mass M are converted to protonated (M+H + ) and cationised (M+Na + ) species, with little fragmentation.
  • the active fractions (29-32) all generated FAB mass spectra (Table 2).
  • fraction 30 ions were present at m/z 242 (at low intensity), m/z 270 and, the major ion, at m/z 272; these correspond with masses of 241, 269 and 271 ( Figure 3a).
  • the base peak in fraction 31 was at m/z 272, with some m/z 270; fraction 32 also contained a lesser amount of m/z 272 ( Figure 3b).
  • Figure 3b the activity present in fractions 31 and 32 is strongly associated with a compound of mass 271 together with smaller amounts of a substance with mass 269.
  • fractions 30 to 32 gave a similar UV spectra, it was clear from the HPLC- UV profile that two closely related substances were present: m/z 272 mainly in fraction 31 and m/z 270 mainly in fraction 30.
  • Table 2 Summary of the ⁇ ,.-,,-., A,--,,-, and FAB-MS derived molecular weights for fractions 20-23 of the final HPLC conditions.
  • HQN 2-alkyl-4-hydroxyquinoline like spectrum.
  • HQNO 2- alky-4-hydroxyquinoline N-oxide like spectrum.
  • the UV absorbance and mass spectrometric data are consistent with the presence of known secondary metabolites of P. aeruginosa, 2-nonyl-4- hydroxyquinoline and 2-nonenyl-4-hydroxyquinoline.
  • the related material, 2-heptyl-4-hydroxyquinoline N-oxide is available commercially from Sigma. It is used as a streptomycin antagonist, and inhibits ⁇ ADH oxidation by mitochondria.
  • Table 3 Inhibition of H. pylori growth in the well plate assay by 2- heptyl-4-hydroxyquinoIine N-oxide.
  • Table 4 Inhibition of H. pylori growth in the well plate assay by 2- heptyl-4-hydroxyquinoIine.
  • the anti-Helicobacter activity of P. aeruginosa has been characterised as 2-nonyl-4-hydroxy quinoline and its nonenyl analogue. This material is active against metronidazole sensitive and resistant strains of H. pylori. Using synthetic 2-heptyl-4-hydroxyquinoline, the MIC of this class of chemicals has been found to be well below that of other antibiotics (Table 6).
  • Antibacterial MICgo ( ⁇ g/ml)
  • Methyl 3-oxodecanoate (48 g) was added dropwise to a stirred suspension of powdered sodium (5.52 g) in toluene (100 ml) and benzene (200 ml) under ⁇ 2 .
  • sodium was dissolved, o-nitrobenzoyl chloride was added slowly with stirring and cooling.
  • dilute H 2 S0 4 was added and the product (84 g) was isolated in the normal manner with the help of some more benzene. It was then boiled with dilute H 2 S0 4 (500 ml of 33%, w/w) and dioxan (68 ml) for 7 hr.
  • the cooled mixture was extracted with ether, and this, after washing with aqueous NaHC0 3 was extracted with 0.5N-NaOH (1 1) in seven portions which were acidified immediately after separation.
  • the acidic product was recovered by means of ether; it was treated with cold light petroleum (bp 40-60°), and a residue (8 g) of ⁇ -nitrobenzoic acid was removed.
  • the light-petroleum- soluble product was a red oil (30 g).
  • a portion (5 g) was added to a mixture of SnCl 2 ,2H 2 0 (14 g) and acetic acid (45 ml), with sufficient dry HC1 to effect dissolution.
  • the mixture became warm; passage of hydrogen chloride was continued until it had cooled.
  • Methyl 3-oxododecanoate (20 g) was condensed, as described above, with o-nitrobenzoyl chloride, and the product was hydrolysed with dioxan- sulphuric acid by boiling for 18 hr.
  • the product was purified by three crystallizations from ethanol; the N- oxide formed colourless leaflets (2.5 g), mp 148-149°. (Found: C, 75.0; H, 8.6; N, 5.1. requires C, 75.3; H, 8.7; N, 4.9% .)
  • the ultraviolet absorption in 0.001 N-NaOH was identical with that of the heptyl analogue.
  • Methyl 3-oxotetradecanoate (11.95 g, mp 29-30°), purified by low- temperature crystallization from methanol, was condensed as described above with ⁇ -nitrobenzoyl chloride, and the product was hydrolysed by boiling for 17 hr with dilute sulphuric acid and dioxan. Copper l-(2- nitrophenyl)-tetradecane- ⁇ :3-dionate was prepared as described above. A sample crystallized from ethanol in blue-grey needles, mp 150-151° (Found: ⁇ , 4.1. C 20 H 2g O 4 ⁇ 2 requires N, 3.7%); from the remainder.
  • 2-alkyl-4-hydroxyquinoline N-oxides of different chain lengths and degrees of saturation can be produced using the above methods by substituting the appropriate methyl 3-oxoalkanoate.
  • Tablets are prepared from the foregoing ingredients by wet granulation followed by compression.
  • formulations 2 and 3 are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • Active ingredient 100 Lactose 200 Starch 50 Povidone 5
  • formulations, 5 and 6 are prepared by direct compression of the admixed ingredients.
  • the lactose used in formulation E is of the direction compression type.
  • the formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet
  • Drug release takes place over a period of about 6-8 hours and was
  • a capsule formulation is prepared by admixing the ingredients of Formulation 5 above and filling into a two-part hard gelatin capsule.
  • Formulation 9 (infra) is prepared in a similar manner.
  • Capsules are prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule.
  • Capsules are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
  • the following controlled release capsule formulation is prepared by extruding ingredients a, b, and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule
  • Sorbitol Solution 1.5000 g Glycerol 2.0000 g
  • the sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added.
  • the active ingredient is added and dispersed.
  • the glycerol is dispersed the thickener (dispersible cellulose). The two dispersions are mixed and made up to the required volume with the purified water. Further thickening is achieved as required by extra shearing of the suspension.

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Abstract

On décrit un composé de formule structurelle (I) ou son N-oxyde, où R1 représente alkyle C1-20 ou alcényle C2-20 dotés d'une ou deux liaisons insaturées, ou bien un de ses sels, esters, ou sels d'un tel ester ou un amide de ce composé tous devant être acceptables sur le plan pharmacologique. Ils entrent dans la composition d'un médicament permettant de traiter une infection due à des bactéries micro-aérophiliques et notamment à Hélicobacter pylori. On préfère l'utilisation de 2-heptyl-4-hydroxyquinoline, 2-nonyl-4-hydroxyquinoline, 2-nonenyl-4-hydroxyquinoline et de leurs N-oxydes.
PCT/GB1995/000886 1994-04-20 1995-04-20 COMPOSES ANTIMICROBIENS A BASE D'AMINOLINE-N-OXYDE UTILISES CONTRE LES INFECTIONS A $i(H. PYLORI) WO1995028929A1 (fr)

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AU22621/95A AU2262195A (en) 1994-04-20 1995-04-20 Aminoline-n-oxide antimicrobials for use against (h. pylori) infections

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GB9407869A GB9407869D0 (en) 1994-04-20 1994-04-20 Antimicrobial compounds

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061438A1 (fr) * 1998-05-23 1999-12-02 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de quinoleine-aminomethyle-pyridyle a activite anti-helicobacter
US6080757A (en) * 1996-06-06 2000-06-27 Pfizer Inc Antibiotic quinolones and derivatives
US6306838B1 (en) 1999-01-25 2001-10-23 Panacea Biotec Limited Targeted vesicular constructs for cyto protection and treatment of h. pylori
WO2002018342A2 (fr) * 2000-08-31 2002-03-07 The University Of Iowa Research Foundation Nouvelles molecules autoinductrices et leurs utilisations
US6576625B2 (en) 2001-03-16 2003-06-10 Panacea Biotic Limited Targeted vesicular constructs for cytoprotection and treatment of H. pylori infections
WO2024009101A1 (fr) * 2022-07-05 2024-01-11 The University Of Nottingham Perturbation de barrières épithéliales pour l'amélioration ou l'extraction de distribution moléculaire de fluides extracellulaires

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US6080757A (en) * 1996-06-06 2000-06-27 Pfizer Inc Antibiotic quinolones and derivatives
WO1999061438A1 (fr) * 1998-05-23 1999-12-02 Byk Gulden Lomberg Chemische Fabrik Gmbh Derives de quinoleine-aminomethyle-pyridyle a activite anti-helicobacter
US6479514B1 (en) 1998-05-23 2002-11-12 Altana Pharma Ag Quinoline-aminomethyl-pyridyl derivatives with anti-helicobacter activity
US6306838B1 (en) 1999-01-25 2001-10-23 Panacea Biotec Limited Targeted vesicular constructs for cyto protection and treatment of h. pylori
WO2002018342A2 (fr) * 2000-08-31 2002-03-07 The University Of Iowa Research Foundation Nouvelles molecules autoinductrices et leurs utilisations
WO2002018342A3 (fr) * 2000-08-31 2002-05-10 Univ Iowa Res Found Nouvelles molecules autoinductrices et leurs utilisations
US7442798B2 (en) 2000-08-31 2008-10-28 The University Of Iowa Research Foundation Autoinducer molecules and uses therefor
US6576625B2 (en) 2001-03-16 2003-06-10 Panacea Biotic Limited Targeted vesicular constructs for cytoprotection and treatment of H. pylori infections
WO2024009101A1 (fr) * 2022-07-05 2024-01-11 The University Of Nottingham Perturbation de barrières épithéliales pour l'amélioration ou l'extraction de distribution moléculaire de fluides extracellulaires

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AU2262195A (en) 1995-11-16
GB9407869D0 (en) 1994-06-15
ZA953209B (en) 1996-01-03

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