CA2104531C - Antimicrobial agent - Google Patents
Antimicrobial agentInfo
- Publication number
- CA2104531C CA2104531C CA002104531A CA2104531A CA2104531C CA 2104531 C CA2104531 C CA 2104531C CA 002104531 A CA002104531 A CA 002104531A CA 2104531 A CA2104531 A CA 2104531A CA 2104531 C CA2104531 C CA 2104531C
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- Prior art keywords
- medicine
- ulcer
- pylori
- gastritis
- benzimidazole
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
An ulcer and/or gastritis are prevented, improved or treated by administering a pharmacologically effective amount of the compound having the below shown formula (I) or (II) or.
a pharmacologically acceptable salt thereof to a mammal suffering from such a disease.
(see fig. I) (see fig. II)
a pharmacologically acceptable salt thereof to a mammal suffering from such a disease.
(see fig. I) (see fig. II)
Description
210~31 Specification ANTIMICROBIAL AGENT
The invention relates to an antimicrobial agent, anti-biotic, anti-bacterial medicine which prevents, improves and therapeutically treats a disease caused by Campylobacter pylori, called hereinafter C. pylori.
The organism is a microaerophilic, gram-negative spirillar rod and it is thought to be participated in recurrent, peptic ulcer, gastric ulcer, duodenal ulcer and gastritis.
St~tement of prior ~rts In the state of arts, many substances have been used for prevention, treatment or cure of peptic ulcer, gastric ulcer, duodenal ulcer or gastritis.
Especially, histamine H2-receptor antagonists such as cimetidine or ranitidine has been widely used.
Histamine H2-receptor antagonist quickly improves damaged stomach and duodenal mucous membrane, and they reduce subjective symptoms such as stomach pain immediately. However, a problelm remains that these diseases will recur very often after they have healed and the medication has been ceased. The reason isn't 2 ~ 3 l~
entirely clear, but after the discovery that C. pylori was detected from the stomach mucous membrane biopsy sample of peptic ulcer patients in 1979, it is thought that there's a close relation between C. pylori and peptic ulcer, gastric ulcer, duodenal ulcer and gastritis. In 1989, it was proposed to rename C.
pylori to Helicobacter pylori by further research in the viewpoint of bacteriology and bacterial taxology.
Therefore, C. pylori is also called H. pylori.
It is reported in the Medical Journal of Australia, volume 142, pages 436-439, 1985 and American Journal of Gastroentelology, volume 82, pages 192-199, 1987 that healthy volunteers administered C.
pylori orally were suffered from acute gastritis.
Gastroentelology, volume 94, pages 33-40, 1988 showed that the injured gastric tissue was found to have been improved when C. pylori was eradicated by administration of antibiotic substance. Such relationship between C. pylori and, peptic ulcer, gastric ulcer, duodenal ulcer and gastritis is at present noticed.
Lancet, pages 1437-1442, 1988 reported that among C. pylori positive peptic ulcer patients, the relapse rate is higher than negative ones. This shows that prevention and treatment of recurrent peptic ulcer, 2~04~3l gastric ulcer, duodenal ulcer and gastritis need eradication of C. pylori.
In the state of arts, medicines which can eradicate C. pylori include antibiotics such as ampicillin, cefalexin, ofloxacin, minocycline and roxithromycin and medicaments for gastritis or gastric ulcer such as plaunotol, sofalcone, benexate hydrochloride and colloidal bismuth subcitrate.
Among these substances which can clear C. pylori, prior medicines for gastritis and gastric ulcer provide too weak eradication activity in a usual dosage of administration. Antibiotics mentioned above have good efficacy against C. pylori, but some side-effects such as allergy or diarrhoea will occur often, and then, after long term administration, it sometimes causes severe irreversible adverse reactions such as hematological disorders or gastrointestinal disorders.
And it produces resistant bacteria easily. From the clinical point of view, a good medicine is expected for reliable prevention and therapy, for a long term medication of recurrent ulcer and gastritis with safety. The research has continued for a medicine which could eradicate C. pylori in a usual dosage of administration with safety in the long term medication. JP-A 2-209809, corresponding to US 5 093 210'1531 342 discloses 5-Methoxy-2-[(4-methyl-3, 5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole, called omeprazole, or a salt thereof, being an acid secretion-inhibiting medicine for gastritis and gastric ulcer, has antibiotic activity against C.
pylori 8005 one of the clinical isolates. JP-A 3-173817, corresponding to US 5 013 743 discloses the compounds (1) to (14) shown below being antibiotic activity against C. pylori NCTC-11916 and NCTC-11637 the standard strains and C. pylori PCL-56, CPY-0011-1, KS-13, CL0-1 and CL0-6 the clinical isolates.
1) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole - 2) 2-(3,5-Dimethyl-4-methoxypyrido-2-yl)methylsulfinyl-5-methoxy-lH-benzimidazole 3) 2-[{3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 4) 2-[{3-Methyl-4-(2,2,3,3-tetrafluoropropoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 5) 2-[{3-Methyl-4-(2,2,3,3,4,4-hexafluorobutoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 6) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-'2104~31 yl)methylthio]-lH-benzimidazole 7) 2-[{(4-Isobutoxy)pyrid-2-yl)methylthio]-lH-benzimidazole 8) 2-[{(4-Isobutoxy)pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 9) 2-[{(4-Isopropoxy)pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 10) 2-[[{4-(2'-Propenyl)oxy}pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 11) 2-[{(4-Propargyl)oxypyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 12) 2-[{3-Methyl-4-(2,2,3,3-tetrafluoropropoxy)pyrid-2-yl}methylthio]-lH-benzimidazole 13) 2-[{3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyrid-2-yl}methylthio~
benzimidazole 14) 2-[{3-Methyl-4-(2,2,3,3,4,4-hexafluorobutoxy)pyrid-2-yl}methylthio]-lH-benzimidazole JP-A 3-48680 discloses the below shown compound being antibiotic to C. pylori, failing to show tested strains.
1) 2-[3-Methyl-4-(1-methyl-2-piperidyl)methoxy-2-pyridyl]methylthio-lH-benzimidazole 21~531 2) 2-[3-Methyl-4-(3-morpholinopropoxy)-2-pyridyl]methylthio-lH-benzimidazole 3) 2-[3-Methyl-4-(2-piperidinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 4) 2-[3-Methyl-4-{2-(2-oxo-1-pyrrolidinyl)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 5) 2-[3-Methyl-4-(2-morpholinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 6) 2-[3-Methyl-4-(3-piperidinopropoxY)-2-pyridyl]methylthio-lH-benzimidazole 7) 5-Methoxy-2-[3-methyl-4-(2-morpholinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 8) 5-Methoxy-2-[3-methyl-4-{2-(N-benzyl-N-methylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 9) 2-[3-Methyl-4-[2-(N-methyl-N-(2-phenylethyl)amino}ethoxy]-2-pyridyl]methylthio-lH-benzimidazole 10) 2-[3-Methyl-4-[2-(N-methyl-N-(3-phenylpropyl)amino}ethoxy]-2-pyridyl]methylthio-lH-benzimidazole 11) 2-[3-Methyl-4-{2-(N-benzyl-N-ethylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 12) 2-[3-Methyl-4-{2-(N-benzyl-N-propylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 13) 2-[3-Methyl-4-[2-{N-methyl-N-(4-methylbenzyl)amino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 14) 2-[3-Methyl-4-[2-{N-(4-chlorobenzyl)-N-methylamino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 15) 2-[3-Methyl-4-[2-{N-(4-bromobenzyl)-N-methylamino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 16) 2-[3-Methyl-4-{2-(1,2,3,4-tetrahydroisoquinoline-2-yl)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 17) 1/2 magnesium salt of 2-[3-methyl-4-{2-(N-benzyl-N-methylamino)ethoxy}-2-pyridyl]methylsulfinyl-lH-benzimidazole 18) 1/2 magnesium salt of 2-[3-Methyl-4-[2-{N-methyl-N-(4-methylbenzyl)amino}ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 19) 1/2 magnesium salt of 2-[3-Methyl-4-[2-{N-(4-bromobenzyl)-N-methylamino}ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 20) 2-[3-Methyl-4-[2-(1,2,3,4-21~31 -tetrahydroisoquinoline-2-yl)ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 21) 2-[3-Methyl-4-[2-(N-benzyl-N-methylamino)ethoxy]-2-pyridyl]methylsulfonyl-lH-benzimidazole 22) 2-[3-Methyl-4-[2-(N-methyl-N-(4-methylbenzyl)amino)ethoxy]-2-pyridyl]methylsulfonyl-lH-benzimidazole In the medication of diseases caused by C.
pylori, it's necessary to have excellent activity against a broad spectrum of C. pylori include standard strains and clinical isolates. The antibiotics effective against C. pylori have minimum inhibitory concentration called M.I.C. (~g/ml) in the range of smaller than 1 ~g/ml. Therefore, whether a compound has a M.I.C. in that range or not is a criterion to evaluate its clinical efficacy against C. pylori.
From the above shown points omeprazol disclosed in JP-A 2-209809 and JP-A 3-173817 has no sufficient antibiotic activity. Among the other 14 compounds shown in JP-A 3-173817, the compounds (12), (13) and (14) only are the antibiotics in the respect of activity against all the tested strains.
JP-A 3-48680 shows that compounds have MIC of 1 microgram per ml or less to only one tested strain.
-It is not expected from the listed data that they will have an antibiotic activity widely to many strains.
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) and 2-[(4-(3-methoxy-propoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) are known in JP-A 1-6270, corresponding to EP-A 268 956 as an acid secretion inhibitor. They can be prepared according to Examples 32 and 31, respectively, disclosed in JP-A 1-6270.
Disclosure of the Invention The inventors studied 2-[(4-(3-methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) and 2-[(4~3-methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) and have found that they have essentially the same C. pylori-eradicating activity as an antibiotic substance. This is how the inventors have reached the invention.
The two compounds of the invention have the follcwing chem_cal structures:
3 o OCH3 2 ~ (I~
21~31 65702-416 -\ ~ S - CH2 ~ ~II) The invention provides a pharmaceutical antimicrobial medicine for preventing, improving or treating an ulcer and/or gastritis in a mammal, which comprises an effective amount of the compound having the above formula (I) or (II) or a pharma-ceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
It is preferable that the mammal is human being, the ulcer is a peptic ulcer, the ulcer is a gastriculcer, and the ulcer and gastritis are recurrent.
The antimicrobial medicine is preferably for eradicating _. pylori from the mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis; for eradicating C. pylori from the mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis; for preventing, improving or treating a disease caused by C. pylorii for preventing recurring of a disease caused by C. pylori; and for restraining the adverse activity of C. pylori to cause a peptic disease.
~ 4~3~ 65702-416 In the invention, the pharmaceutically acceptable salt of the compound (I) or (II) includes an addition salt thereto by an inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid and phosphoric acid, an addition salt thereto by an organic acid such as citric acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, a salt of a metal such as sodium, potassium, calcium and magnesium. Sodium salt is most preferable.
The invention provides medicine which is effective for the C. pylori eradication having the same effect as anti-biotics. The compounds of the invention can be administered for a long time with safety, without side effects. It is pharmacologically effective and clinically useful to recurrent ulcers and gastritis.
2 1 0 4 ~ ~2-416 ._ The compounds of the invention have the following physical properties.
The physical property of 2-[(4-(3-methoxypropoxy)-3-methyl-pyridine-2-yl)-methylsulfinyl]-lH-benzimidazole 2 1 0 d~ rj 3 1 (I) molecular formula : C18H20N30aS
molecular weight : 358.44 property : white crystaline The physical property of 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) molecular formula : C18H20N302S
molecular weight : 342.44 property : pale yellow crystaline Ph~rm~col ogi c~l te~t Standard strains and clinical isolates of C.
pylori derived from the mucous membrane of the stomach were used and determined in vitro according to the agar dilution method determined by Nihon Kagaku Ryoho Gakkai (English name: Japan Society of Chemotherapy).
Sodium salt of 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) was dissolved in a sterilized water. 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) and, as controls, omeprazole, 5-Methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methylthio]-lH-benzimidazole and 2-[(3-Methyl-4-(2,2,2-trifluoroethoxy)-pyrid-2-yl)methylthio]-lH-benzimidazole were dissolved 2 1~ 4~ 3 ~702-416 -separately in a 1% dimethylsulfoxide solution. As an antibiotic substance control, roxithromycin as macrolides, ampicillin as penicillins, ofloxacin as newquinolones were dissolved in a buffer solution of acetic acid having a pH of 5.0, a sterilized water and an lN aqueous solution of NaOH, respectively. Test plates were prepared by adding 7% horse blood to Brucella agar named by BBL Microbiology Systems (trade-mark) being available from Bector Dickson and Company. The incubation was conducted at 37~C at pH
of 7.0 for 3 days under the microaerophilic condition using Canpipack (trade-mark) being available from Bector Dickson and Company. MIC was determined in unit of microgram per ml. Test results are shown in Table 1. NCTC11637 and NCTC11916 are standard stains.
The other references indicate clinical isolates.
The test result is shown in terms of the antibiotic activity (MIC) in unit of microgram/ml, obtained in vitro against C. pylori. The tested compounds are (I) sodium salt of 2-[{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl}methylsulfinyl]-lH-benzimidazole, (II) 2-[{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-lH-benzimidazole, (III) 5-Methoxy-2-[{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl}sulfinyl]-lH-benzimidazole 21~4~31 (omeprazole), (IV) 5-Methoxy-2-{(4-methoxy3,5-dimethyl-2-pyridinyl)methylthio}-lH-benzimidazole, (V) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl}methylthio]-lH-benzimidazole, (VI) roxithromycin (RXM), (VII) ampicillin (ABPC), (VIII) ofloxacin (OFLX).
21()45~1 Table 1 Tested Compunent strain (I) (II) (III) (IV) (V) (VI) (VII) (VIII) NCTC11637 3.13 0.8 50 25 25 0.4 0.4 0.8 NCTC11916 3.13 0.2 25 12.5 12.5 0.1 0.05 0.8 EI-2 3.13 0.4 25 25 25 0.2 0.4 0.8 EI-5 3.13 0.2 50 25 12.5 0.2 0.4 0.8 EI-36 6.25 0.4 25 12.5 12.5 0.2 0.2 0.8 EI-46 3.13 0.4 25 12.5 12.5 >100 0.05 3.13 EI-391 3.13 1.56 50 25 12.5 50 0.1 25 EI-393 3.13 1.56 50 25 25 0.2 0.1 0.8 EI-397 3.13 1.56 50 25 25 0.2 0.1 0.8 EI-429 1.56 1.56 25 25 25 0.2 0.2 0.8 EI-467 1.56 1.56 50 12.5 12.5 0.2 0.05 0.4 EI-612 0.4 0.8 25 12.5 6.25 0.2 0.05 0.8 EI-925 3.13 0.4 25 12.5 12.5 0.2 0.2 0.4 EI-930 3.13 0.4 25 12.5 12.5 0.4 0.4 0.8 EI-933 3.13 0.8 25 12.5 12.5 0.1 0.05 0.4 It is noted from the test results that the compounds of the invention are superior to the known compounds such as omeprazole disclosed in JP-A 2-209809 and lansoprazole derivatives disclosed in JP-A 3-173817. The compounds of the 2104~31 invention evidently provide an equivalent C. pylori eradicating activity to antibiotics. Since the compounds of the invention are not of the antibiotic compounds, the compounds of the invention work effectively to a resistant bacteria such as clinically isolated strains shown in Table, EI-46 and EI-391. This is the reason they provide the antibiotic activity to a wider variety of bacteria than antibiotic substances. They can be administered continuously for long term. They have been found, at a concentration of 100 micrograms per ml, not to inhibit other gram-positive and gram-negative bacillii from growing even. This shows the fact that they can be antibiotic selectively to C. pylori.
~cl]t~ toxic~logic~l t~t The compound (I) of the invention was administered intravenously or orally one time, with a carrier of saline, to Slc:SD rats and Slc:ICR mouse, each being 7 or 8 weeks old, in a group consisting of five males and five females, to determine LD50 values. Results are shown in Table 2.
Acute toxicity of the compound (I) is shown in terms of LD50 in unit of mg/kg.
2101~31 Table 2 medication rats mouce process male female male female intravenous 157 mg/Kg 152 mg/Kg 220 mg/Kg 237 mg/Kg oral1447 mg/Kg 1332 mg/Kg1206 mg/Kg 1012 mg/Kg The obtained LD50 values are 5000 times as much as a clinical dosage of oral administration and for this reason the compounds of the invention are found to be greatly safe, that is, providing no toxicological influence.
t~chnologic~ v~nces of the invention It is evident from the above shown test data that the compounds of the invention are as antibiotic to C. pylori as antibiotic substances and therefore can work pharmacologically to prevent, improve and therapeutically treat recurrent ulcers and gastritis caused by C. pylori.
They can prevent, improve and therapeutically treat peptic ulcers, controlling secretion of gastric acid, and moreover prevent, improve and therapeutically treat recurrent ulcers and gastritis caused by C. pylori, with safety. They can be administered continuously for a long term, without combination of another antibiotic substance. The compounds can be used as an antibiotic medicine.
210~31 ~ppl i c~ti on of the i nventi on The compounds of the invention can be administered, without any limitation, normal ways. Which way and how much amount for medication depend on condition of a patient, the kind of ulcer and gastritis, a degree or extent of the disease, age of a patient and functions of heart, liver and kidney. It is preferable in the invention that they are dosed orally in an amount of 0.01 to 100 mg in a day, more preferably 0.1 to 80 mg, further preferably 0.1 to 60 mg, most preferably 5 to 40 mg. The oral medication can be conducted in the form of powder, granule, tablet or capsule. They can be prepared with a normally used carrier according to prior methods, preferably according to the showing in JP-A 1-290628 and JP-A
2-22225, corresponding to US 5 035 899. The preparation may further include therein a forming filler, a binder, a disintegrating agent, a lubricant, a colorant, a corrigent, a taste-improver and/or a smell-improver.
The filler includes lactose, corn starch, white sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide; the binder, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone; the disintegrating agent, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, 3 ~
dextrin, carboxymethyl cellulose, calcium and pectin; the lubrlcant, magnesium stearate, talc, polyethylene glycol, sillca and hardened vegetable oils; the coloring, any one which is permitted for drugs; the corrigent, cacao powder, mentha herb, aromatic powder, mentha oll, borneol and powdered cinnamon bark. Of course, these tablets and granules may be, if necessary, coated wlth sugar, gelatln or the llke.
For commerclal purpose, the medlclne is normally contained ln a commerclal package. The package usually carries instructlons or dlrectlons that the medicine can be or should be used for preventlng, lmprovlng or treating an ulcer or gastritis.
Examples of medicine's preparatlon, lncludlng orally dosed preparatlon and that wlth an enterlc coatlng of the lnventlon lncludlng the compound (I) or (II) of the lnventlon are shown below. These do not mean any llmltatlon to the inventlon.
Example 1 Tablets includlng the compound (I):
2-[(4-(3-methoxypropoxy)-3-methylpyrldlne-2-yl)-methylsulfinyl]-lH-benzlmldazole were prepared by the below shown prescrlptlon.
2-[(4-(3-methoxypropoxy)-3-methylpyrldlne-2-yl)-methylsulflnyl]-lH-benzlmldazole, mannltol and magneslum oxlde were mlxed wlth one another, hydroxypropylcellulose dlssolved ln ethanol was added to the mlxture, the resultant was granulated, drled and classlfled with a sleve of 28 mesh 3 ~
.~_ accordlng to ASTM, the product belng called (A). Then crystalllne cellulose and corn starch were mlxed wlth the product (A), hydroxypropylcellulose dlssolved ln water was - 20a -added to the mixture, the resultant was granulated, dried and classified with a sieve of 28 mesh, the product being called (B). The products (A) and (B), calcium salt of carboxymethylcellulose, talc and magnesium stearate were mixed with one another and the mixture was formed into plain .
tablets with a single shot tablet-formulating machine, being available from Okada Seiko-sha.
Prescription in 1 plain tablet weighing 120.2 mg is shown below in unit of mg:
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole 5.0 mannitol 45.3 magnesium oxide 40.0 hydroxypropylcellulose 2.5 crystalline cellulose 10.0 corn starch 10.0 carboxymethylcelulose calcium 5.0 talc 2.0 magnesium stearate 0.2 The obtained plain tablets were coated with a enteric coating to obtain tablets.
~x~mple ~
Tablets including 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) were 2104~31 prepared by the below shown prescription.
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole and mannitol were mixed with each other, hydroxypropylcellulose dissolved in ethanol was added to the mixture, the resultant was granulated, dried and.
classified with a sieve of 28 mesh according to ASTM, the product being called (A). Then (A), crystalline cellulose, corn starch, calcium salt of carboxymethylcellulose, talc and magnesium stearate were mixed with one another and the mixture was formed into plain tablets with a single shot tablet-formulating machine, being available from Okada Seiko-sha.
Prescription in 1 plain tablet weghing 99.7 mg is shown below in unit of mg:
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole 5.0 mannitol 65.3 hydroxypropylcellulose 2.5 crystalline cellulose 10.0 corn starch 10.0 carboxymethylcelulose calcium 5.0 talc 2.0 magnesium stearate 0.2 The obtained plain tablets were coated with a enteric 2 ~ Q 45 3 ~
coating to obtain tablets.
The invention relates to an antimicrobial agent, anti-biotic, anti-bacterial medicine which prevents, improves and therapeutically treats a disease caused by Campylobacter pylori, called hereinafter C. pylori.
The organism is a microaerophilic, gram-negative spirillar rod and it is thought to be participated in recurrent, peptic ulcer, gastric ulcer, duodenal ulcer and gastritis.
St~tement of prior ~rts In the state of arts, many substances have been used for prevention, treatment or cure of peptic ulcer, gastric ulcer, duodenal ulcer or gastritis.
Especially, histamine H2-receptor antagonists such as cimetidine or ranitidine has been widely used.
Histamine H2-receptor antagonist quickly improves damaged stomach and duodenal mucous membrane, and they reduce subjective symptoms such as stomach pain immediately. However, a problelm remains that these diseases will recur very often after they have healed and the medication has been ceased. The reason isn't 2 ~ 3 l~
entirely clear, but after the discovery that C. pylori was detected from the stomach mucous membrane biopsy sample of peptic ulcer patients in 1979, it is thought that there's a close relation between C. pylori and peptic ulcer, gastric ulcer, duodenal ulcer and gastritis. In 1989, it was proposed to rename C.
pylori to Helicobacter pylori by further research in the viewpoint of bacteriology and bacterial taxology.
Therefore, C. pylori is also called H. pylori.
It is reported in the Medical Journal of Australia, volume 142, pages 436-439, 1985 and American Journal of Gastroentelology, volume 82, pages 192-199, 1987 that healthy volunteers administered C.
pylori orally were suffered from acute gastritis.
Gastroentelology, volume 94, pages 33-40, 1988 showed that the injured gastric tissue was found to have been improved when C. pylori was eradicated by administration of antibiotic substance. Such relationship between C. pylori and, peptic ulcer, gastric ulcer, duodenal ulcer and gastritis is at present noticed.
Lancet, pages 1437-1442, 1988 reported that among C. pylori positive peptic ulcer patients, the relapse rate is higher than negative ones. This shows that prevention and treatment of recurrent peptic ulcer, 2~04~3l gastric ulcer, duodenal ulcer and gastritis need eradication of C. pylori.
In the state of arts, medicines which can eradicate C. pylori include antibiotics such as ampicillin, cefalexin, ofloxacin, minocycline and roxithromycin and medicaments for gastritis or gastric ulcer such as plaunotol, sofalcone, benexate hydrochloride and colloidal bismuth subcitrate.
Among these substances which can clear C. pylori, prior medicines for gastritis and gastric ulcer provide too weak eradication activity in a usual dosage of administration. Antibiotics mentioned above have good efficacy against C. pylori, but some side-effects such as allergy or diarrhoea will occur often, and then, after long term administration, it sometimes causes severe irreversible adverse reactions such as hematological disorders or gastrointestinal disorders.
And it produces resistant bacteria easily. From the clinical point of view, a good medicine is expected for reliable prevention and therapy, for a long term medication of recurrent ulcer and gastritis with safety. The research has continued for a medicine which could eradicate C. pylori in a usual dosage of administration with safety in the long term medication. JP-A 2-209809, corresponding to US 5 093 210'1531 342 discloses 5-Methoxy-2-[(4-methyl-3, 5-dimethyl-2-pyridinyl)methylsulfinyl]-lH-benzimidazole, called omeprazole, or a salt thereof, being an acid secretion-inhibiting medicine for gastritis and gastric ulcer, has antibiotic activity against C.
pylori 8005 one of the clinical isolates. JP-A 3-173817, corresponding to US 5 013 743 discloses the compounds (1) to (14) shown below being antibiotic activity against C. pylori NCTC-11916 and NCTC-11637 the standard strains and C. pylori PCL-56, CPY-0011-1, KS-13, CL0-1 and CL0-6 the clinical isolates.
1) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole - 2) 2-(3,5-Dimethyl-4-methoxypyrido-2-yl)methylsulfinyl-5-methoxy-lH-benzimidazole 3) 2-[{3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 4) 2-[{3-Methyl-4-(2,2,3,3-tetrafluoropropoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 5) 2-[{3-Methyl-4-(2,2,3,3,4,4-hexafluorobutoxy)pyrid-2-yl)methylsulfinyl]-lH-benzimidazole 6) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-'2104~31 yl)methylthio]-lH-benzimidazole 7) 2-[{(4-Isobutoxy)pyrid-2-yl)methylthio]-lH-benzimidazole 8) 2-[{(4-Isobutoxy)pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 9) 2-[{(4-Isopropoxy)pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 10) 2-[[{4-(2'-Propenyl)oxy}pyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 11) 2-[{(4-Propargyl)oxypyrid-2-yl)methylthio]-5-trifluoromethyl-lH-benzimidazole 12) 2-[{3-Methyl-4-(2,2,3,3-tetrafluoropropoxy)pyrid-2-yl}methylthio]-lH-benzimidazole 13) 2-[{3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyrid-2-yl}methylthio~
benzimidazole 14) 2-[{3-Methyl-4-(2,2,3,3,4,4-hexafluorobutoxy)pyrid-2-yl}methylthio]-lH-benzimidazole JP-A 3-48680 discloses the below shown compound being antibiotic to C. pylori, failing to show tested strains.
1) 2-[3-Methyl-4-(1-methyl-2-piperidyl)methoxy-2-pyridyl]methylthio-lH-benzimidazole 21~531 2) 2-[3-Methyl-4-(3-morpholinopropoxy)-2-pyridyl]methylthio-lH-benzimidazole 3) 2-[3-Methyl-4-(2-piperidinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 4) 2-[3-Methyl-4-{2-(2-oxo-1-pyrrolidinyl)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 5) 2-[3-Methyl-4-(2-morpholinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 6) 2-[3-Methyl-4-(3-piperidinopropoxY)-2-pyridyl]methylthio-lH-benzimidazole 7) 5-Methoxy-2-[3-methyl-4-(2-morpholinoethoxy)-2-pyridyl]methylthio-lH-benzimidazole 8) 5-Methoxy-2-[3-methyl-4-{2-(N-benzyl-N-methylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 9) 2-[3-Methyl-4-[2-(N-methyl-N-(2-phenylethyl)amino}ethoxy]-2-pyridyl]methylthio-lH-benzimidazole 10) 2-[3-Methyl-4-[2-(N-methyl-N-(3-phenylpropyl)amino}ethoxy]-2-pyridyl]methylthio-lH-benzimidazole 11) 2-[3-Methyl-4-{2-(N-benzyl-N-ethylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 12) 2-[3-Methyl-4-{2-(N-benzyl-N-propylamino)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 13) 2-[3-Methyl-4-[2-{N-methyl-N-(4-methylbenzyl)amino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 14) 2-[3-Methyl-4-[2-{N-(4-chlorobenzyl)-N-methylamino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 15) 2-[3-Methyl-4-[2-{N-(4-bromobenzyl)-N-methylamino}ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 16) 2-[3-Methyl-4-{2-(1,2,3,4-tetrahydroisoquinoline-2-yl)ethoxy}-2-pyridyl]methylthio-lH-benzimidazole 17) 1/2 magnesium salt of 2-[3-methyl-4-{2-(N-benzyl-N-methylamino)ethoxy}-2-pyridyl]methylsulfinyl-lH-benzimidazole 18) 1/2 magnesium salt of 2-[3-Methyl-4-[2-{N-methyl-N-(4-methylbenzyl)amino}ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 19) 1/2 magnesium salt of 2-[3-Methyl-4-[2-{N-(4-bromobenzyl)-N-methylamino}ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 20) 2-[3-Methyl-4-[2-(1,2,3,4-21~31 -tetrahydroisoquinoline-2-yl)ethoxy]-2-pyridyl]methylsulfinyl-lH-benzimidazole 21) 2-[3-Methyl-4-[2-(N-benzyl-N-methylamino)ethoxy]-2-pyridyl]methylsulfonyl-lH-benzimidazole 22) 2-[3-Methyl-4-[2-(N-methyl-N-(4-methylbenzyl)amino)ethoxy]-2-pyridyl]methylsulfonyl-lH-benzimidazole In the medication of diseases caused by C.
pylori, it's necessary to have excellent activity against a broad spectrum of C. pylori include standard strains and clinical isolates. The antibiotics effective against C. pylori have minimum inhibitory concentration called M.I.C. (~g/ml) in the range of smaller than 1 ~g/ml. Therefore, whether a compound has a M.I.C. in that range or not is a criterion to evaluate its clinical efficacy against C. pylori.
From the above shown points omeprazol disclosed in JP-A 2-209809 and JP-A 3-173817 has no sufficient antibiotic activity. Among the other 14 compounds shown in JP-A 3-173817, the compounds (12), (13) and (14) only are the antibiotics in the respect of activity against all the tested strains.
JP-A 3-48680 shows that compounds have MIC of 1 microgram per ml or less to only one tested strain.
-It is not expected from the listed data that they will have an antibiotic activity widely to many strains.
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) and 2-[(4-(3-methoxy-propoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) are known in JP-A 1-6270, corresponding to EP-A 268 956 as an acid secretion inhibitor. They can be prepared according to Examples 32 and 31, respectively, disclosed in JP-A 1-6270.
Disclosure of the Invention The inventors studied 2-[(4-(3-methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) and 2-[(4~3-methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) and have found that they have essentially the same C. pylori-eradicating activity as an antibiotic substance. This is how the inventors have reached the invention.
The two compounds of the invention have the follcwing chem_cal structures:
3 o OCH3 2 ~ (I~
21~31 65702-416 -\ ~ S - CH2 ~ ~II) The invention provides a pharmaceutical antimicrobial medicine for preventing, improving or treating an ulcer and/or gastritis in a mammal, which comprises an effective amount of the compound having the above formula (I) or (II) or a pharma-ceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
It is preferable that the mammal is human being, the ulcer is a peptic ulcer, the ulcer is a gastriculcer, and the ulcer and gastritis are recurrent.
The antimicrobial medicine is preferably for eradicating _. pylori from the mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis; for eradicating C. pylori from the mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis; for preventing, improving or treating a disease caused by C. pylorii for preventing recurring of a disease caused by C. pylori; and for restraining the adverse activity of C. pylori to cause a peptic disease.
~ 4~3~ 65702-416 In the invention, the pharmaceutically acceptable salt of the compound (I) or (II) includes an addition salt thereto by an inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid and phosphoric acid, an addition salt thereto by an organic acid such as citric acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, a salt of a metal such as sodium, potassium, calcium and magnesium. Sodium salt is most preferable.
The invention provides medicine which is effective for the C. pylori eradication having the same effect as anti-biotics. The compounds of the invention can be administered for a long time with safety, without side effects. It is pharmacologically effective and clinically useful to recurrent ulcers and gastritis.
2 1 0 4 ~ ~2-416 ._ The compounds of the invention have the following physical properties.
The physical property of 2-[(4-(3-methoxypropoxy)-3-methyl-pyridine-2-yl)-methylsulfinyl]-lH-benzimidazole 2 1 0 d~ rj 3 1 (I) molecular formula : C18H20N30aS
molecular weight : 358.44 property : white crystaline The physical property of 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) molecular formula : C18H20N302S
molecular weight : 342.44 property : pale yellow crystaline Ph~rm~col ogi c~l te~t Standard strains and clinical isolates of C.
pylori derived from the mucous membrane of the stomach were used and determined in vitro according to the agar dilution method determined by Nihon Kagaku Ryoho Gakkai (English name: Japan Society of Chemotherapy).
Sodium salt of 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole (I) was dissolved in a sterilized water. 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) and, as controls, omeprazole, 5-Methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methylthio]-lH-benzimidazole and 2-[(3-Methyl-4-(2,2,2-trifluoroethoxy)-pyrid-2-yl)methylthio]-lH-benzimidazole were dissolved 2 1~ 4~ 3 ~702-416 -separately in a 1% dimethylsulfoxide solution. As an antibiotic substance control, roxithromycin as macrolides, ampicillin as penicillins, ofloxacin as newquinolones were dissolved in a buffer solution of acetic acid having a pH of 5.0, a sterilized water and an lN aqueous solution of NaOH, respectively. Test plates were prepared by adding 7% horse blood to Brucella agar named by BBL Microbiology Systems (trade-mark) being available from Bector Dickson and Company. The incubation was conducted at 37~C at pH
of 7.0 for 3 days under the microaerophilic condition using Canpipack (trade-mark) being available from Bector Dickson and Company. MIC was determined in unit of microgram per ml. Test results are shown in Table 1. NCTC11637 and NCTC11916 are standard stains.
The other references indicate clinical isolates.
The test result is shown in terms of the antibiotic activity (MIC) in unit of microgram/ml, obtained in vitro against C. pylori. The tested compounds are (I) sodium salt of 2-[{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl}methylsulfinyl]-lH-benzimidazole, (II) 2-[{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-lH-benzimidazole, (III) 5-Methoxy-2-[{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl}sulfinyl]-lH-benzimidazole 21~4~31 (omeprazole), (IV) 5-Methoxy-2-{(4-methoxy3,5-dimethyl-2-pyridinyl)methylthio}-lH-benzimidazole, (V) 2-[{3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl}methylthio]-lH-benzimidazole, (VI) roxithromycin (RXM), (VII) ampicillin (ABPC), (VIII) ofloxacin (OFLX).
21()45~1 Table 1 Tested Compunent strain (I) (II) (III) (IV) (V) (VI) (VII) (VIII) NCTC11637 3.13 0.8 50 25 25 0.4 0.4 0.8 NCTC11916 3.13 0.2 25 12.5 12.5 0.1 0.05 0.8 EI-2 3.13 0.4 25 25 25 0.2 0.4 0.8 EI-5 3.13 0.2 50 25 12.5 0.2 0.4 0.8 EI-36 6.25 0.4 25 12.5 12.5 0.2 0.2 0.8 EI-46 3.13 0.4 25 12.5 12.5 >100 0.05 3.13 EI-391 3.13 1.56 50 25 12.5 50 0.1 25 EI-393 3.13 1.56 50 25 25 0.2 0.1 0.8 EI-397 3.13 1.56 50 25 25 0.2 0.1 0.8 EI-429 1.56 1.56 25 25 25 0.2 0.2 0.8 EI-467 1.56 1.56 50 12.5 12.5 0.2 0.05 0.4 EI-612 0.4 0.8 25 12.5 6.25 0.2 0.05 0.8 EI-925 3.13 0.4 25 12.5 12.5 0.2 0.2 0.4 EI-930 3.13 0.4 25 12.5 12.5 0.4 0.4 0.8 EI-933 3.13 0.8 25 12.5 12.5 0.1 0.05 0.4 It is noted from the test results that the compounds of the invention are superior to the known compounds such as omeprazole disclosed in JP-A 2-209809 and lansoprazole derivatives disclosed in JP-A 3-173817. The compounds of the 2104~31 invention evidently provide an equivalent C. pylori eradicating activity to antibiotics. Since the compounds of the invention are not of the antibiotic compounds, the compounds of the invention work effectively to a resistant bacteria such as clinically isolated strains shown in Table, EI-46 and EI-391. This is the reason they provide the antibiotic activity to a wider variety of bacteria than antibiotic substances. They can be administered continuously for long term. They have been found, at a concentration of 100 micrograms per ml, not to inhibit other gram-positive and gram-negative bacillii from growing even. This shows the fact that they can be antibiotic selectively to C. pylori.
~cl]t~ toxic~logic~l t~t The compound (I) of the invention was administered intravenously or orally one time, with a carrier of saline, to Slc:SD rats and Slc:ICR mouse, each being 7 or 8 weeks old, in a group consisting of five males and five females, to determine LD50 values. Results are shown in Table 2.
Acute toxicity of the compound (I) is shown in terms of LD50 in unit of mg/kg.
2101~31 Table 2 medication rats mouce process male female male female intravenous 157 mg/Kg 152 mg/Kg 220 mg/Kg 237 mg/Kg oral1447 mg/Kg 1332 mg/Kg1206 mg/Kg 1012 mg/Kg The obtained LD50 values are 5000 times as much as a clinical dosage of oral administration and for this reason the compounds of the invention are found to be greatly safe, that is, providing no toxicological influence.
t~chnologic~ v~nces of the invention It is evident from the above shown test data that the compounds of the invention are as antibiotic to C. pylori as antibiotic substances and therefore can work pharmacologically to prevent, improve and therapeutically treat recurrent ulcers and gastritis caused by C. pylori.
They can prevent, improve and therapeutically treat peptic ulcers, controlling secretion of gastric acid, and moreover prevent, improve and therapeutically treat recurrent ulcers and gastritis caused by C. pylori, with safety. They can be administered continuously for a long term, without combination of another antibiotic substance. The compounds can be used as an antibiotic medicine.
210~31 ~ppl i c~ti on of the i nventi on The compounds of the invention can be administered, without any limitation, normal ways. Which way and how much amount for medication depend on condition of a patient, the kind of ulcer and gastritis, a degree or extent of the disease, age of a patient and functions of heart, liver and kidney. It is preferable in the invention that they are dosed orally in an amount of 0.01 to 100 mg in a day, more preferably 0.1 to 80 mg, further preferably 0.1 to 60 mg, most preferably 5 to 40 mg. The oral medication can be conducted in the form of powder, granule, tablet or capsule. They can be prepared with a normally used carrier according to prior methods, preferably according to the showing in JP-A 1-290628 and JP-A
2-22225, corresponding to US 5 035 899. The preparation may further include therein a forming filler, a binder, a disintegrating agent, a lubricant, a colorant, a corrigent, a taste-improver and/or a smell-improver.
The filler includes lactose, corn starch, white sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide; the binder, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone; the disintegrating agent, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, 3 ~
dextrin, carboxymethyl cellulose, calcium and pectin; the lubrlcant, magnesium stearate, talc, polyethylene glycol, sillca and hardened vegetable oils; the coloring, any one which is permitted for drugs; the corrigent, cacao powder, mentha herb, aromatic powder, mentha oll, borneol and powdered cinnamon bark. Of course, these tablets and granules may be, if necessary, coated wlth sugar, gelatln or the llke.
For commerclal purpose, the medlclne is normally contained ln a commerclal package. The package usually carries instructlons or dlrectlons that the medicine can be or should be used for preventlng, lmprovlng or treating an ulcer or gastritis.
Examples of medicine's preparatlon, lncludlng orally dosed preparatlon and that wlth an enterlc coatlng of the lnventlon lncludlng the compound (I) or (II) of the lnventlon are shown below. These do not mean any llmltatlon to the inventlon.
Example 1 Tablets includlng the compound (I):
2-[(4-(3-methoxypropoxy)-3-methylpyrldlne-2-yl)-methylsulfinyl]-lH-benzlmldazole were prepared by the below shown prescrlptlon.
2-[(4-(3-methoxypropoxy)-3-methylpyrldlne-2-yl)-methylsulflnyl]-lH-benzlmldazole, mannltol and magneslum oxlde were mlxed wlth one another, hydroxypropylcellulose dlssolved ln ethanol was added to the mlxture, the resultant was granulated, drled and classlfled with a sleve of 28 mesh 3 ~
.~_ accordlng to ASTM, the product belng called (A). Then crystalllne cellulose and corn starch were mlxed wlth the product (A), hydroxypropylcellulose dlssolved ln water was - 20a -added to the mixture, the resultant was granulated, dried and classified with a sieve of 28 mesh, the product being called (B). The products (A) and (B), calcium salt of carboxymethylcellulose, talc and magnesium stearate were mixed with one another and the mixture was formed into plain .
tablets with a single shot tablet-formulating machine, being available from Okada Seiko-sha.
Prescription in 1 plain tablet weighing 120.2 mg is shown below in unit of mg:
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylsulfinyl]-lH-benzimidazole 5.0 mannitol 45.3 magnesium oxide 40.0 hydroxypropylcellulose 2.5 crystalline cellulose 10.0 corn starch 10.0 carboxymethylcelulose calcium 5.0 talc 2.0 magnesium stearate 0.2 The obtained plain tablets were coated with a enteric coating to obtain tablets.
~x~mple ~
Tablets including 2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole (II) were 2104~31 prepared by the below shown prescription.
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole and mannitol were mixed with each other, hydroxypropylcellulose dissolved in ethanol was added to the mixture, the resultant was granulated, dried and.
classified with a sieve of 28 mesh according to ASTM, the product being called (A). Then (A), crystalline cellulose, corn starch, calcium salt of carboxymethylcellulose, talc and magnesium stearate were mixed with one another and the mixture was formed into plain tablets with a single shot tablet-formulating machine, being available from Okada Seiko-sha.
Prescription in 1 plain tablet weghing 99.7 mg is shown below in unit of mg:
2-[(4-(3-Methoxypropoxy)-3-methylpyridine-2-yl)-methylthio]-lH-benzimidazole 5.0 mannitol 65.3 hydroxypropylcellulose 2.5 crystalline cellulose 10.0 corn starch 10.0 carboxymethylcelulose calcium 5.0 talc 2.0 magnesium stearate 0.2 The obtained plain tablets were coated with a enteric 2 ~ Q 45 3 ~
coating to obtain tablets.
Claims (16)
1. A pharmaceutical antimicrobial medicine for preventing, improving or treating an ulcer or gastritis in a mammal, which comprises (1) an anitmicrobial effective amount of a compound having the formula:
or or a pharmaceutically acceptable salt thereof and (2) a pharmaceutically acceptable carrier.
or or a pharmaceutically acceptable salt thereof and (2) a pharmaceutically acceptable carrier.
2. The medicine as claimed in claim 1, in which the mammal is human being.
3. The medicine as claimed in claim 1, in which the ulcer is a peptic ulcer.
4. The medicine as claimed in claim 1, in which the ulcer is a gastric ulcer.
5. The medicine as claimed in claim 1, in which the ulcer and gastritis are recurrent.
6. The medicine as claimed in claim 1, which is for eradicating C. pylori from a mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis.
7. The medicine as claimed in claim 1, which is for eradicating C. pylori from a mucous membrane of the stomach of a patient suffering from a gastric ulcer, duodenal ulcer or gastritis.
8. The medicine as claimed in claim 1, which is for preventing, improving or treating a disease caused by C. pylori.
9. The medicine as claimed in claim 1, which is for preventing recurring of a disease caused by C. pylori.
10. The medicine as claimed in claim 1, which is for restraining the adverse activity of C. pylori to cause a peptic disease.
11. The medicine as claimed in claim 1, which is in a dosage unit form adapted to be administered orally in an amount of 0.01 to 100 mg per day.
12. The medicine as claimed in claim 1, which is in a dosage unit form adapted to be administered orally in an amount of 5 to 40 mg per day.
13. The medicine as claimed in claim 1, which is in a dosage unit form adapted to be administered orally in an amount of 5 to 60 mg per day of the compound or salt to human being patient suffering from a gastric ulcer, duodenal ulcer or gastritis caused by C. pylori.
14. The medicine as claimed in claim 1, 2, 11 or 12, which is contained in a commercial package carrying instructions that the medicine is to be used for preventing, improving or treating an ulcer or gastritis.
15. The medicine as claimed in claim 13, which is contained in a commercial package carrying instructions that the medicine is to be used for preventing, improving or treating a gastric ulcer, duodenal ulcer or gastritis caused by C. pylori in human being.
16. A use of a compound of the formula:
or or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for preventing, improving or treating an ulcer or gastritis in a mammal.
or or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for preventing, improving or treating an ulcer or gastritis in a mammal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24404292 | 1992-08-21 | ||
| JP4-244042 | 1993-06-21 |
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| CA2104531A1 CA2104531A1 (en) | 1994-02-22 |
| CA2104531C true CA2104531C (en) | 1999-01-05 |
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|---|---|
| US (1) | US5916904A (en) |
| EP (1) | EP0585722B1 (en) |
| AT (1) | ATE137969T1 (en) |
| CA (1) | CA2104531C (en) |
| DE (1) | DE69302646T2 (en) |
| DK (1) | DK0585722T3 (en) |
| ES (1) | ES2087623T3 (en) |
| FI (1) | FI933681L (en) |
| GR (1) | GR3019917T3 (en) |
| NO (1) | NO307689B1 (en) |
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| US5504082A (en) * | 1992-06-01 | 1996-04-02 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridine compound and pharmaceutical compostions |
| IL137229A0 (en) * | 1998-01-14 | 2001-07-24 | Uab Research Foundation | Methods of synthesizing and screening inhibitors of bacterial nad synthetase enzyme, compounds thereof, and methods of treating bacterial and microbial infections with inhibitors of bacterial nad synthetase enzyme |
| US6861448B2 (en) | 1998-01-14 | 2005-03-01 | Virtual Drug Development, Inc. | NAD synthetase inhibitors and uses thereof |
| US6673827B1 (en) | 1999-06-29 | 2004-01-06 | The Uab Research Foundation | Methods of treating fungal infections with inhibitors of NAD synthetase enzyme |
| DE69913712T2 (en) * | 1998-08-25 | 2004-10-07 | Uab Res Foundation Birmingham | INHIBITORS OF BACTERIAL NAD SYNTHETASE |
| US6174902B1 (en) | 1999-04-28 | 2001-01-16 | Sepracor Inc. | R-rabeprazole compositions and methods |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6369087B1 (en) * | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US7608625B2 (en) * | 2003-03-13 | 2009-10-27 | Eisai R & D Management Co., Ltd. | Method for treating bruxism and bruxism-related diseases |
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| FI90544C (en) * | 1986-11-13 | 1994-02-25 | Eisai Co Ltd | Process for Preparation as Drug Useful 2-Pyridin-2-yl-methylthio- and sulfinyl-1H-benzimidazole derivatives |
| DK0382489T3 (en) * | 1989-02-10 | 1995-01-16 | Takeda Chemical Industries Ltd | Monoclonal Anti-Human Papillomavirus Antibody, Hybridoma Cell Producing This, and Method of Preparation thereof |
| JPH0348680A (en) * | 1989-07-18 | 1991-03-01 | Yoshitomi Pharmaceut Ind Ltd | Antimicrobial agent |
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1993
- 1993-08-17 ES ES93113149T patent/ES2087623T3/en not_active Expired - Lifetime
- 1993-08-17 EP EP93113149A patent/EP0585722B1/en not_active Expired - Lifetime
- 1993-08-17 AT AT93113149T patent/ATE137969T1/en active
- 1993-08-17 DE DE69302646T patent/DE69302646T2/en not_active Expired - Lifetime
- 1993-08-17 DK DK93113149.4T patent/DK0585722T3/en active
- 1993-08-19 NO NO932947A patent/NO307689B1/en not_active IP Right Cessation
- 1993-08-20 FI FI933681A patent/FI933681L/en unknown
- 1993-08-20 CA CA002104531A patent/CA2104531C/en not_active Expired - Lifetime
-
1996
- 1996-05-16 GR GR960400242T patent/GR3019917T3/en unknown
- 1996-06-20 US US08/670,213 patent/US5916904A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2104531A1 (en) | 1994-02-22 |
| NO307689B1 (en) | 2000-05-15 |
| FI933681A0 (en) | 1993-08-20 |
| NO932947D0 (en) | 1993-08-19 |
| DK0585722T3 (en) | 1996-08-05 |
| DE69302646D1 (en) | 1996-06-20 |
| ES2087623T3 (en) | 1996-07-16 |
| US5916904A (en) | 1999-06-29 |
| EP0585722A1 (en) | 1994-03-09 |
| GR3019917T3 (en) | 1996-08-31 |
| NO932947L (en) | 1994-02-22 |
| ATE137969T1 (en) | 1996-06-15 |
| EP0585722B1 (en) | 1996-05-15 |
| FI933681A7 (en) | 1994-02-22 |
| DE69302646T2 (en) | 1996-10-31 |
| FI933681L (en) | 1994-02-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |