TWI310375B - Methods and compositions for treating bacterial infection - Google Patents

Description

1310375 A7 B7 V. INSTRUCTIONS (1) TECHNICAL FIELD The present invention relates to the treatment or prevention of diseases caused or related to infection by certain bacteria, in particular H. pylori or E. coli. Or methods and compositions for lesions. Background Art Since the commercialization of antibiotics in the 1940s, they have been regarded as miraculous bullets because they destroy bacteria and do not harm patients. However, over time, a large number of antibiotics are no longer effective because of the increasing number of strains with antibiotics for antibiotics. For example, the infection of tuberculosis and pneumonia is becoming more and more dead, just as antibiotics were not found before. Humanity is facing a global public health crisis (Neu, Science, 257: 1064-1073, (1992)). Since the discovery of penicillin in 1929, there are now more than 150 antibiotics. They fall into several broad categories, each with its own reaction mechanism (Lyon and II Skurray, Microbiol. Rev., 88-134, (1987)). In general, these compounds are produced by living organisms that inhibit bacterial growth and proliferation. For example, vancomycin and/5-naprost can block bacterial cell wall synthesis (Chopra et al., Antimicrob. Agents Chemother., 4i_: 497-503, (1997)); and (Nicolaou et al., Scientific American , 48-52 May (2001)) 0 Erythromycin and tetracycline can interfere with protein synthesis. Sulfonamide interferes with folate metabolism, rifajnpin blocks RNA synthesis, and quinolone inhibits DNA replication. __ In order to overcome the drug resistance of bacteria, a new method for treating cell infection is under research. These new methods include giving new life to existing antibiotics, such as changing molecules. Recently, a new class of antibiotics & "self-assembled peptide nanotubes" caused people -4- this paper scale applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1310375 A7 ______B7 V. Invention Description (2) Interest (Associated Press New, July 25, 2001). This compound can be observed under the microscope, and the tube formed by the amino acid ring can pass through the surface of the bacteria. There are also many new developments in the field of genomics. They interfere with bacterial RNA (rRNA). And messenger RNA (mRNA), a new technology called "in vivo expression technology (I VET), which is capable of labeling bacterial genes. Another promising approach is the use of antisense oligonucleotides to treat bacterial infections (Jasny et al., Science, 286: 443-491, (1999)). There is a class of antibacterial compounds that have been identified for specific proteases involved in the synthesis of DN A (!^〇61&1_, 61〇1.?1^1:111.81111.,: 120-124 (1998)); Irisawa et al., Biol. Pharm. Bull, 16:621-626 (1993); Irisawa et al., Biol. Pharm. Bull., 16:1211-1215 (1993); Kato et al., J. Enzyme Inhibition , 8.:25-37 (1994); Kato et al., Eur. J. Biochem., 210:1007-1014 (1992) and Kato et al., Biol. Pharm. Bull., 16:552-557 ( 1993)) » These compounds consist of a variety of aromatic di- 4-indolylcyclohexanecarboxylic acid (GMCHA) aromatic esters, which act as competitive trypsin inhibitors in vitro (see formula I below):

COOR Helicobacter pylori (H. pylori) is a Gram-negative spiral bacterium that was first isolated in 1983 by Warren and Marshall from a patient with chronic gastritis (W-afren et al., Lancet, 1273-1275 (1983) )). There is much evidence that there is a close correlation between gastroduodenal disease and Helicobacter pylori. Therefore, it is considered that Helicobacter pylori is an important bacterial pathogen, induces chronic gastritis in humans, and is suitable for the gastroduodenal ulcer, distal gastric adenocarcinoma and -5- this paper scale applies to the Chinese painting S standard (CNS) A4 specification ( 210X 297 mm) 1310375 A7 B7 V. Description of invention (3) Gastric lymphoma. Recently, the World Health Organization classified Helicobacter pylori as a five-member carcinogen that plays a leading role in the development of gastric cancer (Internationa丨 Agency for Research on Cancer. World Health Organization, Lyon, France, Monograph on the evaluation of carcinogenic risk to humans). 61: 177-240, 1994). In 1994, the National Institutes of Health (NIH) recommended that Helicobacter Pylori in peptic ulcer disease (NIH consensus development ^ panel on Helicobacter Pylori in peptic) be administered simultaneously with PPI and antibacterial agents. Ulcer disease. (JAMA, 211:65-69 (1994)). Since then, oral methotrexate, PPI, ciarithr〇mycin and erythromycin-hydroxylamine blue Amoxicillin has been introduced into practice and has a cure rate of 80-90% for infected cases. However, the application of antibacterial agents can cause a serious problem, that is, the resistant strain of Helicobacter pylori against bacterial agents will be developed. On the other hand, the resistance strain of A. sinensis and amoxicillin has been reported frequently (Zwet et al., Lancet, ϋ 2:1595 (1998)). Taking PPI and antibacterial agents Another serious problem is that 1 will induce indigestion, and a large number of antibacterial agents will cause serious destruction of colonies in the digestive tract. Therefore, it is very important to find new compounds to eliminate Helicobacter pylori. The present invention addresses this need. Other needs of the related art. SUMMARY OF THE INVENTION The present invention enters the rank of antibacterial agents by providing a drug which inhibits the initial replication of certain bacterial DNA. One aspect of the present invention relates to a compound of the following formula II. Or a pharmaceutically acceptable salt thereof: -6-

1310375 A7 B7 V. DESCRIPTION OF THE INVENTION (6) Method of lesions \ Brief description of the schema Figure 1 shows the effect of compound PH04 on cell growth, DN A synthesis and protease I η activity of synchronized E. coli cells. Figure 2 Α and 2 Β illustrate the anti-Helicobacter pylori effect of the compound (ΝΕ-200 1). Figures 3A and 3B illustrate the anti-Helicobacter pylori effect of compound NE-2001 at different pHs. BEST MODE FOR CARRYING OUT THE INVENTION In order to clarify the contents of the invention without being limited thereto, the present invention is divided into the following subsections in detail. A. Definitions Unless defined otherwise, all technical and scientific terms used in the present invention are the same as those commonly understood by those skilled in the art to which the invention pertains. All patents, applications, published claims, and their literature and sequences from the Group Bank and other data repositories are fully incorporated herein. If the definitions set forth in this section are contrary to the definitions of all applications cited in this case, the applications filed and other documents and sequences from Gene Bank and other data repositories, or if not, the definitions set forth in this section are Prevail. The article '"一" or "a" means "5,〗 〖, Λο _1, & 扣 buckle at least one, • or " one or more, 0 used in this article - '•• Spirulina "指蟫斿耶 ^, Boss-spinning, curled or straight, with rounded ends and a little flagellation 'flagellate at the end of the glass-- „ + Μ上不王坏 早 彤 (Early or Bipolar and lateral) of the low-milk fine genus. It opens the main t- 匕邶 into pigmented, translucent colonies, usually 1-2 mm in diameter. Pairs of servants and w, emulsified hydrogenase and Emulsifying enzymes are usually positive _ -9- This paper scale applies to China National Standard (CNS) A4 specifications ^^^97 public $~~ ----- _ 1310375 A7 _____ B7 Five, issued 5 instructions (7-) ' - Sexual reaction. It occurs in the gastric mucosa of primates (including humans) and white pelicans. Some species are associated with stomach and peptic ulcer. As used herein, "Helicobacter pylori refers to a genus of the genus Spirulina. It is a shaped or curly Gram-negative bacterium that does not form spores and can have flagella. Found in the same place, the earliest known as Helicobacter pylori. Helicobacter pylori infection produces urease, which is associated with several gastroduodenal diseases including gastritis and gastric ulcer, duodenal ulcer and ulceration. As used herein, • a disease or condition caused by a Helicobacter pylori infection" refers to a disease or condition caused by a Helicobacter pylori infection alone or in combination with other agents and/or conditions of hereditary and/or acquired nature. As used herein, "anti-Helicobacter pylori preparation" does not include a compound of the invention, i.e., a compound of formula 11 below:

7NH(CH2)tt-^ jj—COOR _, “E. coli” refers to the original bacteria widely used by biochemists in laboratory work. It is a rod-like gram-negative bacillus, which is abundantly present in the mammalian large intestine. (colon). It is non-pathogenic under normal conditions, but some strains, such as E. coli 0157, are usually found in the small intestine of the cattle and have recently caused death in several cases. As used herein, diseases or lesions caused by E. coli infection " refers to a disease or condition caused by infection with E. coli, or a combination of hereditary and/or acquired other agents and/or disease. [The compounds used herein to treat a particular disease" Effective amount " refers to the paper size that is sufficient to improve or to some extent alleviate the symptoms associated with this disease. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1310375 A7 ______ B7 V. Invention Description (8) ~ Quantity. This amount of sword can be administered in a single dose or it can be administered effectively as a course of treatment. This dose may cure the disease, but is typically administered to improve the symptoms of the disease. Repeated administration may be required to improve symptoms. As used herein, "pharmaceutically acceptable salts, esters or other derivatives" include any salt vinegar or derivative which is readily prepared by persons skilled in the art using such derivatives, and the resulting compounds Can be administered to animals and humans 'is not substantially toxic, and the compound can be pharmaceutically active or a prodrug. As used herein, "treatment" means that the symptoms of a condition, disease or condition are improved in any way, or other beneficial changes. Treatment also includes any medical use of the compositions of the invention. As used herein, the administration of a particular pharmaceutical composition "improving" the symptoms of a particular lesion refers to any mitigating effect caused or associated with administration of the composition, whether permanent or temporary, long-term or transitional. The _, "substantially pure" used refers to a standard analytical method used to achieve this purity by a person skilled in the art using standard analytical methods to measure its uniform homogeneity without detectable dye. Thin layer chromatography (TLC), gel electrophoresis, and high performance liquid chromatography (HPLC), or of sufficient purity, does not alter the physicochemical properties of the material, such as enzymes and biological activities, even if further purified. Methods for purifying compounds for substantial purification are known to those skilled in the art. However, the substantially pure chemical compound may be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound. As used herein, "prodrug" refers to a compound that is administered in vivo, which is 1310375 A7 __________B7 _ V. Illustrative (9) The compound can be metabolized or converted to biological, pharmaceutical or medical Active form. To produce a prodrug, the pharmaceutically active compound is modified to render the active compound reproducible through metabolic processes. Prodrugs can be designed to alter the metabolic stability of the drug. Or transfer characteristics to mask its side effects or toxicity, improve the taste of the drug, or change other characteristics. Once a person skilled in the art knows a pharmaceutically active compound, a prodrug of the compound can be designed based on the kinetics of the drug and its metabolism in vivo. (See, for example, Nogrady Medicinal Chemistry A Biochemical ^£-r〇ach, Oxford University Press, New York, pages 3 88-392 (1985)). The use of the terms "substantially" the same or uniform or similar may vary depending on the understanding of the person skilled in the art, and is generally at least 70% identical, preferably at least 80%, more preferably at least 90. %, the best is at least 95%. As used herein, "composition" means any mixture "may be a solution, suspension, liquid, powder, paste, aqueous, non-aqueous or any combination thereof. As used herein, ''combination'" means two or more Any combination between the two. The term "subject" as used herein includes human and other animal species, such as 'dog', cow, pig, and ritual animals. Those skilled in the art are acquainted with individuals who are willing to receive treatment or to prevent certain bacterial infections, for example, diseases or lesions caused or associated with pyloric helix B and large bowel fistula infection. Any protective group used here, the amino acid of the amino acid and other compounds - this paper scale is applicable to the Chinese national standard <CNS) A4 specification (210X 297 mm) 1310375 V. Invention description (n 2: its - a mixture of, for example, a racemic mixture. The chemical substances contemplated herein include all pharmaceutically active compound species, or solutions or templating compounds thereof. = Compounds, such as aqueous solutions, hydrolysates or ionized products of these compounds: And these compounds may contain different amounts of bound water molecules. The compounds of the present invention may be prepared by any suitable method for each synthesis. The compound is prepared by the synthesis described in Section F below. Further, preferably, the compound or The pharmaceutically acceptable hydrazine salt can be in the form of a pharmaceutical composition, either alone or in combination with blood or excipients. U-Acceptable Carrier The compound of the present invention can be formulated into a pharmaceutically acceptable form using any suitable acid. In the form of a salt, for example, a mineral acid such as hydrochloric acid, a gas desert acid 'nitric acid, sulfuric acid, or the like can be used. In other examples, the acid can be made so that acetic acid can be used. Acid, benzoic acid, maleic acid, fumaric acid, succinic acid (tetra), =, followed by, etc. Another example, the use of a hydrazine-based acid such as acetamidine acid, etc. may be used as an example. The use of aryl hydrazine, such as winter acid, p-toluene sulfonic acid, etc. C. Therapeutic and preventive methods. The invention is a method for treating and preventing a disease or a disease caused by a bacterial infection, the method comprising Requires or is willing to receive this treatment t-protection with an effective amount of selective inhibition of bacterial visceral replication initiation or money-acceptable (four), "therapy or ribs of the above diseases or lesions. Preferably - the above diseases or lesions by Escherichia coli or Helicobacter pylori causes -14«

1310375 A7 B7 V. Description of invention (13) 1: Wang et al., Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J. Immunol. 2001 Jul 15; 167(2):926 -34. 2: Peek RM Jr., Helicobacter pylori strain-specific activation of signal transduction cascades related to gastric inflammation. J Physiol Gastrointest Liver Physiol. 2001 Apr; 280(4): G525-30 ° 3: Israel et al., Helicobacter pylori strain -specific differences in genetic content, identified y microarray, influence host inflammatory responses. Clin Invest. 2001 Mar; 107(5): 61 1-20. 4: Vitkute et al., Specificities of eleven different DNA methyltransferases of Helicobacter pylori train 26695. Bacteriol. 2001 Jan; 183(2): 443-50. 5: DeLoiv&y and Schiller, Characterization of an In vitro-selected amoxicillin-resistant strain of Helicobacter pylori. Antimicrob Agents Chemother. 2000 Dec; 44(12):3368-73 ° 6: Hua et al., Isolation of a single Strain of Helicobacter pylori from the antrum and body of individual patients. Eur J Gastroenterol Hepatol. 2000 Oct; 12(10):1 129-34. 7: Occhiaifni et al., Distribution of open reading frames of plasticity region of strain J99 in Helicobacter pylori strains isolated from gastric carcinoma and gastritis patients in Costa Rica. Infect Immun. 2000 Nov; 68(1 1):6240-9 0 - 16- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310375 A7 B7 V. Invention description (14) 8: Fassbinder et al., Structural and functional, analysis of the riboflavin synthesis genes encoding GTP cyclohydrolase II (ribA), DHBP synthase (ribBA), riboflavin synthase (ribC), and riboflavin deaminase/reductase (ribD) from Helicobacter pylori strain PI. FEMS Microbiol Lett. 2000 Oct 15; 191(2): 191-7. 9: Enroth et al., Helicobacter pylori strain types and risk of gastric cancer: a case-control study. Cancer Epidemiol Biomarkers Prev. 2000 Sep; 9(9): 981-5 0 10: Petersen et al., Role of strain Type, AGS cells and fetal calf serum in Helicobacter pylori adhesion and invasion assays. FEMS Immunol Med Microbiol. 2000 Sep; 29(1): 59-67 0 11: Matsui et al., Recurrence of blood capillary dependent strain-differences of Helicobacter pylori in urease B gene. Dig Dis Sci. 2000 Jan; 45(1):49-54 0 12: Queiroz et al., Factors associated with Helicobacter pylori infection by a cagA-positive strain in childern. J Infect Dis· 2000 Feb; 181(2): 626-30. 13: Monteiro et al., Lipopoly saccharide structures of Helicobactet-pylori genomic strains 26695 and J99, mouse model H. pylori Sydney strain, H. pylori P466 carrying sialy Lewis X, and H. pylori UA915 expressing Lewis B classification of H. pylori Lipopolysaccharides into glycotype -17- ... This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1310375 A7 _B7 . _·_ V. Description of invention (15 ) , families. Eur J Biochem. 2000 Jan; 267(2):305-20 〇14: Peek et al., Helicobacter pylori strain-specific genotypes and modulation of the Gastric epithelial cell cycle. Cancer Res. 1999 Dec 15; 59(24):6124-3 1. 15: Aspinall et al., A structural comparison of lipopolysaccharides from two strains of Helicobacter pylori, of which one strain (442) does and the other strain (471) does not stimulate pepsinogen secretion. Glycobiology. 1999 Nov; 9(1 1) : 1235-45. 16: Enroth et al., Occurrence of resistance mutation and clonal expansion in Helicobacter pylori multiple-strain infection: a potential risk in clarithromycin-based therapy. Clin Infect Dis. 1999 Jun; 28(6): 1305-7. 17: Hua et al., Predominance of a single strain of Helicobactex pylori in gastric antrum. Helicobacter. 1999 Mar; 4(1): 28-32. 18: van Doom et al., Helicobacter pylori-associated gastritis in mice is host and strain specific. Infect Immun. 1999 Jun; 67(6): 3040-6. 19: van Doom et al., The inflammatory response in CD1 mice shortly after infection with a CagA+/VacA+ Helicobacter pylori strain. Clin Exp Immunol. 1999 Mar; 115(3): 421-7. 20: De Ungria et al., Molecular characterization and -18- This paper scale applies to China® Standard (CNS) A4 size (210 x 297 mm) 1310375 A7 B7 V. Description of invention (16) interstrain variability of pHPSl, a plasmid isolated from the Sydney strain (SSI) of Helicobacter pylori. Plasmid. 1999 Mar; 41(2): 97-109. In the prevention or treatment of diseases or diseases caused by H. pylori infection, the compounds of the present invention can be used alone or in combination with anti-Helicobacter pylori agents. Any suitable anti-Helicobacter pylori agent can be used in combination with the compounds of the present invention. Examples of such anti-Helicobacter pylori agents include proton pumping inhibitors (PPI), metronidazole 'clarithromycin, hydroxylamine = amoxicillin and famotidine (Gaschwantler) Et al., Eur, J. Gastroenterol Hepatol, 10(7): 579-82 (1998)). In a preferred embodiment, the compounds of the invention may be used, but no anti-Helicobacter pylori agents such as PPI, metronidazole, guanidine, amoxicillin and famotidine are administered. More preferably, the compounds of the present invention are useful for the treatment or pre-treatment of diseases or pathologies caused by a drug-resistant Helicobacter pylori strain induced by the treatment of PPI, t-nitrozol, naphthomycin 'hydroxylamine valinomycin and famotidine. . The compounds of the invention may be administered alone or in combination with other suitable anti-Helicobacter pylori agents by any suitable method. For example, the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered by intracavitary injection of a 'subcutaneous injection' intravenous injection, intramuscular injection, intradermal injection, oral administration or topical administration. ... In a specific embodiment, the method includes a method for the diagnosis or prognosis (pragn〇sing) of a subject infected with Helicobacter pylori. Any suitable method can be used to diagnose or prognose H. pylori infection. Diagnosis or 1310375 _________B7 V. INSTRUCTIONS (18) ~~---- In another item - a specific example, provide a treatment or prevention of a disease caused by a bacterial infection, such as Helicobacter pylori, or E. coli infection or In the case of a lesion, the method comprises administering to a subject in need and willing to receive such treatment or prevention an effective amount of the above combined preparation, or a pharmaceutically acceptable salt thereof, for treating or preventing the above-mentioned disease or condition. In another specific embodiment, a kit of parts comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above or a pharmaceutically acceptable salt thereof for treating or preventing a bacterium, is provided, For example, instructions for use of diseases or lesions caused by anti-Helicobacter pylori or E. coli infection. In another specific embodiment, a kit is provided comprising the above-described combined preparation and instructions for using the combination preparation to treat or prevent a disease or condition caused by a bacterial infection, such as Helicobacter pylori, or E. coli infection book. E. Formulations and Doses According to the present invention, the compounds of the present invention may be formulated, either alone or in combination with other agents 'carriers or excipients', for any suitable route of administration, such as intraluminal, subcutaneous, intravenous, intramuscular injection. , intradermal injection, oral or topical medication. The method can be administered by injection using a formulation which is administered as a single dose in an ampule or in a multi-dose container with the addition of a preservative. The formulations may take the form of suspensions or liquids in oily or aqueous vehicles, and may contain formulary agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, sterile pyrogen-free water or other solvent before use. The topical medication of the present invention can be foam, gel, ointment, oil-21- This paper scale is applicable to Chinese national standard (CNS> A4 specification (210 X 297 mm) 1310375 A7 B7 V. Invention description (19) Paste, wear The pharmaceutically acceptable compositions and methods for use in the present invention include, but are not limited to, those described in U.S. Patent Nos. 5,736,154; 6,197,801 B1; 5,741,511; 5,886,039; 5,941,868; 6,258,374 B1; and 5,686,102. The dose size for treatment or prophylaxis will vary depending on the severity of the condition to be treated and the route of administration. The frequency of dosing and administration will vary depending on age, body weight, condition and individual patient response. The follow-up doctor should also know when and how to terminate, interrupt or reduce the therapeutic dose due to toxicity and side effects. Conversely, if the clinical response is inappropriate (excluding toxic side effects), the doctor should also know when and how to adjust the treatment. Increasing the dosage. Any suitable route of administration can be used. The dosage forms include tablets, lozenges, lenticular capsules, and dispersion 'suspension' solution. , capsules, stickers and the like. See, Remington's Pharmaceutical Sciences ° - In practical applications, the compounds of the invention, alone or in combination with other preparations, can be used in accordance with general pharmaceutical mixing techniques, and in medicine. The carrier or excipient, for example, cyclodextrin and 2-hydroxy-propyl-indole-cyclodextrin are uniformly mixed. The carrier may be in various forms depending on the need of administration, depending on the local or parenteral route. For compositions for enteral dosage forms, such as intravenous injection or infusion, a similar pharmaceutical medium known to those skilled in the art, water, glycol, oil 'buffering agent' sugar preservatives, liposomes, etc. can be used. Examples of parenteral compositions include, but are not limited to, 5% w/v dextrose, normal saline or other solutions. Compounds of the invention alone or in combination with other formulations-22- This paper scale applies to China ® Home ( (CNS) A4 size (210.X 297 mm) 1310375 A7

= Dosing with vial IV, the total dose volume is approximately measured: The volume of the diluent will vary depending on the total dose administered. The sputum provides a kit for the treatment of the present invention. The kit will include: the inventive compound in a pharmaceutically acceptable form, alone or in combination with other tests, in one or more containers. The preferred form of the medicine is combined with the physiological saline solution of the sputum bacteria, the dextrose solution, or the buffer solution, or other medically combined black bacillus liquid β or the composition; the dried or dried; in 14 cases The kit may optionally include a pharmaceutically acceptable solution, preferably in a sterile container, in a container to reconstitute the complex to form a drop for injection. An example of a pharmaceutically acceptable solution is a physiological saline solution and a dextrose solution. In another specific embodiment, the kit of the present invention further comprises a needle or syringe for injecting the composition, preferably a sterile pad packaged and/or packaged in sterile form. Instructions for the use of the pharmaceutical composition by the physician or patient may be included as needed. F. Examples ― _Example 1. Synthesis of a new series of anti-Helicobacter pylori compounds Since the discovery of Helicobacter pylori in gastric mucus of patients with chronic stomach diseases in 1983, scientists have conducted detailed studies. As a result, there is strong evidence supporting the hypothesis that Helicobacter pylori can cause gastric and duodenal ulcers. About 60% of the world's people are infected with Helicobacter pylori, and it has become the most common infection of the mouth and intestines in the world. Some people will develop this infection into gastritis, peptic ulcer and even stomach cancer. Because it is a spiral type, the outer shell is thick, and the outer shell has bacteria that help it move freely, making it very suitable for the upper part of the gastrointestinal (GI) tract and difficult to base. -23- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1310375 A7 _ B7 V. Invention description (21 ) We are committed to 'developing a series of compounds and found that compound NE-2001 has a specificity for Helicobacter pylori And selective action: Multi-drug therapy is therefore a more cost-effective method. Synthesis Reaction Figure 1 H0-〇--〇-C00H CH3〇H' Back 4· HO-^-^-COOCHj H2S〇4 H〇O^〇-COOCH3+ H3C^Q-CH2OH ^Wa^HO^Q-〇COOCH2HQ -CH3 2 CH 二-产仏啊心一η=0,1 3 HO-R + H〇OC-^^-[CHz)n~H〇fiCl-R-〇〇〇-^-(CH2)n- HN-^^2 ~ »Bipyridine n=0,l, a· 〇—O-cooc^-O-0^ b. lower alkyl group> c. aryl group, etc. R» < -24 - The paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1310375 A7 B7 V. Invention description (22) f-test - '$ instrument and reagent HP 11 〇〇HPLC system, including two Yuanpu, connected to the hollow degasser, automatic sampler, thermostat tube box, photodiode array detector. The chromatography column was B 0118 八 parent 008 (4.6*250 〇1111), and the mobile phase was methanol/water = 9 〇: 1 〇 (0 · 1% acetic acid). The flow rate was 1 ml/min. The detection wavelength is 254 nm. All solvents were HPLC grade. The MS spectrum was measured by an API 2000 LC/MS/MS mass spectrometer. 1H NMR data was measured by the Institute of Analytical Testing at the Prefectural University of Technology. All synthetic starting materials are commercially available products. 4-(4-methyl-methyl)-4^ via the basic 4-phenyl-acid acid synthesis 4 4-methyl-4, hydroxy phenyl -4-# oxime ester in Soxhlet filling with A4 molecular sieve A solution of 214 g (0.1 mol) of 4-(4-hydroxyphenyl)benzoic acid in methanol (500 mL) was added. Drop - add 2 ml of concentrated sulfuric acid. The mixture was heated to reflux for 72 hours. After removing the solvent by hollowing out, the oily residue was dissolved in a stupid (1 ml) and washed with water until pH = 7. The organic layer was dried over anhydrous magnesium sulfate and filtered. An appropriate amount of activated carbon was added to the filtrate, which was then heated to reflux for 10-15 minutes and passed through. The solvent was removed to give 18.2 g (yield: 80%) of 4-methyl·4'-# to bisbiphenyl-4- oxalate white crystals. 4-(4-Methylbenzyl)-4, hydroxybutan-4-carboxylate containing 9.0 g (40.0 mmol) of 4-methyl-4-hydroxybenzyl-4-carboxylate. 24.4 g (200.0 mmol) of 4 methylmethylbenzyl alcohol, ι_〇克 (4. 〇 millimoles) sodium decyl alcohol and 20.0 ml of a suspension of succinct' under nitrogen protection, heated to reflux 2.5 hour. During the reaction, add another 2 〇. 〇 ml 甲笨, using the Chinese National Standard (CNS) A4 specification <21〇X 297 mm by the -25- paper scale. 1310375 A7 B7 V. Invention Description ( twenty three )

Bring out the reaction to produce methanol. Then, it was cooled to room temperature, and 1 ml of acetic acid and 40 g of ice were added to adjust to pH = 5, and the resulting organic layer was concentrated under reduced pressure to remove solvent and excess 4-methyl alcohol. Cooled to a full color oil. Resting slowly and slowly. Recrystallization from toluene/n-hexane gave 7.3 g (yield: 71%) of white crystals of 4-(4-methyl:f-yl)-hydrazino-4-carboxylate. 'H-NMR (500MHz, CDC13): ^2.35 (s, 3H), 5.35 (s, 2H), 6.9〇(d, 2H), 7.15 (d, 2H), 7.35 (d, 2H), 7.50 (d , 2H), 7.60 (d, 2H) 8.10 (d, 2H) 4·decyl benzoate hydrochloride synthesis 4 - mercaptobenzoic acid hydrochloride under ice cooling, add 7 2 ml 2N NaOH solution was added to a solution of 20.0 g (〇 14 mol) of methyl isothiourea disulfate in 36 ml of water and stirred. A solution of 21.0 g (0.138 mol) of 4-aminomethylbenzoic acid in 140 ml of 2N NaOH was added dropwise. The mixture was allowed to stand at room temperature overnight, and then cooled to a small body in an ice bath. The precipitated white crystals were filtered off and washed with cold water. The filtrate was dissolved in hot IN HCl and filtered to remove insolubles. The solution was concentrated to crystallization in vacuo. The cooled solution crystallized as colorless prisms, which were then filtered and dried to give <RTI ID=0.0>> LC/MS=194(M+H) 4-decyl benzoate hydrochloride was added to an ice bath under cold J ,, and 3 6 ml of 2N NaOH solution was added to contain 1 〇·〇克 (0.07 mol) methyl A solution of thiourea disulfate in 3 6 ml of water was mixed with β, and then a solution of 9.5 g (0.069 mol) of 4-aminomethylbenzoic acid in 7 ml of 2N NaOH was added dropwise. The mixture was allowed to stand at room temperature overnight, and then used in ice water -26- this paper scale using the national standards of the ten countries (CNS) A4 size (210X 297 mm)

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1310375 A7 _____B7 V. Cooling in the invention (24) for 1 hour. The precipitated ruthenium crystals were removed and washed with cold water. The filtrate was contained in warm IN HC1 and filtered to remove insolubles. The solution was concentrated to crystallization. The cooled solution crystallized as colorless prisms, which were then filtered and dried to give &lt;RTI ID=0.0&gt;&gt; LC/MS=180(M+H) 4-nonylalkyl benzoate synthesis 4-(4-methylindenyl)-4·-Γ胍methylbenzhydryl 1 biphenyl-4_ The carboxylic acid ester hydrochloride salt contains 2.42 g (0.010 mol) of 4-methylindolyl-4,-hydroxybiphenyl-4-carboxylate, 2.3 g (0.010 mol) of 4 胍methylbenzoic acid. A suspension of 15 ml of pyridine hydrochloride and 4.1 g (0.020 mol) of dicyclohexylcarbodiimide was stirred at room temperature for 48 hours and then filtered to remove insolubles. The filtrate was evaporated to dryness. EtOAc (EtOAc m. The crystals obtained were recrystallized from ethanol/hexane to give 4-(4-methylbenzyl)-4,-[胍methylbenzyloxy]biphenyl-4-per ester hydrochloride 2.9 g ( Yield 55%). LC/MS=494(M+H) 4-(4-methylindolyl)-4mercaptobenzhydrylhydrol-l-l--4-yl ester hydrochloride salt containing 2.42 g (0.010 mol) Ear) 4-methylmercapto-4·-hydroxybiphenyl-4-carboxylate, 2_2 g (0.010 mol) 4-mercaptobenzoic acid hydrochloride and 4.1 g (0.020 mol) dicyclohexyl A 150 ml portion of a pyridine suspension of carbodiimide was stirred at room temperature for 48 hours and then filtered to remove insolubles. After the filtrate was evaporated to dryness, EtOAc m. Then, the aqueous layer was washed again with diethyl ether and concentrated to 20 ml.妍得晶磕在乙-27- This paper size is applicable to 8 standards of Chinese painting (CNS) A4 specification (210 X 297 mm) 1310375 A7 __ B7 V. Invention description (25) Alcohol/hexane in #crystal, get 4-(4-Methylmercapto)-41-[indolyl phenyloxy] benzyl 4-carboxylate hydrochloride 3.0 g (yield 60%). LC/MS = 482 (M+H) 4-phenyl-41-indole methyl carbamic acid hydrochloride </ br> </ RTI> </ RTI> </ RTI> </ RTI> containing 1.0 gram (0.011 mole) of phenol, 2.3 grams (0.010 moles) of 4-mercaptobenzene Toluene hydrochloride and a suspension of 4.1 g (0.020 mol) of dicyclohexylcarbodiimide in 15 ml of pyridine were stirred at room temperature for 48 hours. After the insoluble material was filtered, the filtrate was evaporated to dryness. Subsequently, the aqueous layer was concentrated to 20 mL. The product was crystallized and washed with isopropyl alcohol / isopropyl ether to afford (yield: 75%) of 4-phenyl-4'-indole methyl benzoate hydrochloride. LC/MS=269 (M+H) 4-phenyl-4, decyl-formate hydrochloride salt containing 1.0 g (0.011 mol) phenol, 2.2 g (0.010 mol) 4-mercaptobenzoic acid A suspension of the hydrochloride salt and 4.1 g (0.020 mol) of dicyclohexylcarbodiimide in 150 ml of pyridine was stirred at room temperature for 48 hours. After the insoluble material was filtered, the filtrate was evaporated to dryness. Subsequently, the aqueous layer was concentrated to 20 mL, and the product was crystallized, washed with isopropyl alcohol / isopropyl ether to give 2.2 g of 4-phenyl-4'-mercaptobenzoate hydrochloride (yield 75%) ). LC/MS = 255 (M+H) 4-(4- benzylidene V-Umbrella-indole methyl carbamic acid ester hydrochloride - 1.7 g (0.010 mol) of 4-phenylphenol, 2.3 g (0.010 mol) a suspension of 4-nonylmethylbenzoate and 4.1 g (0.020 mol) of dicyclohexylcarbodiimide in 150 ml of pyridine, stirred at room temperature for 48 hours. -28- The paper size is 中国 China National Standard (CNS) A4 size (210 X 297 mm) 1310375 A7 — _ B7 V. Description of invention (26) After removing insolubles, 'Evaporate the filtrate to dry, use 0.1 N The residual solid was treated with EtOAc (50 mL). EtOAc (EtOAc)EtOAc. '- armor, benzoate hydrochloride 2.5 g (yield 65%). LC/MS = 346 (M+H). 4-(4-Lumyl)-4'-mercaptobenzoic acid The acid ester hydrochloride salt contains 1.7 g (0.010 mol) of 4-phenylphenol, 2.2 g (0.010 mol) of 4-mercaptobenzoic acid hydrochloride and 4.1 g (0.020 mol) of dicyclohexylcarbodiimide. A 150 ml portion of the pyridine suspension of the amine was stirred at room temperature for 48 hours. After that, the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4-(4-Biphenyl)-4,-mercaptobenzoic acid hydrochloride 2.6 g (yield 70%) was obtained. LC/MS= 332 (M+H) 4-(4-methylphenyl) -4'-A certain carbamate hydrochloride salt contains 1.1 g (0.010 mol) of 4-methylphenol, 2.3 g (0.010 mol) of 4-nonylmethylbenzoate and A suspension of 4.1 g (0.020 mol) of dicyclohexylcarbodiimide in 150 ml of pyridine was stirred at room temperature for 48 hours. After insolubles were removed, the filtrate was evaporated to dryness using 0.1N EtOAc (50 ml) The residual solid was treated and washed with diethyl ether. Then, the aqueous layer was concentrated to 20 ml, and the product was crystallized and washed with isopropyl alcohol/isopropyl ether to give 4-(4-methylphenyl)-4'-indole. Methyl benzoate hydrochloride 2.4 g (yield 75%) LC/MS = 284 (M+H) 4-(4-methylphenyl)-4'·indole phthalic acid hydrochloride Salt -29- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1310375 A7 B7 Five DESCRIPTION OF THE INVENTION (27) Take 1.1 g (〇'〇1〇莫耳) 4-nonylphenol, 2.2 g (0.010 mol) 4· decyl benzoate hydrochloride and 4.1 g (0.020 mol) A suspension of cyclohexylcarbodiimide in 50 ml of pyridine was stirred at room temperature for 48 hours. After the insoluble material was filtered, the filtrate was evaporated to dryness. Subsequently, the aqueous layer was concentrated to 20 ml, and the product was crystallized and washed with isopropyl alcohol / isopropyl ether to give 4-(4-methylphenyl)-4,-mercaptobenzoate hydrochloride. 2 g (yield 75%). LC/MS=270(M+H) References and Notes: 1. US Patent No. 4,348,410 2 · Organic Chemistry Monthly (JOC) 3 3 (1985) 652 3 · Drug Synthesis Reaction 4. Organic drug synthesis method Chen Fener editor China Medical Science and Technology Press Example 2. The GMCHA derivative method found that different modifications of GMCHA have different inhibitory effects on E. coli growth (Table 1). For example, 'phenyl ester (ΡΗ01) derivative inhibits the growth of Escherichia coli IC5〇&gt;200 #Μ, in 4-tolyl (ph〇2), 4·ethyl stupyl (ΡΗ03) ' 4 - third Different modifications of phenyl (ρΗ〇4) and 4·biphenyl (ΒΡ01) 1 (:50 decreased from &gt;200 to 167, to 45, and 26 &quot; Μ. Importantly, the role of these compounds Not limited to E. coli (Irisawa et al, Biol. Pharm. Bull., 1^.: 121 1-1215 (1993); and Kato et al., J.

Enzyme Inhibition’ [25-37 (1994)). Regardless of whether the target cell is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, or Staphylococcus epidermidis, the relative roles of individual members of such molecules remain the same (Table 2). For every -30

1310375 A7 B7 V. INSTRUCTIONS (28) The most effective compound of the bacterium is still a 4-biphenyl (ΒΡ0 1) derivative. Interestingly, specific compounds are quite different for IC5〇 of different bacterial species, and the difference between the tested subjects is almost 2 logarithmic. For example, for 4-biphenyl ester (BP01), the sensitivity of Staphylococcus seems to be one log higher than that of Bacillus, while Bacillus is one log higher than E. coli. Table 1 · Effect of GMCHA derivatives on E. coli growth and protease I η activity Tryptone κ, (μΜ) 110 78 48 64 46 273 54 187 Compound ΡΗ Phenyl ΡΗ 02 4-曱phenyl ΡΗ 03 4-Ethyl FH04 4-third-but stupid base 05 2,4-one gas base ΡΗ 06 2,4,6-tri-gas phenyl 3Ρ0 〖 4-linked stupid ΒΡΠ 2 2-linked stupid Escherichia coli growth iCM (μΜ)

&gt;200 &gt;200 167 45 92 44 26 74 E. coli egg enzyme ICh, (μΜ) &gt;200 &gt;200 &gt;200 33 62 35 17 83 -31- This paper scale applies to Chinese National Standard (CNS) Α4 Specification (210 x 297 mm) 1310375 A7 B7 V. Description of invention (29) Table 2. Effect of various GMCHA aromatic esters on the growth of different bacteria Compound PH01 Phenyl PII02 4-Tolyl PH03 4-Ethyl PH04 4- Tri-Butyl BPOI 4-biphenyl

Escherichia coli tc,, ic„„ &gt;20ϋ &gt;200 &gt;200 i(i7 &gt;200 45 90 26 4〇Bacillus subtilis Staphylococcus aureus S. epidermidis IC;;. IC”·· IC^. IC^, IClt· &gt;2W) &gt;200 151 &gt;200 丨28 &gt;200 &gt;200 &gt;200 47 120 4Χ 120 129 &gt;200 15 3〇L4 51) 26 50 3Λ 15 2.^ l〇^ 10 0.6 2 0.4 1.5 Figure 1 illustrates the effect of GMCHA derivatives on cell growth, DNA synthesis, and protease I η activity in E. coli synchronized cells. Figure left, in the absence of PH04 compound, the growth of synchronized cells in the temple. (a), The number of viable cells [3H] thymidine uptake was measured every 5 minutes, and the protease I η activity was measured every 30 seconds. The first cell differentiation was set to zero time. (b) and (c), respectively Protease that occurs at -30 and +30 minutes. P, Q and R represent the interval between cell division, cell division and initiation of chromosomal replication, and the interval between chromosomal replication initiation and cell division, respectively. 27 A 同步 Synchronized cell growth in the presence of PH04 compound. (a) Add inhibitor at -8 minutes (arrow The sample description is as above. Note that in the absence of PH04, P, Q, Rl, and R2 are 15, 15, 15 and 10 minutes, respectively, and in the presence of PH04, DNA synthesis starts at 30 minutes, and DNA synthesis activity is 6 doubling at 5 minutes. R 1 phase was extended from 15 minutes to 35 minutes. (b) The control group showed protease activity at about 30 minutes, but the half-life was prolonged. Since the GMCHA derivative was first identified as an in vitro pancreas Protease-32- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310375 A7 _____B7 V. Invention description (30) Inhibitor' so we can study whether fluorescent acceptor B can be used 〇c_VaNPr〇_Arg-NH-Mec detected trypsin-like protease activity in E. coli extract (Kato et al., Eur. J. Biochem., 210: 1007-1014. (1992)). Single activity, and purified to homogeneity. Purified by 2 steps, 2,880 times 'yield is 15% ^ purified enzyme molecular weight is about 66 kDa, isoelectric point is 4.9. According to the optimum pH, for various synthetic substrates Hydrolysis activity' and various known proteolytic enzyme inhibitors Effects, which have very different E. coli protease specificity than any known mammalian trypsin and bacterial enzymes. Most encouragingly, the sensitivity of various Gmcha derivatives to purified enzymes was found to be parallel to their inhibition of E. coli (Table 1). This finding suggests that this protease may be a target molecule for such growth inhibitors in E. coli cells. We have demonstrated that in synchronized E. coli cultures, the performance of this protease is limited to the start of chromosomal DNA replication (Fig. 2 left) (Kat〇 et al, Biol·Pharm)

Bull·, iJ_: 552-557 (1993)). Moreover, the addition of the 4-tris-butylphenyl (PH04) derivative after the initiation of DNA synthesis does not affect the cell division cycle, but delays cell division in the next cycle. However, the addition of an inhibitor prior to the initiation of DNA replication results in an extended cycle of cell division (Figure 1 right). Taken together, these results indicate that this protease may directly participate in the replication initiation of E. coli chromosomal DNA and is the target of GMCHA aryl ester inhibition. We named this enzyme protease as protease 丨n, which has the same gene as the prlC gene. The pric gene encodes a 67 kDa protein with two active centers for protease 1 {1 and oligopeptidase A, respectively (Jiang Er al. Biochem., 121: 980-985 (1998)). From Bacillus subtilis __________-33- This paper scale is applicable (4) Home 揉 (CNS) A4 specification (2 brain 297 dong) ------ 1310375 A7 B7 V. Invention description (31 ) Purification to a protease-like protease η protease is also strongly inhibited by various GMCHA esters, and its inhibition is also associated with inhibition of bacterial growth (Irisawa et al., Biol. Pharm. Bull., ΙΑ: 121 1-1215 (1993)). These results strongly suggest that protease In or a protease similar to Pro protease In is ubiquitous in various bacteria, and their strong inhibitors can be used as novel antibacterial agents. Example 3. Activity of NE-2001 The novel compound NE-2001 described herein is 4-(4-methylindenyl)-4.-[indolylmethylbenzylideneoxy]biphenyl-4-carboxylate, It specifically inhibits the growth of Helicobacter pylori and completely eradicates Helicobacter pylori at various pHs. The minimum inhibitory concentration (MICs) (micrograms per milliliter) of several substances against 9 strains of Helicobacter pylori (ATCC43504, ATCC43629, ATCC43526, ATCC43579, ATCC49503, ATCC51110, ATCC51652, ATCC5 1653, ATCC51932), and the minimum inhibition of NE-2001 were detected. Concentrations (MICs) ranged from 0.10 to 0.48 μg/ml. Summarized in Table 3. Table 3. Summary of MIC for Helicobacter pylori _ range of substance MIC (μg/ml) NE-2001 0.10-0.48 Hydroxylamine patulin 〇.〇 0.08 Naxomycin 0.01-〇〇9 - Metronidazole 0.65- 2.45 Figure 2 shows the anti-Helicobacter pylori effect of compound NE-2001. Sterilization was measured for 168 hours at various concentrations (from 0,15 to 2.50 μg/ml). -34- This paper size is applicable to ® ® 棣 ( (CNS) A4 size (210 X 297 mm) 1310375 A7 B7 V. Description of invention (32) Figure 2 shows a representative curve. NE-2001 showed a strong anti-Helicobacter pylori effect. 1.2 At a concentration of 5 μg/ml or more, no visible viable bacteria were detected within 3 hours. NE-2001 showed anti-Helicobacter pylori activity in all tested pH ranges (pH 3-7) (see Figure 3). Figure 3 shows the anti-Helicobacter pylori effect of NE-200 1 compound under various pH conditions. The frequency of occurrence of natural resistance mutants against NE-2001 was determined (Table 4). At NE-2001 various assay concentrations (from 0.30 to 1.20 μg/ml), it was apparent that no naturally resistant strains appeared. Table 4. NE-2001 natural resistance mutation frequency strain NE-2001 selection concentration frequency (micrograms / ml) Helicobacter pylori 0.30 &lt; 3.4 X 1 〇 '8 ATCC43504 0.60 &lt; 3.4 X 1 〇 * 8 1.20 &lt; 3.4 X 1〇'8 A single-dose toxicity study of male NE-2001 was performed on male mice. There was no animal at a dose of 2000 mg per kg of body weight NE-2001 (maximum dose of 0.5% methylcellulose suspension). Death, all animals gained weight. None of the cases found systemic toxicity, and it is clear that NE-2001 is safe. (Table 5) Table 5. Toxicity of single dose NE-2001 to mice Animal/age Mouse/6 weeks Route of administration Oral Gender Male Number of animals/group 5 ld50 (mg/kg) &gt;2000 -35-

This paper scale applies to China's 8 standards (CNS) A4 specifications (210 X 297 mm) 1310375 A7 B7 V. Inventive Note (33) The above examples are for illustrative purposes only, and the scope of the present invention is not limited thereto. It will be apparent to those skilled in the art that modifications may be made thereto, and thus the present invention is limited only by the scope of the appended claims. -36- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

A8 B8 C8 -3⁄48 13 1 Law 3^^27657 Patent Application Chinese Patent Application Substitution (November 1997) Patent Application 1. A compound of the formula I or a pharmaceutically acceptable salt thereof: VNH(CH2&gt;r^ _c HN. HjN -COOR where n is an integer from 0 to 1, R is selected from Cm oxime, c&quot; aryl and Cooch2-(a group consisting of, and wherein when η is 0, R is not c, the compound of the first term or the pharmaceutically acceptable cooch2-·〇CH, 3· A medicinal composition of Helicobacter pylori (H-(1) sensation (4) or a lesion comprising an effective amount of a compound as claimed in the patent specification: r. 2, or a pharmaceutically acceptable salt thereof, as claimed in claim 3 A pharmaceutical composition, a carrier or a form of a drug that can be received on a bovine drug. 5. A pharmaceutical composition as claimed in claim 3, a compound of the second category or a pharmaceutically acceptable compound thereof For the application of the pharmaceutical composition of claim 3, the disease and pathology caused by the infection of the bacterium are chronic gastritis: 幽: spiral cancer, distal gastric adenocarcinoma, gastric lymphoma or gastric cancer. —曰曰曰溃74922-971113.doc 1〇&gt;&lt;297 mm). This paper scale applies to China National Standard (CNS) 1310375 VI. Application for patent Fangu 7·If you order the patent scope 3 Is due to the use of proton (four) inhibitor: m for the treatment of Helicobacter spirulina The anti-drug, the chloramphenicol, the medicinal-acceptable salt of the medical treatment of the third paragraph of the patent application, the medicinally acceptable salt is compounded: or:: one shot, one heart 9. one for Therapeutic preparation consists of a combination of pyloric or pathological conditions, which includes a disease compound as claimed or a pharmaceutically acceptable salt thereof and an anti-pyloric II: 1:2 sex component. The combined preparation agent of the patent scope item 9 is a proton-based smear inhibitor, spirulina penicillin. 丨妗-mycin or hydroxylamine H. A group for treatment of pyloric helix, comprising: (4) an adduct or a lesion (4) The salt of the application for the scope of the patent or the second item; and the 4 liters of the salt, and the indication of the use of the compound or its medicinally acceptable infection of the Helicobacter pylori infection. 12-- for treatment. The disease group caused by Helicobacter pylori infection includes: a combination of (a) a combination preparation as claimed in claim 9; and (8) description of treatment of infection by Helicobacter pylori using the combination preparation The resulting live-Vi- sets of holster 74922-971113.do c -2- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public attack:) Patent application scope 1310375 Instructions for the use of diseases or lesions. 3. For example, the compound of the genus &amp; + # ^ ^ m ^ m ^ shell of the patent application scope 1 or 2 or its medicinal smear, ', is used to prepare the treatment by Helicobacter pylori A medicine for a disease or disease caused by an infection. &quot;, which is caused by Helicobacter pylori fungus, duodenal ulcer, gastric sulcus, which is due to the age of the serotonin, the amine medicinal medicinal system is blended 14 · as claimed in the scope of the first 13 items The diseases and diseases caused by the use are chronic gastritis, adenocarcinoma, gastric lymphoma or gastric cancer. 15. For the use of the scope of the patent application, use the proton pump inhibitor, metronidazole treatment induced strain. 16. The use of paragraph 13 of the patent application for intraluminal, subcutaneous, intravenous, intramuscular injection, intradermal injection, oral or topical administration. -3- 74922-971113.doc This paper scale uses Chinese National Standard (CNS) Α 4 specifications (210 X 297