WO2023198095A1 - Utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber helicobacter pylori - Google Patents

Utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber helicobacter pylori Download PDF

Info

Publication number
WO2023198095A1
WO2023198095A1 PCT/CN2023/087744 CN2023087744W WO2023198095A1 WO 2023198095 A1 WO2023198095 A1 WO 2023198095A1 CN 2023087744 W CN2023087744 W CN 2023087744W WO 2023198095 A1 WO2023198095 A1 WO 2023198095A1
Authority
WO
WIPO (PCT)
Prior art keywords
helicobacter pylori
compound
use according
group
preparing
Prior art date
Application number
PCT/CN2023/087744
Other languages
English (en)
Chinese (zh)
Inventor
广兵
阳泰
董韧涵
刘进
占伟
覃传军
黄胜
彭向阳
赖永新
许庆
Original Assignee
成都贝诺科成生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都贝诺科成生物科技有限公司 filed Critical 成都贝诺科成生物科技有限公司
Publication of WO2023198095A1 publication Critical patent/WO2023198095A1/fr

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/58—Nitro radicals

Definitions

  • the invention belongs to the field of pharmaceuticals, and specifically relates to the use of a nitrothiazole derivative in preparing a bacteriostatic agent for inhibiting Helicobacter pylori.
  • Helicobacter pylori is a spiral-shaped, slightly anaerobic bacterium that has very demanding growth conditions. It was first successfully isolated from the gastric mucosal biopsy tissue of a patient with chronic active gastritis in 1983. It is currently the only microbial species known to be able to survive in the human stomach. On October 27, 2017, the World Health Organization's International Agency for Research on Cancer released a preliminary reference list of carcinogens, and Helicobacter pylori (infection) was included in the list of carcinogens.
  • Helicobacter pylori lives in the pylorus of the human stomach and is one of the most common bacterial pathogens. More than half of the world's population is infected with Helicobacter pylori, and in some countries almost 90% of the population is infected with this bacterium. People are usually infected at an early age, with 50% of cases under 5 years old. This bacterial infection first causes chronic gastritis, and leads to gastric ulcers and gastric atrophy. In severe cases, it may develop into gastric cancer.
  • Nitazoxanide is a derivative of nitethyl salicylic acid amide. Although its actual mechanism of action has not yet been clarified, it is believed to be related to the inhibition of the enzyme-dependent electron transfer reaction of pyruvate and ferredoxin oxidoreductase. , the latter is crucial for anaerobic energy metabolism. Studies have found that in addition to Cryptosporidium and Giardia intestinalis, nitazoxanide is also effective against many intestinal parasites, such as Isospora burnetii, amoeba, human roundworms, hookworms, Trichuris trichuris, Beef tapeworm, brevis tapeworm and Fasciola hepatica are all active. However, there are research reports (Foreign Medicine and Antibiotics Volume, July 2004, Volume 25, Issue 4, Pages 191-192) that nitazoxanide cannot eradicate Helicobacter pylori as a single therapeutic agent.
  • the object of the present invention is to provide the use of a nitrothiazole derivative in the preparation of bacteriostatic agents for inhibiting Helicobacter pylori and medicaments for preventing and/or treating Helicobacter pylori infection and related diseases caused by it.
  • the present invention provides the use of the compound represented by formula (I), or its crystal form, or its salt in the preparation of a bacteriostatic agent for inhibiting Helicobacter pylori:
  • R is selected from C 3 and C 4 linear alkanes, C 5 -C 15 linear or branched alkanes.
  • the compound is one of the following compounds:
  • the bacteriostatic agent can inhibit the growth of Helicobacter pylori.
  • the bacteriostatic agent is a drug for preventing and/or treating Helicobacter pylori infection.
  • the bacteriostatic agent is a drug for preventing and/or treating diseases caused by Helicobacter pylori.
  • the diseases caused by Helicobacter pylori are gastritis, gastric ulcer, duodenal ulcer, and gastric cancer.
  • the bacteriostatic agent is a preparation made of the compound, or its crystal form, or its salt as an active ingredient, and adding pharmaceutically acceptable excipients or auxiliary ingredients.
  • auxiliary materials or auxiliary ingredients are selected from one or more of diluents, fillers, colorants, glidants, lubricants, adhesives, stabilizers, suspending agents and buffers.
  • the compounds of the present invention can effectively inhibit the growth of Helicobacter pylori, and the inhibitory activities of compounds I-1 to I-4 are much stronger than the control compound lauric acid, and the inhibitory activities of compounds I-1, I-3, and I-4 are much stronger than the control.
  • the compound nitazoxanide is much stronger than the control compound lauric acid, and the inhibitory activities of compounds I-1, I-3, and I-4 are much stronger than the control.
  • the compound of the present invention can effectively treat mice infected with Helicobacter pylori, eliminate Helicobacter pylori infection in the stomach and reduce the inflammatory reaction of gastric tissue. Its therapeutic effect is equivalent to that of the positive control clarithromycin, and the therapeutic effect is obviously superior at equimolar doses. to the control compounds nitazoxanide and lauric acid.
  • the compounds provided by the invention can be used to prepare bacteriostatic agents that inhibit Helicobacter pylori, and can be used to prepare drugs for preventing and/or treating Helicobacter pylori infection and related diseases caused by it.
  • the scenery is vast.
  • Figure 1 shows the gastric histopathological scoring results of mice in each group in Example 2.
  • Figure 2 shows the results of OD value detection of Helicobacter pylori urease in each group of mice in Example 2.
  • the raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.
  • Test compounds I-1 to I-4 were prepared with reference to the preparation method disclosed in CN114044761A. The specific operations are as follows:
  • the filtrate is diluted with 20 ml of ethyl acetate, washed twice with 10 ml of 0.1M dilute hydrochloric acid, once with 10 ml of 10% sodium bicarbonate solution, and finally with Wash with 10 ml saturated saline until neutral.
  • the ethyl acetate layer was dried with 2.5 g of anhydrous sodium sulfate for 30 minutes; the sodium sulfate was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
  • the crude product was purified by silica gel column chromatography to obtain compound I-1.
  • n-butyryl chloride was replaced with octanoyl chloride, lauroyl chloride, and myristanoyl chloride to prepare compounds I-2, I-3, and I-4 respectively:
  • Example 1 In vitro inhibitory activity of test compounds against Helicobacter pylori
  • DMSO DMSO was used to dissolve the test compounds I-1 to I-4, the control compounds nitazoxanide and lauric acid.
  • DMSO DMSO was used to dissolve the test compounds I-1 to I-4, the control compounds nitazoxanide and lauric acid.
  • a 12-well culture plate add 10 ⁇ l of diluted test sample solution to each well, then add 1 ml of Columbia blood agar culture medium melted at 50°C, shake and mix until the concentration of the test compound is 0-200 ⁇ g/ml, twice Concentration dilution, a total of 10 concentration gradients.
  • Helicobacter pylori strain ATCC26695 frozen at -80°C was resuscitated and inoculated on Columbia blood agar plates, and cultured microaerobically at 37°C for 48 hours.
  • Use a pipette tip to scrape well-growing colonies, resuspend them in Brucella's medium containing 5% peptide bovine serum, and adjust the OD value of the bacterial solution to 0.2.
  • Use a micropipette to absorb 2 ⁇ l of the bacterial solution and inoculate it onto the Columbia blood agar containing the test sample in a 12-well plate. Inoculate 3 bacterial spots in each well and wait until the bacterial solution dries. Place in a microaerophilic environment and incubate at 37°C for 48 hours.
  • the minimum inhibitory concentration (MIC) of the test compound against Helicobacter pylori After culturing the 12-well culture plate for 48 hours, take photos to record the colony growth, and determine the minimum inhibitory concentration (MIC) of the test compound against Helicobacter pylori. DMSO dissolved the control group, and the colonies in the plate wells grew well and formed obvious colonies. For the test sample group, the minimum concentration at which bacterial colonies do not grow is the minimum inhibitory concentration of the test sample against Helicobacter pylori.
  • test compounds of the present invention can effectively inhibit the growth of Helicobacter pylori, and the inhibitory activities of compounds I-1 to I-4 are much stronger than the control compound lauric acid.
  • the inhibitory activities of compounds I-1, I-3, and I-4 are The inhibitory activity is much stronger than that of the control compound nitazoxanide.
  • test compound of the present invention can be used to prepare a bacteriostatic agent that inhibits Helicobacter pylori, and can be used to prevent and/or treat Helicobacter pylori infection and related diseases caused by it.
  • Example 2 Therapeutic effect of test compounds on mouse Helicobacter pylori infection model
  • Helicobacter pylori SS1 strain preparation Use Columbia blood plate to resuscitate bacteria. After 48 hours of culture, select bacterial colonies and inoculate them into Brucella broth medium containing 5% fetal calf serum and selective additives. After culturing for 48 hours under microaerophilic conditions at 37°C, take them out. Centrifuge and adjust the bacterial concentration to 5 ⁇ 10 9 CFU for later use.
  • mice Female, 6-8 weeks old, were randomly divided into 6 groups after adaptive feeding for one week, namely blank group, model group, positive control clarithromycin group, and compound I-3 group. , control compound nitazoxanide group and control compound lauric acid group, 7 animals in each group. Except for the blank group, the other mice were orally administered 200 ⁇ l of the above bacterial resuspension system, that is, 1 ⁇ 10 9 CFU per mouse.
  • the dosage of clarithromycin was 50 mg/kg, the dosage of compound I-3 was 100 mg/kg, and the dosage of nitazoxanide was The dosage of lauric acid was 68 mg/kg, the dosage of lauric acid was 45 mg/kg, and the blank group was given an equal volume of physiological saline; the mice were killed two weeks after the administration, and the materials were collected for analysis.
  • the stomachs of mice in each group were cut off from the cardia to the pylorus, placed in a sterile dish, and cut open along the greater curvature of the stomach. Parts were taken for histopathological examination.
  • the stomach contents were gently removed with sterile cotton swabs, and the stomach contents were removed with a physiological After rinsing with saline, they were fixed with 10% neutral formaldehyde.
  • HE staining observe the inflammatory changes in the stomach of mice after live bacteria challenge, score and record the results.
  • the scoring standards are as follows:
  • stomach tissues of equal weight from each group of mice were taken and homogenized using a high-throughput homogenizer for later use.
  • Prepare a rapid urease kit add 100 ⁇ L of enzymatic reaction solution to each well, add tissue homogenate after the drug film is completely dissolved, incubate at room temperature for 5 minutes to develop color, test the OD value of the test solution in each well and record the results.
  • mice showed that in the gastric histopathological scores of mice, treatment in the I-3 group and the clarithromycin group significantly reduced the inflammatory response of mice after live bacteria challenge, with statistical differences compared with the model group; Treatment in the nitazoxanide group and the lauric acid group slightly reduced the inflammatory response, but there was no statistical difference compared with the model group.
  • test compound of the present invention can effectively treat mice infected with Helicobacter pylori, clear the Helicobacter pylori infection in the stomach and reduce the inflammatory reaction of gastric tissue. Its therapeutic effect is equivalent to that of the positive control clarithromycin, and in et al. The therapeutic effect at molar dosage was significantly better than that of the control compounds nitazoxanide and lauric acid.
  • test compound of the present invention can effectively inhibit Helicobacter pylori infection and can be used to prevent and/or treat Helicobacter pylori infection and related diseases caused by it.
  • the present invention provides the use of nitrothiazole derivatives represented by formula I in the preparation of bacteriostatic agents for inhibiting Helicobacter pylori.
  • Experimental results show that the compound can effectively inhibit the growth of Helicobacter pylori, and the inhibitory effect is better than the control compounds nitazoxanide and lauric acid; the compound can effectively treat mice infected with Helicobacter pylori, clear the Helicobacter pylori infection in the stomach and Reduce the inflammatory response of gastric tissue, and its therapeutic effect is better than that of the control compounds nitazoxanide and lauric acid.
  • the compounds provided by the invention can be used to prepare bacteriostatic agents that inhibit Helicobacter pylori, and can be used to prepare drugs for preventing and/or treating Helicobacter pylori infection and related diseases caused by it, and have broad application prospects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine des produits pharmaceutiques et concerne en particulier l'utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber Helicobacter pylori. Le dérivé aminonitrothiazole présente une structure de Formule I. Des résultats expérimentaux montrent que le composé peut inhiber efficacement la croissance d'Helicobacter pylori, avec un effet inhibiteur supérieur à celui des composés de référence de type nitazoxanide et acide laurique ; le composé peut traiter efficacement des souris infectées par Helicobacter pylori, éliminer efficacement Helicobacter pylori touchant l'estomac et améliorer efficacement la réponse inflammatoire du tissu gastrique, avec un effet thérapeutique supérieur à celui des composés de référence de type nitazoxanide et acide laurique. Le composé peut être utilisé pour préparer un bactériostatique destiné à inhiber Helicobacter pylori et peut être utilisé pour préparer un médicament pour prévenir et/ou traiter une infection par Helicobacter pylori et une maladie associée provoquée par une infection par Helicobacter pylori, présentant ainsi de vastes perspectives d'application.
PCT/CN2023/087744 2022-04-12 2023-04-12 Utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber helicobacter pylori WO2023198095A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210379882 2022-04-12
CN202210379882.1 2022-04-12

Publications (1)

Publication Number Publication Date
WO2023198095A1 true WO2023198095A1 (fr) 2023-10-19

Family

ID=88328979

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/087744 WO2023198095A1 (fr) 2022-04-12 2023-04-12 Utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber helicobacter pylori

Country Status (2)

Country Link
CN (1) CN116898846A (fr)
WO (1) WO2023198095A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3950351A (en) * 1973-08-08 1976-04-13 S.P.R.L. Phavic New derivatives of 2-benzamido-5-nitro thiazoles
US20060194853A1 (en) * 2004-10-08 2006-08-31 Rossignol Jean F Alkyl benzamides
CN102480967A (zh) * 2009-06-26 2012-05-30 罗马克实验室有限公司 用于治疗流感的化合物和方法
CN104277012A (zh) * 2013-07-04 2015-01-14 中国人民解放军军事医学科学院毒物药物研究所 替唑尼特氨基羧酸酯,及其在药学中的应用
US20170362261A1 (en) * 2014-12-23 2017-12-21 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Tizoxanide Phosphate and Alkane Sulfonate and Pharmaceutical Applications Thereof
WO2021035114A1 (fr) * 2019-08-22 2021-02-25 Board Of Regents Of The University Of Nebraska Promédicaments et formulations de ceux-ci
CN114044761A (zh) * 2021-02-24 2022-02-15 成都贝诺科成生物科技有限公司 一种新的硝基噻唑衍生物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3950351A (en) * 1973-08-08 1976-04-13 S.P.R.L. Phavic New derivatives of 2-benzamido-5-nitro thiazoles
US20060194853A1 (en) * 2004-10-08 2006-08-31 Rossignol Jean F Alkyl benzamides
CN102480967A (zh) * 2009-06-26 2012-05-30 罗马克实验室有限公司 用于治疗流感的化合物和方法
CN104277012A (zh) * 2013-07-04 2015-01-14 中国人民解放军军事医学科学院毒物药物研究所 替唑尼特氨基羧酸酯,及其在药学中的应用
US20170362261A1 (en) * 2014-12-23 2017-12-21 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Tizoxanide Phosphate and Alkane Sulfonate and Pharmaceutical Applications Thereof
WO2021035114A1 (fr) * 2019-08-22 2021-02-25 Board Of Regents Of The University Of Nebraska Promédicaments et formulations de ceux-ci
CN114044761A (zh) * 2021-02-24 2022-02-15 成都贝诺科成生物科技有限公司 一种新的硝基噻唑衍生物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IQBAL UMAIR, KHARA HARSHIT S., AKHTAR DAUD, HU YIRUI, ANWAR HAFSA, HAQ KHWAJA F., SIDDIQUI HAFIZ U., BERGENSTOCK MARIKA K., SHELLE: "Safety and Efficacy of Nitazoxanide-Based Regimen for the Eradication of Helicobacter pylori Infection: A Systematic Review and Meta-Analysis", GASTROENTEROLOGY RESEARCH, vol. 13, no. 6, 1 January 2020 (2020-01-01), pages 260 - 268, XP093099037, ISSN: 1918-2805, DOI: 10.14740/gr1342 *

Also Published As

Publication number Publication date
CN116898846A (zh) 2023-10-20

Similar Documents

Publication Publication Date Title
JP5132865B2 (ja) イソチオシアネートを用いたヘリコバクターの治療方法
CN101959429B (zh) 抗微生物肽系统的激动剂
WO2018135719A1 (fr) Composition destinée à la prévention ou au traitement de l'arthrose contenant comme principe actif du sialyllactose ou un sel correspondant
CN111343999B (zh) 减少脂毒性损伤的化合物
JPS6229566A (ja) 新規グアニジノメチル安息香酸誘導体
CN108836956B (zh) 甘草查耳酮a在制备治疗鸡坏死性肠炎药物中的用途
WO2023198095A1 (fr) Utilisation d'un dérivé de nitrothiazole dans la préparation d'un bactériostatique pour inhiber helicobacter pylori
JPH07110874B2 (ja) エリスロマイシンａ誘導体
PT655249E (pt) Moenomicina como medicamento para o tratamento de ulceras gastricas
EP4299565A1 (fr) Nouveau dérivé de nitrothiazole et son utilisation
JP5650642B2 (ja) メチオニンアナログおよびそれらを使用する方法
CN110215445B (zh) 香草酸在抑制多重耐药霍氏肠杆菌生长中的应用
US11491135B2 (en) Medical use of tectorigenin in treatment of chicken necrotic enteritis
CN101780266A (zh) 防治畜禽呼吸道疾病的复方制剂
CN113387909A (zh) 2,3-环氧丁二酰衍生物的医药用途
WO2017026830A1 (fr) Utilisation d'une composition pharmaceutique comprenant un dérivé de thio-urée pour la prévention ou le traitement de maladies auto-immunes
LAMB et al. Pregnenolone acetate in treatment of mycetoma (nocardiosis)
JPH11189529A (ja) 抗ヘリコバクター・ピロリ剤
CN116077513B (zh) 七叶皂苷或其盐在制备抗幽门螺杆菌药物及制备治疗幽门螺杆菌感染型胃溃疡药物中的应用
CN116687932B (zh) ((3-氨甲酰-5-氟吡嗪-2-基)氧基)甲基异丁酸酯的医药用途
RU2776343C2 (ru) Соединения для снижения липотоксического повреждения
WO2021091210A2 (fr) Composition pour thérapie dirigée vers l'hôte
JP2006522054A (ja) 結晶性ｎ−ホルミルヒドロキシルアミン化合物
JPH0466538A (ja) 抗潰瘍剤
US20240082263A1 (en) Pharmaceutical composition for combination therapy comprising melatonin and prostaglandin e2 for treating intestinal epithelial injury as an active ingredient

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23787738

Country of ref document: EP

Kind code of ref document: A1