[go: up one dir, main page]

CN118978524A - Nitazoxanide derivatives and their medical uses - Google Patents

Nitazoxanide derivatives and their medical uses Download PDF

Info

Publication number
CN118978524A
CN118978524A CN202410391334.XA CN202410391334A CN118978524A CN 118978524 A CN118978524 A CN 118978524A CN 202410391334 A CN202410391334 A CN 202410391334A CN 118978524 A CN118978524 A CN 118978524A
Authority
CN
China
Prior art keywords
nitazoxanide
novel
derivative
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
CN202410391334.XA
Other languages
Chinese (zh)
Inventor
仲伯华
王晓再
李宏武
杨家俊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shaoxing Junke Zhenyuan Pharmaceutical Technology Co ltd
Original Assignee
Shaoxing Junke Zhenyuan Pharmaceutical Technology Co ltd
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 Shaoxing Junke Zhenyuan Pharmaceutical Technology Co ltd filed Critical Shaoxing Junke Zhenyuan Pharmaceutical Technology Co ltd
Priority to CN202410391334.XA priority Critical patent/CN118978524A/en
Publication of CN118978524A publication Critical patent/CN118978524A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • 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
    • 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
    • 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
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Environmental Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及式I所代表的新的硝唑尼特衍生物：其中，R为H，CH3，C1或F，其连接于苯环上任意位置；X为NO2，Cl或Br。The present invention relates to novel nitazoxanide derivatives represented by formula I: Wherein, R is H, CH 3 , Cl or F, which is connected to any position on the benzene ring; X is NO 2 , Cl or Br.

Description

Nitrazonit derivative and medical application thereof
Technical Field
The present invention relates to novel nitazoxanide derivatives and their non-toxic pharmaceutically acceptable salts and their hydrates.
Background
Nitazoxanide (chemical name: o-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-acetate) is a nitrothiazole salicylamide, has the efficacy of resisting protozoa, intestinal parasites, bacteria and the like, and has a wider antiparasitic spectrum and antibacterial spectrum than albendazole and metronidazole.
Further studies have found that nitazoxanide and its analogues such as RM-5038 also have broad-spectrum antiviral activity, inhibiting various respiratory viruses, hepatitis C virus and hepatitis B virus.
Nitazoxanide also has better anti-tumor activity. Recent research results show that nitazoxanide also has a certain hypoglycemic effect. These results bring new prospects for old drugs for nitazoxanide.
However, as with most old drugs with new application prospects, these new pharmacological actions of nitazoxanide have yet to be enhanced in activity. For example, in a rat model of diabetes induced by high fat/streptavidin, the hypoglycemic effective dose is up to 200mg/kg (Samah M. Elaidy, et al, can. J. Physiol. Pharmacol.2008; 96:485-497.) and the dose for a human (body weight 60 kg) is 1944mg, which is far greater than the clinically safe dose of nitazoxanide (500 mg/time).
Therefore, how to improve the curative effect of the old medicine becomes a bottleneck for restricting the new medicine effect application.
Disclosure of Invention
The object of the present invention is to provide novel nitazoxanide derivatives represented by formula I:
Wherein R is H, CH 3, cl or F, which is connected to any position on the benzene ring; x is NO 2, cl or Br.
The invention also provides non-toxic pharmaceutically acceptable salts of the novel nitazoxanide derivatives represented by formula I.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a pharmaceutical composition taking non-toxic pharmaceutically acceptable salt thereof as an active ingredient.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a nontoxic pharmaceutically acceptable salt thereof, and a pharmaceutical composition taking the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof as active ingredients, and application thereof in preparing antiviral drugs.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a nontoxic pharmaceutically acceptable salt thereof, and a pharmaceutical composition taking the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof as active ingredients, and application of the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof in preparation of anti-hepatitis B virus drugs.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a nontoxic pharmaceutically acceptable salt thereof, and a pharmaceutical composition taking the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof as active ingredients, and application of the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof in preparing medicines for treating metabolic diseases.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a nontoxic pharmaceutically acceptable salt thereof, and a pharmaceutical composition taking the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof as active ingredients, and application of the novel nitazoxanide derivative and the nontoxic pharmaceutically acceptable salt thereof in preparation of hypoglycemic drugs.
The invention also provides a novel nitazoxanide derivative represented by the formula I and a non-toxic pharmaceutically acceptable salt thereof, and a pharmaceutical composition taking the novel nitazoxanide derivative and the non-toxic pharmaceutically acceptable salt thereof as active ingredients, and application of the novel nitazoxanide derivative and the non-toxic pharmaceutically acceptable salt thereof in preparing medicines for treating non-alcoholic steatohepatitis.
Detailed Description
The invention will be further described by the following examples, which should not be construed as limiting the scope of the invention.
Taking the derivatives of nitazoxanide as an example, the target compounds of the present invention can be prepared according to the following synthetic route:
hydrolyzing nitazoxanide to obtain deacetylated nitazoxanide; the latter is reacted with pyridine carbonyl chloride to give the target compound.
Reference example 12 preparation of N- (5-chlorothiazol-2-yl) amide of hydroxybenzoic acid (RM-4848) (J Med chem.2011;54 (12): 4119-4132.) the synthetic route is as follows:
To 500ml of anhydrous diethyl ether, 18g of acetylsalicylic acid, 9.5g of pyridine and ice bath were added, and 14.3g of thionyl chloride was added dropwise under stirring; after the addition, stirring is continued for 4 hours at 0 ℃, filtering is carried out, the filtrate is decompressed and evaporated to dryness, and the acetyl salicyl chloride is obtained and is directly used for the next reaction.
33.6G of NaHCO 3, 500ml of ethyl acetate are added to 500ml of water, and 17.1g of 2-amino-5-chlorothiazole hydrochloride are added with vigorous stirring. A solution of acetylsalicyl chloride in 100ml of ethyl acetate was added dropwise with vigorous stirring, and the reaction mixture was stirred at room temperature for 12 hours. Separating out an organic layer, and extracting a water layer with ethyl acetate; the ethyl acetate extracts were combined and washed sequentially with 0.5N hydrochloric acid 2 times and saturated brine once. Drying, evaporating under reduced pressure, separating by silica gel column chromatography, eluting with ethyl acetate-n-hexane (1:1), collecting the desired eluting component, evaporating under reduced pressure to obtain RM-503827.8g.
25G RM-5038 is added into 200ml concentrated hydrochloric acid and stirred and dispersed at room temperature; the system was heated to 50 ℃ and stirred for about 15 hours. Cooled to room temperature, filtered and the filter cake was washed with 50 ml x 3 times purified water. The mixture was drained and the filter cake was air dried at 60℃for 12 hours to give RM-484819.2 g. Nuclear magnetic resonance hydrogen spectrum (ppm, DMSO-d 6): 7.00 (1H, t); 7.04 (1H, d), 7.48 (1H, t); 7.60 (1H, s); 7.96 (1H, d).
EXAMPLE 1 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-3-carboxylic acid ester (I-1)
EXAMPLE 1.1 deacetylation Synthesis of nitazoxanide
Taking 30.00 g of nitazoxanide, adding the nitazoxanide into a 250 ml single-port bottle, adding 180 ml of concentrated hydrochloric acid, and stirring and dispersing at room temperature; the system was heated to 50 ℃ and stirred for about 15 hours. After the reaction, the reaction system was cooled to room temperature, filtered, and the cake was washed with 50 ml×3 times of purified water. The mixture was drained and the filter cake was air-dried at 60℃for 12 hours to give 21.1 g of desacetylnitazoxanide as a pale yellow solid.
EXAMPLE 1.2 Synthesis of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-3-carboxylic acid ester (I-1)
Under the protection of argon, 3.0g of desacetyl nitazoxanide is added into 75ml of tetrahydrofuran solvent, 5.6g of triethylamine is added under stirring, and the mixture is stirred and dissolved until the mixture is clear; cooling to 0 ℃ in an ice bath, adding 5.8g of pyridine-3-formyl chloride hydrochloride in batches under stirring, stirring for 0.5 hour under ice bath condition and argon protection after the addition, and then standing at room temperature for reaction for 15 hours. Insoluble matter was filtered off, the filter cake was washed with 5ml of tetrahydrofuran, and the washing filtrates were combined and evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography, eluting with methylene chloride/methanol (10/1), collecting the desired components, and evaporating under reduced pressure to give I-12.3g. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)：9.25(d,1H);8.89-8.91(m,1H);8.65(s,1H);8.43-8.46(m,1H);7.94-7.96(m,1H);7.74-7.79(m,1H);7.64-7.66(m,1H);7.51-7.55(m,1H);7.51-7.55(m,1H).
EXAMPLE 2 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-2-carboxylic acid ester (I-2)
Referring to the procedure of example 1.2, pyridine-2-formyl chloride hydrochloride was used in place of pyridine-3-formyl chloride hydrochloride to react with desacetylnitazoxanide; the reaction product was separated by silica gel column chromatography to give I-2.7 g. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)：9.23(d,1H);8.85-8.89(m,1H);8.64(s,1H);8.33-8.36(m,1H);7.97-7.99(m,1H);7.76-7.80(m,2H);7.63-7.65(m,1H);7.50-7.54(m,1H).
EXAMPLE 3 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-4-carboxylic acid ester (I-3)
Referring to the procedure of example 1.2, pyridine-4-formyl chloride hydrochloride was used in place of pyridine-3-formyl chloride hydrochloride to react with desacetylnitazoxanide; the reaction product was separated by silica gel column chromatography to give 1.9g of I-3. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)：9.22(d,1H);8.90-8.92(d,2H);8.63(s,1H);7.95-7.97(d,2H);7.73-7.78(m,1H);7.62-7.64(m,1H);7.49-7.53(m,1H).
EXAMPLE 4 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-3-carboxylic acid ester (I-4)
Referring to the procedure of example 1.2, RM-4848 was used instead of desacetylnitazoxanide to react with pyridine-3-carbonyl chloride; the reaction product was separated by silica gel column chromatography to give I-4.2 g. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)：9.20(d,1H);8.88-8.90(m,1H);8.42-8.45(dt,1H);7.93-7.95(m,1H);7.59(1H,s);7.71-7.76(m,1H);7.60-7.62(m,1H);7.50-7.54(m,2H).
EXAMPLE 5 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-2-carboxylic acid ester (I-5)
Referring to the procedure of example 1.2, RM-4848 was used instead of desacetylnitazoxanide to react with pyridine-2-carbonyl chloride; the reaction product was separated by silica gel column chromatography to give I-5.0 g. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)：9.21(d,1H);8.82-8.86(m,1H);8.31-8.34(m,1H);7.96-7.98(m,1H);7.76-7.80(m,2H);7.56(1H,s);7.63-7.65(m,1H);7.49-7.53(m,1H).
EXAMPLE 6 preparation of O-N- (5-nitrothiazol-2-yl) carbamoyl-phenol-pyridine-4-carboxylic acid ester (I-6)
Referring to the procedure of example 1.2, RN-4848 was used instead of desacetylnitazoxanide to react with pyridine-4-carbonyl chloride; the reaction product was separated by silica gel column chromatography to give 1.7g of I-6. Nuclear magnetic resonance hydrogen spectrum (ppm,DMSO-d6)∶9.24(d,1H);8.90-8.92(d,2H);8.61(s,1H);7.95-7.97(d,2H);7.72-7.77(m,1H);7.63-7.65(m,1H);7.49-7.53(m,1H).
EXAMPLE 7 in vitro anti-HBV Activity and cytotoxicity assay
EXAMPLE 7.1 determination of cytotoxicity
Culturing Hep G2.2.15 cells in DMEM culture solution containing 10% calf serum, inoculating in 96-well plates, incubating in a 5% CO2 incubator, discarding old culture solution when cell density reaches 80%, adding new culture solution containing different concentrations of the drug to be tested, 200 μl/well, and arranging 3 parallel wells; the culture medium was changed every 2 days. On day 10 after administration, 7.5mg/ml MIT, 30. Mu.l/well was added, incubation was continued for 3 hours, the supernatant was discarded, an acidic isopropanol solution containing 10% Tween X-100 was added, 120. Mu.l/well, and the absorption at 540nm was measured by an ELISA, and the 50% inhibitory concentration was calculated as the CC 50 value.
EXAMPLE 7.2 determination of anti-hepatitis B Virus Activity
Hep G2.2.15 cells are cultivated in DMEM culture solution containing 10% calf serum, inoculated in 96-well plates, the cell number is 3X10 4/well, incubated in a 5% CO2 incubator, when the cell density reaches 80%, old culture solution is discarded, new culture solution containing different concentrations of drugs to be tested is added, 200 μl/well is added, and 3 parallel wells are arranged; the culture medium was changed every 2 days. On day 10 after administration, 100. Mu.l of the supernatant was taken, the HBV DNA content was determined by quantitative PCR, and the 50% inhibition concentration was calculated as IC 50 value.
The experimental results are shown in table 1:
TABLE 1 in vitro anti-HBV Activity and cytotoxicity
EXAMPLE 8 evaluation of anti-hepatitis B Virus Effect in vivo
Duckling positive for vertical transmission of infection, DHBV DNA detection were randomly grouped with 8 duckling in each group. Nitazoxanide, RM-5038 and various doses of the test compound are formulated as suspensions with 0.1% sodium carboxymethylcellulose and administered by gavage once a day. Blood was collected intravenously before administration (T 0 days), 7 days (T 7 days), 14 days (T 14 days), 21 days (T 21 days) and 28 days (T 28 days), and serum was isolated and frozen at-70 ℃.
Determination of DHBV DNA levels in serum using spot molecular hybridization: : taking the duck serum, measuring the change of the DHBV DNA level in the duck serum by using each batch of synchronous membranes, marking DHBVDNA probes by 32 P according to the specification method of a notch translation kit, and performing a duck serum spot hybridization (Dot Blot) experiment. After autoradiography, the higher the OD 490,OD490 value of the spectral absorbance (with a filter wavelength of 490 nm) of the spot on the autoradiogram X-ray film, which indicates that the virus level is higher.
The measurement results are shown in Table 2:
TABLE 2 evaluation results of in vivo anti-Duck hepatitis B Virus Effect
Note that: drug groups were dosed at different times compared to pre-dose (T 0): * Drug groups with P < 0.01P < 0.05 compared to control groups for the same time: example 9 evaluation of the hypoglycemic and hypolipidemic Effect of the target Compounds Using db/db mouse model
After 60 db/db mice of 9-10 weeks age and 8C 57 wild control mice are fed for 13 days in an adaptive environment, the db/db mice are tested for 4h fasting blood glucose values and randomly grouped according to body weight and blood glucose values (G1: normal group, C57 mice; G2: solvent group; G3: I 1100mg/kg;G4：I1 mg/kg; G5: nitazoxanide 200mg/kg; G6: nitazoxanide 200mg/kg + pyridine-3-carboxylic acid 80 mg/kg); nitrazonite, RM-5038 and different doses of the test compound are formulated as suspensions with 0.1% sodium carboxymethylcellulose and administered by gavage once daily. Mice fasted for 4 hours on day 14 of dosing, followed by dosing with the test drug, and blood glucose was measured by blood sampling from the tail tip after 1 hour. The measurement results are shown in Table 3.
OGTT assay: animals were fasted overnight for 16 hours on day 15, and the animals were weighed the next day and blood glucose was measured with a glucometer for 0 min. The glucose solution (2 g/kg) was administered orally and parenterally immediately at the same time as the test substance was administered orally and parenterally, and blood glucose values of 30min,60min,120min and 180min after administration were measured. The area under the blood glucose time curve AUC was calculated. The measurement results are shown in Table 4.
TABLE 3 evaluation results of in vivo hypoglycemic Effect
*p＜0.05，**p＜0.01，***p＜0.001vs.Vehicle
TABLE 4 evaluation results of sugar tolerance
*p＜0.05，***p＜0.01，***p＜0.001vs.Vehicle
EXAMPLE 10 pharmacodynamic evaluation of nonalcoholic steatohepatitis
Reference (Xue Chang, liu Zezhou, chen Jia, et al. Comparison of animal models of high fat and MCD diet-induced nonalcoholic steatohepatitis. Progress in modern biomedical science, 2014;14 (18): 3451-3455)
C57BL/6 mice were fed with normal maintenance diet for 1 week and then randomized (G1: normal group; G2: solvent group; G3: I 1100mg/kg;G4：I1 mg/kg; G5: nitazoxanide 200mg/kg; G6: nitazoxanide 200mg/kg + pyridine-3-carboxylic acid 80 mg/kg). Feeding MCS feed to a normal control group; the rest groups were fed MCD feed, ingested freely, and drunk for 4 weeks. After 4 weeks, a dose of drug or solvent control was administered by gavage, 1 time/day, and the anti-NASH effect was measured at week 3 post-administration. Fasted for 12 hours after the last administration before measurement, weighed for anesthesia, collected from eyeballs for blood collection, paraformaldehyde fixed liver tissue to make paraffin sections, OCT fixed liver tissue to make frozen sections.
Liver histopathological detection: conventional paraffin embedding, paraffin slicing, HE staining, and optical observation and film shooting; frozen sections were stained with conventional oil red O, observed with a light mirror and photographed. NASH pathology diagnosis criteria were evaluated using NAFLD activity Score (NAFLD ACTIVITY Score, NAS). Semi-quantitative evaluation scores are shown in the following table:
the evaluation results are shown in Table 5:
Compounds of formula (I) NAS
G1 1.02±0.1
G2 8.20±3.27
G3 2.50±1.07
G4 3.20±1.27
G5 4.21±1.55
G6 3.42±1.26

Claims (7)

1. Novel nitazoxanide derivatives represented by formula I:
Wherein R is H, CH 3, cl or F, which is connected to any position on the benzene ring; x is NO 2, cl or Br.
2. According to claim 1, the novel nitazoxanide derivative represented by formula I:
wherein R is H, CH 3, cl or F, which is connected to any position on the benzene ring; x is NO 2.
3. According to claim 1, the novel nitazoxanide derivative represented by formula I:
Wherein R is H, CH 3, cl or F, which is connected to any position on the benzene ring; x is Cl.
4. The compound of claim 1 selected from the structures:
5. a pharmaceutical composition comprising the novel nitazoxanide derivative as claimed in claims 1-4 and a non-toxic pharmaceutically acceptable salt thereof as an active ingredient.
6. The novel nitazoxanide derivative and its non-toxic pharmaceutically acceptable salt as claimed in claims 1-4, and the use of the nitazoxanide derivative and its non-toxic pharmaceutically acceptable salt as pharmaceutical composition of active ingredient in the preparation of hypoglycemic drugs.
7. The novel nitazoxanide derivative and its non-toxic pharmaceutically acceptable salt as claimed in claims 1-4, and the use of the same as an active ingredient in the preparation of a medicament for treating non-alcoholic steatohepatitis.
CN202410391334.XA 2019-09-11 2019-09-11 Nitazoxanide derivatives and their medical uses Pending CN118978524A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410391334.XA CN118978524A (en) 2019-09-11 2019-09-11 Nitazoxanide derivatives and their medical uses

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910855408.XA CN112480104B (en) 2019-09-11 2019-09-11 Nitrazonit derivative and medical application thereof
CN202410391334.XA CN118978524A (en) 2019-09-11 2019-09-11 Nitazoxanide derivatives and their medical uses

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201910855408.XA Division CN112480104B (en) 2019-09-11 2019-09-11 Nitrazonit derivative and medical application thereof

Publications (1)

Publication Number Publication Date
CN118978524A true CN118978524A (en) 2024-11-19

Family

ID=74866109

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202410391334.XA Pending CN118978524A (en) 2019-09-11 2019-09-11 Nitazoxanide derivatives and their medical uses
CN201910855408.XA Active CN112480104B (en) 2019-09-11 2019-09-11 Nitrazonit derivative and medical application thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201910855408.XA Active CN112480104B (en) 2019-09-11 2019-09-11 Nitrazonit derivative and medical application thereof

Country Status (2)

Country Link
CN (2) CN118978524A (en)
WO (1) WO2021047688A1 (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008299781B2 (en) * 2007-08-03 2013-11-14 Romark Laboratories L.C. Alkylsulfonyl-substituted thiazolide compounds
MX341877B (en) * 2009-06-26 2016-09-06 Romark Laboratories L C * COMPOUNDS AND METHODS TO TREAT INFLUENZA.
AU2011323682B2 (en) * 2010-11-01 2016-06-23 Romark Laboratories L.C. Alkylsulfinyl-substituted thiazolide compounds
EP2890370B1 (en) * 2012-08-31 2019-10-09 The Regents of the University of California Agents useful for treating obesity, diabetes and related disorders
WO2015000431A1 (en) * 2013-07-04 2015-01-08 中国人民解放军军事医学科学院毒物药物研究所 Tizoxanide carbamate and pharmaceutical use thereof
JP2019513762A (en) * 2016-04-11 2019-05-30 ジェンフィＧｅｎｆｉｔ Method of treating cholestasis and fibrosis

Also Published As

Publication number Publication date
CN112480104B (en) 2024-06-18
CN112480104A (en) 2021-03-12
WO2021047688A1 (en) 2021-03-18

Similar Documents

Publication Publication Date Title
US12152017B2 (en) Ketoamide compound and preparation method, pharmaceutical composition, and use thereof
CN100368411C (en) 7-azaindoles as c-Jun N-terminal kinase inhibitors for the treatment of neurodegenerative diseases
CN113181339B (en) Medicinal application of aldehyde compound
JP3204901B2 (en) N- (3-benzofuranyl) urea derivative
EP1935892A1 (en) Glycyrrhetinic acid-30-amide derivatives and the uses thereof
CN103524318B (en) One class is preparing the application in anti-inflammatory drug containing allylic single carbonyl curcumin analogue
JP5404607B2 (en) Aniline derivative having anti-RNA virus action
CN113582969B (en) Application of an acylthiourea compound in the preparation of anti-enterovirus drugs
CN108947952A (en) 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application
EP4135715B1 (en) Bi- and monocyclic nucleoside analogs for treatment of hepatitis e
DE10109856A1 (en) Use of N-phenyl arylamide for treating or preventing chronic or acute hepatitis B viral infections in humans or animals, including co-infections with hepatitis D virus
CN118978524A (en) Nitazoxanide derivatives and their medical uses
JP5932827B2 (en) Thiazoleamine derivatives and their use as anti-picornavirus infectious agents
CN115141206B (en) Alpha-lipoic acid lycorine conjugate and preparation method and application thereof
CN107513055B (en) A kind of Ribavirin derivative compound and its pharmaceutical composition
CN118005694B (en) A cyclic nucleoside analogue and its preparation method and application
CN115197164B (en) Novel thiazole compound and its preparation method and use
CN103304556B (en) Schiff bases compounds containing chromene, Preparation Method And The Use
HK40085931A (en) Bi- and monocyclic nucleoside analogs for treatment of hepatitis e
CN120647578A (en) A 7-acylhydrazone-cyclopentapyridine compound, preparation method and application thereof, pharmaceutical composition and application thereof
SU1711673A3 (en) Method for the synthesis of ethanolamine or theirs physiologically acceptable salts or solvates
CN109134419A (en) A kind of 2,2- dimethyl -1,3- dioxolanes analog derivative, preparation method and use
CN119118968A (en) A compound for inhibiting IL-1β and its preparation method and application
CN108148049B (en) Preparation method and application of 5-pyrazole amide compound with triazinone structure
CN108689958A (en) A kind of indoleamine 2 containing diazanyl, 3- is bis- to add oxidase inhibitor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination