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WO2018177218A1 - Procédé de préparation et utilisations d'analogues et de dérivés de méthylpyrazolo[1,5-a]pyrimidine-7-phénolate 3,5-disubstitués - Google Patents

Procédé de préparation et utilisations d'analogues et de dérivés de méthylpyrazolo[1,5-a]pyrimidine-7-phénolate 3,5-disubstitués Download PDF

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Publication number
WO2018177218A1
WO2018177218A1 PCT/CN2018/080281 CN2018080281W WO2018177218A1 WO 2018177218 A1 WO2018177218 A1 WO 2018177218A1 CN 2018080281 W CN2018080281 W CN 2018080281W WO 2018177218 A1 WO2018177218 A1 WO 2018177218A1
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WIPO (PCT)
Prior art keywords
difluorophenyl
methylpyrazolo
pyrimidin
sodium
pyrimidine
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PCT/CN2018/080281
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English (en)
Chinese (zh)
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徐利锋
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辽宁利锋科技开发有限公司
徐利锋
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Publication of WO2018177218A1 publication Critical patent/WO2018177218A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs as antibacterial and antibiotic Discovery of fungal activity, medicinal chemistry research and preparation methods.
  • the invention also relates to the use of such compounds as medicaments for diseases such as antibacterial and antifungal agents.
  • the effective antibacterial drugs used may have drug-resistant strains, which are resistant to various antibacterial drugs, such as methicillin-resistant Staphylococcus aureus (called super bacteria). MRSA), vancomycin-resistant enterococci (VRE), etc.
  • super bacteria methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • the spread of infection "super bacteria” has become a serious threat to human health, so the development of new antibacterial drugs that are active against resistant bacteria is already imminent.
  • the present invention has a 3-(2,4-difluorophenyl)-5-substituted structure of the compound represented by the structural formula I.
  • the patented inventions and articles on the antibacterial and antifungal biological activity of the 2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs have not been reported.
  • the object of the present invention is to provide a chemistry of a 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative. Synthesis and preparation, having the following formulas and prodrugs, and providing their preparation, pharmacological activity test methods and pharmacologically active applications.
  • M + as defined by structural formula I is: Li + , K + , Na + , Ca + /2, Mg + /2, one of Cu + /2 and Fe + /2, which can pass through heterocyclic phenolic hydroxyl groups and various
  • the alkali and the alkali metal are reacted to form a salt, for example, an inorganic base such as metal Li, metal Na, metal K, sodium carbonate, sodium hydride, sodium hydroxide or potassium hydroxide, or an organic base to form a phenate or a double salt;
  • the atom is alkaline and can form a mineral acid salt, an organic acid salt or an acid by reacting with an acid such as hydrochloric acid, sulfuric acid, nitric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like.
  • Double salt is: Li + , K + , Na + , Ca +
  • R of the formula I is H, an optionally substituted aryl ring group, an alicyclic group and/or an aromatic ring fused ring combination, which may be a substituent 1, 2, 3, 4, 5 in the formula II.
  • X of the formula II may be absent, may be the same or different substituents, and is optionally substituted hydrogen, halogen, hydroxy, thiol, cyano, carbonyl, substituted carbonyl, aldehyde, keto, nitro, carboxy , substituted carboxyl, carboxylate, secondary, tertiary, di, tri, tetra, penta or hexaalkyloxy, arylalkoxy, aryloxy, heteroaryloxy, alkane Thio group, decyl ester group, arylalkylthio group, arylthio group, heteroarylthio group, ester group, acyloxy group, phosphoric acidoxy group, sulfonic acidoxy group, aromatic oxy group, quaternary ammonium salt group, amide group, Sulfhydryl, fluorenyl, fluorenyl, nitrogen-containing aliphatic hydrocarbon group, nitrogen-containing aromatic hydrocarbon group, nitrogen-containing cyclo
  • Respiratory infections urinary tract infections, skin and soft tissue infections, sepsis, bone and joint infections, and abdominal, pelvic infections, hemolytic streptococcus, pneumococci, and Staphylococcus aureus infections caused by sensitive strains; Streptococcus viridans and Endocarditis caused by Enterococcus and gas gangrene, anaerobic infection, anthrax, syphilis, gonorrhea, etc.
  • the administration route of the pharmaceutical compound of the present invention includes: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, sheath Administration is carried out intraluminally, intracranically, intranasally or topically.
  • the preparation method is characterized in that: the intermediate reaction is carried out by a cyclization reaction under the action of a catalyst, and an ethyl carbonyl compound containing various substituents is reacted with 4-(2,4-difluorophenyl) under the action of a catalyst.
  • the -3-methyl-1H-pyrazole-5-amine reacts to form a CN bond, completing the cyclization reaction.
  • the catalyst is one of a dehydrating agent, an organic acid and/or a mineral acid catalyst, and uses tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethyl B.
  • One of the amide, n-hexane, toluene and the like is a solvent, and the reaction temperature is controlled at -40 ° C to 180 ° C to form a key intermediate 2,3-(2,4-difluorophenyl)-2-methyl Pyrazolo[1,5-a]pyrimidin-7-phenol, the reaction formula is as follows:
  • 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs are prepared by: Under the action of a base, one of the following reagents (tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc.) is used as a solvent. The reaction temperature is controlled at -40 ° C to 180 ° C to form a phenate compound 3, the reaction formula is as follows:
  • the pharmaceutically acceptable salts of the compounds of the invention are also within the scope of the invention, the acid of which can be converted to a salt by reaction with a base such as sodium carbonate, sodium hydride, potassium hydroxide or the like.
  • a base such as sodium carbonate, sodium hydride, potassium hydroxide or the like.
  • the structure containing a nitrogen atom is basic and can be converted into a salt such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like by reaction with an acid.
  • Prodrugs of the compounds of the invention are also within the scope of the invention.
  • the medicament of the present invention can be modified into a prodrug to increase its water solubility and molecular volume, and to reduce its toxicity.
  • Standard strains Bacillus cereus 2, Bacillus subtilis 168, Enterococcus faecalis 29212, Enterococcus faecalis F2518 (vre), Staphylococcus aureus 29231, Staphylococcus aureus 43300 (MRSA), Staphylococcus aureus 703 ( MRSA), Streptococcus pneumoniae 6303 (PRSP), Streptococcus pneumoniae M2, Streptococcus agalactia B group, Streptococcus pneumoniae 10351, Bacillus anthracis, Diphtheria, Clostridium perfringens, Oral Candida, Peel fungus.
  • Test sample Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,
  • Sterilization The required experimental equipment and culture solution were autoclaved at 121 ° C for 30 min; sterile ultraviolet irradiation for 30 min.
  • Preparation of broth culture medium Accurately weigh 6 g of tryptic soy broth culture medium in a 500 ml beaker, add 200 ml of distilled water, fully dissolve by heating, transfer into a conical flask, add a cotton plug, and wrap the autoclave.
  • slant culture medium 3.8 g of tryptic soy agar was weighed into a 500 ml beaker, 100 ml of distilled water was added, dissolved sufficiently by heating, transferred into an Erlenmeyer flask, tampon added, and autoclaved by dressing. After a little cooling, it is divided into 7 tubes, about 10-15 ml per tube, tilted at an appropriate angle, and cooled for later use.
  • Bacterial amplification Open the ATCC 4300 sealed vial, take a small amount of bacterial powder block with a small ophthalmology clip after disinfection, transfer it into a 5 ml centrifuge tube, add 0.6 ml of tryptic soy broth medium, and mix well. The average was divided into 7 slant mediums, 80 ⁇ l/test tube, and evenly coated. It was placed in an incubator and cultured at 37 ° C for 24 hours.
  • Preparation of bacterial suspension and bacterial count The bacteria in the large test tube were washed with the culture solution and transferred into a sterile centrifuge tube. Mix well and prepare a bacterial suspension. A drop of the pipette was taken for bacterial density determination. Take a clean blood cell counting plate, cover a counting piece on the counting area, dilute the bacterial suspension with physiological saline for a certain multiple, and blow evenly. Pipette a little, from the sides of the intermediate plate of the counting plate. A drop (not too much) is dropped into the groove along the lower edge of the cover glass, so that the bacterial suspension fills the counting area with the surface tension of the liquid, so that bubbles are not generated. The plate was placed under a microscope for bacterial count. Count the total number of bacteria in 16 cells, and calculate the concentration of the bacteria using the following formula:
  • Bacterial density (pieces/ml) 16 small bacteria number ⁇ 10 4 ⁇ dilution factor
  • Preparation of the sample First, the drug to be tested is fully dissolved in a small amount of DMSO, and then the culture medium is formulated into a desired initial concentration, and sequentially diluted to each test gradient.
  • Preparation of bacterial solution According to the measurement result of the bacterial concentration, the bacterial suspension was diluted with a culture solution (TSB) to a bacterial solution having a concentration of 1.07 ⁇ 10 7 cf ⁇ / ml.
  • TBS culture solution
  • Dosing regimen The experiment was divided into positive control group, normal saline group, blank control group and each test group. Among them, there were 6 gradient wells in each test group, saline group and blank group. The positive control group was 7 gradient holes. 50 ⁇ l of the bacterial suspension, 30 ⁇ l of the culture solution, and 20 ⁇ l of each sample solution were sequentially added to each well.
  • the 96-well plate was added and placed in an incubator for cultivation.
  • the culture temperature was 37 ° C and the culture time was 24 hours.
  • the cultivation was completed in a clean bench to observe the growth of colonies in each group.
  • the bacterial liquid is clear, no turbidity, and the bottom of the well is aseptic.
  • the concentration is determined as the minimum inhibitory concentration (MIC) of the drug.
  • - represents MIC value ( ⁇ M) > 150 ⁇ g / mL
  • + represents MIC value ( ⁇ M) ⁇ 150 ⁇ g / / mL
  • ++ represents MIC value ( ⁇ M) ⁇ 100 ⁇ g / / mL
  • + + + represents MIC value ( ⁇ M) ⁇ 50 ⁇ g //mL.
  • Table 2 shows that the compounds of the examples of the present invention have excellent antibacterial activity.
  • Test sample Compound 3, Compound 5, Compound 9, Compound 10, Compound 30, Compound 1, Compound 2
  • Test animals Kunming healthy mice, weighing 19-21 g, male and female, are divided into groups, and other groups are used by single sex. They are provided by the Animal Center of the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • mice were randomly divided into a blank control group, a positive control group, and a test drug group, with 10 rats in each group, half male and half female.
  • the mouse body weight 0.2ml/10g abdominal cavity bacteria (MRSA-2152)
  • the bacterial concentration was 5.0 ⁇ 10 6 cfu/ml
  • the tail vein injection was administered, and after 6 hours, the second dose was administered.
  • the survival period of each group of animals was recorded, and the life extension rate of the positive control group and the sample group was calculated:
  • Life extension rate% (the number of days in the test group - the number of days in the blank group) / the number of days in the blank group ⁇ 100%
  • Compound 2 is compound 5 + ciprofloxacin, ratio 1:1

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

Abstract

Un objet de la présente invention concerne : en tant qu'invention d'une activité antibactérienne et antifongique, les dérivés et analogues de 3-(2,4-difluorophényl)-2-méthylpyrazolo[1,5-a]pyrimidin-7-phénolate substitués en 5ème position présentant la formule générale suivante ou un promédicament, un procédé de préparation et une procédure d'essai d'activité pharmacologique associés et l'activité pharmacologique correspondante ; et un procédé de recherche et de préparation chimique pharmaceutique et des utilisations des composés en tant que médicaments antibactériens et antifongiques. Les définitions de R et de M + dans la formule générale I sont présentées dans la description. Les dérivés et analogues de 3-(2,4-difluorophényl)-2-méthylpyrazolo[1,5-a]pyrimidine-7-phénolate substitués en 5ème position de formule I de la présente invention peuvent être compatibles avec les autres médicaments antibactériens et antifongiques connus et des médicaments pour le traitement d'infections bactériennes accompagnées de diverses complications, telles qu'une inflammation, des virus et des maladies du système immunitaire.
PCT/CN2018/080281 2017-04-01 2018-03-23 Procédé de préparation et utilisations d'analogues et de dérivés de méthylpyrazolo[1,5-a]pyrimidine-7-phénolate 3,5-disubstitués WO2018177218A1 (fr)

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CN201710212683.0A CN108658991B (zh) 2017-04-01 2017-04-01 3,5-二取代甲基吡唑并[1,5-a]嘧啶-7-酚盐类似物和衍生物制备方法和用途
CN201710212683.0 2017-04-01

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Cited By (3)

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CN109534498A (zh) * 2018-12-29 2019-03-29 江苏索普（集团）有限公司 一种生化处理有机含酸含so42-废水的处理方法
CN117887031A (zh) * 2024-01-18 2024-04-16 智元柏迈(杭州)科技有限公司 一种高分子量高生物安全性的磺胺类聚合物及其制备方法
CN119606977A (zh) * 2025-02-12 2025-03-14 深圳国家感染性疾病临床医学研究中心 头孢硫脒与克拉维酸联合制剂在结核病治疗中的应用

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CN109999031A (zh) * 2019-04-16 2019-07-12 周锡明 一种含有苯唑西林的医药组合物
CN112076201A (zh) * 2020-10-19 2020-12-15 中南大学湘雅三医院 一种抗菌药物及其应用
WO2023134692A1 (fr) * 2022-01-13 2023-07-20 浙江同源康医药股份有限公司 Composé polycyclique et son utilisation

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN109534498A (zh) * 2018-12-29 2019-03-29 江苏索普（集团）有限公司 一种生化处理有机含酸含so42-废水的处理方法
CN117887031A (zh) * 2024-01-18 2024-04-16 智元柏迈(杭州)科技有限公司 一种高分子量高生物安全性的磺胺类聚合物及其制备方法
CN119606977A (zh) * 2025-02-12 2025-03-14 深圳国家感染性疾病临床医学研究中心 头孢硫脒与克拉维酸联合制剂在结核病治疗中的应用
CN119606977B (zh) * 2025-02-12 2025-04-29 深圳国家感染性疾病临床医学研究中心 头孢硫脒与克拉维酸联合制剂在结核病治疗中的应用

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