WO2023284420A1 - Utilisation d'un composé arylique polycyclique dans la préparation d'un médicament antifongique - Google Patents

Utilisation d'un composé arylique polycyclique dans la préparation d'un médicament antifongique Download PDF

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Publication number
WO2023284420A1
WO2023284420A1 PCT/CN2022/094745 CN2022094745W WO2023284420A1 WO 2023284420 A1 WO2023284420 A1 WO 2023284420A1 CN 2022094745 W CN2022094745 W CN 2022094745W WO 2023284420 A1 WO2023284420 A1 WO 2023284420A1
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Prior art keywords
compound
polycyclic aryl
candida
pharmaceutically acceptable
preparation
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PCT/CN2022/094745
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English (en)
Chinese (zh)
Inventor
张宏
叶文才
张艺山
胡利军
李水秀
赵亚婧
唐川燕
翁泺棓
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暨南大学附属第一医院
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Priority to CA3224558A priority Critical patent/CA3224558A1/fr
Publication of WO2023284420A1 publication Critical patent/WO2023284420A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicine. More specifically, the present invention relates to the application of a polycyclic aryl compound S1 in the preparation of drugs against pathogenic fungi represented by Candida, Aspergillus, Mucor and Cryptococcus.
  • Fungal infection is a serious threat to the healthy life of human beings. According to the parts that invade the human body, fungal infection can be divided into superficial mycosis and deep mycosis.
  • the main pathogens of the latter are conditional pathogens represented by Candida, Aspergillus, Mucor and Cryptococcus Fungi, which cause more than 13 million infections and 1.6 million deaths each year, surpass the deaths from malaria, tuberculosis and breast cancer. What's more serious is that even with standard antifungal therapy, the mortality rate is as high as 67% in immunosuppressed patients.
  • azoles triazoles such as fluconazole and voriconazole
  • polyenes amphotericin B
  • echinocandins carboxyl Porfungin, micafungin
  • azoles have their own advantages and disadvantages.
  • azoles have high safety and oral bioavailability, their antibacterial effects lead to serious drug resistance; Acute kidney injury occurs in % of adults treated with amphotericin B, leading to significant increases in mortality, length of hospital stay, and costs; echinocandins are a new class of antifungal drugs approved in 30 years, but oral bioavailability low rate. Therefore, the choice of drugs for the treatment of deep fungal infections is limited, unable to meet the growing clinical needs, and there is an urgent need to develop new antifungal drugs.
  • the present invention provides a polycyclic aryl compound S1 for preparing antifungal infections.
  • the structural formula of the polycyclic compound is:
  • the invention relates to a method for preparing polycyclic aryl compound S1: compound 1-1 reacts with compound 1-2 to generate thiourea compound 1-3. The latter removes the Boc protecting group under the condition of hydrochloric acid to generate the hydrochloride compound 1-4.
  • Compound 1-5 reacts with N,N-dimethylformamide dimethyl acetal to generate diketone compound 1-6. Under the condition of ethanol as solvent, compound 1-4 reacts with compound 1-6 to obtain polycyclic compound S1.
  • the present invention also relates to a pharmaceutical composition, which contains a therapeutically effective dose of the polycyclic aryl compound represented by S1 and its pharmaceutically acceptable salt, and a pharmaceutical combination composed of one or more pharmaceutically acceptable carriers things.
  • the "pharmaceutically acceptable salt” mentioned in this application refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity, and is usually used in the form of free acid .
  • the acid addition salts of the free amino compounds of this invention can be prepared by methods well known in the art and can be prepared from organic and inorganic acids.
  • Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, Lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, toluenesulfonic acid and benzenesulfonic acid.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acids. Accordingly, "pharmaceutically acceptable salts" of the compounds of the present invention shall include and all acceptable salt forms.
  • the present invention also relates to polycyclic aryl compounds represented by S1 containing therapeutically effective doses, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof used in the preparation of anti-candida, aspergillus, cryptococcus and other pathogenic fungal infections Uses in medicine.
  • the present invention also relates to the polycyclic aryl compound represented by S1 containing a therapeutically effective dose, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the preparation for treating superficial and deep lesions caused by fungal infections. Use in medicines for fungal infection diseases.
  • a "pharmaceutical composition” as used herein means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutical Pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the compound S1 described in this application has a broad-spectrum antifungal effect on pathogenic fungi including but not limited to Candida, Aspergillus, Mucor, etc.;
  • the compound S1 described in this application can treat systemic fungal infection through oral administration and injection;
  • the compound S1 described in this application can be used to treat mucosal fungal infection through local application.
  • Fig. 1 is the 1H-NMR nuclear magnetic spectrum figure of compound S1;
  • Figure 2 is a graph showing the change in survival rate of compound S1 in the treatment of wax moth fungus infection
  • Figure 3 is a graph showing the change in bacterial load of compound S1 in the treatment of vaginal candida infection
  • Figure 4 is a graph showing the change in survival rate of mice with systemic fungal infection treated with compound S1;
  • Figure 5 is a graph showing the changes in the organ load of mice with systemic fungal infection treated with compound S1;
  • Fig. 6 is a pathological diagram of the kidneys of mice with systemic fungal infection treated with compound S1.
  • the structure of the S1 compound described in this application is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in the unit of 10 -6 (ppm), and the determination of NMR is carried out with a Bruker AVANCE-400 nuclear magnetic instrument, the measurement solvent is deuterated chloroform (CDCl 3 ), and the internal standard is tetramethylsilane (TMS) .
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Bailingwei, Anaiji, Darui Chemicals Waiting for the company.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • compound 1-5 (8.00g, 35.9mmol, 1.00eq) was dissolved in N,N-dimethylformamide (100mL), and then N,N-dimethylformamide dimethyl acetal was added (35.9 g, 301 mmol, 40.0 mL, 8.38 eq). After stirring and reacting for 2 hours, the reaction solution was filtered to obtain a filtrate. The filtrate was spin-dried and concentrated under reduced pressure to obtain light yellow solid compound 1-6 (8.50 g, 30.6 mmol, yield 85.2%).
  • Candida albicans standard strain SC5314
  • Candida albicans clinical strain CA1-3
  • Candida parapsilosis standard strain ATCC 22019
  • Candida krusei standard strain ATCC2 8870,
  • Candida tropicalis standard strain ATCC750
  • Standard strain of Aspergillus fumigatus ATCC 1022
  • clinical strain of Aspergillus fumigatus AF1-3
  • Mucor NRRL3631
  • Standard strain of Cryptococcus neoformans ATCC 32609
  • Standard strain of Pneumocystis sp. ATCC PRA-159.
  • the strains were stored in YPD+glycerol medium at -80°C, subcultured on YPD agar plates, and activated in YPD liquid medium.
  • the minimum inhibitory concentration (MIC 50 ) of compound S1 against the above-mentioned fungi was detected by micro liquid base dilution method.
  • the strain was cultured with YEPD agar medium at 35°C for 24 hours, and after being activated twice, the activated Candida albicans was picked up with an inoculation loop, diluted with RPMI 1640 culture medium, counted by a cell counting plate, and the concentration of the bacterial suspension was adjusted to the required working concentration (2.0 ⁇ 2.5) ⁇ 10 3 CFU/mL, freshly prepared before use. Dilute the drug stock solution to 2 times the working concentration with RPMI 1640 liquid medium.
  • the biological activity of the compound in the present invention is determined by the above experimental method, and the results of the measured antifungal activity of the compound in vitro are shown in Table 1.
  • Compound S1 has broad-spectrum antifungal activity.
  • LO-2 and RAW264.7 cells were cultured in the medium of DMEM+10% FBS+1% penicillin/streptomycin; HK-2 was cultured in the medium of DMEM/F-12+10%FBS+1% penicillin/streptomycin cultivated in culture medium;
  • CCK-8 method 100 ⁇ l of 5 ⁇ 10 4 CFU/ml cells were added to a 96-well plate, and placed in a 37° C., 5% CO 2 incubator for pre-cultivation for 24 hours. Small molecule compounds with different concentration gradients were added to each culture well, and the 96-well plate was placed in an incubator at 37° C. and 5% CO 2 for 6 hours. After 6 hours, 10 ⁇ l of CCK-8 solution was added to the sample to be tested. Place the 96-well plate in the incubator for 1-4 hours. The absorbance at 450 nm was measured with a multifunctional microplate reader. The results are expressed as the average of three independent experiments.
  • Destruction toxicity detected by LDH method 100 ⁇ l of 5 ⁇ 10 4 CFU/ml cells were added to a 96-well plate, and placed in an incubator at 37° C. and 5% CO 2 overnight. Replace medium by 100 ⁇ l. Small molecule compounds with different concentration gradients were added to each culture well and incubated for 24 hours. After adding 10 ⁇ l of Lysis Buffer to the positive control wells, incubate in an incubator with 5% CO 2 at 37°C for 30 min. After adding 100 ⁇ l of Working Solution to each well, incubate for 30 min at room temperature in the dark. Immediately after adding 50 ⁇ l Stop Solution to each well, detect the absorbance at 490 nm with a multifunctional microplate reader. Calculate the LDH release percentage according to the formula. The results are expressed as the average of three independent experiments.
  • the results are shown in Table 2 below.
  • the IC 50 values of the small molecule S1 on the growth of LO-2, HK-2, and RAW264.7 at 24 hours were 78.44, 73.61, and 86.57 ⁇ g/ml, respectively;
  • RAW264.7 growth IC 50 values were 53.91, 105.21, 35.64 ⁇ g/ml, significantly higher than the MIC 50 of S1 against pathogenic fungi more than 10 times.
  • the destructive toxicity to cells showed that S1 caused 50% cell destruction required a higher dose than inhibited growth, 131.91, 106.1, and 68.74 ⁇ g/ml were required in LO-2, HK-2, and RAW264.7 cells, respectively.
  • the above results indicate that the small molecule is selective between Candida and mammals.
  • Candida albicans as an example, the in vivo antifungal activity of compound S1 was evaluated.
  • Example 8 The efficacy of compound S1 in the local treatment of vaginal candida infection
  • mice 18-20 g female BALB/c mice were intraperitoneally injected with 100 ⁇ l estrogen (100 ⁇ l sesame oil containing 0.5 mg ⁇ -estradiol) and 100 ⁇ l cyclophosphamide (100 mg/kg) three days before infection, and then once every three days.
  • Candida albicans SC5314 activated overnight in liquid YPD was collected, washed twice with PBS, and adjusted to a concentration of 1 ⁇ 10 7 CFU/ml.
  • the mice were anesthetized with chloral hydrate, and 10 ⁇ l of bacterial solution was injected into the vaginal cavity of each mouse, and the buttocks of the mice were raised, and left to stand for half an hour.
  • Candida albicans SC5314 was activated to the end of logarithmic growth in YPD liquid medium, and the cells were collected and washed twice with PBS. Adjust the bacterial concentration to 2 ⁇ 10 6 CFU/ml with physiological saline.
  • 18-22g female BALB/c mice were randomly divided into groups, 10 in each group, respectively NS (injection of normal saline), WT (injection of SC5314), WT+drug treatment group of different concentrations (oral, injection), and drug control group alone.
  • the bacterial solution was injected into different mice through the tail vein, 100 ⁇ l per mouse (the amount of bacteria used for modeling was 2 ⁇ 10 5 cells/mouse), and the NS group was injected with an equal volume of normal saline.
  • Survival rate observe and record the survival status of the mice in each group regularly every day, calculate the survival rate after 30 days of observation, and kill the surviving mice. The survival curves were drawn and statistically tested by the Log-rank test.
  • Histopathology the above-mentioned right kidney for the detection of pathogenic indicators was fixed in 10% formaldehyde, and made into HE-stained and PAS-stained pathological sections.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un composé arylique polycyclique S1 pour la préparation d'un médicament contre une infection fongique. La formule développée du composé polycyclique est S1. Le composé arylique polycyclique présentant la structure noyau-enveloppe et représenté par S1 dans la présente invention est approprié pour la préparation de médicaments contre les infections fongiques pathogènes à Candida, Aspergillus, Mucor et autres, et présente les effets bénéfiques suivants : le composé S1 de la présente demande a un effet antifongique à large spectre contre les champignons pathogènes comprenant, entre autres, Candida, Aspergillus, Mucor, etc., est efficace contre les Candida résistant à l'azole, présente une faible toxicité vis-à-vis des mammifères, et permet de traiter une infection fongique systémique par administration orale, et peut également être utilisé localement pour traiter une infection à Candida des muqueuses.
PCT/CN2022/094745 2021-07-15 2022-05-24 Utilisation d'un composé arylique polycyclique dans la préparation d'un médicament antifongique WO2023284420A1 (fr)

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CN202110803698.0A CN113956215B (zh) 2021-07-15 2021-07-15 一种多环芳基化合物在抗真菌药物制备中的应用

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CN113956215B (zh) * 2021-07-15 2022-08-12 暨南大学附属第一医院 一种多环芳基化合物在抗真菌药物制备中的应用

Citations (3)

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US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
CN108947985A (zh) * 2017-05-22 2018-12-07 苏州偶领生物医药有限公司 用作自噬调节剂的化合物及其制备方法和用途
CN113956215A (zh) * 2021-07-15 2022-01-21 暨南大学附属第一医院 一种多环芳基化合物在抗真菌药物制备中的应用

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US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
CN108947985A (zh) * 2017-05-22 2018-12-07 苏州偶领生物医药有限公司 用作自噬调节剂的化合物及其制备方法和用途
CN113956215A (zh) * 2021-07-15 2022-01-21 暨南大学附属第一医院 一种多环芳基化合物在抗真菌药物制备中的应用

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HIROTAKA INODA; TAIHEI NISHIYAMA; TAKASHI YOSHIKADO; YUSUKE SUWANAI; TOMOFUMI SANTA: "Compounds having thiourea moiety as derivatization reagents in liquid chromatography/electrospray ionization–tandem mass spectrometry (LC/ESI‐MS/MS): synthesis of derivatization reagents for carboxylic acids", BIOMEDICAL CHROMATOGRAPHY, JOHN WILEY & SONS LTD., GB, vol. 25, no. 6, 1 September 2010 (2010-09-01), GB , pages 635 - 640, XP071548878, ISSN: 0269-3879, DOI: 10.1002/bmc.1501 *

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