WO2021129723A1 - 抗真菌水溶性前药及其制备方法 - Google Patents

抗真菌水溶性前药及其制备方法 Download PDF

Info

Publication number
WO2021129723A1
WO2021129723A1 PCT/CN2020/138944 CN2020138944W WO2021129723A1 WO 2021129723 A1 WO2021129723 A1 WO 2021129723A1 CN 2020138944 W CN2020138944 W CN 2020138944W WO 2021129723 A1 WO2021129723 A1 WO 2021129723A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solution
add
reaction
Prior art date
Application number
PCT/CN2020/138944
Other languages
English (en)
French (fr)
Inventor
刘伟
刘国强
王延东
Original Assignee
上海英诺富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 上海英诺富成生物科技有限公司 filed Critical 上海英诺富成生物科技有限公司
Publication of WO2021129723A1 publication Critical patent/WO2021129723A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an antifungal water-soluble prodrug and a preparation method thereof.
  • Itraconazole is a new generation of triazole high-efficiency broad-spectrum antifungal drugs, which can combine with fungal cytochrome P450 isoenzymes to inhibit the synthesis of ergosterol.
  • This product is suitable for dermatophytes, Candida, Cryptococcus neoformans, Pityrosporum, Aspergillus, Histoplasma, Paracoccus Brazil, Sporothrix Schenker, Coloring Fungi, Cladosporium , Dermatitis blastomycetes and other infections are effective.
  • the compound shown in formula 1 is one of the metabolites of itraconazole, and has antifungal activity similar to that of itraconazole (comparison of in vitro antibacterial activity of itraconazole and hydroxy itraconazole; Chinese Journal of Mycology, 2013- 01-009), which has inhibitory activity against a variety of fungi (see PCT, WO 00/66100, 2R, 4S-hydroxyitraconazole isomers).
  • Itraconazole is insoluble in water and difficult to be made into liquid preparations. Therefore, itraconazole injections on the market need to adopt techniques such as cyclodextrin inclusion, and prepare injections with a large amount of excipients. Cyclodextrin compounds have hemolysis, etc. Side effects have a greater potential safety hazard, thereby increasing the risk of clinical use. Therefore, it is particularly important to find an antifungal compound with suitable solubility, good solution stability, and no irritation.
  • the purpose of the present invention is to provide a compound whose general structural formula is shown in formula I:
  • n can be an integer from 0 to 4.
  • R 1 is methyl and R 2 is H;
  • n is an integer of 1-4 (specifically, 1 , 2, 3, or 4), R 1 is H, -CH 3 or -C 2 H 5 , and R 2 is H or NH 2 .
  • R 1 is H, -CH 3 or -C 2 H 5
  • R 2 is H or NH 2 .
  • the representative form of the compound represented by formula I is as follows:
  • the compound represented by the above formula I is prepared by a method including the following steps:
  • n can be an integer from 0 to 4.
  • R 1 is methyl and R 2 is H;
  • n is an integer of 1-4 (specifically, 1 , 2, 3, or 4), R 1 is H, -CH 3 or -C 2 H 5 , and R 2 is H or NH 2 .
  • the molar ratio of the compound represented by formula II to the compound represented by formula III may be 1-2:1;
  • the esterification reaction is carried out under the catalysis of carbodiimide; the carbodiimide may specifically be EDCI;
  • the esterification reaction is carried out under alkaline conditions, and the esterification reaction is carried out in an organic solvent, and the organic solvent may specifically be dichloromethane;
  • the temperature of the esterification reaction may be 20-60°C, specifically 45°C;
  • the time of the esterification reaction can be 10-15h, specifically 12h.
  • the fungus may be: Candida, Cryptococcus, Aspergillus;
  • Candida albicans Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida krusei, Cryptococcus neoformans or Aspergillus fumigatus.
  • the present invention also provides an antifungal liquid preparation, which uses the compound represented by the above formula I or a pharmaceutically acceptable salt or optical isomer thereof as an active ingredient.
  • the liquid formulation may specifically be an injection; the liquid formulation uses water as a solvent and does not contain a co-solvent. Specifically, the liquid formulation may not contain cyclodextrin.
  • the compound shown in formula 1 has similar antifungal activity.
  • the compounds of Examples 1-6 have good solubility, and their solubility at pH 5-6 can be It meets the requirements for preparing injections.
  • the solution prepared by compound 1-6 is more stable than room temperature at 2-8°C.
  • the prepared solution can be partially converted into itraconazole by enzymatic incubation in plasma. It shows that compound 1-6 can become a prodrug of the compound represented by formula I, and the solution prepared from compound 1-6 is non-irritating and hemolytic, and is suitable for preparing injection.
  • Figure 1 is a synthetic route diagram for preparing compound 1 in Example 1 of the present invention.
  • reaction solution was lowered to room temperature, filtered with suction, the filter cake was rinsed with a small amount of DMF, and 500 ml of water was slowly added dropwise to the filtrate under stirring. After dripping, stir for 30 min. After suction filtration, the filter cake was once again dispersed with 500 ml of water, and a white solid was obtained by suction filtration, which was dried by blowing at 40° C. to obtain 6.0 g of compound SZY1402-14.
  • Sample preparation the sample is dissolved in purified water and diluted to 0.5mg/mL
  • the stability of the aqueous solution at 2-8°C is better than that at room temperature, which can meet the clinical needs of preparing injection dosage forms.
  • the compounds of the examples were added to fresh human whole blood collected at 37°C, the initial incubation concentration was 10ug/ml, and samples were taken after 0, 0.083, 0.25, 0.5, 1, 2, and 4 hours, and the plasma was tested. 1
  • the concentration of the compound, the results are as follows (ng/ml):
  • Examples 1-6 can be partially metabolized into compounds of Formula 1 in whole blood incubation, and Compounds 1-6 can become prodrugs of Formula 1.
  • Example 1-6 Take 1 bottle of the injection solution (4mL:94mg/bottle) prepared in Example 1-6, aspirate 1.0mL and dilute to 12.5mL with 0.9% sodium chloride injection to make a solution with a concentration of 1.88mg/mL.
  • Animal weighing weighed once before administration and once at 48 hours and 14 days after the last administration.
  • the solution prepared by the compound of the example reacts to rabbit muscle irritation (visual observation result)
  • the rabbit's visual observation time is 48 hours after the last dose
  • Example 1-6 The compound solution of Example 1-6 (7.5 and 22.5 mg/kg ⁇ bw) was negative in the guinea pig systemic active allergy test; the compound solution of Example 1-6 (1.88 mg/mL) had no irritation to the venous blood vessels and surrounding tissues of rabbit ear margins The compound solution of Example 1-6 (1.88 mg/mL) has no irritation to the muscle tissue at the injection site of the rabbit; the solution of Example Compound 1-6 (1.88 mg/mL) is negative for the rabbit in vitro hemolysis test.
  • the compound 1-6 of Example has suitable solubility, the solution stability meets the requirements, the solution is non-irritating, non-allergenic, and non-hemolytic, and is suitable for preparing liquid dosage forms such as injections.
  • Positive control drug itraconazole injection, specification 25ml: 0.25g, manufactured by GlazoSmithkline Manufacturing S.p.A, Italy, product batch number: 14KQ163;
  • mice (clean grade) provided by the Comparative Medicine Center of Yangzhou University, 6 weeks old, weighing 18.0 ⁇ 20.0g, were randomly divided into groups; each group consisted of 10 mice, half male and half male. An experimental group, a positive control group, and an infection control group were set up at the same time.
  • Candida albicans ATCC5314 provided by the Chinese Medical Fungi Collection.
  • Path of infection One-time attack of mouse tail vein.
  • the Candida albicans ATCC5314 which was restored to the animal’s virulence, was subcultured on Sandcastle agar medium and incubated at 30°C for 48 hours. The fresh and mature colonies were washed with saline and counted with a hemocytometer to adjust the concentration to 2.0 ⁇ 10 7 cfu/ml, 1.0 ⁇ 10 7 cfu/ml, 2.0 ⁇ 10 6 cfu/ml, 1.0 ⁇ 10 6 cfu/ml, 2.0 ⁇ 10 5 cfu/ml.
  • the injection volume of each mouse was 0.5ml/mouse, the number of days of death of the animal was determined, and the minimum amount of infection (100% MLD) of 100% dead mice within 7 days was determined.
  • the minimum amount of infection (100% MLD) of 100% dead mice within 7 days was determined.
  • This dose was used as the one-time tail vein challenge dose of the example compound for the Candida albicans ATCC5314 system infection protection test.
  • Dosage positive control drug-itraconazole injection 5mg/kg, six groups of example test drugs are administered equimolar, respectively, experimental groups 1-6, pre-test and formal test respectively set up infection control at the same time, once 0.9% Nacl solution was given intravenously.
  • the dosage is calculated based on the average weight of each mouse about 20.0g, dissolved in 0.5ml 0.9% NaCl solution, and administered through the tail vein at one time; infection control group A 0.9% NaCl solution was given as a placebo.
  • Compound 1-6 can be partially converted into itraconazole by enzymatic incubation in plasma, and has similar antifungal activity to the compound represented by formula I.
  • Example 11 verified the effect of compound 1-6 on Candida albicans ATCC5314. Inhibition.
  • the compound shown in formula 1 has similar antifungal activity.
  • the compounds of Examples 1-6 have good solubility, and their solubility at pH 5-6 can be It meets the requirements for preparing injections.
  • the solution prepared by compound 1-6 is more stable than room temperature at 2-8°C.
  • the prepared solution can be partially converted into itraconazole by enzymatic incubation in plasma. It shows that compound 1-6 can become a prodrug of the compound represented by formula I, and the solution prepared from compound 1-6 is non-irritating and hemolytic, and is suitable for preparing injection.

Landscapes

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

Abstract

本发明提供一种抗真菌水溶性前药及其制备方法。其结构式如式(Ⅰ)所示：式(Ⅰ)中，n为0时，R1为甲基，R2为H；n为1-4的整数时，R1为H、-CH3或-C2H5，R2为H或NH2。本发明实施例1-6化合物具有较好的溶解性，在pH5-6时的溶解度能够满足制备注射液的要求，在pH5-6时化合物1-6配制的溶液在2-8℃时较室温更稳定，所制备的溶液在血浆中能够部分通过酶的孵育转化成羟基伊曲康唑，说明化合物1-6可以成为式（1）所示化合物的前体药物，由化合物1-6所制备的溶液无刺激性、溶血性，适于制备成注射液。

Description

抗真菌水溶性前药及其制备方法 技术领域
本发明属于医药领域，具体涉及抗真菌水溶性前药及其制备方法。
背景技术
伊曲康唑(Itraconazole)为新一代三唑类高效广谱抗真菌药，可结合真菌细胞色素P450同工酶，抑制其麦角甾醇合成。本品对皮肤癣菌、念珠菌属、新生隐球菌、糠秕孢子菌属、曲霉菌属、组织胞浆菌属、巴西副球孢子菌、申克孢子丝菌、着色真菌属、枝孢霉属、皮炎芽生菌等感染有效。
式1所示化合物为伊曲康唑的代谢物之一，具有与伊曲康唑近似的抗真菌活性(伊曲康唑和羟基伊曲康唑体外抗菌活性比较；中国真菌学杂志，2013-01-009)，其对多种真菌具有抑制活性(见PCT,WO 00/66100,2R,4S-hydroxyitraconazole isomers)。
Figure PCTCN2020138944-appb-000001
伊曲康唑不溶于水，难于做成液体制剂，因此市售伊曲康唑注射液需要采用环糊精包合等技术，通过大量辅料制备成注射液，而环糊精类化合物具有溶血等副作用，具有较大的安全隐患，从而加大了临床使用的风险。因此寻找一个具有适宜溶解度、溶液稳定性好、无刺激性的抗真菌化合物尤为重要。
发明公开
本发明的目的是提供一种化合物，其结构通式如式Ⅰ所示：
Figure PCTCN2020138944-appb-000002
Figure PCTCN2020138944-appb-000003
上述式Ⅰ中，n可为0-4的整数；
n为0时，R 1为甲基，R 2为H；
n为1-4的整数(具体可为1、2、3或4)时，R 1为H、-CH 3或-C 2H 5，R 2为H或NH 2。具体的，式Ⅰ所示化合物具有代表意义的形式如下：
Figure PCTCN2020138944-appb-000004
Figure PCTCN2020138944-appb-000005
上述式Ⅰ所示化合物药学上可接受的盐和其光学异构体也属于本发明的保护范围。
上述式Ⅰ所示化合物通过包括如下步骤的方法制备得到：
使得式Ⅱ所示化合物与式Ⅲ所示化合物发生酯化反应，得到式Ⅰ所示化合物；
Figure PCTCN2020138944-appb-000006
上述式Ⅲ中，n可为0-4的整数；
n为0时，R 1为甲基，R 2为H；
n为1-4的整数(具体可为1、2、3或4)时，R 1为H、-CH 3或-C 2H 5，R 2为H或NH 2。
上述方法中，式Ⅱ所示化合物与式Ⅲ所示化合物的摩尔比可为：1-2:1；
所述酯化反应在碳二亚胺催化下进行；所述碳二亚胺具体可为EDCI；
所述酯化反应在碱性条件下进行，所述酯化反应在有机溶剂中进行，所述有机溶剂具体可为二氯甲烷；
所述酯化反应的温度可为20-60℃，具体可为45℃；
所述酯化反应的时间可为10-15h，具体可为12h。
上述式Ⅰ所示化合物在制备抗真菌药物或制备预防和/或治疗由真菌引起的疾病 的药物中的应用也属于本发明的保护范围。
所述应用中，所述真菌可为：念珠菌属、隐球菌属、曲霉属真菌；
具体可为：白念珠菌、近平滑念珠菌、光滑念珠菌、热带念珠菌、克柔念珠菌、新生隐球菌或烟曲霉。
本发明还提供一种用于抗真菌的液体制剂，所述用于抗真菌的液体制剂以上述式Ⅰ所示化合物或其药学上可接受的盐或光学异构体为活性成分。
所述液体制剂具体可为注射剂；所述液体制剂以水为溶剂，不含助溶剂，具体地，所述液体制剂中可以不含环糊精。
与式1所示化合物具有类似的抗真菌活性，我们制备了系列化合物，通过筛选获得实施例1-6化合物，实施例1-6化合物具有较好的溶解性，在pH5-6时的溶解度能够满足制备注射液的要求，在pH5-6时化合物1-6配制的溶液在2-8℃时较室温更稳定，所制备的溶液在血浆中能够部分通过酶的孵育转化成伊曲康唑，说明化合物1-6可以成为式Ⅰ所示化合物的前体药物，由化合物1-6所制备的溶液无刺激性、溶血性，适于制备成注射液。
附图说明
图1为本发明实施例1中制备化合物1的合成路线图。
实施发明的最佳方式
下述实施例中的实验方法，如无特别说明，均为常规方法
下面结合实施例对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所做的任何变更或改进，均属于本发明的保护范围。
实施例1、化合物1的合成
根据图1所示的合成路线图合成化合物1，具体步骤如下：
1.1、SZY1402-3的合成：
Figure PCTCN2020138944-appb-000007
50L反应釜中依次加入起始物料1(2kg)，起始物料2(1.3kg)和二甲基亚砜 (20L)，搅拌均匀，加入碳酸钾(3.5kg)，升温至130℃搅拌反应20h。HPLC监测至原料消失，将反应液温度降至室温，倾入到20L冰水中，搅拌30分钟，抽滤，滤饼用水淋洗至滤液pH为中性，滤饼烘干得2.15kg化合物SZY1402-3。
1.2、SZY1402-4的合成：
Figure PCTCN2020138944-appb-000008
50L反应釜中依次加入化合物SZY1402-3(1.5kg)，甲醇(14L)，乙酸(4.5L)和湿钯炭(150g)，搅拌均匀，室温下常压氢化反应20h。HPLC监测至原料消失，向反应液中加入9.0L水和1.5L浓盐酸，搅拌30分钟，通过硅藻土过滤除去钯炭，滤液减压浓缩除去甲醇，浓缩液在冰水浴降温下用氢氧化钠溶液调pH＝13，抽滤，滤饼用水淋洗至滤液pH为中性，滤饼晾干得到1.3kg化合物SZY1402-4。
1.3、SZY1402-7的合成：
Figure PCTCN2020138944-appb-000009
50L反应釜中依次加入化合物SZY1402-4(1.3kg)，碳酸钾(1.27kg)和二氧六环(20L)，搅拌均匀，降温至5-10℃，将化合物5(943g)的二氧六环溶液缓慢滴加到反应液中，滴毕，20℃搅拌反应2小时。HPLC监测至原料消失。
向反应液中加入一水水合肼(700ml)和二氧六环(5L)，反应液升温至80℃反应2小时，HPLC监测至原料消失。反应液降至室温，向反应液中加入20L水，搅拌30分钟，抽滤，滤饼用水淋洗至滤液pH为中性，40℃鼓风干燥得1.45kg化合物SZY1402-7。
1.4、SZY1402-8的合成：
Figure PCTCN2020138944-appb-000010
20L三口瓶中依次加入DMF(13L)，化合物SZY1402-7(1.3kg)和醋酸甲脒(603g)，室温搅拌1小时，将2.65L冰乙酸加入到反应液中，然后升温至70℃反应2h。HPLC监测至原料消失。反应液降至室温，抽滤，滤饼用无水乙醇淋洗，抽至近干，滤饼再次用无水乙醇打浆1h，抽滤，滤饼40℃鼓风干燥得1.2kg化合物SZY1402-8。
1.5、SZY1402-10的合成：
Figure PCTCN2020138944-appb-000011
3L烧瓶内分别加入化合物SZY1402-8(100g)，3-氯-2-丁酮(60g)，碳酸钾(120g)和DMF(1L)，搅拌均匀，然后升温至80℃反应3h。HPLC监测原料消失，将反应液导入到冰水中(3L)，过滤，收集滤饼，水淋洗至滤液呈中性，滤饼鼓风干燥得130g化合物SZY1402-10。
1.6、SZY1402-11的合成：
Figure PCTCN2020138944-appb-000012
5L三口瓶中化合物SZY1402-10(130g)，溶于甲醇(2L)，与0度下分次加入硼氢化钠(30g)，加毕搅拌2小时，监测原料消失。减压除去一半溶剂，然后反应液倒入3L水中，二氯甲烷萃取(1.0L*3)，干燥浓缩得70g化合物SZY1402-11.
1.7、SZY1402-12的合成：
Figure PCTCN2020138944-appb-000013
2.0L三口瓶中加入二氯甲烷(800mL)，化合物SZY1402-11(40.0g)，降温至-30℃，缓慢滴加BBr 3(39.5ml)，滴毕，升至25-30℃搅拌反应20h。HPLC监测原料消失。向反应液中缓慢加入88％的乙醇水溶液150ml，补加500ml水，搅拌30min，分液，有机相弃去，水相用饱和NaHCO 3调节pH＝7-8，抽滤，滤饼干燥得到21g化合物SZY1402-12。
1.8、SZY1402-14的合成：
Figure PCTCN2020138944-appb-000014
250ml三颈烧瓶中加入DMF(135ml)，依次加入化合物SZY1402-12(4.5g)、化合物cis-甲磺酸-[2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基]甲酯(SZY1402-13)(5.39g)和粒状氢氧化钾(1.54g)，加入甲基异丁基酮(9ml)，搅拌均匀，N 2置换气体3次，升温至60℃反应4h。TLC中控至反应完毕。反应液降至室温，抽滤，滤饼用少量DMF淋洗，搅拌下向滤液中缓慢滴加500ml水。滴毕，搅拌30min。抽滤，滤饼再次用500ml水分散一次，抽滤得到白色固体，40℃鼓风烘干得到6.0g化合物SZY1402-14。
1.9、化合物01-1的合成：
Figure PCTCN2020138944-appb-000015
500ml三颈烧瓶中加入二氯甲烷(200ml)，加入化合物SZY1402-14(10g)搅拌溶解，依次加入Boc-N-肌氨酸(5.3g)、EDCI(5.3g)和DMAP(5.1g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到10.0g白色泡沫状固体化合物01-1。
1.10、化合物1的合成：
Figure PCTCN2020138944-appb-000016
500ml三颈烧瓶中加入乙酸乙酯(100ml)，加入化合物01-1(10g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(100ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体盐酸盐，滤饼先经EA淋洗,后经EA浆洗除HCl，抽滤，滤饼经减压旋干得到10g白色粉末状固体化合物1。
1HNMR CH 3OHδ:10.07(s,1H),8.91(s,1H),8.20(s,1H),7.85-7.82((d,J＝9.2Hz,3H),7.63-7.59(m,3H),7.46-7.44(d,J＝9.2Hz,1H),7.31-7.29(d,J＝8.8Hz,2H),7.16-7.13(d,J＝8.8Hz,2H),5.38-5.35(m,1H)，5.20-5.10(m,2H)，4.51-4.46(m,2H)，4.23-4.19(m,1H)，4.05-3.85(m,13H)，2.74(s,3H)，2.04(s,1H)，1.49-1.47(d,J＝7.2Hz,3H),1.41-1.40(d, J＝6.4Hz,3H).
LC-MS:m/z＝793.7(M+1).
实施例2、化合物2的合成
Figure PCTCN2020138944-appb-000017
50ml三颈烧瓶中加入二氯甲烷(20ml)，加入化合物SZY1402-14(1g)搅拌溶解，依次加入Boc-3-氨基丙酸(0.5g)、EDCI(0.54g)和DMAP(0.5g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到0.9g白色泡沫状固体化合物02-1。
Figure PCTCN2020138944-appb-000018
50ml三颈烧瓶中加入乙酸乙酯(20ml)，加入化合物02-1(0.9g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(10ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体，引湿严重，将滤饼用EA淋洗后减压旋干得到粉末状固体化合物2(0.5g)。
1H NMR(400MHz DMSO)：δ8.21(s,1H),7.95(s,1H),7.65(s,1H),7.59-7.57(d,J＝8.4Hz,1H),7.48-7.47(d,J＝2.0Hz,1H),7.43-7.40(m,2H),7.27-7.24(m,1H),7.05-7.03(d,J＝8.4Hz,2H),6.95-6.93(d,J＝8.8Hz,2H),6.82-6.81(d,J＝2.4Hz,2H),4.86-4.75(dd,J1＝32.4Hz,J2＝14.8Hz,2H),4.38-4.34(m,1H),4.27-4.22(m,1H),4.03-3.97(m,1H), 3.94-3.92(m,1H),3.84-3.78(m,2H),3.72-3.68(m,2H),3.51-3.47(m,2H),3.39-3.36(m,4H),3.25-3.22(m,4H),3.06-3.00(m,3H),1.48-1.46(d,J＝7.2Hz,3H),1.26-1.24(d,J＝6.4Hz).MS：[M+H]+＝793.7
实施例3、化合物3的合成
Figure PCTCN2020138944-appb-000019
50ml三颈烧瓶中加入二氯甲烷(20ml)，加入化合物SZY1402-14(1g)搅拌溶解，依次加入N-甲基-Boc-2,4-二氨基丁酸(1.2g)、EDCI(0.54g)和DMAP(0.5g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到1.8g白色泡沫状固体化合物03-1。
Figure PCTCN2020138944-appb-000020
50ml三颈烧瓶中加入乙酸乙酯(20ml)，加入化合物03-1(1.8g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(10ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体，引湿严重，将滤饼用EA淋洗后减压旋干得到粉末状固体化合物3(1g)。
1H NMR(400MHz DMSO)：δ8.19(s,1H),7.88(s,1H),7.65(s,1H),7.59-7.57(d,J＝8.4Hz,1H),7.48-7.47(d,J＝2.0Hz,1H),7.43-7.40(m,2H),7.27-7.24(m,1H),7.08-7.03(m,2H),6.95-6.93(d,J＝8.8Hz,2H),6.82-6.81(d,J＝2.4Hz,2H),4.86-4.75(m,2H), 4.40-4.39(m,1H),4.38-4.34(m,1H),4.27-4.22(m,1H),4.03-3.97(m,1H),3.94-3.92(m,1H),3.84-3.78(m,2H),3.51-3.47(m,2H),3.39-3.36(m,4H),3.25-3.22(m,4H),3.06-3.04(d,J＝8.8Hz,1H),2.66-2.62(m,4H),1.48-1.46(d,J＝7.2Hz,3H),1.26-1.24(d,J＝6.4Hz,1H).MS：[M+H]+＝822.7
实施例4、化合物4的合成
Figure PCTCN2020138944-appb-000021
500ml三颈烧瓶中加入二氯甲烷(200ml)，加入化合物14(10g)搅拌溶解，依次加入Boc-N-甲基氨基丙酸(5.63g)、EDCI(5.3g)和DMAP(5.1g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到10.0g白色泡沫状固体04-1。
Figure PCTCN2020138944-appb-000022
500ml三颈烧瓶中加入乙酸乙酯(100ml)，加入化合物04-1(10g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(100ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体盐酸盐，滤饼先经EA淋洗,后经EA浆洗除HCl，抽滤，滤饼经减压旋干得到10g白色粉末状固体化合物4。
1HNMR CH 3OHδ:10.07(s,1H),8.91(s,1H),8.20(s,1H),7.85-7.82((d,J＝9.2Hz,2H), 7.76-7.74(d,J＝8.4Hz 1H),7.63-7.59(m,3H),7.46-7.44(d,J＝9.2Hz,1H),7.31-7.29(d,J＝8.8Hz,2H),7.16-7.13(d,J＝8.8Hz,2H),5.38-5.35(m,1H)，5.20-5.10(m,2H)，4.51-4.46(m,2H)，4.23-4.19(m,1H)，4.05(m,3H)，3.9(m,4H)，3.85(m,8H)，2.74(s,3H)，2.04(s,1H)，1.49-1.47(d,J＝7.2Hz,3H),1.41-1.40(d,J＝6.4Hz,3H).
LC-MS:m/z＝807.7(M+1).
实施例5、化合物5的合成
Figure PCTCN2020138944-appb-000023
500ml三颈烧瓶中加入二氯甲烷(200ml)，加入化合物SZY1402-14(10g)搅拌溶解，依次加入Boc-氨基丁酸(5.63g)、EDCI(5.3g)和DMAP(5.1g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到10.0g白色泡沫状固体05-1。
Figure PCTCN2020138944-appb-000024
500ml三颈烧瓶中加入乙酸乙酯(100ml)，加入化合物05-1(10g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(100ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体盐酸盐，滤饼先经EA淋洗,后经EA浆洗除HCl，抽滤，滤饼经减压旋干得到10g白色粉末状固体化合物5。
1HNMR CH 3OHδ:8.91(s,1H),8.20(s,1H),7.85-7.82((d,J＝9.2Hz,2H),7.76-7.74(d,J＝8.4Hz 1H),7.63-7.59(m,3H),7.46-7.44(d,J＝9.2Hz,1H),7.31-7.29(d,J＝8.8Hz,2H),7.16-7.13(d,J＝8.8Hz,2H),5.38-5.35(m,1H)，5.20-5.10(m,2H)，4.51-4.46(m,2H)，4.23-4.19(m,1H)，4.05(m,3H)，3.9(m,4H)，3.85(m,8H)，2.74(s,3H)，2.04(s,1H)，1.49-1.47(d,J＝7.2Hz,3H),1.41-1.40(d,J＝6.4Hz,3H).
LC-MS:m/z＝807.7(M+1).
实施例6、化合物6的合成
Figure PCTCN2020138944-appb-000025
500ml三颈烧瓶中加入二氯甲烷(200ml)，加入化合物SZY1402-14(10g)搅拌溶解，依次加入Boc-N甲基氨基丁酸(6.02g)、EDCI(5.3g)和DMAP(5.1g)，室温搅拌反应6h。TLC中控至反应完毕。反应液经饱和NH 4Cl洗和饱和食盐水水洗，分液，有机相减压浓缩至呈油状，经制备液相纯化得到10.0g白色泡沫状固体06-1。
Figure PCTCN2020138944-appb-000026
500ml三颈烧瓶中加入乙酸乙酯(100ml)，加入化合物06-1(10g)搅拌溶解，溶液为澄清溶液，搅拌下逐滴滴加2N的HCl/EA(100ml)，随着HCl/EA的加入，溶液中有白色浑浊生成，室温搅拌反应2h，TLC点板反应完毕。抽滤，得到白色固体盐酸盐， 滤饼先经EA淋洗,后经EA浆洗除HCl，抽滤，滤饼经减压旋干得到10g白色粉末状固体化合物6。
1HNMR CH 3OHδ:10.07(s,1H),8.91(s,1H),8.20(s,1H),7.85-7.82((d,J＝9.2Hz,2H),7.76-7.74(d,J＝8.4Hz 1H),7.63-7.59(m,3H),7.46-7.44(d,J＝9.2Hz,1H),7.31-7.29(d,J＝8.8Hz,2H),7.16-7.13(d,J＝8.8Hz,2H),5.38-5.35(m,1H)，5.20-5.10(m,2H)，4.51-4.46(m,2H)，4.23-4.19(m,1H)，4.05(m,5H)，3.9(m,4H)，3.85(m,8H)，2.74(s,3H)，2.04(s,1H)，1.49-1.47(d,J＝7.2Hz,3H),1.41-1.40(d,J＝6.4Hz,3H).
LC-MS:m/z＝821.7(M+1).
实施例7、溶解度测试
实施例1-6化合物在溶剂是水(pH＝5-6)、甲醇、乙酸乙酯、二氯甲烷的溶解度(表1)
表1实施例1-6化合物在不同溶剂中的溶解度
Figure PCTCN2020138944-appb-000027
实施例8、实施例化合物的稳定性的测试
色谱条件
色谱柱：Waters Xbridge Shield RP C18(4.6×150mm 5μm)
检测波长：254nm
流速：1ml/min
进样量：10μL
柱温：30℃
梯度：A：0.05％磷酸水溶液B：乙腈
表2洗脱流程
时间/min A/％ B/％
0 90 10
20 10 90
25 10 90
26 90 10
35 90 10
样品配制：样品用纯化水溶解并稀释至0.5mg/mL
1、在2-8℃、pH＝5-6时实施例化合物水溶液各时间点的的稳定性，结果如下(HPLC检测的主峰的纯度，％)：
表3实施例化合物水溶液各时间点的的稳定性(2-8℃、pH＝5-6)
Figure PCTCN2020138944-appb-000028
2、室温下(25℃)、pH＝5-6时实施例化合物水溶液各时间点的的稳定性，结果如下(HPLC检测的主峰的纯度，％)：
表4实施例化合物水溶液各时间点的的稳定性(室温下(25℃)、pH＝5-6)
Figure PCTCN2020138944-appb-000029
Figure PCTCN2020138944-appb-000030
在pH＝5-6时，2-8℃时水溶液的稳定性优于室温时的稳定性，能够满足制备注射液剂型的临床需要。
实施例9、化合物在血浆稳定性试验
色谱条件
色谱柱：Waters Xbridge Shield RP C18(4.6×150mm 5μm)
检测波长：254nm
流速：1ml/min
进样量：10μL
柱温：30℃
梯度：A：0.05％磷酸水溶液B：乙腈
表5洗脱流程
时间/min A/％ B/％
0 90 10
20 10 90
25 10 90
26 90 10
35 90 10
在37℃条件下将实施例化合物加入到采集的新鲜人全血中，初始孵育浓度为均为10ug/ml，分别在0、0.083、0.25、0.5、1、2、4h后采样，检测血浆中式1化合物的浓度，结果如下(ng/ml)：
Figure PCTCN2020138944-appb-000031
Figure PCTCN2020138944-appb-000032
表6血浆中式1化合物的浓度
Figure PCTCN2020138944-appb-000033
实施例1-6化合物在全血孵育中均能够部分代谢为式1化合物，化合物1-6可以成为式1的前体药物。
实施例10、实施例化合物的溶液刺激性实验
实施例化合物的注射液肌肉刺激性试验
试验用6只新西兰兔，采用同体左右侧肌肉股四头肌自身对比法，每侧股四头肌内注射给药1.0mL/只，每日一次，连续3天，各给药组给予相应浓度的实施例化合物和注射用水配制的溶液，浓度为1.88mg/mL，右侧给予等体积0.9％(0.9g/100ml)氯化钠注射液作对照。兔于末次给药后48小时剖检，肉眼观察兔的双侧注射部位深层肌肉组织质地富有弹性、光泽，未见红肿、充血等刺激反应症状；病理组织学检查，兔的双侧注射部位深层肌肉组织均未见变性或坏死等显著刺激性反应。说明实施例1-6制备的注射液肌肉刺激性试验符合规定。具体实验方法和实验结果如下：
受试物的配制：
取实施例1-6制备的注射液(4mL:94mg/瓶)1瓶，吸出1.0mL后用0.9％氯化钠注射液稀释至12.5mL，使成浓度为1.88mg/mL的溶液。
动物称重：给药前及末次给药后48小时和14天各称重一次。
给药方法：
取健康的新西兰白兔，以无菌操作法分别于兔左侧股四头肌内注射受试物，于右侧股四头肌内注射等体积0.9％氯化钠注射液作对照。
试验观察：
每天给药前观察并记录动物和肌肉注射部位的反应，末次给药48小时后，取受试动物，放血处死，解剖暴露股四头肌，纵向切开，肉眼观察并记录注射部位的刺激反应情况，然后将注射部位肌肉作病理组织学检查。
结果判定：
根据肉眼观察和组织病理的检查结果进行综合判断。
试验结果：。
实施例化合物配制的溶液对兔肌肉刺激反应(肉眼观察结果)
Figure PCTCN2020138944-appb-000034
兔的肉眼观察时间为末次给药后48小时
表8实施例化合物注射液对兔肌肉刺激反应(病理观察)
Figure PCTCN2020138944-appb-000035
Figure PCTCN2020138944-appb-000036
末次给药后48小时，肉眼观察和病理报告结果表明实施例化合物溶液对新西兰兔注射部位肌肉未见变性坏死等明显刺激性变化。
实施例1-6化合物溶液(7.5和22.5mg/kg·bw)对豚鼠全身主动过敏试验阴性；实施例1-6化合物溶液(1.88mg/mL)对兔耳缘静眿血管及周围组织无刺激性；实施例1-6化合物溶液(1.88mg/mL)对兔注射部位肌肉组织无刺激性；实施例化合物1-6溶液(1.88mg/mL)对兔体外溶血试验阴性。
实验表明实施例化合物1-6具有适宜的溶解度、溶液稳定性满足要求、溶液无刺激性、无过敏性、无溶血性，适于制备注射液等液体剂型使用。
实施例11、实施例化合物抗真菌体内实验：
阳性对照药：伊曲康唑注射液，规格25ml:0.25g,意大利GlazoSmithkline ManufacturingS.p.A生产，产品批号：14KQ163；
CR小鼠(清洁级)扬州大学比较医学中心提供，6周龄，体重18.0～20.0g,随机分组；每组10只，雌雄各半，同时设立实验组、阳性对照组、感染对照组。
感染菌种：白念珠菌ATCC5314,由中国医学真菌保藏中心提供。
感染途径：小鼠尾静脉一次性攻击。
将经动物体内恢复毒力的白念珠菌ATCC5314经沙堡琼脂培养基传代后30℃孵育48小时，新鲜成熟的菌落用生理盐水洗下，经血球计数板计数后，调整浓度至2.0×10 7cfu/ml、1.0×10 7cfu/ml、2.0×10 6cfu/ml、1.0×10 6cfu/ml、2.0×10 5cfu/ml。作为本次感染尾静脉攻击时的菌量，每只小鼠的注射量为0.5ml/只，测定动物死亡天数，确定7天内小鼠100％死亡最小感染菌量(100％MLD)菌量。经测定0.5×10 7/只，平均存活天数7.2±2.216(n＝10)天。以此剂量作为实施例化合物对白念珠菌ATCC5314系统感染保护试验的尾静脉一次性攻击药量。
实施例化合物对白念珠菌系统感染的保护试验：
给药剂量：阳性对照药-伊曲康唑注射液5mg/kg，六组实施例试验药按照等摩尔给药，分别为实验1-6组，预试验和正式试验分别同时设立感染对照，一次性静脉给予0.9％Nacl溶液。
于小鼠尾静脉菌攻击后2小时内给药，给药剂量按每只小鼠平均体重约20.0g计算，溶于0.5ml0.9％NaCl溶液中，尾静脉一次性给药；感染对照组给予0.9％NaCl溶液作为安慰剂。
感染对照全部死亡时，统计各组存活动物数，再进行数据统计。
实施例化合物和阳性对照药伊曲康唑注射液对小鼠白念珠菌ATCC5314系统感染模型的保护试验结果见下表。
Figure PCTCN2020138944-appb-000037
化合物1-6在血浆中能够部分通过酶的孵育转化成伊曲康唑，与式Ⅰ所示化合物具有类似的抗真菌活性，实施例11验证了化合物1-6对小鼠白念珠菌ATCC5314的抑制作用。
工业应用
与式1所示化合物具有类似的抗真菌活性，我们制备了系列化合物，通过筛选获得实施例1-6化合物，实施例1-6化合物具有较好的溶解性，在pH5-6时的溶解度能够满足制备注射液的要求，在pH5-6时化合物1-6配制的溶液在2-8℃时较室温更稳定，所制备的溶液在血浆中能够部分通过酶的孵育转化成伊曲康唑，说明化合物1-6可以成为式Ⅰ所示化合物的前体药物，由化合物1-6所制备的溶液无刺激性、溶血性，适于制备成注射液。

Claims (9)

  1. 一种化合物，其结构式如式Ⅰ所示：
    Figure PCTCN2020138944-appb-100001
    式Ⅰ中，n为0-4的整数；
    n为0时，R 1为甲基，R 2为H；
    n为1-4的整数时，R 1为H、-CH 3或-C 2H 5，R 2为H或NH 2。
  2. 根据权利要求1所述的化合物，其特征在于：式Ⅰ所示化合物具有代表意义的形式如下：
    Figure PCTCN2020138944-appb-100002
    Figure PCTCN2020138944-appb-100003
  3. 权利要求1或2所述化合物药学上可接受的盐或其光学异构体。
  4. 制备权利要求1中式Ⅰ所示化合物的方法，包括如下步骤：
    使得式Ⅱ所示化合物与式Ⅲ所示化合物发生酯化反应，得到式Ⅰ所示化合物；
    Figure PCTCN2020138944-appb-100004
    式Ⅲ中，n为0-4的整数；
    n为0时，R 1为甲基，R 2为H；
    n为1-4的整数时，R 1为H、-CH 3或-C 2H 5，R 2为H或NH 2。
  5. 权利要求1或2中任一项所述化合物在制备抗真菌药物或制备预防和/或治疗由真菌引起的疾病的药物中的应用。
  6. 根据权利要求5所述的应用，其特征在于：所述真菌为：念珠菌属、隐球菌属、曲霉属真菌。
  7. 一种用于抗真菌的液体制剂，所述用于抗真菌的液体制剂以权利要求1或2中式Ⅰ所示化合物或其药学上可接受的盐或光学异构体为活性成分。
  8. 根据权利要求7所述的液体制剂，其特征在于：所述液体制剂以水为溶剂，不含助溶剂。
  9. 根据权利要求7或8所述的液体制剂，其特征在于：所述液体制剂为注射剂。
PCT/CN2020/138944 2019-12-26 2020-12-24 抗真菌水溶性前药及其制备方法 WO2021129723A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911363413.5A CN111138421A (zh) 2019-12-26 2019-12-26 抗真菌水溶性化合物及其制备方法与应用
CN201911363413.5 2019-12-26

Publications (1)

Publication Number Publication Date
WO2021129723A1 true WO2021129723A1 (zh) 2021-07-01

Family

ID=70520273

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/138944 WO2021129723A1 (zh) 2019-12-26 2020-12-24 抗真菌水溶性前药及其制备方法

Country Status (2)

Country Link
CN (2) CN111138421A (zh)
WO (1) WO2021129723A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111138421A (zh) * 2019-12-26 2020-05-12 上海英诺富成生物科技有限公司 抗真菌水溶性化合物及其制备方法与应用
CN114195754B (zh) * 2021-12-28 2023-05-23 苏州昊帆生物股份有限公司 R-甘油缩丙酮中间体及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1236366A (zh) * 1997-02-11 1999-11-24 詹森药业有限公司 含氨基酸酯之唑类抗真菌剂
CN102369198A (zh) * 2008-09-08 2012-03-07 N·吴 三唑抗真菌剂
CN111138421A (zh) * 2019-12-26 2020-05-12 上海英诺富成生物科技有限公司 抗真菌水溶性化合物及其制备方法与应用

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL181947B1 (en) * 1994-01-24 2001-10-31 Janssen Pharmaceutica Nv Water-soluble azole-type antimycotic agents
EP0942907A1 (en) * 1996-11-12 1999-09-22 Sepracor, Inc. 2r, 4s, s, r- and 2s, 4r, s, r-hydroxyitraconazole
ATE286502T1 (de) * 1997-09-25 2005-01-15 Schering Corp Tetrahydrofuran-phosphat- und hydroxy-ester als prodrugs der entsprechenden antifungiziden mittel
EP0957101A1 (en) * 1998-05-14 1999-11-17 Janssen Pharmaceutica N.V. Water soluble azoles as broad-spectrum antifungals
CA2372691C (en) * 1999-05-04 2009-11-17 Janssen Pharmaceutica N.V. Antifungal ethers
WO2001054481A2 (en) * 2000-01-28 2001-08-02 Rohm And Haas Company Enhanced propertied pharmaceuticals
KR20090049001A (ko) * 2007-11-12 2009-05-15 류성열 아미노벤조익 산 유도체를 이용한 이트라코나졸 항진균유도체 합성 및 그 용도
WO2013036866A1 (en) * 2011-09-07 2013-03-14 The Johns Hopkins University Itraconazole analogs and use thereof
CN104151304B (zh) * 2014-07-23 2016-08-17 王庚禹 一种三唑类化合物
WO2017133632A1 (zh) * 2016-02-04 2017-08-10 武汉朗来科技发展有限公司 泊沙康唑衍生物、其药物组合物和用途
CN108329304B (zh) * 2018-04-08 2020-12-08 梯尔希（南京）药物研发有限公司 一种伊曲康唑衍生物的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1236366A (zh) * 1997-02-11 1999-11-24 詹森药业有限公司 含氨基酸酯之唑类抗真菌剂
CN102369198A (zh) * 2008-09-08 2012-03-07 N·吴 三唑抗真菌剂
CN111138421A (zh) * 2019-12-26 2020-05-12 上海英诺富成生物科技有限公司 抗真菌水溶性化合物及其制备方法与应用

Also Published As

Publication number Publication date
CN111138421A (zh) 2020-05-12
CN112521378A (zh) 2021-03-19

Similar Documents

Publication Publication Date Title
JP3519754B2 (ja) 環状ペプチド抗真菌剤およびその製法
KR100655808B1 (ko) 혈관 손상제로서 콜치놀 유도체, 그것의 용도 및 제조 방법
WO2021129723A1 (zh) 抗真菌水溶性前药及其制备方法
US10703729B2 (en) Pyrazine derivative, and preparation method and medical use thereof
JP2018048178A (ja) オキサビシクロヘプタン類、および再灌流障害の治療のためのオキサビシクロヘプタン類
TW201441186A (zh) 用於治療纖維化之經取代之芳族化合物及相關方法
EA021897B1 (ru) Циклические пептиды, специфичные к рецептору меланокортина-1
EP2753613B1 (en) Derivatives of xanthone compounds
EP3760626B1 (en) Novel compound and composition for preventing, ameliorating, or treating fibrosis or nonalcoholic steatohepatitis comprising same as active ingredient
JP2018502909A (ja) オキサチアジン様化合物を作製する方法
WO2004024140A1 (en) Efflux pump inhibitors
AU2020260489A1 (en) Chiral peptides
JPH09500103A (ja) シクロヘキサペプチジルアミノアルキルエーテル
EP1919868B1 (en) New hybrid oligomers. their preparation process and pharmaceutical compositions containing them
WO2008009138A1 (en) Chlorogenic acid derivatives and their use as anti-fungal agents
RU2429843C2 (ru) Фармацевтическая композиция, включающая производное фениламидина, и способ применения фармацевтической композиции в комбинации с противогрибковым средством
WO2021098715A1 (zh) 一种吩噻嗪类铁死亡抑制剂及其制备方法和用途
BRPI0810192B1 (pt) aspartato do ácido 1-ciclopropil-6-fluoro-7-(8-metoxiimino-2,6-diaza-espiro [3,4] oct-6-il)-4-oxo-1,4-diidro- [1,8] naftiridina-3-carboxílico, método para preparação do mesmo e composição farmacêutica antimicrobiana compreendendo o mesmo.
CN109956868B (zh) 一类苯基羧酸衍生物、其制备方法及其用途
CN115135646B (zh) 取代的多环化合物及其药物组合物和用途
EP3502095A1 (en) Compound for use against pathogenic neisseria and haemophilus species and moraxella catarrhalis
CN113527281B (zh) 杂环化合物及其制备方法和应用
DE112011103711T5 (de) Caspofungin-Analogen Herstellungsverfahren dafür und Verwendung desselben
CN113214238A (zh) 一类具有酰化哌嗪结构的吲哚恶二唑衍生物的制备和用途
JPH10101566A (ja) 網膜保護剤

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: 20905791

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20905791

Country of ref document: EP

Kind code of ref document: A1