WO2023065667A1 - 新型氘代苯并噻唑类化合物、其制备方法、组合物及应用 - Google Patents
新型氘代苯并噻唑类化合物、其制备方法、组合物及应用 Download PDFInfo
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- WO2023065667A1 WO2023065667A1 PCT/CN2022/095404 CN2022095404W WO2023065667A1 WO 2023065667 A1 WO2023065667 A1 WO 2023065667A1 CN 2022095404 W CN2022095404 W CN 2022095404W WO 2023065667 A1 WO2023065667 A1 WO 2023065667A1
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- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
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- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- 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 invention relates to a novel deuterated benzothiazole compound, its preparation method, pharmaceutical composition and application.
- R 1 to R 14 are combinations of “hydrogen” isotopes (including isotopes “protium” and “deuterium”).
- the present invention contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein.
- the pharmaceutical compositions are in the form of tablets, capsules, pills, or aqueous buffers, such as saline or phosphate buffers.
- the invention designs and discloses a novel deuterated benzothiazole compound, which realizes better pharmacokinetic properties and therapeutic effects than YH-53 on the basis of equivalent virus inhibitory activity, and better druggability.
- the preparation method, pharmaceutical composition and application thereof are disclosed, the production scale-up of the medicine can be realized, the quality is controllable, and the medicine has good clinical value.
- Compound 2 can be synthesized according to the representative route described in Example 1.
- Compound 14 can be synthesized according to the representative route described in Example 1
- Compound 21 can be synthesized according to the representative route described in Example 1
- Compound 23 can be synthesized according to the representative route described in Example 1
- Compound 25 can be synthesized according to the representative route described in Example 1
- Compound 25 can be synthesized according to the representative route described in Example 1
- Compound 28 can be synthesized according to the representative route described in Example 1
- Compound 29 can be synthesized according to the representative route described in Example 1
- Compound 30 can be synthesized according to the representative route described in Example 1
- Compound 31 can be synthesized according to the representative route described in Example 1
- Compound 32 can be synthesized according to the representative route described in Example 1
- Compound 33 can be synthesized according to the representative route described in Example 1
- Compound 34 can be synthesized according to the representative route described in Example 1
- Compound 35 can be synthesized according to the representative route described in Example 1
- Compound 36 can be synthesized according to the representative route described in Example 1
- Compound 37 can be synthesized according to the representative route described in Example 1
- Compound 39 can be synthesized according to the representative route described in Example 1
- Compound 40 can be synthesized according to the representative route described in Example 1
- Compound 44 can be synthesized according to the representative route described in Example 1
- Compound 45 can be synthesized according to the representative route described in Example 1
- Compound 46 can be synthesized according to the representative route described in Example 1
- Compound 46 can be synthesized according to the representative route described in Example 1
- This example is the antiviral activity of compound S-217622, compound 45, compound 13, compound 37 and compound 42 against SARS coronavirus, MERS coronavirus and HCoV human coronavirus.
- the antiviral activity of compound S-217622, compound 45, compound 13, compound 37 and compound 42 against SARS coronavirus, MERS coronavirus and HCoV human coronavirus was studied on Vero E6 and Vero76 cell lines.
- the neutral red assay was used to determine virus-induced and compound-induced cytopathic inhibition (CPE), and the EC 50 , EC 90 , and CC 50 values of the compounds were calculated.
- CPE virus-induced and compound-induced cytopathic inhibition
- the test compound was dissolved in DMSO at a concentration of 10 mg/mL and serially diluted with 8 half-log diluents up to a maximum test concentration of 50 ⁇ g/mL (86 ⁇ M).
- each dilution was added to 5 wells of a 96-well plate containing 80-100% confluent Vero E6 or Vero76 cells.
- 3 wells were infected with virus, and 2 wells were not infected as toxicity control. 6 wells were untreated and infected as virus control.
- SARS, MERS, and HCoV human coronaviruses the viruses were diluted to MOIs of 0.003, 0.002, 0.001, and 0.03 50% cell culture infectious dose per cell, respectively. Incubate the plate at 37 °C in an incubator with 5% CO2 .
- This embodiment is the detection of inhibition of protease activity targeting SARS-CoV-2 virus M Pro
- the replicase polypeptide needs to be further cut into multiple proteins (such as RdRp, helicase, etc.), and further assembled into the replication transcription machinery required for the virus to initiate the replication of its own genetic material.
- M Pro has at least 11 cleavage sites on the replicase polypeptide, and only when these sites on the replicase polypeptide are cut normally, it is assembled into a replication transcription machine and starts virus replication.
- M Pro protease is very important in the process of virus replication, and there is no similar protein in the human body, the main protease M Pro becomes a potential key drug target against the new coronavirus.
- the inhibitory activity of nucleoside derivatives against SARS-CoV-2-M Pro protease was evaluated by fluorescence resonance energy transfer method.
- the volume of the entire enzymatic reaction system is 120 ⁇ L
- the final concentration of protease is 30 nM
- the final concentration of substrate is 20 ⁇ M
- the buffer solution of the reaction system includes 50 mM Tris, pH 7.3 1 mM EDTA.
- the test time is 10min, and the fluorescence value is read every 30s.
- Plasma samples were processed using a protein precipitation method using acetonitrile:methanol containing 500:50, containing propranolol (50ng/ml) as an internal standard, and then according to a standard curve prepared in blank plasma ( 0.1-2500ng/ml) for quantification. Analytes in plasma samples were quantified using LC-MS/MS. Briefly, a Waters ACQUITY Ultra Performance Liquid Chromatography System coupled to a Sciex 6500 Triple Quadrupole Mass Spectrometer was used. Chromatographic separation was accomplished using a Waters Acquity UPLC BEH C18 column (1.7m, 2.150mm). Optimize mobile phases to achieve good separation between analytes.
- solvent A consisted of 0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (95:5 v/v) and solvent B consisted of 0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (5:95 v/v).
- the gradient generally starts at 3-30% B until approximately 1.2 minutes, then increases to 50-65% B to 1.6 minutes, then decreases to 10-30% B until approximately 1.7-1.9 minutes.
- Analyst 1.7 software was used for peak integration and standard curve regression.
- the pharmaceutical carriers used in oral tablets include regulators, fillers, binders, disintegrants, additives, glidants, lubricants, film coating materials, plasticizers, coloring agents, and the like.
- Compound 6 was ground and sieved according to the above formula, and then mixed evenly with fillers, disintegrants, regulators and additives that had been ground and sieved, and 10% starch slurry was added to make a soft material in a blender.
- the material is made into wet granules on a swinging machine, dried in an oven, mixed evenly with a lubricant, and pressed into tablet cores.
- the tablet core is made into a film-coated tablet with Opadry.
- the pharmaceutical carriers used in capsules include fillers, binders, disintegrants, additives, lubricants and the like.
- compound 6 and various auxiliary materials were ground and sieved, mixed with fillers, binders and disintegrants in a certain proportion, added to a dry granulator and pressed into strips, and then crushed by a crusher to produce into particles.
- the granules are evenly mixed with an appropriate amount of lubricant and disintegrant, and then filled into capsules.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
公开了一种如式I所示的新型氘代苯并噻唑类化合物,或其药学上可接受的盐、异构体或前药。还公开了上述氘代化合物的制备方法、组合物及应用。该类化合物作为3CL蛋白酶抑制剂,在病毒抑制活性相当的基础上,实现了更优的药动学性质和治疗效果,成药性更好。如式I如下所示:
Description
本发明属于医药领域,具体地,涉及新型氘代苯并噻唑类化合物、其制备方法、组合物及应用,上述药物组合物用于制备治疗和预防病毒感染的药物。
人体内的冠状病毒最早于1960年代在英国被分离出来,病毒因其表面皇冠状的突起物而得名。它可能与人、猪、猫、狗、鼠和鸡的呼吸系统感染相关。SARS病毒属于套式病毒目、冠状病毒科、冠状病毒属,为β属B亚群冠状病毒。病毒粒子多呈圆形,有囊膜,外周有冠状排列的纤突,分布于细胞浆中,呈圆形,病毒直径在80~120nm之间。SARS是一种起病急、传播快、病死率高的传染病,被传染的病人多数都与患者直接或间接接触,或生活在流行区内。MERS病毒是一种β属C亚群冠状病毒,全名为中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome Coronavirus,简称MERS-CoV),感染后引发中东呼吸综合征(Middle East Respiratory Syndrome,简称MERS)。MERS-CoV最早于2012年9月在沙特被发现,早期因与SARS临床症状相似得名“类SARS病毒”,也成为第6种已知的人类冠状病毒,也是过去10年内被分离出来的第3种。新型冠状病毒是以前从未在人体中发现的冠状病毒新毒株,2019年首次被发现并报道,至今仍然在全球多个国家流行肆虐,并在很多国家区域并未得到很好的控制。
人感染了冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中,感染可导致肺炎、严重急性呼吸综合征、肾衰竭,甚至死亡。对于新型冠状病毒所致疾病没有特异治疗方法。
Sho Konno等人报告发现了三肽型3CL蛋白酶抑制剂具有抗SARS-CoV病毒活性,Bioorg.Med.Chem.2013,21,412-424;同年在Eur.J.Med.Chem.2013,68,372-384报道了系列二肽型同靶点化合物作为3CL蛋白酶抑制剂对SARS-CoV的抑制效果。
2021年,Sho Konno等人系统研究了带亲电弹头的二肽候选化合物YH-53作为SARS-CoV-2抑制剂的临床前成药性和有效性,并顺利进入临床II-III期研究。但该药物在大鼠中口服绝对生物利用度较低,仅有3.55%,原因为该分子结构P1-P2中酰胺键由于首过效应在体内发生水解代谢。该药物的临床药动学性质和代谢安全性有待改进。
因此,本领域仍需要开发具有更好抑制活性或药代动力学性质的新型3CL蛋白酶抑制剂类化合物,本发明设计、公开了新型氘代苯并噻唑类化合物,在病毒抑制活性相当的基础上,实现了比YH-53更优的药动学性质和治疗效果,成药性更好。同时公开了其制备方法、药物组合物和应用,可实现该药物的生产放大,且质量可控,具有较好的临床价值。
公开内容
本发明涉及新型氘代苯并噻唑类化合物、其制备方法、药物组合物及应用。
在某些实施方案中,本发明涉及具有式I的化合物,
或其药学上可接受的盐、异构体或前药。
其中R
1~R
14为“氢”同位素(包括同位素“氕”和“氘”)的组合。
上述的化合物,其特征在于,R
1~R
3中至少2个是氘;R
9~R
14均为氘;R
4~R
5均为氘;R
6~R
8中至少2个是氘。
本发明公开了氘代苯并噻唑类化合物的制备方法,其包括下列步骤:
(1)碱性条件下,通式化合物I-1经Boc保护后与甲氧基甲胺盐酸盐在缩合剂作用下缩合反应得到Weinreb酰胺I-3;
(2)无水无氧条件下,2-溴苯并噻唑经锂卤交换得金属试剂后与中间体I-3进行亲核加成消除反应,制备通式化合物I-4,酸性条件下,脱保护后得到中间体I-5;
(3)在有机溶剂中,通式化合物I-6与通式化合物I-7进行缩合反应,在碱性条件下水解,制得通式中间体I-9;
(4)在有机溶剂中,在缩合剂作用下,通式中间体I-9与通式化合物I-5进行缩合反应,制得通式I的氘代苯并噻唑环类化合物。
本发明公开了一种药物组合物,其特征在于,它含有药学上可接受载体和式I所述化合物,或其药学上可接受的盐。
本发明公开了一种药物组合物,其特征在于,它包含另外的治疗药物,所述的另外的治疗药物为抗病毒药物。
本发明公开了上述药物组合物的用途,其特征在于,用于制备抑制3CL蛋白酶的药物组合物。
本发明公开了上述药物组合物的用途,其特征在于,所述的药物组合物用于制备治疗和预防病毒感染的药物。
本发明公开了上述药物组合物的用途,其中所述病毒感染是人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒。
在各个不同的实施方案中,所述化合物具有以下表1中所示的结构之一。
表1代表性化合物
在某些实施方案中,本发明考虑了包含药学上可接受的赋形剂和本文公开的化合物的药物组合物。在某些实施方案中,药物组合物为片剂、胶囊剂、丸剂或含水缓冲剂,例如盐水或磷酸盐缓冲剂的形式。
在某些实施方案中,公开的药物组合物可包含本文公开的化合物和推进剂。在某些实施方案中,推进剂是气溶胶化推进剂,例如压缩空气、乙醇、氮气、二氧化碳、一氧化二氮、氢氟烷烃(HFA)、1,1,1,2-四氟乙烷、l,1,l,2,3,3,3-七氟丙烷或其组合。
在某些实施方案中,本发明考虑了包含本文所述的化合物或药物组合物的加压容器或非加压容器。在某些实施方案中,容器是手动泵喷雾器、吸入器、计量吸入器、干粉吸入器、喷雾器、振动筛网喷雾器、喷射喷雾器或超声波喷雾器。
在某些实施方案中,化合物或药物组合物口服施用、静脉内施用或通过肺部,即肺部施用。
在某些实施方案中,本发明涉及本文所述的化合物在制备用于治疗或预防病毒感染的药物中的用途,所述病毒感染例如为人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒感染。
在某些实施方案中,本发明涉及通过在形成本文公开的化合物的条件下混合本文公开的起始材料和试剂来制备化合物的方法。
本发明设计、公开了新型氘代苯并噻唑类化合物,在病毒抑制活性相当的基础上,实现了比YH-53更优的药动学性质和治疗效果,成药性更好。同时公开了其制备方法、药物组合物和应用,可实现该药物的生产放大,且质量可控,具有较好的临床价值。
以下详细的说明都仅是示例性和解释性的,而非限制性的。
以下实施例,除非另外指出,否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
以下描述的程序可用于合成化合物1~47。
本文采用了以下缩写:
LiHMDS:六甲基二硅基氨基锂
ACN:乙腈
THF:四氢呋喃
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯
Boc
2O:二碳酸二叔丁酯
CDI:N,N’-羰基二咪唑
DIEA:N,N-二异丙基乙胺
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐
DMAP:4-二甲氨基吡啶
制备实施例
实施例1:
代表性路线
(2S)-2-叔丁氧羰基氨基-3-[(3S)-2-羰基-3-吡咯烷-4,4-二氘代)]-丙酸(化合物A)的合成
1)化合物A-2的合成
化学式:C
14H
22N
2O
6
分子量:314
在-78℃的条件下,将双(三甲基硅基)氨基锂(78.5mL,1.0M的THF溶液,78.5mmol)缓慢滴加到N-Boc-L-(+)-谷氨酸二甲酯(A-1)(10g,36.4mmol)的无水THF(200mL)溶液中,并将所得溶液在此温度下搅拌30分钟。然后保持温度不变,缓慢滴加溴乙腈(3.4mL),将反应混合物在-78℃的条件下继续搅拌2小时。待反应完毕后,加入饱和氯化铵水溶液(50mL)淬灭反应,搅拌至室温。先减压旋除溶剂,然后加入水(200mL),用DCM(2*200mL)萃取水相,合并的有机相用无水硫酸钠干燥,然后浓缩,得到的粗产物柱层析(PE:EtOAc=2:1)纯化,得到化合物A-2(8.7g,收率76.3%),淡黄色油状液体。
1H-NMR(400MHz,CDCl
3)δ:ppm 5.14(d,J=6.0Hz,1H),4.38-4.40(m,1H),3.77(s,3H),3.76(s,3H),2.85-2.89(m,1H),2.74-2.82(m,2H),2.10-2.23(m,2H),1.45(s,9H)。
2)化合物A-3的合成
化学式:C
13H
20D
2N
2O
5
分子量:288
向2-叔丁氧羰基氨基-4-氰甲基-戊二酸二甲酯(A-2)(5.0g,15.9mmol)的氘代甲醇(80mL)溶液中加入氯化钴(1.0g,7.9mmol),然后在0℃条件下向所得到的粉红色混合物中分多次加入氘代硼氢化钠(6.0g,59.5mmol),室温搅拌18小时。加入饱和氯化铵水溶液30mL淬灭反应,搅拌10分钟。抽滤除去固体杂质,减压蒸除溶剂。加入水,用DCM从水相中萃取,合并的有机相用无水硫酸钠干燥,然后浓缩,得到的粗产品柱层析纯化(EtOAc),得到化合物A-3(2.8g,产率60.9%),为白色泡沫状固体。
1H-NMR(400MHz,CDCl
3)δ:ppm 4.30-4.29(m,1H),3.74(s,3H),2.50-2.43(m,1H),2.12-2.13(m,2H),1.86-1.80(m,1H),1.44(s,9H)。
3)化合物A的制备
化学式:C
12H
18D
2N
2O
5
分子量:274
往化合物A-3(1.2g,4.2mmol)的THF(3mL),ACN(3mL)和水(3mL)的混合溶剂中加入LiOH.H2O(176.4mg,4.2mmol,1.0eq).反应混合物于25℃搅拌反应2小时。反应结束后,浓缩,盐酸调pH值至4,乙酸乙酯萃取,有机相用饱和氯化钠洗涤。有机相减压浓缩得(2S)-2-(叔丁氧羰基氨基)-3-[(3S)-2-氧代吡咯烷酮基]丙酸(1.0g,收率83.3%),化合物A,油状物。
LCMS(ESI),mass calculated for C
12H
18D
2N
2O
5 274.31,m/z found 219.1[M+H-56]。
实施例2:
代表性路线
4-(甲氧基-D3)-1H-吲哚-2-甲酸(化合物B)的合成
1)化合物B-2的制备
化学式:C
11H
8D
3NO
3
分子量:208
往化合物B-1(2.5g,13.1mmol)的THF(25mL)的溶液中加入DBU(2.4g,15.7mmol),搅拌反应1小时后,加入CD3Cl(1.9g,15.7mmol),并于20-30℃保温搅拌反应24小时。将反应液倒入水中,搅拌分液,水相再用THF萃取,合并有机相,硅胶拌样,柱层析纯化得化合物B(2.1g),收率77.8%,白色固体。
1H NMR(400MHz,CD
3Cl)δ7.73(s,1H),7.30~7.24(m,2H),6.94(d,J=6.2Hz,1H),3.96(s,3H)。
2)化合物B的制备
化学式:C
10H
6D
3NO
3
分子量:194
往化合物B-2(1.8g,8.7mmol)的THF(18mL)和水(3mL)的混合溶剂中加入LiOH.H2O(0.37g,8.7mmol).反应混合物于25℃搅拌反应2小时。反应结束后,浓缩,盐酸调pH值至4,乙酸乙酯萃取,有机相用饱和氯化钠洗涤。有机相减压浓缩得4-(甲氧基-D3)-1H-吲哚-2-甲酸(化合物B)(1.4g),收率82.4%,白色固体。
1H NMR(400MHz,CD3Cl)δ7.75(s,1H),7.35-7.20(m,2H),6.97(m,1H)。
实施例3:
代表性路线
2-氘代-L-亮氨酸的制备(化合物C)
化学式:C
6H
12DNO
2
分子量:132
往氢化瓶内投入L-亮氨酸(1.2g,9.2mmol)、Ru/C(60mg,5wt%),NaOH(1.1g,27.6mmol)和重水(20mL)。氢气置换3次,于0.1-0.12MPa,70-75℃保温反应72小时。HNMR监测反应进程。反应结束后,降至室温,过滤,滤液调pH值至5-6,乙酸乙酯萃取,有机相减压浓缩得2-氘代-L-亮氨酸(1.1g),收率91.7%HNMR(400MHz,D2O)δ:ppm 3.64(m,4H),1.70-1.61(m,3H),0.99-0.92(m,6H)
LCMS(ESI):m/z,calculated for C
6H
12DNO
2,132.18,found 133.18,M+H。
实施例4
化合物6的制备
代表性合成路线
1)化合物A2的制备
化学式:C
7H
12N
2O
3
分子量:172
往化合物A(10.0g,33.1mmol)的THF(100mL)和水(10mL)的混合溶剂中加入NaOH(2.0g,49.6mmol),于20-30℃保温搅拌2小时。反应结束后,将反应液倒入水中,6N盐酸调pH值至4-6,乙酸乙酯萃取,合并乙酸乙酯,饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,浓缩。往浓缩所得油状物中加入EtOAc(30mL),冰浴降温至0-10℃,加入4M的HCl(g)/EtOAc(50mL),自然升温反应12小时。过滤,收集析出固体得化合物A2的盐酸盐(5.1g),收率82.3%,白色固体。
1H NMR(400MHz,D
2O)δ:ppm 4.00-3.92(m,1H),3.41-3.36(m,2H),2.82-2.57(m,1H),2.13-2.09(m,2H),1.87-1.81(m,2H)
LCMS(ESI):m/z,calculated for C
7H
12N
2O
3,172,found 173,M+H。
2)化合物A3的制备
化学式:C
7H
11DN
2O
3
分子量:173
往氢化瓶内投入化合物A2(4.8g,27.9mmol)、Ru/C(240mg,5wt%),NaOH(3.3g,83.7mmol)和重水(50mL)。氢气置换3次,于0.1-0.12MPa,70-75℃保温反应52小时。HNMR监测反应进程。反应结束后,降至室温,过滤,滤液调pH值至5-6,EtOAc萃取,有机相减压浓缩得化合物A3(4.1g),收率85.4%
1H NMR(400MHz,D
2O)δppm:3.42-3.35(m,2H),2.82-2.57(m,1H),2.14-2.09(m,2H),1.87-1.82(m,2H)
LCMS(ESI):m/z,calculated for C
7H
11DN
2O
3,189,found 190,M+H。
3)化合物A4的制备
化学式:C
12H
19DN
2O
5
分子量:273
往化合物A3(3.8g,22.0mmol)的THF(40mL)和水(5mL)的混合溶剂中加入NaOH(1.8g,44.0mmol)。冰浴降温至0-10℃,缓慢加入Boc2O(5.3g,24.2mmol)的THF(10mL)溶液。保温反应2小时。监测反应完全后,将反应液倒入水中,2N盐酸调pH值至3-4,乙酸乙酯萃取,有机相合并,减压浓缩得粗品5.5g,直接用于下步反应。
LCMS(ESI):m/z,calculated for C
12H
19DN
2O
5,273.31,found 218.31,M+H-56。
4)化合物A5的制备
化学式:C
14H
24DN
3O
5
分子量:316
往化合物A4(5.0g,18.3mmol)的二氯甲烷(100mL)溶液中加入CDI(3.0g,18.3mmol)。反应液于0-10℃保温搅拌反应30min。加入DIEA(2.6g,19.8mmol)和N-甲基-O-甲基盐酸羟胺(1.8g,18.3mmol)。反应液升温至20-30℃保温搅拌反应3小时。反应结束后,倒入水中,乙酸乙酯萃取,硅胶拌样,柱层析纯化(PE:EtOAc=5:1to 0:1),得化合物A5(4.5g),收率77.6%,油状物。
LCMS(ESI):m/z,calculated for C
14H
24DN
3O
5,316.38,found 317.38,M+H。
5)化合物A6的制备
化学式:C
19H
22DN
3O
4S
分子量:390
于-78℃往2-溴苯并噻唑(3.6g,17.0mmol)的干燥THF(160mL)溶液中加入丁基锂(8.2mL,20.4mmol,2.5M),反应液于-78℃搅拌反应30min。随后加入化合物A5(3.8g,12.0mmol),所得混合液于-78℃保温反应1小时,用饱和氯化铵溶液淬灭,乙酸乙酯萃取,硅胶拌样,柱层析纯化(PE:EtOAc=10:1~0:1),得化合物A6(1.2g),收率25.5%,无色液体。
1H NMR(400MHz,CDCl
3)δ:(ppm)8.05–7.97(m,2H),7.48–7.41(m,2H),7.08(t,J=4.8Hz,1H),3.41–3.30(m,2H),2.52-2.45(m,1H),2.23–2.13(m,2H),1.87-1.81(m,2H),1.42(s,6H)。
LCMS(ESI):m/z,calculated for C
19H
22DN
3O
4S,390.48,found 391.15,M+H。
6)化合物A7的制备
化学式:C
14H
14DN
3O
2S
分子量:290
化合物A6(1.0g,2.6mmol)的EtOAc(5mL)溶液冰浴控温于0-10℃,加入HCl(g)/EtOAc(10mL),自然升温反应12小时。过滤收集析出的白色固体得化合物A7盐酸盐(0.8g),收率90%,白色固体。
LCMS(ESI):m/z,calculated for C
14H
14DN
3O
2S,290.36,found 291.10,M+H。
7)化合物C1的制备
化学式:C
7H
14DNO
2
分子量:146
往化合物C(5.0g,37.9mmol)的干燥甲醇(30mL)溶液中加入SOCl2(6.8g,56.9mmol),反应液升温至回流反应3小时,反应结束后,减压浓缩并用甲苯套蒸除去溶剂得白色固体化合物C1的盐酸盐(6.9g),收率接近100%。
LCMS:m/z,calculated for C
7H
14DNO
2,146.21,found 147.12,M+H。
8)化合物B1的制备
化学式:C
17H
18D
4N
2O
4
分子量:322
化合物B1(4.8g,24.7mmol)的DCM(50mL)溶液中加入EDCI(5.7g,29.6mmol)、DMAP(0.6g,4.9mmol),于20-30℃保温搅拌反应0.5小时。再加入化合物C1(4.5g,24.7mmol)和DIEA(9.6g,74.1mmol),20-30℃反应3小时。监测原料基本反应完全后,将反应液倒入水中,搅拌分液,水相再用水萃取,合并有机相,用饱和氯化钠、水洗涤。有机相硅胶拌样,柱层析纯化(PE:EtOAc=10:1~0:1)得化合物B1(6.5g),淡黄色油状物,收率81.3%。
1H NMR(400MHz,CDCl
3)δ:ppm 7.75(s,1H),7.30-7.25(m,2H),6.95-6.92(m,1H),3.67(s,3H),1.70-1.60(m,3H),0.94(d,J=6.8Hz,6H)
LCMS(ESI):m/z,calculated for C
17H
18D
4N
2O
4,322.40,found 323.19,M+H。
9)化合物B2的制备
化学式:C
16H
16D
4N
2O
4
分子量:308
往化合物B1(6.0g,18.6mmol)的THF(60mL)和水(10mL)的混合溶剂中加入LiOH.H2O(0.94g,22.3mmol).反应混合物于25℃搅拌反应2小时。反应结束后,浓缩,盐酸调pH值至4,乙酸乙酯萃取,有机相用饱和氯化钠洗涤。有机相减压浓缩得化合物B2(4.9g),收率86.0%,白色固体。
LCMS(ESI):m/z,calculated for C
16H
16D
4N
2O
4,308.37,found 309.17,M+H。
10)化合物6的制备
化学式:C
30H
28D
5N
5O
5S
分子量:580
于0-10℃,往化合物B2(1.0g,3.2mmol)的DMF(10mL)溶液中加入DIEA(2.1g,16.0mmol)和HBTU(1.5g,3.8mmol),保温搅拌反应30min。再加入化合物A7(0.9g,3.2mmol),升温至20-30℃反应2小时。反应结束后,将反应液倒入水中,乙酸乙酯萃取,水相再用乙酸乙酯萃取,合并有机相,硅胶拌样,柱层析纯化PE:EtOAc=10:1~0:1,得化合物6(1.1g),收率61.1%,淡黄色固体。
1H NMR(400MHz,CDCl
3)δ9.67(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.90-0.80(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
28D
5N
5O
5S,580.71,found 581.25,M+H。
实施例5
化合物1的合成
化学式:C
30H
28D
5N
5O
5S
分子量:580
化合物1可根据实施例1描述的代表性路线合成。
1H NMR(400MHz,CD3Cl)δ9.65(s,1H),8.14(s,1H),8.12–8.00(m,3H),7.80(s,1H),7.51–7.41(m,2H),7.35-7.25(m,2H),6.95-6.90(m,1H),4.83-4.80(m,1H),4.51–4.43(m,1H),2.50-2.46(m,1H),2.14-2.11(m,1H),2.09–1.97(m,2H),1.71–1.53(m,4H),0.90-0.80(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
28D
5N
5O
5S,580.71,found 581.25,M+H。
实施例6
化合物2的合成
化学式:C
30H
27D
6N
5O
5S
分子量:581
化合物2可根据实施例1描述的代表性路线合成。
1H NMR(400MHz,CD3Cl)δ9.65(s,1H),8.15(s,1H),8.12–8.00(m,3H),7.80(s,1H),7.52–7.41(m,2H),7.37-7.25(m,2H),6.95-6.91(m,1H),4.82–4.80(m,1H),2.50-2.46(m,1H),2.14-2.12(m,1H),2.09–1.97(m,2H),1.71–1.53(m,4H),0.90-0.80(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
27D
6N
5O
5S,581.72,found 582.25,M+H。
实施例7
化合物3的合成
化学式:C
30H
21D
12N
5O
5S
分子量:587
化合物3可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CD3Cl)δ9.65(s,1H),8.15(s,1H),8.12–8.00(m,3H),7.80(s,1H),7.52–7.41(m,2H),7.37-7.25(m,2H),6.95-6.91(m,1H),4.83–4.80(m,1H),2.50-2.46(m,1H),2.14-2.12(m,1H),2.09–1.97(m,2H),1.71–1.53(m,4H)
LCMS(ESI):m/z,calculated for C
30H
21D
12N
5O
5S,587.72,found 588.30,M+H。
实施例8
化合物4的合成
化学式:C
30H
22D
11N
5O
5S
分子量:586
化合物4可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CD3Cl)δ9.65(s,1H),8.15(s,1H),8.12–8.00(m,3H),7.80(s,1H),7.52–7.41(m,2H),7.37-7.25(m,2H),6.95-6.91(m,1H),4.83–4.80(m,1H),4.53-4.40(m,1H),2.50-2.46(m,1H),2.14-2.12(m,1H),2.09–1.97(m,2H),1.71–1.53(m,4H)
LCMS(ESI):m/z,calculated for C
30H
22D
11N
5O
5S,586.75,found 587.29,M+H。
实施例9
化合物5的合成
化学式:C
30H
29D
4N
5O
5S
分子量:579
化合物5可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.67(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.51-4.49(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.90-0.80(m,6H).
LCMS(ESI):m/z,calculated for C
30H
29D
4N
5O
5S,579.71,found 580.25,M+H。
实施例10
化合物7的合成
化学式:C
30H
22D
11N
5O
5S
分子量:586
化合物7可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.12(s,1H),8.10–7.97(m,3H),7.85(s,1H),7.50–7.41(m,2H),7.35-7.25(m,2H),6.95-6.88(m,1H),,3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
22D
11N
5O
5S,586.75,found 587.29,M+H。
实施例11
化合物8的合成
化学式:C
30H
23D
10N
5O
5S
分子量:585
化合物8可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.12(s,1H),8.10–7.97(m,3H),7.85(s,1H),7.50–7.41(m,2H),7.35-7.25(m,2H),6.95-6.88(m,1H),4.52-4.56(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,585.75,found 586.29,M+H。
实施例12
化合物9的合成
化学式:C
30H
27D
6N
5O
5S
分子量:581
化合物9可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.13(s,1H),8.10–7.97(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.34-7.25(m,2H),6.94-6.87(m,1H),4.51-4.49(m,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.80(m,6H).
LCMS(ESI):m/z,calculated forC
30H
27D
6N
5O
5S,581.72,found 582.29,M+H。
实施例13
化合物10的合成
化学式:C
30H
28D
7N
5O
5S
分子量:582
化合物10可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.13(s,1H),8.10–7.97(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.34-7.25(m,2H),6.94-6.87(m,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.80(m,6H).
LCMS(ESI):m/z,calculated for C
30H
28D
7N
5O
5S,582.26,found 583.29,M+H。
实施例14
化合物11的合成
化学式:C
30H
20D
13N
5O
5S
分子量:588
化合物11可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.13(s,1H),8.10–7.97(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.34-7.25(m,2H),6.94-6.87(m,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
20D
13N
5O
5S,588.76,found 589.31,M+H。
实施例15
化合物12的合成
化学式:C
30H
21D
12N
5O
5S
分子量:587
化合物12可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.13(s,1H),8.10–7.97(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.34-7.25(m,2H),6.94-6.87(m,1H),4.51-4.48(m,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
21D
12N
5O
5S,587.76,found 588.31,M+H。
实施例16
化合物13的合成
化学式:C
30H
30D
3N
5O
5S
分子量:578
化合物13可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.67(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),4.51-4.48(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.90-0.80(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
30D
3N
5O
5S,578.70,found 579.24,M+H。
实施例17
化合物14的合成
化学式:C
30H
29D
4N
5O
5S
分子量:579
化合物14可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.90-0.80(m,6H).
LCMS(ESI):m/z,calculated for C
30H
29D
4N
5O
5S,579.25,found 580.25,M+H。
实施例18
化合物15的合成
化学式:C
30H
23D
10N
5O
5S
分子量:585
化合物15可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,585.28,found 586.29,M+H。
实施例19
化合物16的制备
化学式:C
30H
24D
9N
5O
5S
分子量:584
化合物16可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),4.50-4.46(m,1H),3.29–3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
24D
9N
5O
5S,584.28,found 585.25,M+H。
实施例20
化合物17的制备
化学式:C
30H
29D
4N
5O
5S
分子量:579
化合物17可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),4.50-4.46(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0-91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
29D
4N
5O
5S,579.25,found 580.25,M+H。
实施例21
化合物18的合成
化学式:C
30H
28D
5N
5O
5S
分子量:580
化合物18可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
28D
5N
5O
5S,580.25,found 581.25,M+H。
实施例22
化合物19的合成
化学式:C
30H
22D
11N
5O
5S
分子量:586
化合物19可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
22D
11N
5O
5S,586.29,found 587.25,M+H。
实施例23
化合物20的合成
化学式:C
30H
23D
10N
5O
5S
分子量:585
化合物20可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.82-4.78(m,1H),4.51-4.47(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,585.28,found 586.29,M+H。
实施例24
化合物21的合成
化学式:C
30H
30D
3N
5O
5S
分子量:578
化合物21可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.66(s,1H),8.13(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.51-4.47(m,1H),3.93(s,1H),3.28-3.15(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0-91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,578.24,found 579.24,M+H。
实施例25
化合物22的合成
化学式:C
30H
29D
4N
5O
5S
分子量:579
化合物22可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),3.93(s,1H),3.28-3.15(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
29D
4N
5O
5S,579.25,found 580.25,M+H。
实施例26
化合物23的合成
化学式:C
30H
23D
10N
5O
5S
分子量:585
化合物23可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),3.93(s,1H),3.28-3.15(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,585.28,found 586.29,M+H。
实施例27
化合物24的合成
化学式:C
30H
24D
9N
5O
5S
分子量:584
化合物24可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.48-4.44(m,1H),3.93(s,1H),3.28-3.15(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
24D
9N
5O
5S,584.28,found 585.29,M+H。
实施例28
化合物25的合成
化学式:C
30H
28D
5N
5O
5S
分子量:580
化合物25可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.51-4.48(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
28D
5N
5O
5S,580.25,found 581.25,M+H。
实施例29
化合物26的合成
化学式:C
30H
27D
6N
5O
5S
分子量:581
化合物26可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
27D
6N
5O
5S,581.25,found 582.26,M+H。
实施例30
化合物27的合成
化学式:C
30H
21D
12N
5O
5S
分子量:587
化合物25可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
21D
12N
5O
5S,587.30,found 588.30,M+H。
实施例31
化合物28的合成
化学式:C
30H
22D
11N
5O
5S
分子量:586
化合物28可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.50-4.47(m,1H),3.93(s,1H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
22D
11N
5O
5S,586.29,found 587.29,M+H。
实施例32
化合物29的合成
化学式:C
30H
31D
2N
5O
5S
分子量:577
化合物29可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),4.50-4.47(m,1H),3.93(s,1H),3.28-3.25(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
31D
2N
5O
5S,577.23,found 578.23,M+H。
实施例33
化合物30的合成
化学式:C
30H
30D
3N
5O
5S
分子量:578
化合物30可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.97(m,3H),7.84(s,1H),7.49–7.41(m,2H),7.35-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),3.93(s,1H),3.28-3.25(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
30D
3N
5O
5S,578.24,found 579.24,M+H。
实施例34
化合物31的合成
化学式:C
30H
24D
9N
5O
5S
分子量:584
化合物31可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),3.93(s,1H),3.28-3.25(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)。
LCMS(ESI):m/z,calculated for C
30H
24D
9N
5O
5S,584.28,found 585.28,M+H。
实施例35
化合物32的合成
化学式:C
30H
25D
8N
5O
5S
分子量:583
化合物32可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),4.51-4.48(m,1H),3.93(s,1H),3.28-3.25(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)。
LCMS(ESI):m/z,calculated for C
30H
25D
8N
5O
5S,583.27,found 584.27,M+H。
实施例36
化合物33的合成
化学式:C
30H
31D
2N
5O
5S
分子量:577
化合物33可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),4.51-4.48(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
31D
2N
5O
5S,577.23,found 578.24,M+H。
实施例37
化合物34的合成
化学式:C
30H
30D
3N
5O
5S
分子量:578
化合物34可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
30D
3N
5O
5S,578.24,found 579.24,M+H。
实施例38
化合物35的合成
化学式:C
30H
24D
9N
5O
5S
分子量:584
化合物35可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.12(s,1H),8.10–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.87-4.82(m,1H),3.92(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)。
LCMS(ESI):m/z,calculated for C
30H
24D
9N
5O
5S,584.28,found 585.28,M+H。
实施例39
化合物36的合成
化学式:C
30H
25D
8N
5O
5S
分子量:583
化合物36可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),8.12(s,1H),8.10–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.51-4.45(m,1H),4.87-4.82(m,1H),3.92(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)。
LCMS(ESI):m/z,calculated for C
30H
25D
8N
5O
5S,583.28,found 584.28,M+H。
实施例40
化合物37的合成
化学式:C
30H
32DN
5O
5S
分子量:576
化合物37可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.51-4.46(m,1H),3.93(s,3H),3.29-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)。
LCMS(ESI):m/z,calculated for C
30H
32DN
5O
5S,576.23,found 577.23,M+H。
实施例41
化合物38的合成
化学式:C
30H
31D
2N
5O
5S
分子量:577
化合物38可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),3.93(s,3H),3.29-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.91-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
31D
2N
5O
5S,577.23,found 578.24,M+H。
实施例42
化合物39的合成
化学式:C
30H
25D
8N
5O
5S
分子量:583
化合物39可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),3.93(s,3H),3.29-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
25D
8N
5O
5S,583.27,found 584.27,M+H。
实施例43
化合物40的合成
化学式:C
30H
26D
7N
5O
5S
分子量:582
化合物40可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.51-4.47(m,1H),3.93(s,3H),3.29-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
26D
7N
5O
5S,582.26,found 583.27,M+H。
实施例44
化合物41的合成
化学式:C
30H
30D
3N
5O
5S
分子量:578
化合物41可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.51-4.47(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.92-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
30D
3N
5O
5S,578.24,found 579.24,M+H。
实施例45
化合物42的合成
化学式:C
30H
29D
4N
5O
5S
分子量:579
化合物42可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.92-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
29D
4N
5O
5S,579.25,found 580.25,M+H。
实施例46
化合物43的合成
化学式:C
30H
23D
10N
5O
5S
分子量:585
化合物43可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
23D
10N
5O
5S,585.28,found 586.29,M+H。
实施例47
化合物44的合成
化学式:C
30H
24D
9N
5O
5S
分子量:584
化合物44可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.52-4.47(m,1H),3.93(s,3H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H).
LCMS(ESI):m/z,calculated for C
30H
24D
9N
5O
5S,584.28,found 585.28,M+H。
实施例48
化合物45的合成
化学式:C
30H
32DN
5O
5S
分子量:576
化合物45可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.82-4.57(m,1H),3.93(s,3H),3.28-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H),0.92-0.81(m,6H)
LCMS(ESI):m/z,calculated for C
30H
32DN
5O
5S,576.23,found 577.23,M+H。
实施例49
化合物46的合成
化学式:C
30H
26D
7N
5O
5S
分子量:582
化合物46可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.82-4.57(m,1H),3.93(s,3H),3.28-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
26D
7N
5O
5S,582.26,found 583.27,M+H。
实施例50
化合物47的合成
化学式:C
30H
27D
6N
5O
5S
分子量:581
化合物46可根据实施例1描述的代表性路线合成
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),8.12(s,1H),8.09–7.95(m,3H),7.84(s,1H),7.50–7.41(m,2H),7.36-7.25(m,2H),6.94-6.88(m,1H),4.52-4.62(m,1H)4.82-4.57(m,1H),3.93(s,3H),3.28-3.14(m,2H),2.50-2.46(m,1H),2.14-2.11(m,2H),1.89–1.67(m,3H),1.65–1.52(m,2H)
LCMS(ESI):m/z,calculated for C
30H
27D
6N
5O
5S,581.26,found 582.27,M+H。
实施例51:
本实施例为化合物S-217622,化合物45,化合物13,化合物37和化合物42对SARS冠状病毒、MERS冠状病毒和HCoV人冠状病毒的抗病毒活性。
在Vero E6、Vero76细胞系上研究了化合物S-217622,化合物45,化合物13,化合物37和化合物42对SARS冠状病毒、MERS冠状病毒和HCoV人冠状病毒的抗病毒活性。使用中性红试验来确定病毒诱导和化合物诱导的细胞病变抑制(CPE),并统计化合物的EC
50、EC
90、CC
50值。中性红试验,测试化合物以10mg/mL的浓度溶解在DMSO中,并用8个半对数稀释剂连续稀释,最高测试浓度为50μg/mL(86μM)。每一种稀释剂加到含有80-100%汇合度Vero E6或是Vero76细胞的96孔板中的5个孔中。每种稀释液3孔进行病毒感染,2孔未感染作为毒性对照。6孔未经处理并被感染作为病毒对照。对于SARS、MERS和HCoV人冠状病毒,病毒被稀释到每个细胞的MOI分别为0.003、0.002、0.001和0.03 50%细胞培养感染剂量。将板在37℃下含5%CO
2的培养箱中培养。在感染后的第5天(HCoV)或第7天(SARS、MERS),当未经处理的病毒对照孔达到最大CPE时,将平板用中性红染料染色约2小时。去除上清染料,用磷酸盐缓冲液PBS冲洗每孔,并在柠檬酸缓冲液和乙醇1:1的混合液中洗涤染料30分钟。在分光光度计上读取540nm的光密度值并转化为对照的百分比。计算抗病毒的CPE 50%(EC
50)和在没有病毒的情况下导致50%细胞死亡(CC
50)所需的测试化合物浓度。
效果实施例
实施例52:
本实施例为靶向SARS-CoV-2病毒M
Pro蛋白酶活性抑制检测
检测原理:3-胰凝乳蛋白酶样蛋白酶(3-chymotrypsin-like Protease),即主要蛋白酶(M
Pro,也称为3CL
Pro),由ORF1编码(定位于nsp5),位于复制酶基因中心区域,是新型冠状病毒RNA复制时的一个关键蛋白质。其作用机制为:新冠病毒入侵细胞后,会利用宿主细胞合成自身复制必需的两条超长复制酶多肽(ppla和pplab)。复制酶多肽需进一步被剪切成多个蛋白(如RdRp、helicase等),进一步组装成用于病毒启动自身遗传物质复制所需的复制转录机器。M
Pro在复制酶多肽上存在至少11个切割位点,只有当复制酶多肽上这些位点被正常切割后,组装成复制转录机器,启动病毒复制。鉴于M
Pro蛋白酶在病毒复制过程中至关重要,且人体中并无类似的蛋白质,因此主蛋白酶M
Pro成为一个抗新冠病毒的潜在关键药靶。利用荧光共振能量转移方法评价核苷衍生物对SARS-CoV-2-M
Pro蛋白酶的抑制活性。
具体检测方法:整个酶促反应体系的体积为120μL,蛋白酶的终浓度为30nM,底物终浓度为20μM,反应体系的缓冲液包括50mM Tris、pH 7.3 1mM EDTA。在96孔板中加入SARS-CoV-2-M
Pro蛋白酶和不同浓度的目标化合物,30℃孵育10min,加入底物并迅速放入酶标仪中读数。激发光和发射光分别为340nm和405nm。测试时间为10min,每隔30s读一次荧光值。最终结果取前2min的读值拟合反应速率, 并与对照组(DMSO)比较,计算抑制率。以Graghpad prism 7作图,计算SARS-CoV-2病毒核苷衍生物对应时间点IC50值,具体数值见表3。
表3:SARS-CoV-2-M
Pro蛋白酶的IC
50值
IC50(μΜ) | |
化合物45 | 0.977±0.141μΜ |
化合物13 | 0.959±0.122μΜ |
化合物37 | 0.994±0.077μΜ |
化合物42 | 1.008±0.137μΜ |
S-217622 | 1.091±0.085μΜ |
实施例53:
本实施例为化合物在大鼠上的药代动力学研究
在7-10周龄,雄性Wistar-Hannover大鼠进行药代动力学研究。在药代动力学研究期间,所有动物都单独饲养。自由摄取食物和水(动物在进食状态下给药)。动物禁食过夜并在给药后4小时进食。在灌胃给药(30mg/kg)后的预定时间点通过颈静脉插管收集血样。在研究完成时,通过过量吸入麻醉随后放血对动物实施安乐死。将血样收集到含有K
2EDTA的试管中并储存在冰上,直至离心获得血浆,将其储存在-20℃冰箱。
血浆样品的LC-MS/MS分析:血浆样品使用蛋白质沉淀法进行处理,使用含有500:50的乙腈:甲醇,含有propranolol(50ng/ml)作为内标,然后根据空白血浆中制备的标准曲线(0.1-2500ng/ml)进行定量。使用LC-MS/MS对血浆样品中的分析物进行定量。简而言之,使用与配备Sciex 6500三重四极杆质谱仪联用的Waters ACQUITY超高效液相色谱系统。使用Waters Acquity UPLC BEH C18柱(1.7m,2.1 50mm)完成色谱分离。优化流动相以实现分析物之间的良好分离。通常,溶剂A由0.025%甲酸和1mM乙酸铵的水/乙腈溶液(95:5v/v)组成,溶剂B包括0.025%甲酸和1mM乙酸铵的水/乙腈溶液(5:95v/v)。梯度一般从3-30%B开始,直到大约1.2分钟,然后增加到50-65%B到1.6分钟,然后降低到10-30%B,直到约1.7-1.9分钟。Analyst 1.7软件用于峰积分和标准曲线回归。
药代动力学分析:使用非房室分析(Watson v.7.5,Thermo Scientific)计算药代动力学参数。使用线性梯形法则估计从t=0到无穷大(AUC0-∞)的血浆浓度-时间曲线下面积。如表4所示,从结果看出,化合物45,化合物13,化合物37和化合物42在动物体内具有更好的更长的半衰期和更高的血浆暴露量,因而具有更好的治疗效果。
表4:化合物的药代动力学参数
剂量(mg/kg) | C max(ng/mL) | T max(h) | AUC 0-∞(ng·h/mL) | T 1/2(h) | |
化合物45 | 0.5 | 1.13 | 0.35 | 4.12 | 10.5 |
化合物13 | 0.5 | 1.12 | 0.35 | 3.78 | 10 |
化合物37 | 0.5 | 1.06 | 0.35 | 3.47 | 10 |
化合物42 | 0.5 | 1.09 | 0.35 | 3.54 | 10 |
S-217622 | 0.5 | 1.11 | 0.35 | 3.09 | 8.5 |
应用实施例
实施例54:
对于氘代苯并噻唑类化合物的口服片剂制备方法(以化合物6为例)
口服片剂所用的药用载体有调节剂、填充剂、粘合剂、崩解剂、添加剂、助流剂、润滑剂、膜衣材料、增塑剂、着色剂等。
组分 | 作用 | 含量(mg/片) |
化合物6 | 药物成分 | 200 |
淀粉 | 填充剂、崩解剂 | 100 |
磷酸氢钙 | 填充剂 | 20 |
预胶化淀粉 | 填充剂 | 40 |
枸橼酸 | 调节剂 | 2 |
亚硫酸氢钠 | 添加剂 | 0.5 |
10%淀粉浆 | 粘合剂 | 适量 |
硬脂酸镁 | 润滑剂 | 1.5 |
白色欧巴代 | 包衣预混料 | 约4 |
水、乙醇 | 溶剂 | 适量 |
操作方法:
按上述配方将化合物6分别磨粉过筛,然后与填充剂、崩解剂以及经磨粉过筛处理的调节剂、添加剂混合均匀,加入10%的淀粉浆在搅拌机中制成软材,软材在摇摆机上制成湿粒,置烘箱中干燥,再与润滑剂混合均匀,压制成片芯。片芯用欧巴代包制薄膜衣片。
对于含氘代苯并噻唑类化合物的胶囊剂制备方法(以化合物6为例)
胶囊剂所用的药用载体有填充剂、粘合剂、崩解剂、添加剂、润滑剂等。
组分 | 作用 | 含量(mg/粒) |
化合物6 | 药物成分 | 200 |
乳糖一水合物 | 填充剂 | 82 |
预胶化淀粉 | 填充剂、粘合剂 | 38 |
羧甲基淀粉钠 | 崩解剂 | 12.5 |
硬脂酸镁 | 润滑剂 | 1.5 |
操作方法:
按上述配方将化合物6和各辅料分别磨粉过筛,与填充剂、粘合剂和崩解剂等以一定比例混合均匀,加入干法制粒机中压制成条带,后经破碎机破碎制成颗粒。颗粒与适量润滑剂和崩解剂混合均匀后填充胶囊。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对公开专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (12)
- 如权利要求1所述的化合物,其特征在于,R 1~R 3中至少2个是氘。
- 如权利要求1所述的化合物,其特征在于,R 9~R 14均为氘。
- 如权利要求1所述的化合物,其特征在于,R 4~R 5均为氘。
- 如权利要求1所述的化合物,其特征在于,R 6~R 8中至少2个是氘。
- 一种药物组合物,其特征在于,它含有药学上可接受载体和权利要求1-6任一所述化合物,或其药学上可接受的盐。
- 如权利要求8所述的药物组合物,其特征在于,它包含另外的治疗药物,所述的另外的治疗药物为抗病毒药物。
- 一种如权利要求1-6所述的化合物或其药学上可接受的盐,或如权利要求8所述的药物组合物的用途,其特征在于,用于制备抑制3CL蛋白酶的药物组合物。
- 如权利要求10所述的用途,其特征在于,所述的药物组合物用于制备治疗和预防病毒感染的药物。
- 根据权利要求11所述的用途,其中所述病毒感染是人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒。
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Title |
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HATTORI, S. ET AL.: "A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.", NATURE COMMUNICATIONS, vol. 12, 28 January 2021 (2021-01-28), XP055840802, DOI: 10.1038/s41467-021-20900-6 * |
KONNO SHO, KOBAYASHI KIYOTAKA, SENDA MIKI, FUNAI YUTA, SEKI YUTA, TAMAI IKUMI, SCHÄKEL LAURA, SAKATA KYOUSUKE, PILLAIYAR THANIGAIM: "3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 65, no. 4, 24 February 2022 (2022-02-24), US , pages 2926 - 2939, XP093059002, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00665 * |
MASAND, V.H. ET AL.: "Structure features of peptide-type SARS-CoV main protease inhibitors: Quantitative structure activity relationship study.", CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS, vol. 206, 3 October 2020 (2020-10-03), XP086317087, DOI: 10.1016/j.chemolab.2020.104172 * |
THANIGAIMALAI, P. ET AL.: "Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 68, 9 August 2013 (2013-08-09), XP028733714, DOI: 10.1016/j.ejmech.2013.07.037 * |
XING LI; CHEN MING-JIE; ZHANG AO: "Application of unique groups in structural optimization of drug molecules", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, GAI-KAI BIANJIBU, CN, vol. 31, no. 7, 31 July 2021 (2021-07-31), CN , pages 541 - 555, XP009545100, ISSN: 1005-0108 * |
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