WO2022141328A1 - 硫代咪唑烷酮药物在治疗covid-19疾病中的用途 - Google Patents

硫代咪唑烷酮药物在治疗covid-19疾病中的用途 Download PDF

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WO2022141328A1
WO2022141328A1 PCT/CN2020/141880 CN2020141880W WO2022141328A1 WO 2022141328 A1 WO2022141328 A1 WO 2022141328A1 CN 2020141880 W CN2020141880 W CN 2020141880W WO 2022141328 A1 WO2022141328 A1 WO 2022141328A1
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formula
thioimidazolidinone
covid
ace2
use according
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French (fr)
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童友之
马连东
周千翔
严红花
杨剑飞
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苏州开拓药业股份有限公司
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Priority to PCT/CN2021/099571 priority patent/WO2022142154A1/zh
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/075Ethers or acetals
    • A61K31/085Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/275Nitriles; Isonitriles
    • A61K31/277Nitriles; Isonitriles having a ring, e.g. verapamil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles
    • A61K31/41551,2-Diazoles non condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41881,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • AHUMAN NECESSITIES
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    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of antiviral drugs, and in particular relates to the use of a thioimidazolidinone drug in the treatment of COVID-19 disease.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a severe respiratory illness called coronavirus disease 2019 (COVID-19) that broke out in December 2019.
  • SARS-CoV-2 is a beta-coronavirus, the same as SARS-CoV and MERS-CoV.
  • the characteristics of SARS-CoV-2 are highly similar to SARS-CoV.
  • the key to the infection of human cells by the new coronavirus lies in the combination of the S protein (Spike Glycoprotein, TMPRSS2) of the coronavirus and the ACE2 protein (Angiotensin-converting enzyme 2, angiotensin converting enzyme 2) in the human body (Letko , M., Marzi, A. & Munster, V.
  • the present invention provides the use of a thioimidazolidinone compound having the following structure of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases related to ACE2 and TMPRSS2 protein imbalance:
  • the present invention also provides the use of a thioimidazolidinone compound having the structure of the above formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of ACE2 and TMPRSS2 protein disorders related diseases .
  • Y is independently selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O or cyano
  • Z is independently selected from CF 3 , halogen , cyano, C1 - C4 alkyl optionally substituted with one or more halogens, or C1 - C4 alkoxy optionally substituted with one or more halogens.
  • the ACE2 and TMPRSS2 dysregulation is selected from ACE2 and TMPRSS2 protein overexpression.
  • the disease associated with overexpression of ACE2 and TMPRSS2 proteins is a coronavirus, more preferably COVID-19.
  • the present invention provides the use of the thioimidazolidinone of formula (I-A) for the treatment of COVID-19 disease.
  • the present invention also provides the use of the thioimidazolidinone of formula (I-A) in the preparation of a medicament for treating COVID-19 disease.
  • the thioimidazolidinone of formula (I-A) is a polymorph, pseudopolymorph, amorphous or hydrate.
  • the thioimidazolidinone of formula (I-A) is crystal form A, and the 2 ⁇ of X-ray powder diffraction comprises the following peaks: 9.2 ⁇ 0.2, 14.6 ⁇ 0.2, 14.9 ⁇ 0.2, 16.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.2 ⁇ 0.2, 21.8 ⁇ 0.2, 22.4 ⁇ 0.2 and 23.5 ⁇ 0.2. Its specific X-ray powder diffraction pattern can be found in CN 201510861715.0.
  • the medicament is in the form of an oral solid preparation, preferably a tablet, capsule or suspension.
  • the present invention provides any one of Apalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119 and SHR3680 Use in the preparation of medicines for the treatment of COVID-19.
  • the present invention also provides any one of Apalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119 and SHR3680 Use in the treatment of COVID-19 disease.
  • the thioimidazolidinone of the structure of formula (I-A) is crystal form A, which is compatible with Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854 , Use of any one or more of JNJ-63576, TAS-3681, HC-1119 and SHR3680 for the treatment of COVID-19.
  • the thioimidazolidinone of the structure of formula (I-A) is crystal form A, which is compatible with Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854 , Use of any one or more of JNJ-63576, TAS-3681, HC-1119 and SHR3680 in combination in the preparation of a medicine for the treatment of COVID-19.
  • the CAS number of Enzalutamide is 915087-33-1; the CAS number of Apalutamide is 956104-40-8; the CAS number of Bicalutamide is 90357-06-5; the CAS number of Abiraterone is 154229-19-3; the CAS number of ODM-201 The number is 1297538-32-9; the CAS number of EPI-001 is 227947-06-0; the CAS number of ONC1-13B is 1351185-54-0; the CAS number of HC-1119 is 1443331-82-5.
  • the thioimidazolidinone drugs of the following formula (I) described in the present invention can significantly down-regulate the ACE2 and TMPRSS2 proteins in Lncap, A549, and RLE-6TN. and surprisingly found that unexpected technical effects have been achieved in the treatment of COVID-19, which can reduce the hospitalization rate of COVID-19 patients, the use of ventilators, and may also reduce patient mortality, resulting in significant therapeutic effect.
  • Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound, eg, formed from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts disclosed herein can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both; in general, non-aqueous media such as diethyl ether, Ethyl acetate, ethanol, isopropanol or acetonitrile.
  • suitable salts see Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), incorporated herein by reference in its entirety.
  • phrases "pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions and/or dosage forms suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic response and other within the scope of sound medical judgment problems or complications with a reasonable benefit/risk ratio.
  • Figure 1 The effect of thioimidazolidinone of formula (I-A) on the expression of ACE2 and TMPRSS2 proteins, in Figure 1 KT represents the thioimidazolidinone of formula (I-A).
  • the thioimidazolidinone crystal form of the structure of formula (I-A) is crystal form A, and the preparation method can be completed according to the teaching in CN 201510861715.0.
  • the thioimidazolidinone of formula (I-A) structure is prepared with DMSO, and its storage concentration is 10 mM, and the drug is diluted according to the concentration gradient, added to the cell culture medium, and DHT (dihydrotestosterone, Double Hydrogen Testosterone) is added simultaneously to stimulate the cells, Cells were harvested 48 hours after exposure to cells.
  • DHT dihydrotestosterone, Double Hydrogen Testosterone
  • the cells were collected by centrifugation, the supernatant was washed with PBS (Phosphate Buffer Saline), centrifuged, washed again with PBS, and the PBS was completely discarded.
  • PBS Phosphate Buffer Saline
  • the collected cells were added to an appropriate amount of lysis solution (the proteasome inhibitor PMSF was added to the lysis solution), lysed on ice for 30 min, centrifuged at 12,000 rpm for 20 min, and the supernatant was taken.
  • Electrophoresis use 10% precast gel electrophoresis at 200V for 30min;
  • Transfer membrane cut off the stacking gel, transfer the protein on the separating gel to PVDF membrane by wet transfer method, 270mA, 2h;
  • Secondary antibody place the PVDF membrane in the corresponding secondary antibody solution and incubate for 1-2h at room temperature with shaking at room temperature;
  • the thioimidazolidinone with the structure of formula (I-A) was prepared into a tablet with an active ingredient content of 100 mg (refer to CN 201510861715.0) as a test drug.
  • the clinical study was a prospective, interventional, placebo-controlled, double-blind, randomized parallel assignment study.
  • the trial included 214 eligible patients (114 in the experimental group and 100 in the placebo-controlled group).
  • Diagnosis and inclusion must meet the following criteria: 1) male; 2), age ⁇ 50 years; 3), patients with Gabrin's disease, namely androgenetic alopecia, Hamilton-Norwood grade greater than or equal to three; 4), rtPCR Tests were positive for SARS-CoV-2 in the past 7 days; 5) Not hospitalized for acute respiratory symptoms; 6) Patients with adequate bone marrow, liver and kidney function; 7) Serum creatinine ⁇ 1.5xULN or creatinine clearance ⁇ 60 mL/min ( Calculated using the Cockcroft-Gault formula); 8) Coagulation: INR ⁇ 1.5 ⁇ ULN, APTT ⁇ 1.5 ⁇ ULN; 9) Written informed consent was obtained prior to any screening procedure.
  • Inclusion and exclusion criteria 1) Subject participated in a study to study COVID-19 drugs; 2) Subjects taking any type of anti-androgen, including: androgen-lowering therapy, 5-alpha reductase inhibitors etc.; 3) Patients allergic to investigational products or similar drugs (or other excipients); 4) Subjects with malignancy within the past 5 years, except for basal cells and squamous cells that have completed resection 5) Subjects with known severe cardiovascular disease, congenital long QT syndrome, condyloma acuminatum, myocardial infarction, or arterial thrombosis in the past 6 months , unstable angina or congestive heart failure classified as New York Heart Association (NYHA) grade 3 or higher, or ventricular ejection fraction (LVEF) ⁇ 50%, QTcF > 450ms; 6) uncontrolled medical condition Subjects may compromise participation in the study (e.g.
  • Treatment period 30 days.
  • control group male subjects take every day: ivermectin 200mcg/kg, q.d, continuous medication for 5 days; azithromycin 500 mg every day, q.d, continuous medication for 5 days.
  • Clinical evaluation criteria 1. Efficacy, the percentage of subjects hospitalized due to COVID-19; 2. Safety, adverse events during treatment.
  • the co-primary endpoints include within 30 days (the control group was treated according to the "therapy, dose and administration method” for 5 days, no medication was used on days 6-30, and the test statistics were performed on the 30th day; the experimental group was administered according to the "therapy, dose and administration method”. After the end of the drug use in the “medication method”, no medication was taken from the 16th to the 30th day, and the trial statistics were carried out on the 30th day)
  • the percentage of subjects hospitalized due to COVID-19 and the evaluation of clinical symptoms using a 7-point scale
  • the specific classification is as follows :
  • Level a death; level b: receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); level c: hospitalization with non-invasive ventilation or high-flow nasal cannula; level d: hospitalization with supplemental oxygen; level e: hospitalization Supplemental oxygen was not administered; grade f: no hospitalization due to activity limitation (persistent symptoms); grade g: asymptomatic.
  • ECMO invasive mechanical ventilation or extracorporeal membrane oxygenation
  • Clinical results According to the analysis of the results of 114 subjects in the experimental group and 100 subjects in the placebo control group, the hospitalization rate of patients in the experimental group was 0.8% (only 1 in the experimental group was hospitalized after receiving the above therapy) , 0% ventilator use, 0% death, and no adverse events. In the control group, the hospitalization rate was 27.0%, the ventilator use rate was 9%, and the death rate was 2%.
  • rtPCR or RT-PCR, is highly matched to the RNA region specific to the new coronavirus nucleic acid through primers and probes. Once detected, it can be judged as "positive”.
  • the thioimidazolidinone of formula (I-A) can block the entry of SARS-COV-2 virus into host cells by inhibiting the expression of ACE2 and TMPRSS2.
  • Imidazolidinone can reduce the hospitalization rate of patients, the use of ventilators, and may also reduce the mortality rate of patients, thereby producing a significant therapeutic effect. It is an urgent clinical treatment method.

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Abstract

一种硫代咪唑烷酮药物或其药学上可接受的盐在制备用于治疗ACE2和TMPRSS2蛋白失调相关疾病的药物中的用途,尤其是在制备用于治疗COVID-19疾病的药物中的用途。

Description

硫代咪唑烷酮药物在治疗COVID-19疾病中的用途 技术领域
本发明属于抗病毒药物技术领域,具体涉及一种硫代咪唑烷酮药物在治疗COVID-19疾病中的用途。
背景技术
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)是2019年12月爆发的一种名为2019冠状病毒病(COVID-19)引起的严重呼吸道疾病。SARS-CoV-2属于乙型冠状病毒,与SARS-CoV和MERS-CoV相同。SARS-CoV-2的特征与SARS-CoV高度接近。新型冠状病毒感染人体细胞的关键,在于冠状病毒的S蛋白(Spike Glycoprotein,刺突糖蛋白,TMPRSS2)与人体中的ACE2蛋白(Angiotensin-converting enzyme 2,血管紧张素转化酶2)的结合(Letko,M.,Marzi,A.&Munster,V.Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B beta-coronaviruses.Nat.Microbiol.5,562–569(2020)),通过与它的结合入侵人体并诱发感染。新冠病毒使用S蛋白,与细胞上的血管紧张素转化酶酶2(简称ACE2)受体结合,而又通过TMPRSS2激活S蛋白从而协助新冠病毒进入细胞(Hoffmann,M.et al.SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.Cell S0092867420302294(2020)doi:10.1016/j.cell.2020.02.052.)。
目前现有技术中针对Covid-19患者治疗的临床研究工作以及完成或者正在进行,包括辉瑞Covid-19预防疫苗和礼来公司的Covid-19中和抗体bamlanivimab以及吉利德公司的抗病毒药物remdesivir,以上药物虽然具有明确的临床意义,然而关于COVID-19依然没有标准治疗的手段。因此,发现和发展现有的COVID-19治疗方案是迫切需要满足的医疗需求。
发明内容
为了解决上述问题,本发明提供了一种具有如下式(I)结构的硫代咪唑烷酮化合物或其药学上可接受的盐用于治疗ACE2和TMPRSS2蛋白失调相关疾病的用途:
Figure PCTCN2020141880-appb-000001
另一方面,本发明还提供了一种具有如上式(I)结构的硫代咪唑烷酮化合物或其药学上可接受的盐在制备用于治疗ACE2和TMPRSS2蛋白失调相关疾病的药物中的用途。
在一个实施方案中,所述式(I)化合物中Y独立地选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O或氰基,Z独立地选自CF 3、卤素、氰基、任选地被一个或多个卤素取代的C 1-C 4的烷基、或任选地被一个或多个卤素取代的C 1-C 4 的烷氧基。
在另一个实施方案中,所述ACE2和TMPRSS2失调选自ACE2和TMPRSS2蛋白过表达。
在另一个实施方案中,所述ACE2和TMPRSS2蛋白过表达相关疾病是冠状病毒,进一步优选为COVID-19。
在另一个实施方案中,所述式(I)化合物中Y为F,Z为CF 3,其结构式如式(I-A)所示:
Figure PCTCN2020141880-appb-000002
在另一个实施方案中,本发明提供了所述式(I-A)结构的硫代咪唑烷酮用于治疗COVID-19疾病的用途。
在另一个实施方案中,本发明还提供了所述式(I-A)结构的硫代咪唑烷酮在制备用于治疗COVID-19疾病的药物中的用途。在另一个实施方案中,所述式(I-A)结构的硫代咪唑烷酮为多晶型物、假多晶型物、无定型物或水合物。
在另一个实施方案中,所述式(I-A)结构的硫代咪唑烷酮为晶型A,其X射线粉末衍射的2θ包含如下峰:9.2±0.2,14.6±0.2,14.9±0.2,16.5±0.2,17.9±0.2,18.2±0.2,21.8±0.2,22.4±0.2和23.5±0.2。其具体X射线粉末衍射图可参见CN 201510861715.0。
在另一个实施方案中,所述药物为口服固体制剂形式,优选为片剂、胶囊剂或混悬剂。
在另一个实施例方案中,本发明提供了Apalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种在制备用于治疗COVID-19药物中的用途。
在另一个实施例方案中,本发明还提供了Apalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种用于治疗COVID-19疾病中的用途。
在另一个实施方案中,所述式(I-A)结构的硫代咪唑烷酮为晶型A,其与Enzalutamide,Apalutamide,Bicalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种或多种用于治疗COVID-19中的用途。
在另一个实施方案中,所述式(I-A)结构的硫代咪唑烷酮为晶型A,其与Enzalutamide,Apalutamide,Bicalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种或多种联合在制备用于治疗COVID-19药物中的用途。
所述Enzalutamide的CAS号为915087-33-1;Apalutamide的CAS号为956104-40-8;Bicalutamide的CAS号为90357-06-5;Abiraterone的CAS为154229-19-3;ODM-201的CAS号为1297538-32-9;EPI-001的CAS号为227947-06-0;ONC1-13B的CAS号为1351185-54-0;HC-1119的CAS号为1443331-82-5。
EM-5854结构式为
Figure PCTCN2020141880-appb-000003
SHR3680结构式为
Figure PCTCN2020141880-appb-000004
申请人发现,本发明所述下式(I)结构的硫代咪唑烷酮药物,尤其是式(I-A)结构的硫代咪唑烷酮能够明显下调Lncap、A549、RLE-6TN中ACE2和TMPRSS2蛋白的表达水平;并且惊奇的发现在治疗COVID-19中取得了意料不到的技术效果,可以降低COVID-19病人的住院率、呼吸机的使用情况,也可能降低病人的死亡率,从而产生显著的治疗作用。
本发明的药学上可接受盐包括母体化合物的常规无毒盐,例如形成自无毒的无机或有机酸。本发明公开的药学上可接受盐能通过常规化学法合成自含碱性或酸性部分的母体化合物。一般,这种盐能通过如下方法制备:这些化合物的游离酸或碱形式与化学计算量的合适碱或酸在水或有机溶剂或两者的混合物中反应;一般,优选非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。合适盐的列表参见《雷明顿药物科学》(Remington’s Pharmaceutical Sciences),第17版,宾夕法尼亚州伊士顿的麦克出版公司(Mack Publishing Company),1985, 第1418页和Journal of Pharmaceutical Science,66,2(1977),通过引用全文纳入本文。
本文所用的短语“药学上可接受”指在合理医学判断范围内适于用于接触人和动物组织的那些化合物、材料、组合物和/或剂型,而没有过度毒性、刺激、过敏反应和其它问题或并发症,并具有合理的效益/风险比。
附图说明
图1:式(I-A)结构的硫代咪唑烷酮对ACE2和TMPRSS2蛋白表达的影响,图1中KT代表式(I-A)结构的硫代咪唑烷酮。
[根据细则91更正 20.02.2021] 
具体实施方式
还可进一步通过实施例来理解本发明,然而,要理解的是,这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和以下要求保护的本发明范围之内。
实施例中除特殊说明外,使用式(I-A)结构的硫代咪唑烷酮晶型为晶型A,其制备方法可依据CN 201510861715.0中的教导完成。
一、式(I-A)结构的硫代咪唑烷酮对Lncap,A549细胞中ACE2和TMPRSS2蛋白表达的影响
利用Western-blot方法检测式(I-A)结构的硫代咪唑烷酮对前列腺癌细胞株LnCap、肺癌细胞A549中ACE2和TMPRSS2蛋白的降解作用。
1.1实验材料
细胞 来源 培养基
Lncap 中国科学院细胞库 RPMI 1640+10%FBS
A549 中国科学院细胞库 RPMI 1640+10%FBS
1.2试验方法
1.2.1细胞的培养
取液氮罐冻存的LNCaP、A549细胞,细胞复苏培养至生长期,用CSS培养基(Charcoal Stripped FBS,活性炭处理胎牛血清)培养,将其铺至六孔板中(每孔约1×10 6个)。
1.2.2药物配制
用DMSO配制式(I-A)结构的硫代咪唑烷酮,使其储存浓度为10mM,分别按浓度梯度稀释药物,加入细胞培养液中,同时加入DHT(双氢睾酮,Double Hydrogen Testosterone)刺激细胞,作用细胞48小时后收集细胞。
1.2.3收集细胞
离心收集细胞,上清液,PBS(磷酸盐缓冲液(Phosphate Buffer Saline))洗涤,离心,PBS再次洗涤,完全弃PBS。
1.2.4收集蛋白
收集的细胞加入适量的裂解液(裂解液中加入蛋白酶体抑制剂PMSF,)冰上裂解30min,12000rpm离心20min,取上清。
1.2.5 BCA法测定蛋白总量
1)配制梯度浓度的标准蛋白,取20μl于96孔板中;
2)取2μl蛋白裂解液溶于18μl的PBS中,每个样品做一个复孔;
3)每个孔加入200μl的BCA工作液,37℃孵育30min;
4)测定562nM吸光度;
5)计算每个样品的蛋白浓度,计算50μg所需的蛋白裂解液体积。
1.2.6 Western-blot检测蛋白表达水平
1)变性:取蛋白裂解液,加入适量的5×loading buffer,100℃变性5min;
2)电泳:使用10%预制胶电泳200V 30min;
3)转膜:切去浓缩胶,将分离胶上的蛋白通过湿转法转移到PVDF膜上,270mA,2h;
4)封闭:将PVDF膜置于5%脱脂牛奶中,室温封闭1h;
5)一抗:将PVDF膜按Mark的分子量大小剪开,分别置于AR,ACE2,TMPRSS2和GAPDH抗体中,4℃摇床孵育过夜;
6)洗膜:将PVDF膜置于PBST中,摇床振荡清洗4次,每次6分钟;
7)二抗:将PVDF膜置于对应的二抗溶液中,摇床振荡室温孵育1-2h;
8)检测:通过ECL检测。
1.3实验结果
实验结果显示,式(I-A)结构的硫代咪唑烷酮可以下调LNCaP、A549中ACE2和TMPRSS2蛋白的表达水平;此外,双氢睾酮(DHT)诱导LNCaP和A549细胞中ACE2和TMPRSS2蛋白的表达,表明雄激素-AR信号调节了SARS-CoV-2结合并进入宿主细胞的关键蛋白(图1)。
二、式(I-A)结构的硫代咪唑烷酮的治疗COVID-19的临床效果
将式(I-A)结构的硫代咪唑烷酮制备成药物有效成分含量为100mg的片剂(参考CN 201510861715.0),作为试验药。
临床研究为前瞻性、介入性、安慰剂对照、双盲、随机平行分配研究。本次试验纳入214名符合条件的患者(其中实验组114名和100名安慰剂对照 组)。
诊断和纳入需满足下列标准:1)男性;2)、年龄≥50岁;3)、表现为Gabrin症,即雄激素性脱发的患者,汉密尔顿·诺伍德分级大于等于三级;4)、rtPCR测试在过去7天SARS-CoV-2呈现阳性;5)未因急性呼吸道症状住院;6)骨髓,肝和肾功能适当的患者;7)血清肌酐≤1.5xULN或肌酐清除率≥60mL/min(使用Cockcroft-Gault公式计算);8)凝结:INR≤1.5×ULN,APTT≤1.5×ULN;9)在进行任何筛选程序之前已获得书面知情同意。
入组排除标准:1)受试者参加了一项研究以研究COVID-19药物;2)服用任何类型的抗雄激素的受试者,包括:雄激素降低治疗,5-α还原酶抑制剂等;3)对研究产品或类似药物(或其他药物)过敏的患者赋形剂);4)在过去5年中患有恶性肿瘤的受试者,但以下情况除外完成切除的基底细胞和鳞状细胞癌,彻底切除任何类型的原位癌;5)已知患有严重心血管疾病,先天性长QT的受试者过去6个月的综合症,尖锐湿疣,心肌梗塞,或动脉血栓形成,不稳定的心绞痛或充血性心力衰竭被列为纽约心脏协会(NYHA)3级或更高级别,或心室射血分数(LVEF)<50%,QTcF>450ms;6)医疗状况不受控制的受试者可能会妥协参与研究(例如不受控制的高血压,甲状腺功能低下,糖尿病);7)在4周内参加了实验药物研究的患者开始这项研究治疗;8)已知的人类免疫缺陷病毒(HIV)诊断,丙型肝炎,活跃乙型肝炎,梅毒螺旋体(强制性检查);9)不愿意或无法提供知情同意。
治疗周期:30天。
疗法,剂量和给药方式:
1)对照组,男性受试者每天服用:伊维菌素200mcg/kg,q.d,连续用药 5天;阿奇霉素每天500毫克,q.d,连续用药5天。
2)实验组,男性受试者每天服用:伊维菌素200mcg/kg,q.d,连续用药5天;阿奇霉素每日500毫克,q.d,持续5天;试验药200毫克,q.d,持续用药15天。
临床评价标准:1、有效性,因COVID-19而住院的受试者百分比;2、安全性,治疗中出现的不良事件。
其共同主要终点包括30天内(对照组按照“疗法,剂量和给药方式”中用药5天后,第6-30天不用药,在第30天进行试验统计;实验组按照“疗法,剂量和给药方式”中用药结束后,第16-30天不用药,在第30天进行试验统计)因COVID-19住院的受试者百分比和临床症状评估(采用7分等级量表),具体分级如下:
a级:死亡;b级:接受有创机械通气或体外膜氧合(Extracorporeal Membrane Oxygenation,ECMO);c级:使用无创通气或高流量鼻导管住院;d级:补充氧气住院;e级:住院时不补充氧气;f级:未因活动受限而住院(持续症状);g级:无症状。
临床结果:根据114名试验组受试者和100名安慰剂对照组受试者的结果分析显示,试验组的患者住院率为0.8%(试验组中接受上述疗法后仅有1名住院治疗),使用呼吸机百分比为0%,死亡百分比为0%,且未发现不良事件。对照组患者住院率为27.0%,使用呼吸机百分比为9%,死亡百分比为2%。
另外,统计了实验组和对照组的从第0天到第30天的rtPCR阳性试验百分比如下:
Figure PCTCN2020141880-appb-000005
从第7天开始,试验组病毒阳性患者相比较对照组明显减少,该趋势一直延续到第30天的结果。(rtPCR,即RT-PCR,是通过引物和探针与新冠病毒核酸特异性的RNA区域高度匹配,一旦检测到,即可判断为“阳性”。)
综上所述,式(I-A)结构的硫代咪唑烷酮可以通过抑制ACE2和TMPRSS2的表达从而阻断SARS-COV-2病毒进入宿主细胞内,临床数据也显示了式(I-A)结构的硫代咪唑烷酮可以降低病人的住院率、呼吸机的使用情况,也可能降低病人的死亡率,从而产生显著的治疗作用,是目前临床上迫切需要的治疗手段。
本发明内容仅仅举例说明了要求保护的一些具体实施方案,其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合,这些经组合而得到的技术方案也在本申请保护范围内,就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。

Claims (10)

  1. 一种具有如下式(I)结构的硫代咪唑烷酮化合物或其药学上可接受的盐在制备用于治疗ACE2和TMPRSS2蛋白失调相关疾病的药物中的用途:
    Figure PCTCN2020141880-appb-100001
    所述式(I)化合物中Y独立地选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O或氰基,Z独立地选自CF 3、卤素、氰基、任选地被一个或多个卤素取代的C 1-C 4的烷基、或任选地被一个或多个卤素取代的C 1-C 4的烷氧基。
  2. 根据权利要求1所述的用途,其特征在于:所述ACE2和TMPRSS2蛋白失调选自ACE2和TMPRSS2蛋白过表达。
  3. 根据权利要求2所述的用途,其特征在于:所述ACE2和TMPRSS2蛋白过表达相关疾病是冠状病毒。
  4. 根据权利要求2所述的用途,其特征在于:式(I)化合物中Y为F,Z为CF 3,其结构式如式(I-A)所示:
    Figure PCTCN2020141880-appb-100002
  5. 根据权利要求4所述的用途,其特征在于:式(I-A)结构的硫代咪唑烷酮在制备用于治疗COVID-19疾病的药物中的用途。
  6. 根据权利要求5所述的用途,其特征在于:式(I-A)结构的硫代咪唑烷酮为多晶型物、假多晶型物、无定型物或水合物。
  7. 根据权利要求6所述的用途,其特征在于:式(I-A)结构的硫代咪唑烷酮为晶型A,其X射线粉末衍射的2θ包含如下峰:9.2±0.2,14.6±0.2,14.9±0.2,16.5±0.2,17.9±0.2,18.2±0.2,21.8±0.2,22.4±0.2以及23.5±0.2。
  8. 根据权利要求1-7任一项所述的用途,其特征在于:所述药物为口服固体制剂形式,所述口服固体制剂为片剂、胶囊剂、混悬剂或丸剂。
  9. Apalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种用于在制备治疗COVID-19冠状病毒药物中的用途。
  10. 一种如权利要求4所示的式(I-A)结构的硫代咪唑烷酮与Enzalutamide,Apalutamide,Bicalutamide,Abiraterone,ODM-201,EPI-001,ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119和SHR3680中的任意一种或多种联合用于在制备治疗COVID-19冠状病毒药物中的用途。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810542A (zh) * 2015-11-30 2017-06-09 苏州开拓药业有限公司 一种硫代咪唑烷酮化合物的晶型、盐型及其制备方法
US11058647B1 (en) * 2020-03-30 2021-07-13 Applied Biology, Inc. Systems, methods, and kits for diagnostics and treatment of viral respiratory infection
CN113143924A (zh) * 2020-12-31 2021-07-23 苏州开拓药业股份有限公司 硫代咪唑烷酮药物在治疗covid-19疾病中的用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11292782B2 (en) * 2018-11-30 2022-04-05 Nuvation Bio Inc. Diarylhydantoin compounds and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810542A (zh) * 2015-11-30 2017-06-09 苏州开拓药业有限公司 一种硫代咪唑烷酮化合物的晶型、盐型及其制备方法
US11058647B1 (en) * 2020-03-30 2021-07-13 Applied Biology, Inc. Systems, methods, and kits for diagnostics and treatment of viral respiratory infection
CN113143924A (zh) * 2020-12-31 2021-07-23 苏州开拓药业股份有限公司 硫代咪唑烷酮药物在治疗covid-19疾病中的用途

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CADEGIANI FLÁVIO ADSUARA, ZIMERMAN RICARDO ARIEL, DO NASCIMENTO FONSECA DANIEL, DO NASCIMENTO CORREIA MICHAEL, MCCOY JOHN, WAMBIER: "Proxalutamide (GT0918) Reduces the Rate of Hospitalization in mild-to-moderate COVID-19 Female Patients: A Randomized Double-Blinded Placebo-Controlled Two-Arm Parallel Trial", MEDRXIV, 10 July 2021 (2021-07-10), pages 1 - 16, XP055949155, Retrieved from the Internet <URL:https://www.medrxiv.org/content/10.1101/2021.07.06.21260086v1.full.pdf> [retrieved on 20220804], DOI: 10.1101/2021.07.06.21260086 *
GHAZIZADEH ZANIAR, MAJD HOMA, RICHTER MIKAYLA, SAMUEL RYAN, ZEKAVAT SEYEDEH MARYAM, ASGHARIAN HOSSEINALI, FARAHVASHI SINA, KALANTA: "Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men", BIORXIV, 15 May 2020 (2020-05-15), pages 1 - 42, XP055949198, Retrieved from the Internet <URL:https://www.biorxiv.org/content/10.1101/2020.05.12.091082v2.full.pdf> [retrieved on 20220804], DOI: 10.1101/2020.05.12.091082 *
GOREN ANDY, MCCOY JOHN, WAMBIER CARLOS G., VANO‐GALVAN SERGIO, SHAPIRO JERRY, DHURAT RACHITA, WASHENIK KENNETH, LOTTI TORELLO: "What does androgenetic alopecia have to do with COVID‐19? An insight into a potential new therapy", DERMATOLOGIC THERAPY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 33, no. 4, 1 July 2020 (2020-07-01), US , XP055949191, ISSN: 1396-0296, DOI: 10.1111/dth.13365 *
HUANG XIN: "Molecular Mechanism of Bisphenol A on Androgen Receptor Antagonism", PROCEEDINGS OF 2017 ENVIRONMENT AND PUBLIC HEALTH CONFERENCE & 2017 ANNUAL CONFERENCE OF CHINESE SOCIETY FOR ENVIRONMENTAL SCIENCES, ENVIRONMENTAL MEDICINE, CHINESE SOCIETY FOR ENVIRONMENTAL SCIENCES, ENVIRONMENTAL MEDICINE, CN, 31 December 2017 (2017-12-31), CN, pages 140, XP055949197 *
JONATHAN D. STROPE, BS CINDY H.CHAU, WILLIAM D: "Are sex discordant outcomes in COVID-19 related to sex hormones.", SEMINARS IN ONCOLOGY, vol. 47, no. 5, 17 June 2020 (2020-06-17), US , pages 335 - 340, XP009537991, ISSN: 0093-7754, DOI: 10.1053/j.seminoncol.2020.06.002 *
STOPSACK KONRAD H., MUCCI LORELEI A., ANTONARAKIS EMMANUEL S., NELSON PETER S., KANTOFF PHILIP W.: "TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention?", CANCER DISCOVERY, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 10, no. 6, 1 June 2020 (2020-06-01), US , pages 779 - 782, XP055949195, ISSN: 2159-8274, DOI: 10.1158/2159-8290.CD-20-0451 *
WU SIQI, MIAO LIYAN, ZHOU QIANXIANG, GAO CHANG, LIU JIALIN, ZHAN QINGYUAN, GUO BINBIN, LI FANG, WANG YIRONG, XU HONGYANG, YAN HONG: "Suppression of Androgen Receptor (AR)-ACE2/TMPRSS2 Axis by AR Antagonists May Be Therapeutically Beneficial for Male COVID-2019 Patients WuXi People's Hospital Affiliated to", SSRN ELECTRONIC JOURNAL, 18 June 2020 (2020-06-18), pages 1 - 21, XP055949162, Retrieved from the Internet <URL:https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3580526> [retrieved on 20220804] *

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