WO2022142154A1 - 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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WO2022142154A1
WO2022142154A1 PCT/CN2021/099571 CN2021099571W WO2022142154A1 WO 2022142154 A1 WO2022142154 A1 WO 2022142154A1 CN 2021099571 W CN2021099571 W CN 2021099571W WO 2022142154 A1 WO2022142154 A1 WO 2022142154A1
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sars
cov
formula
thioimidazolidinone
disease
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童友之
马连东
周千翔
严红花
任志华
杨剑飞
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苏州开拓药业股份有限公司
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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.
  • virus variants B.1.1.7, B.1.351 and P.1 which first appeared in the United Kingdom, South Africa and Brazil, respectively have mutations in the spike protein, some of which are targeted by currently used antiviral drugs and vaccines Area.
  • 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, hydroxy, trifluoromethoxy or cyano
  • Z is independently selected from trifluoro Methyl, halogen, cyano, C1 - C4 alkyl optionally substituted with one or more halogens, or C1 - C4 alkoxy optionally substituted with one or more halogens.
  • the dysregulation of ACE2 and TMPRSS2 is selected from diseases associated with overexpression of ACE2 and TMPRSS2 proteins.
  • the disease related to the overexpression of ACE2 and TMPRSS2 proteins is a disease caused by a coronavirus, and the disease caused by the coronavirus is COVID-19, more preferably a mutated coronavirus caused by SARS-CoV-2 disease;
  • the SARS-CoV-2 mutation refers to SARS-CoV-2 B.1.351, SARS-CoV-2 P.1, SARS-CoV-2 B.1.1.7, SARS-CoV-2 B.1.617 .2, SARS-CoV-2 A.23.1, SARS-CoV-2 B.1.525, SARS-CoV-2 B.1.427, SARS-CoV-2 B.1.429 or SARS-CoV-2 B.1.526 variant Any one, preferably SARS-CoV-2 P.1, SARS-CoV-2 B.1.1.7.
  • the present invention provides the use of the thioimidazolidinone of the formula (I-A) for the treatment of COVID-19 disease; the COVID-19 disease is further preferably mutated by SARS-CoV-2
  • the disease caused by the coronavirus, the SARS-CoV-2 mutation refers to SARS-CoV-2 B.1.351, SARS-CoV-2 P.1, SARS-CoV-2 B.1.1.7, SARS-CoV- 2 B.1.617.2, SARS-CoV-2 A.23.1, SARS-CoV-2 B.1.525, SARS-CoV-2 B.1.427, SARS-CoV-2 B.1.429 or SARS-CoV-2 B. Any of the 1.526 variants, preferably SARS-CoV-2 P.1, SARS-CoV-2 B.1.1.7.
  • the present invention also provides the use of the thioimidazolidinone of the formula (I-A) in the preparation of a medicine for the treatment of COVID-19 disease;
  • the COVID-19 disease is more preferably SARS -Diseases caused by coronaviruses mutated by CoV-2, the SARS-CoV-2 mutations refer to SARS-CoV-2 B.1.351, SARS-CoV-2 P.1, SARS-CoV-2 B.1.1. 7.
  • the thioimidazolidinone of formula (I-A) is in the form of 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 effective dose of the thioimidazolidinone of formula (I-A) in the tablet is 100 mg, and the effective dose that the patient takes every day is 200 mg or 300 mg, once a day, continuously Take 14-15 days; eg, 200mg daily for 15 days, or 300mg daily for 14 days.
  • the present invention provides the thioimidazolidinone compound of formula (I-A) with Apalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS Use of a combination of any one of -3681, HC-1119 and SHR3680 in the manufacture of a medicament for the treatment of COVID-19.
  • the present invention also provides the formula (I-A) thioimidazolidinone compound with Apalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, Use of a combination of any one of TAS-3681, HC-1119 and SHR3680 for the treatment of COVID-19 disease.
  • the present invention also provides any single compound of Apalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119 and SHR3680 for preparation Use in medicines for the treatment of COVID-19 disease.
  • the thioimidazolidinone compound of formula (I) or a pharmaceutically acceptable salt thereof is a thioimidazolidinone compound of formula (I-A) or a pharmaceutically acceptable salt thereof.
  • the thioimidazolidinone of the formula (I-A) is crystal form A
  • the present invention provides the crystal form A and Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI- 001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119 and SHR3680 in the combination of any one or more of the purposes for the treatment of COVID-19 disease; further preferably, the COVID-19 disease is a disease caused by a mutated SARS-CoV-2 coronavirus, the SARS-CoV-2 mutation refers to SARS-CoV-2 B.1.351, SARS-CoV-2 P.1, SARS-CoV -2 B.1.1.7, SARS-CoV-2 B.1.617.2, SARS-CoV-2 A.23.1, SARS-CoV-2 B.1.525, SARS-CoV-2 B.1.427, SARS-CoV- 2 Any
  • the thioimidazolidinone of the formula (I-A) is crystal form A
  • the present invention provides the crystal form A and Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI- 001, the use of any one or more of ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119 and SHR3680 in combination in the preparation of a medicine for the treatment of COVID-19 disease;
  • the COVID-19 disease is a disease caused by a mutated SARS-CoV-2 coronavirus, and the SARS-CoV-2 mutation refers to SARS-CoV-2 B.1.351, SARS-CoV-2 P.1, SARS-CoV-2 B.1.1.7, SARS-CoV-2 B.1.617.2, SARS-CoV-2 A.23.1, SARS-CoV-2 B.1.525, SARS-CoV-2 B.1.427, SARS-CoV-2 B
  • 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.
  • the compound of the present invention still has an effect; for the SARS-CoV-2 mutation patients of the P.1 type (both male and female patients), the Chinese formula (I-A of the experimental group of the present invention) is used.
  • the thioimidazolidinone compound of ) structure was used as the test drug, all the patients survived (14/14), and no death case occurred; among the 16 patients in the control group, the death cases reached 5 cases (5/16), so the drug of the present invention It can effectively reduce the mortality of patients with SARS-CoV-2 P.1 mutation.
  • cytological experiments show that the drug of the present invention can also be effective against SARS-CoV-2 B.1.1.7 infection.
  • 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.
  • SARS-CoV-2 P.1 refers to the P.1 strain according to the "Pango lineages" typing method; other classifications are named similarly.
  • 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).
  • Figure 2 Graph of the effect of thioimidazolidinone of formula (I-A) in inhibiting SARS-COV-2 infection.
  • 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 control 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 Squamous cell carcinoma, complete resection of carcinoma in situ of any type; 5) Subjects known to have severe cardiovascular disease, congenital long QT syndrome syndrome in the past 6 months, condyloma acuminatum, myocardial infarction, or arterial Thrombosis, 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) Medical conditions not limited by Controlled subjects may compromise study participation (e.g.
  • Treatment period 30 days.
  • Control group male subjects took daily: ivermectin 200mcg/kg, q.d, for 5 consecutive days; azithromycin 500 mg per day, q.d, for 5 consecutive 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 uses primers and probes that are highly matched to the RNA region specific to the nucleic acid of the new coronavirus, and is judged as "positive” or “negative” according to the CT value defined in the instructions of the detection kit used.
  • 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.
  • 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; it was used to evaluate the effect of the test drug on patients with SARS-CoV-2 P.1 mutation ( male and female) clinical effects.
  • Subject inclusion criteria 1) Inpatients diagnosed with symptoms of COVID-19; 2) Male and female patients aged ⁇ 18 years; 3) Laboratory rtPCR test confirmed SARS-CoV-2 seven days prior to randomization 2 Positive; 4) Clinical status for COVID-19: a, hospitalized, no supplemental oxygen required - no need for ongoing medical care; b, hospitalized, no need for supplemental oxygen - ongoing medical care (related to COVID-19 or other ); and c Hospitalization, Supplemental Oxygen Required; 5) Coagulation: INR ⁇ 1.5 ⁇ ULN, APTT ⁇ 1.5 ⁇ ULN; 6) Subjects have given written informed consent prior to any study procedure 7) Subjects agree not to Participate in other COVID-19 clinical trials.
  • Inclusion and exclusion criteria 1) Subject participated in a study to study COVID-19 drugs; 2) Mechanical ventilation was required; 3) Subject participated in any kind of antiandrogen therapy: androgen deprivation therapy, 5- Alpha reductase inhibitors, etc.; 4) Patients who are allergic to investigational products or similar drugs (or any excipients); 5) Subjects with malignant tumors in the past 5 years, except for the following cases, those who have completed resection Basal cell and squamous cell carcinoma, complete excision of any type of carcinoma in situ; 6) Subjects with known severe cardiovascular disease, congenital long QT syndrome, condyloma acuminatum, myocardial infarction in the past 6 months, or arterial thrombosis, unstable angina or congestive heart failure classified as New York Heart Association (NYHA) class 3 or higher, or ventricular ejection fraction (LVEF) ⁇ 50%, QTcF >450ms; 7) Medical conditions Uncontrolled subjects may compromise study participation (e.g.
  • Treatment cycle 28 days, of which the drug is administered from the 1st day to the 14th day, and the drug is not administered from the 14th day to the 28th day (only medical observation).
  • Control group The subjects took daily: placebo 300 mg, once a day, for 14 days; 14-day placebo treatment was combined with the hospital's standard therapy.
  • the placebo refers to the teaching in the technical solution with a specification of 100 mg in the existing CN 201510861715.0 (see its Table 6), and replaces the thioimidazolidinone of its formula (I-A) structure with microcrystalline cellulose.
  • Test group The subjects took daily: 300 mg of the test drug (calculated on the effective dose of the active ingredient), once a day, for 14 days; while the test drug was used for 14 days, it was treated with the standard therapy of the hospital.
  • the clinical evaluation standard is: count the number of deaths of subjects within 28 days after taking the medicine, and the results are shown in Table 2 (the sample data comes from some samples in the NCT04728802 experiment, and 30 cases of SARS-CoV-2 detected as P.1 type were randomly selected.
  • the average age was 47.0 years old
  • the results of clinical experiments showed that among 30 hospitalized patients with SARS-CoV-2 P.1 mutation, 14 patients in the experimental group survived and none died; 16 patients in the control group had 5 deaths. There was a very significant difference between the experimental group and the control group. Therefore, the compounds of the present invention can effectively treat diseases caused by mutant SARS-CoV-2, especially the mutation of P.1 SARS-CoV-2.
  • the patients with P.1 strains were confirmed by the following detection methods: the nasopharyngeal swab samples were collected after admission to the hospital to extract viral RNA, and the positive infection samples with ct ⁇ 26 confirmed by RT-PCR were sent to the sequencing laboratory, and the RT-PCR confirmed the high viral load samples for library construction and next-generation sequencing. After the original off-machine data was de-connected, the genome was assembled. The assembled genome after quality control used PANGOLIN (https://github.com/hCoV- 2019/pangolin) for strain classification to confirm the P.1 mutant.
  • the detection method can be completed with reference to the teaching in the prior art (Genes(Basel). 2020 Aug; 11(8):949.doi:10.3390/genes11080949).
  • Test article The compound of formula (I-A) was dissolved in DMSO and stored at -20°C.
  • Test cell lines LNCaP cells were purchased from American Type Culture Collection (ATCC).
  • Evaluation method Films were taken under a fluorescence microscope to analyze the antiviral effect of the drug by detecting the fluorescence intensity.
  • LNCaP cell culture RPMI1640 medium with 10% fetal bovine serum was cultured in a cell incubator under the conditions of 5% CO 2 and 37° C. saturated humidity. Subculture according to ATCC instructions.
  • LNCaP cells in logarithmic growth phase were seeded in 384-well plates (Corning, 3603) at 1 ⁇ 10 4 cells, and the cells were cultured in 384-well plates under the conditions of 5% CO 2 and 37°C for 18 hours.
  • IA Compounds were treated for 24 hours, and the highest concentration was 3 ⁇ M starting with 2-fold dilution. There were 10 concentrations in total, and 5 replicate wells were repeated for each concentration.
  • SARS-COV-2 isolated from: USA-WA1/2020, https://www.beiresources.org/Catalog/animalviruses/NR-52281.aspx
  • SARS- CoV-2 B1.1.7 virus was cultured for 48h.
  • SARS-CoV-2 viral nucleocapsid proteins were detected and quantified using high-content immunofluorescence imaging, and nuclei were counted with Hoechst-33342.
  • SARS-CoV-2 bioassay platform we demonstrated that in LNCaP cells, the compound of formula (IA) can effectively inhibit the infection of LNCaP cells by SARS-CoV-2 and SARS-CoV-2 B.1.1.7 viruses, and the dose-dependent.

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Abstract

属于医药技术领域，具体涉及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
本申请要求于2020年12月31日提交至PCT/CN局、申请号为PCT/CN2020/141880、发明名称为“硫代咪唑烷酮药物在治疗COVID-19疾病中的用途”的PCT申请的优先权，其全部内容通过引用结合在本申请中。
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。
在SARS-CoV-2大流行之初，这种病毒相对稳定，但最近发现了这种病毒的几种变种，而且它们在迅速蔓延。最早出现在英国、南非和巴西的病毒变种B.1.1.7、B.1.351和P.1分别在刺突蛋白中发生突变，其中的一些突变发生在目前使用的抗病毒药物和疫苗所靶向的区域。
现有技术(Cell.2021 Apr 29；184(9):2384-2393.e12.doi:10.1016/j.cell.2021.03.036)中，德国灵长类动物中心-莱布尼茨灵长类动物研究所的Markus Hoffmann和Stefan
Figure PCTCN2021099571-appb-000001
德国乌尔姆大学医学中心的Jan Münch领导的一个研究团队发现，SARS-CoV-2变种B.1.351和P.1不再被用于COVID-19治疗的抗体所抑制。此外，这些变种被来自康复患者和疫苗接种者的抗体抑制的效率较低。因此，从COVID-19中康复以及疫苗接种可能仅提供针对这些病毒变种的不完全保护。
所以，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，尤其是针对SARS-CoV-2变种引发的疫情，如B.1.351、P.1和B.1.1.7等变种。
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 PCTCN2021099571-appb-000002
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、三氟甲氧基或氰基，Z独立地选自三氟甲基、卤素、氰基、任选地被一个或多个卤素取代的C 1-C 4烷基、或任选地被一个或多个卤素取代的C 1-C 4烷氧基。
在另一个实施方案中，所述ACE2和TMPRSS2失调选自ACE2和TMPRSS2蛋白过表达相关疾病。
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引发的疾病，所述冠状病毒引发的疾病为COVID-19，进一步优选为SARS-CoV-2突变后的冠状病毒引起的疾病；所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为 SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
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 PCTCN2021099571-appb-000003
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；所述COVID-19疾病进一步优选为SARS-CoV-2突变后的冠状病毒引起的疾病，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
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；所述COVID-19疾病进一步优选为SARS-CoV-2突变后的冠状病毒引起的疾病，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
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、无定型物或水合物的形式。
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。在所述口服固体制剂为片剂的情况下，式(I-A)结构的硫代咪唑烷酮在片剂中有效剂量为100mg，患者每天服的用有效剂量为200mg或300mg，每天服用一次，连续服用14-15天；例如每天服用200mg，连续服用15天，或每天服用300mg，连续服用14天。
在另一个实施例方案中，本发明提供了所述式(I-A)硫代咪唑烷酮化合物与Apalutamide，Abiraterone，ODM-201，EPI-001，ONC1-13B，EM-5854，JNJ-63576，TAS-3681，HC-1119和SHR3680中的任意一种之组合在制备用于治疗COVID-19的药物中的用途。
在另一个实施例方案中，本发明还提供了所述式(I-A)硫代咪唑烷酮化合物与Apalutamide，Abiraterone，ODM-201，EPI-001，ONC1-13B，EM-5854，JNJ-63576，TAS-3681，HC-1119和SHR3680中的任意一种之组合用于治疗COVID-19疾病中的用途。
此外，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中的任意一种单独化合物在制备用于治疗COVID-19疾病的药物中的用途。
优选地，在上述用途中，所述式(I)硫代咪唑烷酮化合物或其可药用盐 为式(I-A)的硫代咪唑烷酮化合物或其可药用盐。
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，本发明相应提供了所述晶型A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之组合用于治疗COVID-19疾病中的用途；进一步优选地，所述COVID-19疾病为SARS-CoV-2突变后的冠状病毒引起的疾病，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
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，本发明相应提供了所述晶型A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疾病的药物中的用途；进一步优选地，所述COVID-19疾病为SARS-CoV-2突变后的冠状病毒引起的疾病，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
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 PCTCN2021099571-appb-000004
SHR3680结构式为
Figure PCTCN2021099571-appb-000005
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。
尤其是针对P.1型的SARS-CoV-2突变，本发明化合物仍然具有效果；针对P.1型的SARS-CoV-2突变患者(男女患者均有)，采用本发明实验组中式(I-A)结构的硫代咪唑烷酮化合物作为试验药，患者全部存活(14/14)，无一例死亡病例发生；对照组16例患者中，死亡病例达到5例(5/16)，所以本 发明药物可以有效降低SARS-CoV-2 P.1突变患者的死亡率。另外，细胞学实验表明，本发明药物也可以对SARS-CoV-2 B.1.1.7感染有效。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。
定义：SARS-CoV-2 P.1系指按照"Pango lineages"分型法为P.1系病毒株；其它分类命名同理。
"Pango lineages"分型法及其病毒株相关信息可以参见 https://cov-lineages.org/index.html。
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。
图2：式(I-A)结构的硫代咪唑烷酮抑制SARS-COV-2感染的效果图。
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药物治疗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综合征的受试者过去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(非强制性检查)；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阳性试验百分比如表1：
表1 rtPCR阳性随时间变化的百分比
Figure PCTCN2021099571-appb-000006
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，按照所使用检测试剂盒说明书界定的CT值，判断为“阳性”或者“阴性”。)
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。
三、式(I-A)结构的硫代咪唑烷酮的化合物治疗SARS-CoV-2 P.1突变的住院患者的临床效果
将式(I-A)结构的硫代咪唑烷酮制备成化合物有效成分含量为100mg的片剂(参考CN 201510861715.0)，作为试验药；用于评估试验药对于SARS-CoV-2 P.1突变患者(男性和女性)的临床效果。
受试者入组标准：1)诊断为COVID-19症状的住院病人；2)年龄≥18岁的男性和女性患者；3)在随机入组的七天前实验室rtPCR检测确认为SARS-CoV-2阳性；4)COVID-19的临床状态：a，住院，不需要补充氧气-不再需要持续的医疗；b，住院，不需要补充氧气-需要持续的医疗护理(与COVID-19相关或其他)；和c住院，需要补充氧气；5)凝血：INR≤1.5×ULN，APTT≤1.5×ULN；6)受试者在进行任何研究程序之前已获得书面知情同意7)受试者同意不会参加其它COVID-19的临床试验研究。
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)需要机械通气；3)受试者参与了任何种类的抗雄激素疗法：雄激素剥夺疗法，5-α还原酶抑制剂等；4)对研究产品或类似药物(或任何赋形剂)过敏的患者；5)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；6)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；7)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)；8)确诊为人类免疫缺陷病毒(HIV)诊断，丙型肝炎， 活跃乙型肝炎，梅毒螺旋体(强制性检查)；9)丙氨酸转氨酶(ALT)或天冬氨酸转氨酶(AST)>正常上限的5倍；10)估计肾小球滤过率(eGFR)<30ml/min；11)需要透析的严重肾脏疾病；12)有生育潜力的女性，定义为所有生理上有能力成为孕妇，除非他们使用高效的避孕措施。13)性活跃的男性在服用试验药期间必须在性交时使用避孕套，停止服药治疗后3个月内，在此期间不应生育孩子。输精管切除的男性也需要使用避孕套，以防止通过精液传递药物。14)受试者可能在接下来的28天内转移到另一家医院；15)受试者不愿意或者不能够提供知情同意。
治疗周期：28天，其中第1天至14天用药，第14天至28天不用药(仅医疗观察)。
疗法，剂量和给药方式：
1)对照组：受试者每天服用：安慰剂300毫克，每天一次，持续用药14天；14天安慰剂用药的同时联合医院的标准疗法治疗。
安慰剂参照现有CN 201510861715.0中规格为100mg的技术方案(参见其表6)中的教导，将其式(I-A)结构的硫代咪唑烷酮替代为微晶纤维素。
2)实验组：受试者每天服用：试验药300毫克(活性成分有效剂量计算)，每天一次，持续用药14天；14天试验药用药的同时联合医院的标准疗法治疗。
临床评价标准为：统计服药后28天内受试者的死亡数，结果如表2所示(样本数据来源于NCT04728802实验中部分样本，随机选择了30例检测为P.1型的SARS-CoV-2突变的住院患者(男性/女性＝18/12,年龄在38.0-58.0之间，平均年龄为44.5岁)，其中实验组为14例(男性/女性＝9/5，年龄在38.7-60.5之间，平均年龄为47.0岁)，对照组为16例(男性/女性＝9/7，年龄在37.2-51.7 之间，平均年龄为44.5)。
表2临床结果：
Figure PCTCN2021099571-appb-000007
Figure PCTCN2021099571-appb-000008
临床实验结果表明，30例SARS-CoV-2 P.1突变的住院患者中，实验组14例患者均存活，无一例死亡；对照组中的16例发生5例死亡。实验组与对照组结果存在极显著差异。所以，本发明化合物可以有效治疗变异型的SARS-CoV-2引起的疾病，尤其是P.1型的SARS-CoV-2突变。
其中P.1系病毒株的患者是以如下检测方法确认的：患者入院后采集鼻咽拭子样本提取病毒RNA，经RT-PCR确认ct<26的阳性感染样本送至测序实 验室，并再次RT-PCR确认为高病毒载量样本进行建库和二代测序，原始下机数据经去接头后，进行基因组组装，质控后的组装基因组利用PANGOLIN(https://github.com/hCoV-2019/pangolin)进行株系分类，确认P.1突变株。其检测方法可以参考现有技术(Genes(Basel).2020 Aug；11(8):949.doi:10.3390/genes11080949)中教导完成。
四、式(I-A)结构的硫代咪唑烷酮的化合物对SARS-COV-2以及SARS-CoV-2 B.1.1.7感染细胞的作用
供试品：式(I-A)化合物使用DMSO溶解后储存于-20℃。
测试细胞株：LNCaP细胞购买于美国模式培养物集存库(ATCC)。
观察指标：荧光显微镜下AlexaFluor 647荧光强度。
评价方法：荧光显微镜下拍片通过检测荧光强度分析药物的抗病毒作用。
实验方法：
1)LNCaP细胞培养：10％胎牛血清的RPMI1640培养基培养于5％CO 2、37℃饱和湿度条件下的细胞培养箱中培养。按照ATCC说明书传代培养。
2)病毒感染实验
取对数生长期LNCaP细胞以1×10 4个细胞接种于384孔板中(Corning，3603)，细胞在384孔板中在5％CO 2、37℃条件下培养18个小时后加入式(I-A)化合物处理24h，作用最高浓度为3μM起始，2倍稀释，共有10个浓度，每个浓度重复5个复孔。24h后在BSL3实验室中向LNCaP细胞中加入SARS-COV-2(分离自:USA-WA1/2020，https://www.beiresources.org/Catalog/animalviruses/NR-52281.aspx)以及SARS-CoV-2 B1.1.7病毒培养48h。4％多聚甲醛固定，用0.03％Triton X-100 渗透，用抗体缓冲液(1.5％牛血清白蛋白，1％山羊血清，0.0025％吐温-20)封闭。封板，表面去污，转移到BSL2实验室染色。用SARS-CoV-2核蛋白一抗(ProSci目录编号:ProSci；35-579,1:2000)，然后用抗小鼠IgG:AlexaFluor 647 secondary(Invitrogen目录编号:A21235,1:10 00)和Hoechst 33342(Invitrogen公司目录编号:H3570下)染色。每个孔共有两个荧光通道(Hoechst-386/23nm,N-protein-650/13nm)，每个孔共拍摄9个视野。使用CellProfiler定量分析感染细胞的百分比。首先在N蛋白图像中通过两类Otsu分割识别感染细胞区。然后以类似的方式鉴定细胞核，并使用related objects模块将其与感染的细胞区相关联。如果细胞核位于被感染的细胞区域内，则确定被感染的细胞，并根据被感染的细胞/总细胞计数计算每个孔的百分比。同时检测细胞的活力，分析化合物对细胞活力(Viability)的影响。
数据分析：
观察荧光显微镜下荧光结合的强弱情况。采用Graphpad Prism中的四参数logistic模型拟合剂量-反应曲线并列出IC 50值。使用32个感染(0％效果)和32个未感染(100％效果)对照孔(平均LNCaP感染性范围:18-25％)进行基于平板的归一化。通过比较处理孔中的细胞计数与32个未感染对照孔中的平均细胞计数(100％的存活率)来评估存活率。
实验结果
申请人评估了式(I-A)化合物对SARS-CoV-2以及SARS-CoV-2 B.1.1.7病毒感染LNcap细胞的影响。采用高含量免疫荧光成像技术对SARS-CoV-2病毒核衣壳蛋白进行检测和定量，而细胞核用Hoechst-33342进行计数。利用这个SARS-CoV-2生物检测平台，我们证明了在LNCaP细胞中，式(I-A)化 合物可有效抑制SARS-CoV-2和SARS-CoV-2 B.1.1.7病毒感染LNCaP细胞，且呈剂量依赖性。其抑制病毒SARS-Cov-2和SARS-CoV-2 B.1.1.7感染的IC 50值分别为69nm和48nM(图2)，证明本发明式(I-A)化合物对SARS-CoV-2 B.1.1.7病毒感染有治疗效果。
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 (11)

  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 PCTCN2021099571-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，其中所述ACE2和TMPRSS2蛋白失调相关疾病选自ACE2和TMPRSS2蛋白过表达相关疾病。
  3. 根据权利要求2所述的用途，其中所述ACE2和TMPRSS2蛋白过表达相关疾病是冠状病毒引起的疾病。
  4. 根据权利要求3所述的用途，其中式(I)化合物中Y为F，Z为CF 3，其结构式如式(I-A)所示：
    Figure PCTCN2021099571-appb-100002
  5. 根据权利要求4所述的用途，所述用途为式(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或式(I-A)结构的硫代咪 唑烷酮在制备用于SARS-CoV-2突变后的冠状病毒引起的疾病的药物中的用途；所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
  6. 根据权利要求5所述的用途，其中所述式(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。
  7. 根据权利要求6所述的用途，其中所述式(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以及23.5±0.2。
  8. 根据权利要求1-7任一项所述的用途，其中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. 根据权利要求8所述的用途，其中所述口服固体制剂为片剂，式(I-A)结构的硫代咪唑烷酮在片剂中有效剂量为100mg，患者每天服的用有效剂量为200mg或300mg，每天服用一次，连续服用14-15天。
  10. 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冠状病毒引起的疾病的药物中的用途；或在制备用于SARS-CoV-2突变后的冠状病毒引起的疾病的药物中的用途，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427， SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，优选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
  11. 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之组合在制备用于治疗COVID-19疾病的药物中的用途；或在制备用于SARS-CoV-2突变后的冠状病毒引起的疾病的药物中的用途，所述SARS-CoV-2突变是指SARS-CoV-2 B.1.351，SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7，SARS-CoV-2 B.1.617.2,SARS-CoV-2 A.23.1、SARS-CoV-2 B.1.525、SARS-CoV-2 B.1.427，SARS-CoV-2 B.1.429或SARS-CoV-2 B.1.526型变种中的任意一种，选为SARS-CoV-2 P.1，SARS-CoV-2 B.1.1.7。
PCT/CN2021/099571 2020-12-31 2021-06-11 硫代咪唑烷酮药物在治疗covid-19疾病中的用途 WO2022142154A1 (zh)

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