WO2021227887A1 - 一种治疗和/或预防冠状病毒引发的疾病的化合物及其应用 - Google Patents
一种治疗和/或预防冠状病毒引发的疾病的化合物及其应用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
Definitions
- the invention belongs to the technical field of biomedicine, and specifically relates to a compound for treating and/or preventing diseases caused by coronavirus and its application.
- Coronavirus is a type of virus closely related to humans and animals. Coronavirus HCoV-229E and HCoV-OC43 can cause the common cold (van der Hoek, L., Pyrc, K., Jebbink, M. et al. Identification of a new human coronavirus. Nat Med 2004, 10, 368-373). From 2002 to 2003, the severe acute respiratory syndrome (SARS) caused by the SARS coronavirus caused 8,098 people worldwide to infect and 774 patients died, with a fatality rate of 10% (Stadler, K., Massignani) ,V.,Eickmann,M.et al.SARS—beginning to understand a new virus. Nat Rev Microbiol 2003, 1,209–218).
- SARS severe acute respiratory syndrome
- the HCoVNL63 identified in 2004 can also cause cold-like respiratory diseases (van der Hoek, L., Pyrc, K., Jebbink, M. et al. Identification of a new human coronavirus. Nat Med 2004, 10, 368-373).
- the 2012 Middle East Respiratory Syndrome Coronavirus (MERS-CoV) appeared. As of April 26, 2016, it had caused 1,728 infections in 27 countries, including 624 deaths (de Wit, E., van Doremalen, N., Falzarano, D). .et al.SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016, 14, 523–534).
- coronavirus SARS-CoV-2
- COVID-19 coronavirus pneumonia
- the clinical manifestations are fever, dry cough and dyspnea, and severe illness can cause death (Jeannette Guarner, MD, Three Emerging Coronaviruses in Two Decades: The Story of SARS, MERS, and Now COVID-19, American Journal of Clinical Pathology,, aqaa029).
- Coronavirus also has a huge impact on the livestock industry: Porcine Epidemic Diarrhea Virus (PEDV), Gastroenteritis Virus (TGEV) and Porcine Delta Coronavirus (PDCoV, also called Delta Virus), which can cause severe enteritis in pigs , Diarrhea, vomiting and dehydration have brought huge losses to the pig industry (Akimkin V, Beer M, Blome S, et al. New Chimeric Porcine Coronavirus in Swine Feces, Germany, 2012. Emerge Infect Dis. 2016, 22(7) ):1314–1315.). Feline infectious peritonitis virus (FIPV) can cause a fatal disease in cats. Avian infectious bronchitis virus (IBV) infects poultry and is a widespread poultry disease that has a huge impact on the poultry industry.
- PEDV Porcine Epidemic Diarrhea Virus
- TGEV Gastroenteritis Virus
- PDCoV Porcine Delta Coronavirus
- FIPV Feline infectious peritonitis virus
- coronavirus is a single-stranded sense RNA with a length of about 28 kb, which mainly encodes structural proteins required for virus packaging and non-structural proteins related to replication and transcription.
- the development of drugs and vaccines for the treatment of coronavirus-related diseases mainly targets the above two types of proteins.
- Two-thirds of the genes in the viral genome mainly encode non-structural proteins, which are used to participate in the replication process of the virus.
- coronaviruses encoded two replicase polypeptides, pp1a and pp1ab.
- pp1a and pp1ab are cleaved into 16 non-structural proteins (nsp1-16) by two proteases encoded by the virus itself, namely main protease and papain-like protease, only when these functions After the subunits are correctly cleaved by proteases into independent protein units, and then assembled into a replication and transcription complex, the virus can complete normal transcription and replication functions.
- Papain-like protease is located in the non-structural protein nsp3, and is responsible for cutting the three restriction sites at the N-terminus of the replicase polypeptide during the cleavage process, thereby releasing nsp1, nsp2 and nsp3 (Ziebuhr, J.; Snijder, EJ; Gorbalenya, Aevirus) -encoded proteinases and proteolytic processing in the Nidovirales.J Gen Virol 2000,81,853-79.;Ziebuhr,J.Molecular biology of severe acute respiratory syndrome coronavirus.Curr Opin Microbiol 2004,7,412-9.;Ratia,Kiira,et al.
- papain-like protease structure of a viral deubiquitinating enzyme. Proceedings of the National Academy of Sciences 103.15(2006):5717-5722.). Because papain-like protease has important functions such as restriction enzyme cleavage, deubiquitination, and antagonism of host IFN, it plays a key regulatory role in the process of virus transcription and replication, so it has become an important coronavirus drug target. Therefore, looking for inhibitors with strong specificity and high safety for the catalytic sites of papain-like proteases is essential for drug development.
- YM155 is a new type of small molecule survivin inhibitor.
- Survivin is a member of the IAP (Inhibitors of Apoptosis) family and plays a role in inhibiting apoptosis and regulating the cell cycle. Under normal circumstances, survivin is mainly expressed during embryonic development and ceases to be expressed in terminally differentiated cells and tissues. However, in many tumors, the expression of survivin has been up-regulated, which leads to the inhibition of tumor cell apoptosis, which reduces the death of tumor cells and produces certain resistance to chemotherapy. Therefore, survivin has become an important target for the development of cancer treatment drugs (Garg, Himani, et al. "Survivin: a unique target for tumor therapy.” Cancer cell international 16.1 (2016): 49.).
- YM155 can inhibit the expression of survivin, thereby inhibiting the growth and proliferation of tumor cells, and causing tumor cell apoptosis.
- YM155 can cause PC-3, PPC-1 human HRPC cell lines (prostate cancer cell lines) to undergo apoptosis (Nakahara, Takahito, et al. "YM155, a novel small-molecule survivin suppressant, induces) regression of established human hormone-refractoryprostate tumor xenografts. "Cancer research 67.17(2007):8014-8021.).
- YM155 Although YM155 has a significant killing effect on tumor cells, YM155 is safer to normal cell tissues.
- the MTD (maximum tolerated dose) of YM155 is 8.0mg/m 2 /d, indicating that YM155 has a certain potential for clinical development.
- Tanshinone I (molecular formula: C 18 H 12 O 3 , CAS number: 568-73-0) is a chemical molecule extracted from the Chinese herbal medicine Salvia miltiorrhiza Bunge. Its molecular formula is as follows:
- Tanshinone I has anti-inflammatory effects, and can regulate or inhibit the metastasis of breast cancer by regulating adhesion molecules (Nizamutdinova, Irina Tsoy, et al. "Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA) -MB-231, through regulation of adhesion molecules. "Carcinogenesis 29.10(2008):1885-1892).
- CN102552236A discloses the use of tanshinone I for the treatment of diseases mediated by microglia
- CN102988370A also discloses the application of tanshinone I in the preparation of drugs for the treatment of psoriasis.
- Cryptotanshinone (Cryptotanshinone, molecular formula: C 19 H 20 O 3 , CAS number: 35825-57-1) is a quinone diterpene isolated from the Chinese herbal medicine Salvia miltiorrhiza Bunge. Its molecular formula is as follows:
- the technical problem to be solved by the present invention is to provide a compound for treating and/or preventing the disease caused by the coronavirus and its application in view of the defect that there is no effective medicine for treating and/or preventing the disease caused by the coronavirus in the prior art.
- the said compound specifically relates to YM155.
- One of the technical solutions of the present invention is: compound YM155, tanshinone I or cryptotanshinone, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, or its crystal form.
- the CAS number of the compound YM155 is 781661-94-7
- the CAS number of the tanshinone I is 568-73-0
- the CAS number of the cryptotanshinone is 35825 -57-1.
- the second technical solution of the present invention is: compound YM155, tanshinone I or cryptotanshinone, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, or its crystal form.
- the drugs are used for the treatment and/or prevention of diseases caused by coronaviruses;
- the CAS number of the compound YM155 is 781661 -94-7, the CAS number of the tanshinone I is 568-73-0, and the CAS number of the cryptotanshinone is 35825-57-1.
- the third technical solution of the present invention is: a compound YM155, tanshinone I or cryptotanshinone as described in one or two of the above technical solutions, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable A salt solvate, or a pharmaceutical composition of its crystal form.
- the pharmaceutical composition further contains other drugs; wherein the other drugs are used to treat and/or prevent diseases caused by coronaviruses.
- the fourth technical solution of the present invention is: compound YM155, tanshinone I or cryptotanshinone, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, or its crystal form, or
- the pharmaceutical composition is used in the preparation of drugs or papain inhibitors for the treatment and/or prevention of diseases caused by coronaviruses, the CAS number of the compound YM155 is 781661-94-7, and the tanshinone I
- the CAS number of the cryptotanshinone is 568-73-0, and the CAS number of the cryptotanshinone is 35825-57-1.
- the fifth technical solution of the present invention is: a method for treating diseases caused by coronavirus, which comprises administering compound YM155, tanshinone I or cryptotanshinone, its pharmaceutically acceptable salt, its solvate, The solvate of its pharmaceutically acceptable salt, its crystal form, or the pharmaceutical composition containing it; the CAS number of the compound YM155 is 781661-94-7, and the CAS number of the tanshinone I is 568- 73-0, the CAS number of the cryptotanshinone is 35825-57-1.
- the disease is preferably a mammalian or avian disease.
- the mammals preferably include humans, pigs and cats.
- coronavirus of the present invention belongs to the Nidovirales (Nidovirales) Coronaviridae (Coronaviridae) Coronavirus subfamily (Orthocoronavirinae) in systematic classification.
- Coronaviruses are RNA viruses with an envelope and a single positive-stranded genome. They are a large group of viruses that are widespread in nature.
- the purpose of the present invention is to provide a potential treatment plan for diseases caused by coronavirus infection.
- the coronavirus of the present invention preferably belongs to the orthocoronavirus subfamily (Orthocoronavirinae), and more preferably belongs to the genus Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Deltacoronavirus.
- the compound YM155, tanshinone I or cryptotanshinone can be used to treat diseases caused by SARS-CoV-2 (Beta coronavirus), and should also be used to treat other coronaviruses SARS- Major infectious diseases caused by CoV (Beta coronavirus genus) and MERS-CoV, etc., can also be used as a common cold medicine to treat HCoV-HKU1 (Human coronavirus HPU1; Beta coronavirus genus), HCoV-NL63 (Human coronavirus NL63; Alpha coronavirus) Virus), HCoV-OC43 (Human coronavirus OC43) and HCoV-229E (Human coronavirus 22E; Alpha coronavirus genus) and other coronavirus diseases; it can also be used as a veterinary medicine to treat transmissible gastroenteritis virus (Transmissible gastroenteritis virus) , TGEV;
- the coronavirus of the present invention is preferably selected from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43, HCoV-229E, TGEV, PEDV, PDCoV, FIPV or IBV.
- compositions of the present invention using various compounds of the present invention as active ingredients can all be prepared according to methods known in the art.
- the compound of the present invention can be formulated into any dosage form suitable for human or animal use.
- the weight content of the compound of the present invention in its pharmaceutical composition is usually 0.1-99.0%.
- the pharmaceutically acceptable carrier may be a conventional carrier in the art, and the carrier may be any suitable physiologically or pharmaceutically acceptable pharmaceutical excipient.
- the pharmaceutical excipients are conventional pharmaceutical excipients in the field, and preferably include pharmaceutically acceptable excipients, fillers or diluents. More preferably, the pharmaceutical composition comprises 0.01-99.99% of the above-mentioned protein and/or the above-mentioned antibody drug conjugate, and 0.01-99.99% of the pharmaceutical carrier, and the percentage is based on the percentage of the pharmaceutical composition. The mass percentage.
- the compound of the present invention or the pharmaceutical composition containing it can be administered in a unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, eye, lung, and Respiratory tract, skin, vagina, rectum, etc.
- the above-mentioned papain inhibitors can exist in the form of coronavirus inhibitors, for example, conventional drugs used to prevent and treat coronavirus.
- pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
- the "patient” is preferably a mammal, more preferably a human.
- pharmaceutically acceptable salt refers to a salt prepared from the compound of the present invention, the drug containing the same, and the pharmaceutical composition, and a relatively non-toxic, pharmaceutically acceptable acid or base.
- pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt.
- the acid can be obtained by contacting the neutral form of the drug with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
- a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
- the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
- the "plurality” in the term “one or more” may refer to 2, 3, 4, 5, 6, 7, 8, 9, or more types.
- the compound of the present invention, the medicament or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the route of administration can be enteral or parenteral, such as oral, topical, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa , Eyes, lungs and respiratory tract, skin, vagina, rectum, etc., preferably by oral or external application.
- enteral or parenteral such as oral, topical, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa , Eyes, lungs and respiratory tract, skin, vagina, rectum, etc., preferably by oral or external application.
- the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
- Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops
- the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
- the medicament or pharmaceutical composition of the present invention can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various particle delivery systems.
- “Pharmaceutical composition” refers to mixing one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers .
- the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
- “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as but not limited to: calcium carbonate, calcium phosphate , Various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, stearic acid, cellulose, carbonate, acrylic acid polymer or methacrylic acid polymer, gel, water, polyethylene glycol, Propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ sesame oil or polyethoxylated hydrogenated EZ sesame oil, sesame oil, corn oil, peanut oil, etc.
- the aforementioned pharmaceutical composition in addition to including a pharmaceutically acceptable carrier, can also include auxiliary agents commonly used in pharmacology, such as: antibacterial agents, antifungal agents, antimicrobial agents, quality-preserving agents, and conditioning agents.
- auxiliary agents commonly used in pharmacology, such as: antibacterial agents, antifungal agents, antimicrobial agents, quality-preserving agents, and conditioning agents.
- treatment refers to therapeutic therapy.
- treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disorder, (3) Improve one or more symptoms, effects or side effects related to the disorder, or one or more symptoms, effects or side effects related to the disorder or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
- solvate refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent.
- the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
- the solvents include but are not limited to: water, methanol, ethanol and the like.
- pharmaceutically acceptable salt solvate and “solvate” in the term “pharmaceutically acceptable salt” and “solvate” are as described above, and mean that the compound of the present invention is combined with 1, and relatively non-toxic, pharmaceutically acceptable 2.
- solvate of a pharmaceutically acceptable salt includes, but is not limited to, the hydrochloric acid monohydrate of the compound of the present invention.
- crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.
- amorphous means that the ions or molecules present in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.
- the "including, containing or containing” may mean that in addition to the ingredients listed below, there are other ingredients; it may also mean “consisting of”, that is, only including the ingredients listed below but not There are other ingredients.
- YM155 can be used to treat related diseases caused by the coronavirus.
- the YM155 treatment program can fill the deficiencies of the existing technology, with strong antiviral activity and low toxic and side effects.
- Figure 3 shows that YM155 has low cytotoxicity (CC 50 >133 ⁇ M).
- Figure 4 shows the inhibitory activity of Tanshinone I on the novel coronavirus papain-like protease; 1: DMSO (negative control), 2: compound molecule; 3: positive control (GRL-0617).
- Figure 5 shows the inhibitory activity of cryptotanshinone on the new coronavirus papain-like protease
- 1 DMSO (negative control)
- 2 compound molecule
- 3 positive control (GRL-0617).
- Tanshinone I (CAS number: 568-73-0) was purchased from Approved Drug Library (Target Mol), and cryptotanshinone (CAS number: 35825-57-1) was purchased from Natural Product Library (Selleck).
- Vero E6 cells were cultured in 96-well plates. After 1 day, YM155 of different concentrations (0.06 ⁇ M-400 ⁇ M) was added to DMEM medium for another day, and then the relative number of viable cells was measured by CCK8 assay to obtain cell viability data. All experiments have 3 biological replicates.
- Enzyme activity experiment fluorescent substrate Z-Arg-Leu-Arg-Gly-Gly-AMC (from Gill Biochemical), the excitation wavelength and emission wavelength of this fluorescent substrate are 340nm and 460nm, respectively.
- the enzyme activity reaction buffer used in the experiment step is 50mM HEPES, pH 7.5, 0.1mg/ml BSA, 2mM DTT; enzyme activity reaction temperature: 30°C.
- 50 ⁇ M inhibitor tanshinone I, cryptotanshinone
- enzyme activity experiment fluorescent substrate Z-Arg-Leu -Arg-Gly-Gly-AMC at a concentration of 20 ⁇ M
- In vitro enzyme activity experiment steps are: SARS-CoV-2 papain-like protease at a final concentration of 200nM, inhibitor solutions of different concentration gradients, and 20 ⁇ M fluorescent substrate (Arg-Leu-Arg-Gly-Gly-AMC) added in 60 ⁇ l reaction
- Incubate at room temperature for 10min use the emission light 340nm and excitation light 460nm to detect the initial reaction rate of the fluorescent substrate, and compare it with the initial rate of the control group without drug , Obtain the inhibition rate curve.
- the experiment was done 3 biological replicates.
- Tanshinone I and cryptotanshinone have strong inhibitory activity on the new coronavirus papain-like protease, with IC 50 of 2.21 ⁇ M and 5.63 ⁇ M, respectively.
- tanshinone I and cryptotanshinone can significantly inhibit the replication ability of SARS-CoV-2 in cells, and the cytotoxicity is low.
- the EC 50 values were 2.26 ⁇ M and 0.7 ⁇ M, respectively (see Figure 7 and Figure 9).
- the CC50 values are all greater than 300 ⁇ M.
- Vero E6 cells were cultured in 96-well plates. After 1 day, different concentrations of inhibitors were added to the DMEM medium for another day, and then the relative number of viable cells was measured by the CCK8 assay to obtain cell viability data. All experiments have 3 biological replicates.
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Abstract
化合物YM155、丹参酮I或隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，用于治疗和/或预防冠状病毒引发的疾病。
Description
本申请要求申请日为2020年05月18日的中国专利申请CN202010418069.1的优先权，以及申请日为2020年05月15日的PCT申请PCT/CN2020/090534的优先权。本申请引用上述两份专利申请的全文。
本发明属于生物医药技术领域，具体涉及一种治疗和/或预防冠状病毒引发的疾病的化合物及其应用。
冠状病毒是一类与人畜密切相关的病毒。冠状病毒HCoV-229E和HCoV-OC43会引起普通感冒(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a new human coronavirus.Nat Med 2004,10,368–373)。2002至2003年期间由SARS冠状病毒引起的严重急性呼吸系统综合征(SARS，severe acute respiratory syndrome)在全球造成8098人感染，774名患者死亡，致死率达到了10％(Stadler,K.,Masignani,V.,Eickmann,M.et al.SARS—beginning to understand a new virus.Nat Rev Microbiol 2003,1,209–218)。2004年鉴定出的HCoVNL63同样能引起类似感冒的呼吸道疾病(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a new human coronavirus.Nat Med 2004,10,368–373)。2012中东呼吸综合征冠状病毒(MERS-CoV)出现，截至2016年4月26日，在27国造成1,728例感染，其中624人死亡(de Wit,E.,van Doremalen,N.,Falzarano,D.et al.SARS and MERS:recent insights into emerging coronaviruses.Nat Rev Microbiol 2016,14,523–534)。最近在全球范围流行的新型冠状病毒(SARS-CoV-2)会引发新型冠状病毒肺炎(COVID-19)，临床表现为发烧，干咳和呼吸困难，重症会造成死亡 (Jeannette Guarner,MD,Three Emerging Coronaviruses in Two Decades:The Story of SARS,MERS,and Now COVID-19,American Journal of Clinical Pathology,,aqaa029)。冠状病毒对于畜牧业同样影响巨大：猪流行性腹泻病毒(PEDV)、肠胃炎病毒(TGEV)和猪丁型冠状病毒(Porcine delta coronavirus，PDCoV，也叫德尔塔病毒)，可引起猪的严重肠炎、腹泻、呕吐和脱水，给养猪业带来巨大的损失(Akimkin V,Beer M,Blome S,et al.New Chimeric Porcine Coronavirus in Swine Feces,Germany,2012.Emerg Infect Dis.2016,22(7):1314–1315.)。猫传染性腹膜炎病毒(FIPV)可引起的猫科动物的致死性疾病。禽传染性支气管炎病毒(IBV)感染禽类，是一种分布广泛的家禽疾病，对家禽业造成了巨大的影响。
冠状病毒的基因组为单股正义RNA，长度约28kb，主要编码病毒包装所需的结构蛋白以及与复制转录相关的非结构蛋白。开发治疗冠状病毒相关疾病的药物和疫苗主要针对上述两类蛋白。病毒基因组的三分之二的基因主要编码非结构蛋白，用于参与病毒的复制过程。在成熟的非结构蛋白产生之前，冠状病毒编码了两种复制酶多肽pp1a和pp1ab。pp1a和pp1ab通过两种由病毒自身编码的蛋白酶，即主蛋白酶(main protease)和木瓜样蛋白酶(papain-like protease)，将其切割成16个非结构蛋白(nsp1-16)，只有当这些功能亚基被蛋白酶正确切割成独立的蛋白单元，进而组装成复制转录复合物后，病毒才能完成正常的转录、复制功能。
木瓜样蛋白酶位于非结构蛋白nsp3中，在剪切过程中负责切割复制酶多肽N端的3个酶切位点，从而释放出nsp1、nsp2以及nsp3(Ziebuhr,J.；Snijder,E.J.；Gorbalenya,A.E.Virus-encoded proteinases and proteolytic processing in the Nidovirales.J Gen Virol 2000,81,853-79.；Ziebuhr,J.Molecular biology of severe acute respiratory syndrome coronavirus.Curr Opin Microbiol 2004,7,412-9.；Ratia,Kiira,et al.Severe acute respiratory syndrome coronavirus papain-like protease:structure of a viral deubiquitinating enzyme. Proceedings of the National Academy of Sciences 103.15(2006):5717-5722.)。由于木瓜样蛋白酶具有酶切，去泛素化、拮抗宿主IFN等重要功能，在病毒的转录、复制过程中发挥着关键的调节作用，因此成为一个重要的冠状病毒药物靶点。因此寻找针对木瓜样蛋白酶催化位点专一性强、安全性高的抑制剂对于药物开发必不可少。针对冠状病毒木瓜样蛋白酶的抑制剂，特别是靶向其底物结合口袋的小分子化合物有可能成为治疗冠状病毒的潜在药物。Sepantronium Bromide(YM155，分子式：C
20H
19BrN
4O
3，CAS号：781661-94-7)，结构式如下：
YM155是一种新型的小分子survivin抑制剂。
Survivin是IAP(Inhibitors of apoptosis)家族中的一员，起到抑制细胞凋亡以及调控细胞周期的作用。正常情况下，survivin主要在胚胎发育期进行表达，在终末分化的细胞及组织中停止表达。但是在许多肿瘤中，survivin的表达出现了上调，导致肿瘤细胞的凋亡受到抑制，从而使得肿瘤细胞的死亡减少且对化疗产生一定的抗性。故此survivin成为了癌症治疗药物开发的一个重要靶点(Garg,Himani,et al."Survivin:a unique target for tumor therapy."Cancer cell international 16.1(2016):49.)。
根据研究显示，YM155可以抑制survivin的表达，从而抑制肿瘤细胞的生长及增殖，并引起肿瘤细胞的凋亡。在10nM的浓度下，YM155就可以使PC-3，PPC-1人类HRPC细胞系(前列腺癌细胞系)发生凋亡(Nakahara,Takahito,et al."YM155,a novel small-molecule survivin suppressant,induces regression of established human hormone-refractory prostate tumor xenografts."Cancer research 67.17(2007):8014-8021.)。
虽然YM155对肿瘤细胞的杀伤作用较为显著，但是YM155对正常细胞组织是较为安全的。在YM155的一期临床实验(Satoh,Taroh,et al."Phase I study of YM155,a novel survivin suppressant,in patients with advanced solid tumors."Clinical Cancer Research 15.11(2009):3872-3880.)中，YM155的MTD(maximum tolerated dose)为8.0mg/m
2/d，说明YM155有一定走向临床的潜力。
丹参酮Ⅰ(Tanshinone I，分子式：C
18H
12O
3，CAS号：568-73-0)是一种从中草药丹参(Salvia miltiorrhiza Bunge)中提取出来的化学分子，其分子式如下所示：
丹参酮Ⅰ具有抗炎症的作用，并且可以通过调节粘附分子对乳腺癌的转移起到调节或者抑制的作用(Nizamutdinova,Irina Tsoy,et al."Tanshinone I suppresses growth and invasion of human breast cancer cells,MDA-MB-231,through regulation of adhesion molecules."Carcinogenesis 29.10(2008):1885-1892)。CN102552236A中公开了丹参酮Ⅰ用于治疗小胶质细胞介导的疾病的用途，CN102988370A中还公开了丹参酮I在制备治疗银屑病药物中的应用。
隐丹参酮(Cryptotanshinone，分子式：C
19H
20O
3，CAS号：35825-57-1)是一种从中草药丹参(Salvia miltiorrhiza Bunge)中分离出的醌类二萜，其分子式如下所示：
研究表明，隐丹参酮的药物靶点是STAT3，可以有效抑制STAT3。隐丹参酮可以通过JAK2非依赖性机制快速抑制STAT3 705位Tyr的磷酸化。隐丹参酮通过与单体STAT3结合从而阻断STAT3二聚化，最终抑制STAT3的转录调节活性(Shin,Dae-Seop,et al."Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells."Cancer research 69.1(2009):193-202)。另外，还有研究报道了隐丹参酮可以通过抑制环加氧酶II的活性来起到抗炎症的作用(Jin,Dao-Zhong,et al."Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression."European journal of pharmacology 549.1-3(2006):166-172)。CN106798737A还公开了隐丹参酮在用于防治肺纤维化的作用。JP2004517939A中还公开了隐丹参酮用于预防和治疗早期阿尔茨海默氏病的作用。
现有技术中尚无以上药物可用于治疗冠状病毒引起的相关疾病。
发明内容
本发明所要解决的技术问题是针对现有技术中尚无有效治疗和/或预防冠状病毒所引发的疾病的药物的缺陷，提供一种治疗和/或预防冠状病毒引发的疾病的化合物及其应用，所述的化合物具体涉及YM155。
以下详细介绍本发明的技术方案。
本发明的技术方案之一为：化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其 晶型，其用于治疗和/或预防冠状病毒引发的疾病；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
本发明的技术方案之二为：化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其用于制备用于治疗和/或预防冠状病毒引发的疾病的药物或者木瓜样蛋白酶抑制剂，所述的药物用于治疗和/或预防冠状病毒引发的疾病；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
本发明的技术方案之三为：一种包含如上技术方案之一或二所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型的药物组合物。
在本发明一优选实施方案中，所述药物组合物还包含其他药物；其中所述其他药物用于治疗和/或预防冠状病毒引发的疾病。
本发明的技术方案之四为：化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，或者包含其的药物组合物在制备用于治疗和/或预防冠状病毒引发的疾病的药物或者木瓜样蛋白酶抑制剂中的应用，所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
本发明的技术方案之五为：一种治疗冠状病毒引发的疾病的方法，其包括向有需要的患者施用化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，或者包含其的药物组合物；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
本发明中，所述的疾病较佳地为哺乳动物或者禽类疾病。
本发明中，所述的哺乳动物较佳地包括人、猪和猫。
本发明所述的冠状病毒，其定义为本领域熟知，在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)。冠状病毒是具有囊膜(envelope)、基因组为单股正链的RNA病毒，是自然界广泛存在的一大类病毒。
本发明的目的是提供冠状病毒感染引起的疾病的潜在治疗方案。本发明所述的冠状病毒较佳地属于正冠状病毒亚科(Orthocoronavirinae)，更佳地属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
在本发明一较佳实施例中，所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮除可用于治疗SARS-CoV-2(Beta冠状病毒属)引发的疾病以外，还应可治疗其他冠状病毒SARS-CoV(Beta冠状病毒属)和MERS-CoV等引起的重大传染病，亦可作为普通感冒药，治疗HCoV-HKU1(Human coronavirus HKU1；Beta冠状病毒属)、HCoV-NL63(Human coronavirus NL63；Alpha冠状病毒属)、HCoV-OC43(Human coronavirus OC43)以及HCoV-229E(Human coronavirus 22E；Alpha冠状病毒属)等冠状病毒引起的疾病；还可作为兽药，治疗猪传染性胃肠炎病毒(Transmissible gastroenteritis virus，TGEV；Alpha冠状病毒属)、猪流行性腹泻病毒(Porcine epidemic diarrhea virus，PEDV；Alpha冠状病毒属)、猪丁型冠状病毒(Porcine delta coronavirus，PDCoV；Delta冠状病毒属)、猫传染性腹膜炎病毒(Feline infectious peritonitis virus，FIPV；Alpha冠状病毒属)、禽传染性支气管炎病毒(Infectious bronchitis virus，IBV；Gamma冠状病毒属)等动物疾病。
因此，本发明所述冠状病毒的较佳地选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
本发明中涉及的以本发明多种化合物作为活性成份的药物组合物，均可 根据本领域公知的方法制备。可通过将本发明化合物制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的重量含量通常为0.1～99.0％。
所述的药学可接受的载体可为本领域常规的载体，所述的载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料，较佳地包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地，所述的药物组合物包括0.01～99.99％的上述蛋白质和/或上述的抗体药物偶联物，和0.01～99.99％的药用载体，所述百分比为占所述药物组合物的质量百分比。
本发明化合物或含其的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
以上所述的木瓜蛋白酶抑制剂可以冠状病毒抑制剂的形式存在，例如：常规的用于防治冠状病毒的药物。
术语解释
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明的化合物及包含其的药物、药物组合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物及包含其的药物、药物组合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类药物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的药物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类药物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所 述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的药物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“一种或多种”中的“多种”可以是指2种、3种、4种、5种、6种、7种、8种、9种或者更多种。
本发明的化合物、含其的药物或药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，例如口服、外敷、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等，优选通过口服或者外敷。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明的药物或药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镇、纤维素、碳酸镇、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、EZ麻油或氢化EZ麻油或多乙氧基氢化EZ麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”可以以晶型或无定型的形式存在。术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。
本发明中，所述“包括、包含或含有”可以是指除了包括后面所列举的成分，还存在其他成分；也可以是指“由……组成”，即只包括后面所列举的成分而不存在其他成分。
本发明的积极进步效果在于：
本发明通过体外酶活实验和体外细胞病毒实验，意外发现YM155可用于治疗冠状病毒引发的相关疾病。目前没有已批准上市的针对人类冠状病毒的特效药，YM155治疗方案可填补现有技术的不足，抗病毒活性强，毒副作用较低。
图1显示YM155对新型冠状病毒木瓜样蛋白酶有很强的抑制活性(IC
50＝2.47μM)。
图2显示YM155可以抑制细胞中SARS-CoV-2的复制(EC
50＝0.17μM)。
图3显示YM155具有较低的细胞毒性(CC
50>133μM)。
图4显示丹参酮Ⅰ对新型冠状病毒木瓜样蛋白酶的抑制活性；1：DMSO(阴性对照)，2：化合物分子；3：阳性对照(GRL-0617)。
图5显示隐丹参酮对新型冠状病毒木瓜样蛋白酶的抑制活性；1：DMSO(阴性对照)，2：化合物分子；3：阳性对照(GRL-0617)。
图6显示丹参酮Ⅰ对新型冠状病毒木瓜样蛋白酶有很强的抑制活性(IC50＝2.21μM)。
图7显示丹参酮Ⅰ可以抑制细胞中SARS-CoV-2的复制(EC50＝2.26μM)，且具较低的细胞毒性(CC50>300μM)。
图8显示隐丹参酮对新型冠状病毒木瓜样蛋白酶有很强的抑制活性(IC50＝5.63μM)。
图9显示隐丹参酮可以抑制细胞中SARS-CoV-2的复制(EC50＝0.7μM)，且具有较低的细胞毒性(CC50>300μM)。
下面结合实施例对本发明作进一步的描述。
丹参酮Ⅰ(CAS号：568-73-0)购于Approved Drug Library(Target Mol)，隐丹参酮(CAS号：35825-57-1)购于Natural Product Library(Selleck)。
所用阳性对照为GRL-0617抑制剂(购于光远生物)，已知其能够有效抑制冠状病毒木瓜样蛋白酶(具体参见Ratia,K.et al.A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.Proceedings of the National Academy of Sciences 105,16119-16124(2008))，其结构式如下所示：
实施例1
通多体外酶活实验发现YM155可显著抑制新型冠状病毒(SARS-CoV-2)的木瓜样蛋白酶活性(图1)。
体外酶活实验步骤为：200nM终浓度的SARS-CoV-2木瓜样蛋白酶，不 同浓度梯度(0.1nM–5μM)的YM155溶液与20μM的荧光底物(Arg-Leu-Arg-Gly-Gly-AMC)加入在60μl反应体系(50mM HEPES,pH＝7.5,0.1mg ml-1BSA)中，室温孵育10min，用发射光340nm和激发光460nm来检测荧光底物的反应初始速率，通过与不加药物的对照组初始速率比较，获得抑制率曲线。实验做了3次生物学重复。
实施例2
通过体外细胞病毒实验，发现YM155可显著抑制SARS-CoV-2在细胞中的复制能力(图2)。同时体外细胞毒性试验(图3)和文献报道的临床I期试验(Satoh,Taroh,et al."Phase I study of YM155,a novel survivin suppressant,in patients with advanced solid tumors."Clinical Cancer Research 15.11(2009):3872-3880.)证实了YM155具有较高的安全性，因此YM155可用于治疗冠状病毒引发的相关疾病。
体外细胞病毒实验的详细实验方法如下：
1)在噬斑法抗病毒试验中，用不同浓度(0.1μM-10μM)的YM155预处理在24孔培养皿中铺好的Vero E6细胞(购于ATCC)1小时后，加入临床分离的病毒株SARS-CoV-2(nCoV-2019BetaCoV/Wuhan/WIV04/2019)(MOI＝0.05)，感染1小时。然后，移除病毒-药物混合液，用DMEM培养基清洗两次后，细胞重新加入新的含预处理对应浓度药物和0.9％琼脂糖的培养基。继续培养4天后，细胞被4％的聚甲醛固定30分钟后，用结晶紫染色，观察并计数。所有病毒试验均在生物安全3级实验室完成，并有3次生物学重复。
2)在细胞活性实验中，Vero E6细胞培养在96孔板中。1天后，将不同浓度(0.06μM–400μM)的YM155加入DMEM培养基中继续1天，然后用CCK8测定法测量存活细胞的相对数量，得出细胞活性数据。所有实验均有3次生物学重复。
体外酶活实验和体外细胞病毒实验的详细实验方法可参见Jin,Z.,Du,X., Xu,Y.et al.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.Nature,doi:10.1038/s41586-020-2223-y(2020).。
实施例3
体外酶活实验条件具体为：
酶活实验荧光底物：Z-Arg-Leu-Arg-Gly-Gly-AMC(来源于吉尔生化)，此荧光底物的激发波长和发射波长分别为340nm和460nm。
实验步骤中所用的酶活反应buffer为50mM HEPES,pH 7.5,0.1mg/ml BSA,2mM DTT；酶活反应温度：30℃。
具体实验步骤为：反应起始通过添加木瓜样蛋白酶，木瓜样蛋白酶的终浓度为0.2μM，将50μM的抑制剂(丹参酮Ⅰ、隐丹参酮)溶液与酶活实验荧光底物(Z-Arg-Leu-Arg-Gly-Gly-AMC，浓度为20μM)加入在60μl反应体系(50mM HEPES,pH＝7.5,0.1mg/ml BSA)中，室温孵育10min，用发射光340nm和激发光460nm来检测荧光底物的反应初始速率，通过与不加药物的对照组初始速率比较，获得抑制率曲线。实验做了3次生物学重复(具体步骤参考Lee,H.,et al.(2019)."Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling."Bioorganic&medicinal chemistry 27(10):1981-1989.，Jin,Z.,Du,X.,Xu,Y.et al.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.Nature,doi:10.1038/s41586-020-2223-y(2020))。
所得结果如图4、图5所示，图中显示了丹参酮Ⅰ和隐丹参酮的酶活实验曲线。实验表明丹参酮Ⅰ和隐丹参酮可显著抑制新型冠状病毒(SARS-CoV-2)的木瓜样蛋白酶活性，明显区别于阴性对照，两个化合物均对冠状病毒木瓜样蛋白酶有明显抑制活性。
实施例4
通多体外酶活实验发现丹参酮I和隐丹参酮可显著抑制新型冠状病毒(SARS-CoV-2)的木瓜样蛋白酶活性(图4)。
体外酶活实验步骤为：200nM终浓度的SARS-CoV-2木瓜样蛋白酶，不同浓度梯度的抑制剂溶液与20μM的荧光底物(Arg-Leu-Arg-Gly-Gly-AMC)加入在60μl反应体系(50mM HEPES,pH＝7.5,0.1mg ml-1BSA)中，室温孵育10min，用发射光340nm和激发光460nm来检测荧光底物的反应初始速率，通过与不加药物的对照组初始速率比较，获得抑制率曲线。实验做了3次生物学重复。
所得结果如图6和图8所示，丹参酮Ⅰ和隐丹参酮对新型冠状病毒木瓜样蛋白酶有很强的抑制活性，IC
50分别为2.21μM和5.63μM。
实施例5
通过体外细胞病毒实验，发现丹参酮I和隐丹参酮可显著抑制SARS-CoV-2在细胞中的复制能力，且细胞毒性较低。EC
50值分别为2.26μM和0.7μM(见图7和图9)。CC50值均大于300μM。
体外细胞病毒实验的详细实验方法如下：
(1)在噬斑法抗病毒试验中，用不同浓度的抑制剂预处理在24孔培养皿中铺好的Vero E6细胞(购于ATCC)1小时后，加入临床分离的病毒株SARS-CoV-2(nCoV-2019BetaCoV/Wuhan/WIV04/2019)(MOI＝0.05)，感染1小时。然后，移除病毒-药物混合液，用DMEM培养基清洗两次后，细胞重新加入新的含预处理对应浓度药物和0.9％琼脂糖的培养基。继续培养4天后，细胞被4％的聚甲醛固定30分钟后，用结晶紫染色，观察并计数。所有病毒试验均在生物安全3级实验室完成，并有3次生物学重复。
(2)在细胞活性实验中，Vero E6细胞培养在96孔板中。1天后，将不同浓度的抑制剂加入DMEM培养基中继续1天，然后用CCK8测定法测量存活细胞的相对数量，得出细胞活性数据。所有实验均有3次生物学重复。
体外酶活实验和体外细胞病毒实验的详细实验方法可参见Jin,Z.,Du,X.,Xu,Y.et al.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature,doi:10.1038/s41586-020-2223-y(2020).。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。
Claims (18)
- 化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型；其用于治疗和/或预防冠状病毒引发的疾病；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
- 化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其用于制备用于治疗和/或预防冠状病毒引发的疾病的药物或者木瓜样蛋白酶抑制剂，所述的药物用于治疗和/或预防冠状病毒引发的疾病；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
- 如权利要求1或2所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其特征在于，所述的疾病为哺乳动物或者禽类疾病，所述的哺乳动物优选包括人、猪和猫；和/或，所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)，优选属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属，更优选选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
- 如权利要求1或2所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其特征在于，所述的冠状病毒选自引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如SARS相关冠状病毒和中东呼吸综合征冠状病毒中的一种或多种；较佳地，所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠状病毒HKU1、人冠状病毒OC43、人冠状病毒NL63和/或小鼠肝炎病毒A59；和/或，所述SARS相关冠状病毒为SARS-CoV或SARS-CoV-2。
- 如权利要求1或2所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其特征在于，所述冠状病毒为猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪丁型冠状病毒、猫传染性腹膜炎病毒和/或禽传染性支气管炎病毒。
- 一种包含如权利要求1～5任一项所述的化合物YM155、丹参酮Ⅰ或者隐丹参酮，或其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型的药物组合物。
- 如权利要求6所述的药物组合物，其特征在于，所述的疾病为哺乳动物或者禽类疾病，所述的哺乳动物优选包括人、猪和猫；和/或，所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)，优选属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属，更优选选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
- 如权利要求6所述的药物组合物，其特征在于，所述的冠状病毒选自引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如SARS相关冠状病毒和中东呼吸综合征冠状病毒中的一种或多种；较佳地，所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠 状病毒HKU1、人冠状病毒OC43、人冠状病毒NL63和/或小鼠肝炎病毒A59；和/或，所述SARS相关冠状病毒为SARS-CoV或SARS-CoV-2。
- 如权利要求6所述的药物组合物，其特征在于，所述冠状病毒为猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪丁型冠状病毒、猫传染性腹膜炎病毒和/或禽传染性支气管炎病毒。
- 如权利要求6～9任一项所述的药物组合物，其特征在于，所述的药物组合物包含药学上可接受的载体、赋形剂和/或溶剂；和/或，所述药物组合物还包含其他药物；其中所述其他药物用于治疗和/或预防冠状病毒引发的疾病。
- 化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，或者包含其的药物组合物在制备用于治疗和/或预防冠状病毒引发的疾病的药物或者木瓜样蛋白酶抑制剂中的应用；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
- 如权利要求11所述的应用，其特征在于，所述的疾病为哺乳动物或者禽类疾病，所述的哺乳动物优选包括人、猪和猫；和/或，所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)，优选属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属，更优选选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
- 如权利要求11所述的应用，其特征在于，所述的冠状病毒选自引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如SARS相关冠状病毒和中东呼吸综合征冠状病毒中的一种或多种；较佳地，所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠状病毒HKU1、人冠状病毒OC43、人冠状病毒NL63和/或小鼠肝炎病毒A59； 和/或，所述SARS相关冠状病毒为SARS-CoV或SARS-CoV-2。
- 如权利要求11所述的应用，其特征在于，所述冠状病毒为猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪丁型冠状病毒、猫传染性腹膜炎病毒和/或禽传染性支气管炎病毒。
- 一种治疗冠状病毒引发的疾病的方法，其包括向有需要的患者施用化合物YM155、丹参酮Ⅰ或者隐丹参酮，其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，或者包含其的药物组合物；所述的化合物YM155的CAS号为781661-94-7，所述丹参酮Ⅰ的CAS号为568-73-0，所述隐丹参酮的CAS号为35825-57-1。
- 如权利要求15所述的方法，其特征在于，所述的疾病为哺乳动物或者禽类疾病，所述的哺乳动物优选包括人、猪和猫；和/或，所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)，优选属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属，更优选选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
- 如权利要求15所述的方法，其特征在于，所述的冠状病毒选自引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如SARS相关冠状病毒和中东呼吸综合征冠状病毒中的一种或多种；较佳地，所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠状病毒HKU1、人冠状病毒OC43、人冠状病毒NL63和/或小鼠肝炎病毒A59；和/或，所述SARS相关冠状病毒为SARS-CoV或SARS-CoV-2。
- 如权利要求15所述的应用，其特征在于，所述冠状病毒为猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪丁型冠状病毒、猫传染性腹膜炎病毒和/或禽传染性支气管炎病毒。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004517939A (ja) | 2001-01-16 | 2004-06-17 | 中山大学 | 初期アルツハイマー病の予防および治療に用いられるクリプトタンシノン |
| CN102552236A (zh) | 2012-02-13 | 2012-07-11 | 天津中医药大学 | 丹参酮i治疗小胶质细胞介导的疾病的用途 |
| CN102988370A (zh) | 2012-11-23 | 2013-03-27 | 广东省中医院 | 丹参酮i在制备治疗银屑病药物中的应用 |
| CN106798737A (zh) | 2017-01-09 | 2017-06-06 | 中山大学 | 用于防治肺纤维化的隐丹参酮类及其应用 |
| CN109620816A (zh) * | 2018-11-16 | 2019-04-16 | 天津大学 | 一种纳米免疫制剂及其制备方法与应用 |
-
2021
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- 2021-04-29 EP EP21802901.5A patent/EP4151216A4/en active Pending
- 2021-04-29 KR KR1020227042917A patent/KR20230011972A/ko unknown
- 2021-04-29 JP JP2022569212A patent/JP2023525855A/ja active Pending
- 2021-04-29 US US17/924,802 patent/US20230302019A1/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004517939A (ja) | 2001-01-16 | 2004-06-17 | 中山大学 | 初期アルツハイマー病の予防および治療に用いられるクリプトタンシノン |
| CN102552236A (zh) | 2012-02-13 | 2012-07-11 | 天津中医药大学 | 丹参酮i治疗小胶质细胞介导的疾病的用途 |
| CN102988370A (zh) | 2012-11-23 | 2013-03-27 | 广东省中医院 | 丹参酮i在制备治疗银屑病药物中的应用 |
| CN106798737A (zh) | 2017-01-09 | 2017-06-06 | 中山大学 | 用于防治肺纤维化的隐丹参酮类及其应用 |
| CN109620816A (zh) * | 2018-11-16 | 2019-04-16 | 天津大学 | 一种纳米免疫制剂及其制备方法与应用 |
Non-Patent Citations (24)
| Title |
|---|
| "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH |
| AKIMKIN VBEER MBLOME S ET AL.: "New Chimeric Porcine Coronavirus in Swine Feces, Germany, 2012", EMERG INFECT DIS., vol. 22, no. 7, 2016, pages 1314 - 1315 |
| BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104 |
| CAS , no. 35825 -57-1 |
| DE WIT, E.VAN DOREMALEN, N.FALZARANO, D. ET AL.: "SARS and MERS: recent insights into emerging coronaviruses", NAT REV MICROBIOL, vol. 14, 2016, pages 523 - 534, XP037065680, DOI: 10.1038/nrmicro.2016.81 |
| GARG, HIMANI ET AL.: "Survivin: a unique target for tumor therapy", CANCER CELL INTERNATIONAL, vol. 16.1, 2016, pages 49 |
| JEANNETTE GUARNER, MD: "three emerging coronaviruses in two decades: The Story of SARS, MERS, and Now COVID-19", AMERICAN JOURNAL OF CLINICAL PATHOLOGY, pages aqaa029 |
| JIN, DAO-ZHONG ET AL.: "Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 549, 2006, pages 166 - 172 |
| JIN, Z.DU, X.XU, Y. ET AL.: "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors", NATURE, 2020 |
| JI-YOUNG PARK, JANG HOON KIM, YOUNG MIN KIM, HYUNG JAE JEONG, DAE WOOK KIM, KI HUN PARK, HYUNG-JUN KWON, SU-JIN PARK, WOO SONG LEE: "Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases", BIOORGANIC, ELSEVIER, AMSTERDAM, NL, vol. 20, no. 19, 1 October 2012 (2012-10-01), AMSTERDAM, NL, pages 5928 - 5935, XP055567436, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2012.07.038 * |
| LEE, H. ET AL.: "Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 27, no. 10, 2019, pages 1981 - 1989, XP085664301, DOI: 10.1016/j.bmc.2019.03.050 |
| LIU WEIRONG; XIANG TANTING; FANG SHOUGUO: "Research progress on oapain of avian infectious Bronchitis virus", HEILONGJIANG ANIMAL SCIENCE AND VETERINARY MEDICINE, no. 7, 10 April 2020 (2020-04-10), CN , pages 49 - 53,158, XP009531810, ISSN: 1004-7034, DOI: 10.13881/j.cnki.hljxmsy.2019.03.0050 * |
| NAKAHARA, TAKAHITO ET AL.: "YM155, a novel small-molecule survivin suppressant, induces regression of established human.) hormone-refractory prostate tumor xenografts", CANCER RESEARCH, vol. 67.17, 2007, pages 8014 - 8021, XP055738981, DOI: 10.1158/0008-5472.CAN-07-1343 |
| NIZAMUTDINOVA, IRINA TSOY ET AL.: "Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation.) of adhesion molecules", CARCINOGENESIS, vol. 29.10, 2008, pages 1885 - 1892 |
| RATIA, K ET AL.: "A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 105, 2008, pages 16119 - 16124, XP055887377, DOI: 10.1073/pnas.0805240105 |
| RATIA, KIIRA ET AL.: "Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 103.15, 2006, pages 5717 - 5722 |
| SATOH, TAROH ET AL.: "Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors", CLINICAL CANCER RESEARCH, vol. 15.11, 2009, pages 3872 - 3880 |
| See also references of EP4151216A4 |
| SHIN, DAE-SEOP ET AL.: "Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells", CANCER RESEARCH, vol. 69.1, 2009, pages 193 - 202 |
| STADLER, K.MASIGNANI, V.EICKMANN, M. ET AL.: "SARS - beginning to understand a new virus.", NAT REV MICROBIOL, vol. 1, 2003, pages 209 - 218, XP037065560, DOI: 10.1038/nrmicro775 |
| VAN DER HOEK, L.PYRE, K.JEBBINK, M. ET AL.: "Identification of a new human coronavirus", NAT MED, vol. 10, 2004, pages 368373 |
| ZHANG YINGYING; WANG RONGLI: "Advances in the Study of the Relationship between Survivin and Pulmonary Diseases", JOURNAL OF MILITARY SURGEON IN SOUTHWEST CHINA, vol. 18, no. 5, 15 September 2016 (2016-09-15), pages 464 - 467, XP009531809, ISSN: 1672-7193 * |
| ZIEBUHR, J.: "Molecular biology of severe acute respiratory syndrome coronavirus", CURR OPIN MICROBIOL, vol. 7, 2004, pages 412 - 9, XP002993120, DOI: 10.1016/j.mib.2004.06.007 |
| ZIEBUHR, J.SNIJDER, E. J.GORBALENYA, A. E.: "Virus-encoded proteinases and proteolytic processing in the Nidovirale", J GEN VIROL, vol. 81, 2000, pages 853 - 79 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024170920A1 (en) * | 2023-02-14 | 2024-08-22 | Eötvös Loránd Tudományegyetem | Compounds for use against coronavirus infection |
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| EP4151216A4 (en) | 2024-09-04 |
| CN115666576A (zh) | 2023-01-31 |
| EP4151216A1 (en) | 2023-03-22 |
| US20230302019A1 (en) | 2023-09-28 |
| KR20230011972A (ko) | 2023-01-25 |
| JP2023525855A (ja) | 2023-06-19 |
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