CN116531361B - Application of oxygen bridge bicyclo- [2.2.1] -heptene compound in preparation of anti-novel coronavirus drugs - Google Patents
Application of oxygen bridge bicyclo- [2.2.1] -heptene compound in preparation of anti-novel coronavirus drugs Download PDFInfo
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- 241000711573 Coronaviridae Species 0.000 title claims abstract description 68
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 44
- 239000001301 oxygen Substances 0.000 title claims abstract description 44
- -1 bicyclo- [2.2.1] -heptene compound Chemical class 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 229940079593 drug Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical class C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims abstract description 14
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical group C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940016667 resveratrol Drugs 0.000 claims abstract description 6
- 235000021283 resveratrol Nutrition 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 23
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 9
- 241000700605 Viruses Species 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 4
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241001493065 dsRNA viruses Species 0.000 description 3
- HTNPEHXGEKVIHG-ZJTJHKMLSA-N molnupiravir Chemical compound CC(C)C(=O)OC[C@H]1O[C@H](C(O)C1O)N1C=C\C(NC1=O)=N\O HTNPEHXGEKVIHG-ZJTJHKMLSA-N 0.000 description 3
- 229940075124 molnupiravir Drugs 0.000 description 3
- 241000008904 Betacoronavirus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940125675 paxlovid Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000004176 Alphacoronavirus Species 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 241001461743 Deltacoronavirus Species 0.000 description 1
- 241000008920 Gammacoronavirus Species 0.000 description 1
- 241001292005 Nidovirales Species 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940125808 covalent inhibitor Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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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
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Oncology (AREA)
- Molecular Biology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of an oxygen bridge bicyclo- [2.2.1] -heptene compound in preparing an anti-novel coronavirus drug, and belongs to the technical field of medicines. The oxygen bridge bicyclo- [2.2.1] -heptene compounds comprise oxygen bridge bicyclo- [2.2.1] -heptene structural compounds containing alkaline side chains, oxygen bridge bicyclo- [2.2.1] -heptene structural compounds containing alkyl side chains, oxygen bridge bicyclo- [2.2.1] -heptene structural compounds containing resveratrol and oxygen bridge bicyclo- [2.2.1] -heptene structural compounds containing covalent structures, and the compounds can effectively inhibit the activity of novel coronaviruses and can be used for preparing medicaments for resisting the novel coronaviruses.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an oxygen bridge bicyclo- [2.2.1] -heptene compound containing different side chain structures and application thereof in preparation of anti-novel coronavirus medicines.
Background
Coronaviruses are a large virus family and are known to cause severe diseases such as common cold and Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). From the point of view of system taxonomy, coronaviruses (Coronavirus) are a linear single-stranded positive strand RNA virus, which are from the order of the reticuloviridae (Nidovirales), the family of coronaviridae (Coeonaviridase), and the genus coronavirus (Coronavirus). Coronaviruses can be divided into 4 genera based on serological and genetic composition characteristics, including: alpha, beta, gamma and delta coronaviruses. SARS-CoV-2 belongs to the genus beta coronavirus, has a typical coronavirus morphology, the virus particle is round or oval, has polymorphism, has a diameter of 60-140nm, and has a genome full length of about 30kb. It has envelope, genome is linear single-strand positive strand RNA virus, the particle is round or oval, and the diameter is about 60-140nm.
Currently, there are 3 FDA approved anti-novel coronavirus drugs in the united states, adefovir, molnupiravir, paxlovid. REMDESIVIR can only be administered by intravenous injection, and can not meet the requirement of oral antiviral drugs which are more convenient to use in treatment, and Molnupiravir and REMDESIVIR both belong to RNA polymerase (RdRp) inhibitors, namely RdRp is taken as an action target point. The novel coronavirus is an RNA virus, and RNA-dependent RNA polymerase (RdRps) is a key enzyme for replication and transcription of RNA viral genetic material, and RdRp is therefore also considered one of the most promising targets for anti-RNA viral drug development. Molnupiravir showed consistent efficacy in different viral variants Gamma, delta and Mu. Paxlovid is a proteasome inhibitor, which is required when the patient has early symptoms of infection. By binding to viral enzymes, the replication of the new coronavirus in the cell can be prevented. In addition, the novel crown monoclonal neutralizing antibody An Bawei mab/romidepuzumab combination therapy (previously known as BRII-196/BRII-198 combination therapy) was marketed with emergency approval by the chinese drug administration (NMPA). However, due to the emergence of novel coronavirus mutant strains, the development of novel, low-toxicity and high-efficiency anti-novel coronavirus small molecule inhibitors is particularly urgent.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides an oxygen bridge bicyclo- [2.2.1] -heptene compound containing different side chain structures and application thereof in preparing anti-novel coronavirus medicines.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The invention discovers that the oxygen bridge bicyclo- [2.2.1] -heptene compounds containing different side chain structures have the activity of resisting novel coronaviruses, and have the application of preparing medicaments for resisting the novel coronaviruses.
The oxygen bridge bicyclo- [2.2.1] -heptene compound containing different side chain structures comprises: an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing an alkaline side chain, an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing an alkyl side chain, an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing resveratrol (Resveratrol, RES), and an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing a covalent inhibitor.
The oxygen bridge bicyclo- [2.2.1] -heptene structural compound containing the alkaline side chain comprises the following compounds A1-A29:
The preparation of the above-mentioned compounds A1-A29 is shown in the patent publication No. CN109942595A, which is an oxygen bridge bicyclo- [2.2.1] -heptenes compound containing different functional side chain structures, and its preparation and application.
The oxygen bridge bicyclo- [2.2.1] -heptene structural compounds containing alkyl side chains comprise the following compounds B1a-B13a, B1B-B13B and B14-B16:
B1a-13a：
B1b-13b：
B14-B16：
The preparation of the compounds B1a-13a, B1B-B13B and B14-B16 is shown in patent publication No. CN108864127A, which is an oxygen bridge bicycloheptene sulfonamide compound with different alkyl chain lengths, and a preparation method and application thereof.
The oxygen bridge bicyclo- [2.2.1] -heptene structural compound containing resveratrol comprises the following compounds C1-C21:
C1-21：
the preparation of the compound C1-C21 is shown in patent publication No. CN107188896A, which is an oxygen bridge bicycloheptene compound containing resveratrol group and its preparation and application method.
The oxygen bridge bicyclo- [2.2.1] -heptene structural compound containing a covalent structure comprises the following compounds D1-D27:
The preparation of the compounds D1-D27 is disclosed in patent publication No. CN113582949A, an oxygen bridge bicyclo- [2.2.1] -heptene compound containing different covalent warhead structures, and preparation and application thereof.
In a first aspect, the invention provides the use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound as described above for the preparation of a medicament against a novel coronavirus.
In a second aspect, the invention provides the use of a pharmacologically or physiologically acceptable salt of an oxo-bridged bicyclo- [2.2.1] -heptene compound as described above in the manufacture of a medicament against a novel coronavirus.
In a third aspect, the present invention provides a pharmaceutical composition against a novel coronavirus comprising at least one of the aforementioned oxo-bridged bicyclo- [2.2.1] -heptenes compounds or a pharmacologically or physiologically acceptable salt thereof. Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, the present invention provides the use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound as described above, or a pharmacologically or physiologically acceptable salt thereof, for combating novel coronaviruses for non-disease therapeutic purposes.
The oxygen bridge bicyclo- [2.2.1] -heptene compound containing different side chain structures can effectively inhibit the activity of novel coronaviruses, has low toxicity to cells, and can be used for preparing medicaments for resisting the novel coronaviruses.
Drawings
FIG. 1 is a graph showing the results of the activity of compounds A1 to 29 in example 1 against the novel coronavirus SARS-Cov-2, wherein NC is a negative control and M is a blank control group of uninfected virus.
FIG. 2 shows the results of the anti-novel coronavirus SARS-Cov-2 activity of the compounds B1a-B13a, B1B-B13B, B14-16 of example 1.
FIG. 3 is the result of the anti-novel coronavirus SARS-Cov-2 activity of compounds C1-C21 of example 1.
FIG. 4 is the result of the anti-novel coronavirus SARS-Cov-2 activity of the compounds D1-D27 of example 1.
FIG. 5 is the result of example 2. A is the inhibition activity curve graph of the compound A6 on the novel coronavirus SARS-Cov-2, B is the inhibition rate bar graph of the compound A6 on the novel coronavirus SARS-Cov-2 at different concentrations, wherein Remd is the control drug remdesivir. C is the inhibition activity curve graph of the compound A14 on the novel coronavirus SARS-Cov-2, D is the inhibition rate bar graph of the compound A14 on the novel coronavirus SARS-Cov-2 at different concentrations, wherein Remd is the control drug remdesivir.
FIG. 6 is the result of example 3. A is the inhibition rate of the compound A6 to the novel coronavirus SARS-Cov-2 under the conditions of 0.6 mu M and 0.005 mu M, and the contrast medicine is remdersivir; panel B is the inhibition rate of compound A6 at concentrations of 2ng/μl and 10ng/μl for novel coronavirus variants (Alpha, beta, gamma, nigeria Nigeria, delta Deita, and Omicron). C is the inhibition rate of the compound A14 to the novel coronavirus SARS-Cov-2 under the conditions of 0.7 mu M and 0.006 mu M, and the control medicine is remdersivir. Panel D is the inhibition of novel coronavirus variants (alpha, beta, gamma, nigeria, delta, and Omikou) by compound A14 at concentrations of 2ng/μl and 10ng/μl.
Detailed Description
A further understanding of the nature and advantages of the present invention may be realized by the following detailed description. The examples provided are merely applications of the methods of the present invention and are not intended to limit the remainder of the disclosure in any way whatsoever.
EXAMPLE 1 in vitro anti-novel coronavirus Activity test of oxo-bridged bicyclo- [2.2.1] -heptenes
(1) Calu3 cells spread 24 orifice plates a day in advance, and experiments are carried out when the cell density is 100%, and medicines are diluted into different concentrations (such as 0.1mg/mL, 1mg/mL, 10mg/mL, 1 ng/[ mu ] L, 2 ng/[ mu ] L and 10 ng/[ mu ] L) by using DMSO, and 5 [ mu ] L is added to each orifice. Infection with the novel coronavirus SARS-Cov-2, and mutants of alpha, beta, gamma, nigeria, delta, and armstrong, were performed according to 0.02 MOI. After 24 hours of incubation at 37℃with 5% CO 2, the virus and drug containing medium was removed. Wash with PBS one time and add 500 μl TRIZOL to each well.
(2) Transferring TRIZOL in the pore plate into 1.5mL EP pipes, adding 100 mu L chloroform into each pipe, covering the EP pipe cover, forcefully shaking for 15 seconds, standing at room temperature (15-30 ℃) for 2-3 minutes, and centrifuging at 4 ℃ for 15 minutes by 12000 g; placing the upper water phase into a new EP pipe, adding 250 mu L of isopropanol, standing at room temperature (15-30 ℃) for 10 minutes, and centrifuging at 4 ℃ for 10 minutes by 12000 g; discarding the supernatant, adding 500 mu L of 75% ethanol for washing, vortex mixing, centrifuging at 4 ℃ and 7500g for 5 minutes, and discarding the supernatant; allowing the precipitated RNA to naturally dry at room temperature; RNA pellet was solubilized with RNase-FREE WATER. And then reverse transcription is carried out on RNA, and qPCR detection is carried out after the obtained DNA is diluted, and a fluorescence value is detected by an enzyme-labeling instrument and is positively correlated with the virus infection amount. Wherein qPCR primers: f: TAATCAGACAAGGAACTGATTA, R: CGAAGGTGTGACTTCCATG.
The four series of oxygen bridge bicyclo- [2.2.1] -heptene compounds of the invention have preliminary screening activity against novel coronavirus SARS-Cov-2, and the results are shown in figures 1-4. Most of oxygen bridge bicyclo- [2.2.1] -heptenes compounds containing alkaline side chains have good activity against novel coronaviruses SARS-Cov-2, such as compounds A6 and A14, and the like, and especially compounds A6 and A14 show good activity against novel coronaviruses at 2 ng/[ mu ] L and 10 ng/[ mu ] L. Most of the oxygen bridged bicyclo- [2.2.1] -heptenes compounds containing alkyl side chains have good anti-novel coronavirus activity, for example, compounds B6a, B11a, B15 and B16, etc., and especially compounds B6a and B15 show good anti-novel coronavirus activity at 2 ng/mu L. Most of the oxygen bridged bicyclo- [2.2.1] -heptenes compounds containing RES side chains have good anti-novel coronavirus activity, for example compounds C4, C45, C10, etc., especially compound C4 shows good anti-novel coronavirus activity at 2ng/μl. Most of the oxygen bridged bicyclo- [2.2.1] -heptenes compounds containing covalent structure have good anti-novel coronavirus activity, such as compounds D13, D22-D24, etc., especially compound D23 shows good anti-novel coronavirus activity at 2 ng/[ mu ] L.
Example 2 test of Compounds A6 and A14 against novel coronavirus IC 50
Compounds A6 and A14 were tested for IC 50 against the novel coronavirus according to the method of example 1 for in vitro anti-SARS-Cov-2 activity against the novel coronavirus.
The experimental results are shown in FIG. 5. The results show that the compounds A6 and A14 have inhibitory activity on the novel coronavirus SARS-Cov-2 in vitro, and the IC 50 is respectively 1.08 mu M and 1.14 mu M.
Example 3 broad-spectrum antiviral detection of novel coronaviruses by Compounds A6 and A14
The inhibitory activity of compounds A6 and a14 against different new coronaviruses was examined according to the method of in vitro anti-new coronavirus activity in example 1. In vitro anti-novel coronavirus activity (figure 6) shows that the compounds A6 and A14 can reach 50% or more inhibition activity on various novel coronaviruses such as SARS-Cov-2 and virus variants alpha, beta, gamma, nigeria, delta, omega and the like under the conditions of 10 ng/mu L and 2 ng/mu L.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (8)
1. The application of the oxygen bridge bicyclo- [2.2.1] -heptene compounds in preparing anti-novel coronavirus drugs is characterized in that:
The oxygen bridge bicyclo- [2.2.1] -heptene compound comprises: an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing an alkaline side chain, an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing an alkyl side chain, an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing resveratrol, and an oxygen bridged bicyclo- [2.2.1] -heptene structure compound containing a covalent structure;
the oxygen bridge bicyclo- [2.2.1] -heptene structural compound containing the alkaline side chain comprises the following compounds:
the oxygen bridge bicyclo- [2.2.1] -heptene structural compound containing the alkyl side chain comprises the following compounds:
the oxygen bridge bicyclo- [2.2.1] -heptene structure compound containing resveratrol comprises the following compounds:
The oxygen bridge bicyclo- [2.2.1] -heptene structure compound containing covalent structure comprises the following compounds:
。
2. The use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound according to claim 1 for the preparation of an anti-novel coronavirus drug, characterized in that: the oxygen bridge bicyclo- [2.2.1] -heptene compound is selected from the group consisting of compounds A1, A2, A3, A5, A6, A7, A10, A13, A14, A15, A17, A18, A19, A23, A24, A26, A27, A28 and A29.
3. The use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound according to claim 1 for the preparation of an anti-novel coronavirus drug, characterized in that: the oxygen bridge bicyclo- [2.2.1] -heptene compound is selected from compounds B1B, B2a, B6a and B11a.
4. The use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound according to claim 1 for the preparation of an anti-novel coronavirus drug, characterized in that: the oxygen bridge bicyclo- [2.2.1] -heptene compound is selected from compounds C4, C5, C7, C9, C10 and C14.
5. The use of an oxo-bridged bicyclo- [2.2.1] -heptenes compound according to claim 1 for the preparation of an anti-novel coronavirus drug, characterized in that: the oxygen bridge bicyclo- [2.2.1] -heptene compound is selected from compounds D3, D4, D5, D11, D14, D15, D17, D22 and D25.
6. Use of a pharmacologically or physiologically acceptable salt of an oxo-bridged bicyclo- [2.2.1] -heptene compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament against a novel coronavirus.
7. Use of an oxo-bridged bicyclo- [2.2.1] -heptene compound according to any one of claims 1-5 for the anti-novel coronavirus of non-disease therapeutic or prophylactic purposes.
8. Use of a salt as claimed in claim 6 against novel coronaviruses for non-disease therapeutic or prophylactic purposes.
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| CN105111244A (en) * | 2015-08-17 | 2015-12-02 | 铱诺(武汉)药业有限公司 | Ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound |
| CN107188896A (en) * | 2017-07-17 | 2017-09-22 | 苏州楚凯药业有限公司 | A kind of oxygen bridge double-heptene class compound and its preparation and application containing resveratrol group |
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| BRPI0806365B8 (en) * | 2007-02-06 | 2021-05-25 | Lixte Biotechnology Holdings Inc | compound, use of compound, pharmaceutical composition and use of pharmaceutical composition |
| GB0714649D0 (en) * | 2007-07-27 | 2007-09-05 | Univ Leuven Kath | Novel viral replication inhibitors |
| US8058268B2 (en) * | 2008-08-01 | 2011-11-15 | Lixte Biotechnology, Inc. | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases |
| US8227473B2 (en) * | 2008-08-01 | 2012-07-24 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
| CN108864127B (en) * | 2018-08-02 | 2020-06-23 | 武汉大学 | A kind of oxygen-bridged bicycloheptene sulfonamide compounds containing different alkyl chain lengths and preparation method and application thereof |
| CN109942595B (en) * | 2019-01-28 | 2020-08-25 | 武汉大学 | Oxygen-bridged bicyclo-[2.2.1]-heptene compounds with different functional side chain structures and their preparation and application |
| CN112618547B (en) * | 2020-12-23 | 2022-02-11 | 中国医学科学院医药生物技术研究所 | Application of a kind of quinoline compound in the preparation of anti-coronavirus preparation |
| CN113582949B (en) * | 2021-08-19 | 2023-06-30 | 武汉大学 | Oxygen bridge bicyclo- [2.2.1] -heptene compound containing different covalent warhead structures and preparation and application thereof |
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| CN105111244A (en) * | 2015-08-17 | 2015-12-02 | 铱诺(武汉)药业有限公司 | Ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound |
| CN107188896A (en) * | 2017-07-17 | 2017-09-22 | 苏州楚凯药业有限公司 | A kind of oxygen bridge double-heptene class compound and its preparation and application containing resveratrol group |
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