CN114605419A - Pyrrolidine compound with anti-new coronavirus activity and application thereof in medicines - Google Patents
Pyrrolidine compound with anti-new coronavirus activity and application thereof in medicines Download PDFInfo
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- CN114605419A CN114605419A CN202210384054.7A CN202210384054A CN114605419A CN 114605419 A CN114605419 A CN 114605419A CN 202210384054 A CN202210384054 A CN 202210384054A CN 114605419 A CN114605419 A CN 114605419A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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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Abstract
The invention discloses a pyrrolidine compound with anti-new crown virus activity and application thereof in anti-new crown drugs, and the key points of the technical scheme are as follows: in a method of treating or preventing 2019-nCoV comprising administering an effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I, the compound of the invention has excellent resistance to 3CL hydrolase (M)pro) The inhibitory activity of the compound can inhibit viruses by cell membrane channels and resisting enzymatic degradation. Meanwhile, the pharmaceutical composition of the main active ingredients of the compound can also be applied to products for treating, preventing and relieving diseases mediated by coronavirus.
Description
[ technical field ] A method for producing a semiconductor device
The invention belongs to the field of medical application, and particularly relates to a pyrrolidine compound with anti-new coronavirus activity and application thereof in medicines.
[ background of the invention ]
Novel coronaviruses, in particular SARS-CoV-2, are found, which are known as infectious acute respiratory syndrome (TARS coronavirus), clustered acute respiratory syndrome coronavirus (CARS coronavirus), or rapidly spreading respiratory syndrome coronavirus (RARS-COV)), and are persistently epidemic, and infections of which are mostly without significant clinical symptoms or exhibit common cold-like symptoms, and a minority can develop into pneumonia. However, severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and 2019 novel coronavirus (SARS-CoV-2) cause severe acute respiratory syndrome, and coronaviruses are widely noticed due to their high pathogenicity.
The novel Coronavirus is an enveloped single-stranded positive-strand RNA virus belonging to the genus Coronavir (Coronavir) of the family Coronaviridae (Coronavir) of the order Nidovirales (nested). So far, no specific treatment medicine exists for human coronavirus infection. Common coronavirus infections are generally self-limiting and require no special treatment. The clinical treatment of SARS-CoV and MERS-CoV mainly uses the combination of antiviral drugs ribavirin, interferon and glucocorticoid, but SARS-CoV-2 is still abused worldwide, the death rate is about 10%, the SARS-CoV-2 is still treated by antiviral drugs, interferon and other supportive treatment drugs, and no drug plays a good role in clinical treatment so far.
[ summary of the invention ]
The invention discloses a pyrrolidine compound with anti-new coronavirus activity, and aims to provide a piperazine compound and medical application thereof
The invention also discloses application of the pyrrolidine compound with the anti-new crown virus activity in anti-new crown drugs.
The invention also discloses a preparation method of the pyrrolidine compound with the anti-new coronavirus activity.
A pyrrolidine compound with anti-new coronavirus activity has a structure shown in formula I
Preferably, in the formula I:
said R1 and R2 represent H, or halogen, or are optionally substituted by nRaSubstituted groups as follows: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl;
said R3 is optionally selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl, or optionally substituted with one or more halogens, hydroxyl groups, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may optionally be replaced with-O-, -S-or-NR;
said R4 is an aromatic or heterocyclic group optionally selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20, or optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may optionally be replaced with-O-, -S-, or-NR
Said R5 is selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl or heterocyclyl, or is optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may be optionally substituted with: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl;
said R6 is selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl or heterocyclyl, or is optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may be optionally substituted with: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl.
Preferably, the aromatic group is selected from phenyl or naphthyl.
Preferably, the aromatic or heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S.
Preferably, the heterocyclic group is selected from the following components: morpholinyl, tetrahydrofuryl, tetrahydrothiazolyl, dioxanyl, dioxolanyl.
Preferably, the heterocyclic group is selected from the group consisting of: benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrolyl, benzofuranyl, benzothienyl, indolyl, indazolyl.
Preferably, the heterocyclic group is selected from the group consisting of: benzodioxan, benzodioxole.
Preferably, the compound is selected from:
a method for treating or preventing 2019-nCoV by using pyrrolidine compound with anti-new coronavirus activity, which comprises the step of administering an effective amount of a pharmaceutical composition containing an effective amount of a compound shown as a formula I, wherein the compound has excellent effect on 3CL hydrolase (M)pro) The inhibitory activity of the compound can inhibit viruses by cell membrane channels and resisting enzymatic degradation.
The pharmaceutical composition with the compound as the main active ingredient can be used for preparing products for treating, preventing and relieving diseases mediated by coronavirus.
[ detailed description ] embodiments
The pyrrolidine compounds having anti-new coronavirus activity according to the present invention are described in conjunction with specific examples 1-2.
Example 1:
a preparation method of pyrrolidine compounds with anti-new coronavirus activity comprises the following steps:
step 1, preparing 3-methylmorpholine by using 3-methylpiperidine, further preparing 2-methylpiperazine, mixing 2-methylpiperazine and ethyl acetate for reaction, continuously reacting the reaction solution for 1.5 hours at room temperature (25-35 ℃), adding the reaction solution into saturated sodium bicarbonate aqueous solution, after the reaction is quenched, extracting with dichloromethane, and distilling under reduced pressure to obtain an intermediate product 1, namely 2,4,5, 7-tetramethylpyrrolo [2,1-f ] [1,2,4] triazacyclo-cyclohexane (380g, 88.5%);
step 2, to a reaction flask containing 10g of intermediate 1, 20mL of DMF solvent was added followed by the sequential addition of K2CO3(8.1g,55mmol), the reaction was carried out at 55 ℃ and the completion of the reaction was checked by TLC, after completion of the reaction, H was added2O (15mL) quench the reaction and after quenching the reaction CH was added2Cl2(20 mL. times.2), the organic phase solution was collected and extracted with Na2SO4And (5) drying. Na was filtered off2SO4Then, spin-drying the organic solvent, and separating by using a column chromatography separation technology to obtain an intermediate product 2;
step 3, to a reaction flask containing 120mg of intermediate 2, 18ml of a mixed solvent of THF and MeOH (volume ratio: 1:2) was added, followed by addition of an aqueous solution of NaOH (300mg,15 mmol). Reacting at 60 ℃, detecting whether the reaction is complete or not by TLC (thin layer chromatography), obtaining a solid mixture by utilizing a decompression rotary solvent after the reaction is finished, dissolving the solid mixture by using methanol, filtering solid impurities, collecting an organic solvent, and obtaining an intermediate product 3 after rotary drying;
and 4, adding 12mL of ACN solvent into a reaction bottle containing 180mg of the intermediate product 3, then adding DEA (100mg,360umol), reacting at room temperature, detecting whether the reaction is complete or not by TLC, after the reaction is finished, drying the organic solvent in a spinning mode, and separating by utilizing a column chromatography separation technology to obtain a final product, wherein the final product is a white solid, and the yield is 25mg,13umol and 13.8%.
The second embodiment: research on inhibitory activity of pyrrolidine compound with anti-new coronavirus activity on target protein
The test method comprises the following steps: the compounds of the present application were prepared by the above method, and a parallel sample was obtained three times for comparative testing, known as SARS-CoV-23CL MproThe cysteine protease covalent inhibitor GC376 was used as a positive control for the enzyme activity assay. For enzymatic assays, we combined the test compound with SARS-CoV-23CL MproPreincubation was carried out for 80 minutes at room temperature, which was identical to the covalent selection conditions. After incubation, the substrate was added to the mixture and cleavage of the substrate was started at 37 ℃. The fluorescent signal was recorded in a time-dependent manner to evaluate the inhibitory effect of the compounds, and the test results are shown in table 1.
Table 1:
as can be seen from the above experimental results, the compounds of the present invention are effective against coronavirus MproHas certain inhibition effect on SARS-2, 229E and SARS coronavirus MproHas high inhibitory activity against SARS and SARS-2 coronavirus MproThe application discloses pyrrolidine compounds with anti-new coronavirus activity, and a method for treating or preventing 2019-nCoV, wherein the pyrrolidine compounds with slightly weak inhibitory activity and anti-new coronavirus activity comprise an effective amount of a pharmaceutical composition containing an effective amount of a compound shown in formula I, and the compound has excellent p-3 CL hydrolase (M)pro) The inhibitory activity of the compound can inhibit viruses by cell membrane channels and resisting enzymatic degradation.
Claims (9)
1. A pyrrolidine compound having an activity against a novel coronavirus, which is characterized in that: the structure is shown as formula I
2. The pyrrolidine compound of claim 1, having anti-neocoronavirus activity, wherein formula I:
said R1 and R2 represent H, or halogen, or are optionally substituted by nRaSubstituted with the following groups: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl;
said R3 is optionally selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl, or optionally substituted with one or more halogens, hydroxyl groups, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may optionally be replaced with-O-, -S-or-NR;
said R4 is an aromatic or heterocyclic group optionally selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20, or optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may optionally be replaced with-O-, -S-, or-NR
Said R5 is selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl or heterocyclyl, or is optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may be optionally substituted with: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl;
said R6 is selected from H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C20 aryl or heterocyclyl, or is optionally substituted with one or more halogen, hydroxy, and wherein each of said one or more non-terminal carbon atom (C1-C8) alkyl groups may be optionally substituted with: C1-C8 alkyl, C4-C8 carbocyclic glyceroalkyl, C4-C8 carbocyclic glyceroalkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl or C2-C8 substituted alkynyl.
3. A pyrrolidine compound according to claim 1, having activity against a novel coronavirus, wherein the aromatic group is selected from phenyl or naphthyl.
4. The pyrrolidine compound of claim 1, wherein the aromatic or heterocyclic group comprises 1 to 3 heteroatoms selected from N, O, S, wherein the heteroatoms are anti-neocoronaviruses.
5. The pyrrolidine compound of claim 1, wherein the heterocyclic group is selected from the group consisting of: morpholinyl, tetrahydrofuryl, tetrahydrothiazolyl, dioxanyl, dioxolanyl.
6. A pyrrolidine compound according to claim 1, having anti-neocoronaviral activity, wherein the heterocyclic group is selected from the group consisting of: benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrolyl, benzofuranyl, benzothienyl, indolyl, indazolyl.
7. The pyrrolidine compound of claim 1, wherein the heterocyclic group is selected from the group consisting of: benzodioxan, benzodioxole.
8. The pyrrolidine compound of claim 1, having anti-neocoronaviral activity, which is selected from the group consisting of:
9. use of a pyrrolidine compound of any one of claims 1 to 8 having anti-neocoronavirus activity for the preparation of a medicament for inhibiting coronavirus.
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| CN202111656862 | 2021-12-30 | ||
| CN2021116568626 | 2021-12-30 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024083099A1 (en) * | 2022-10-18 | 2024-04-25 | 福建广生中霖生物科技有限公司 | Drug intermediate and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021213288A1 (en) * | 2020-04-20 | 2021-10-28 | 中国科学院上海药物研究所 | Antiviral application of nucleoside analog or combination formulation containing nucleoside analog |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021213288A1 (en) * | 2020-04-20 | 2021-10-28 | 中国科学院上海药物研究所 | Antiviral application of nucleoside analog or combination formulation containing nucleoside analog |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024083099A1 (en) * | 2022-10-18 | 2024-04-25 | 福建广生中霖生物科技有限公司 | Drug intermediate and preparation method therefor |
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