CN115894443A - Compound Iquasivir and application thereof - Google Patents
Compound Iquasivir and application thereof Download PDFInfo
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- CN115894443A CN115894443A CN202211442078.XA CN202211442078A CN115894443A CN 115894443 A CN115894443 A CN 115894443A CN 202211442078 A CN202211442078 A CN 202211442078A CN 115894443 A CN115894443 A CN 115894443A
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- 238000002360 preparation method Methods 0.000 claims abstract description 4
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Abstract
The invention discloses a compound, namely, iquassivir and application thereof. The structural formula of the compound is shown as a formula (I). The invention discovers for the first time that the above-mentioned compounds of the eqisivir series can target and inhibit the function of main protease Mpro of the new coronavirus, so that the main protease Mpro can not hydrolyze polyprotein pp1a and pp1ab, thereby affecting the assembly and replication process of the new coronavirus. Based on the above, the invention also provides the application of the compound, namely the quinis, in the preparation of coronavirus main protease inhibitors and novel coronavirus resistant medicines, and provides a new way for human anti-new coronavirus infection work.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound, namely, iquisvir and application thereof.
Background
The genomic RNA of coronaviruses contains at least 6 Open Reading Frames (ORFs), the first ORF accounts for about two thirds of the genome length and is capable of directly translating two polyproteins: pp1a and pp1ab; these two polyproteins are bound by the major proteolytic enzyme of coronavirus (main protease M for short) pro Also known as 3C-like protease 3CL pro ) And one or two papain-like proteases (PLPs) to convert into 16 nonstructural proteins, which are involved in the production of subgenomic RNA, encoding four major structural proteins: envelope (E), membrane (M), spinous process (S) and nucleocapsid (N) and other accessory proteins to complete the viral replication and invasion process.
M pro The proteolytic cleavage of the overlapping pp1a and pp1ab polyproteins into functional proteins is a key step in the viral replication process; if not hydrolyzed correctly, the coronavirus will not complete replication. Meanwhile, M in different coronaviruses is found in the research pro The substrate binding sites of (a) are identical and well conserved; and M is absent from a host (e.g., human) pro Nor that the protease has M and M on the substrate pro Same preference for substrates, thus inhibiting M by targeting pro Can prevent the generation of infectious virus particles, thereby alleviating the symptoms of host infection with new coronavirus.
M is developed from Chinese patent application publication Nos. CN115260282A, CN104592349A, CN1763002A, CN113801187A, CN115260282A, CN115043900A and the like, and Chinese patent application publication Nos. CN114057702B, CN101418334B, CN114057702B, CN113368241B and the like pro Inhibitors to target inhibition of M pro To develop more and more effective M pro The inhibitor can provide more and more effective ways for human to resist the infection of the new coronavirus.
Disclosure of Invention
The invention aims to provide a compound, namely, the iquisvir and application thereof, and the compound can be used for inhibiting main protease of the new coronavirus in a targeted manner so as to achieve the aim of inhibiting the replication of the new coronavirus.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound, iquinivir (Aegivir), having the formula shown in formula (I):
in the formula (I), X is an electron-withdrawing group;
the A ring is selected from saturated quadricyclic group or saturated pentacyclic group which is unsubstituted or has substituent;
R 1 selected from unsubstituted or substituted aromatic nitrogen heterocycles, R 2 Is selected from-H, -OH, -CH 3 、-CH 2 CH 3 Or an electron withdrawing group;
R 3 and R 4 Independently selected from O or S.
The invention discovers for the first time that the above-mentioned compounds of the series of Iuquivir can target and inhibit coronavirus main protease M pro Function of (2) major protease M pro The polyproteins pp1a and pp1ab cannot be hydrolyzed, thereby affecting the assembly and replication process of the new coronavirus.
Based on the above, the invention also provides the application of the compound, namely the iquisitevir, in the preparation of coronavirus main protease inhibitors and novel coronavirus resistant medicines, and provides a new way for human to resist new coronavirus infection. Preferably, in the structural formula (I) of the compound of the invention, X is selected from halogen or halogenated methyl; the halogen is preferably F, cl, br or I; the halomethyl group can be selected from partially halogen-substituted or fully halogen-substituted methyl, preferably fully halogen-substituted methyl, such as-CF 3 or-CCl 3 。
Preferably, in the structural formula (I) of the compound of the invention, A ring is selected from unsubstituted or substituted saturated quadricyclic groups; the substituent can be halogen or-CN, and the substituent can be connected to any position of the saturated four-membered ring, which is not particularly required by the invention.
Preferably, the present inventionIn the structural formula (I) of the compound iqilsivir, R 1 Is selected from
Wherein Y and Z are each-H, -OH, -CH 3 、-CH 2 CH 3 、-C(CH 3 ) 2 Five-membered nitrogen heterocycles or electron withdrawing groups.
As a further preference, the five-membered azacyclic ring is selected from unsubstituted or substituted
Further preferably, the above-mentioned Y and Z are optionally an electron-withdrawing group and R 2 The optional electron withdrawing groups may each be independently selected from halogen, halomethyl, -CN or-N (CH) 3 ) 2 (ii) a Preferably, R 2 Optional electron withdrawing groups include halogen or halomethyl; the halogen is preferably F, cl, br or I; the halomethyl group can be a partially halogen-substituted or fully halogen-substituted methyl group, preferably a fully halogen-substituted methyl group, such as-CF 3 or-CCl 3 。
Preferably, the structural formula of the compound of the invention, namely, the iUquivir, is shown as any one of the following formula (1) to formula (17):
the research of the invention finds that the 17 ehiquivir series compounds not only have IC (integrated Circuit) on novel coronavirus main protease 50 All can reach below 50 mu M or even 10 mu M, and can be used for CC of J774 cells 50 Are all larger than 100 mu M; the 17 compounds of the iUquivir series have obvious inhibitory activity to the novel coronavirus main protease, basically have no cytotoxicity to host cells and have good responseAnd 4, application prospect.
More preferably, the structural formula of the compound of the invention, namely, the iquisvir, is shown as a formula (1), (2), (3), (4), (6), (7), (8), (11), (12), (13), (14), (15), (16) or (17). The research of the invention discovers that the 14 compounds of the Iquasivir series have IC (integrated Circuit) effect on novel coronavirus main protease 50 All reach below 2 MuM; wherein, IC of the compounds of the Iquasivir series shown in the formulas (1), (3), (7), (15) and (16) to the novel coronavirus main protease 50 All reach 10 -1 IC of novel coronavirus main protease by iQuisvir series compounds represented by formulae (2), (4), (8), (12), (13), (14) and (16) at μ M level 50 All reach 10 -2 IC of [ mu ] M-grade iQuisavir series compound shown as formula (11) on novel coronavirus main protease 50 Up to 10 -3 μ M scale, showing excellent M pro Inhibiting the activity.
Compared with the prior art, the technical scheme of the invention has the beneficial effects that:
(1) The invention firstly screens and discovers that the iQuisvir series compounds can target and inhibit the main protease M of the new coronavirus pro Function of (2) major protease M pro The polyproteins pp1a and pp1ab cannot be hydrolyzed, thereby affecting the assembly and replication process of the new coronavirus. Therefore, the compound quinis can be used for preparing coronavirus main protease inhibitors and anti-novel coronavirus drugs, and provides a new way for resisting novel coronavirus infection of human beings.
(2) In the invention, 17 kinds of compounds in the series of the iQuisvir compounds have IC (integrated Circuit) not only for novel coronavirus main protease 50 All can reach below 50 mu M or even 10 mu M and can be used for CC of J774 cells 50 Are all larger than 100 mu M; the 17 compounds of the eqisivir series are shown to have obvious inhibition activity on novel coronavirus main protease, basically have no cytotoxicity on host cells and have good application prospects.
(3) In the invention, the structural formula is 14 Equisetvir series shown as formula (1), (2), (3), (4), (6), (7), (8), (11), (12), (13), (14), (15), (16) or (17)IC of compounds against novel coronavirus main proteases 50 All reach below 2 MuM; wherein, IC of the compounds of the Iquasivir series shown in the formulas (1), (3), (7), (15) and (16) to the novel coronavirus main protease 50 All reach 10 -1 IC of compounds of the eqisivir series represented by the formulae (2), (4), (8), (12), (13), (14) and (16) at the μ M level against novel coronavirus main proteases 50 All reach 10 -2 IC of compounds of the eqisivir series represented by the formula (11) at the μ M level against novel coronavirus main proteases 50 Up to 10 -3 μ M scale, showing excellent M pro Inhibiting the activity.
Drawings
FIG. 1 is a synthetic route for the compound of the present invention, eqilsivir 1;
wherein triphosgene is triphosgene, et3N is triethylamine, DCM is dichloromethane, RT is room temperature, overnight is overnight, TFA is trifluoroacetic acid;
FIG. 2 is an HPLC detection spectrum of compound eqilsvir 1 of the present invention;
wherein min represents retention time-min, mAU represents milliabsorbance unit, aegivir represents Iquasivir, the same applies below;
FIG. 3 is an ESI-MS detection spectrum of a compound of the present invention, namely, eqinsivir 1;
wherein m/z represents a charge-to-mass ratio, the same applies below;
FIGS. 4 and 5 are HPLC and ESI-MS detection spectra of the compound of the invention, namely, eqisivir 2;
FIGS. 6 and 7 are HPLC and ESI-MS detection spectra of the compound of the present invention, eqinosivir 3, in that order;
FIGS. 8 and 9 are HPLC and ESI-MS detection spectra of the compound of the invention, namely, eqisivir 4, in sequence;
FIGS. 10 and 11 are HPLC and ESI-MS detection spectra of compound eqilsivir 5 of the present invention in sequence;
FIGS. 12 and 13 are HPLC and ESI-MS detection spectra of compound eqilsivir 6 of the present invention in sequence;
FIGS. 14 and 15 are HPLC and ESI-MS detection spectra of compound eqinosivir 7 of the present invention in sequence;
FIGS. 16 and 17 are HPLC and ESI-MS detection spectra of compound eqilsivir 8 of the present invention in sequence;
FIGS. 18 and 19 are HPLC and ESI-MS detection spectra of the compound of the present invention, eqisivir 9, in sequence;
FIGS. 20 and 21 are HPLC and ESI-MS detection spectra of the compound of the invention, eqisivir 10, in sequence;
FIGS. 22 and 23 are HPLC and ESI-MS detection spectra of compound eqinosivir 11 of the present invention in that order;
FIGS. 24 and 25 are HPLC and ESI-MS detection spectra of compound eqinosivir 12 of the present invention in that order;
FIGS. 26 and 27 are HPLC and ESI-MS detection spectra of compound eqinosivir 13 of the present invention in that order;
FIGS. 28 and 29 are HPLC and ESI-MS detection spectra of compound eqilsivir 14 of the present invention in that order;
FIGS. 30 and 31 are HPLC and ESI-MS detection spectra of compound eqilsivir 15 of the present invention in that order;
FIGS. 32 and 33 are HPLC and ESI-MS detection spectra of compound eqilsivir 16 of the present invention in that order;
FIGS. 34 and 35 are HPLC and ESI-MS detection spectra of compound eqinosivir 17 of the present invention in that order;
FIG. 36 shows the results of the assay of the inhibitory rate of the compound of the invention, eqilsvir 1, on coronavirus main protease;
wherein Concentration (. Mu.M) represents the Concentration of Iquavir 1 (micromolar), M pro inhibition (%) represents the inhibition rate (percentage) of coronavirus main protease; IC (integrated circuit) 50 Represents the median inhibitory concentration; the following steps are carried out;
fig. 37, fig. 38, fig. 39, fig. 40, fig. 41, fig. 42, fig. 43, fig. 44, fig. 45, fig. 46, fig. 47, fig. 48, fig. 49, fig. 50, fig. 51 and fig. 52 are test results of the inhibition rate of coronavirus main protease by inventive compounds of achievevir 2, achievevir 3, achievevir 4, achievevir 5, achievevir 6, achievevir 7, achievevir 8, achievevir 9, achievevir 10, achievevir 11, achievevir 12, achievevir 13, achievevir 14, achievevir 15, achievevir 16 and achievevir 17, in order;
FIG. 53 shows the results of the cytotoxicity test of the compound of the invention, eqilsvir 1, against the mouse macrophage line J774;
wherein Cell viability (%) indicates Cell viability (percentage), and CC50 indicates half toxic concentration; the following steps are carried out;
fig. 54, fig. 55, fig. 56, fig. 57, fig. 58, fig. 59, fig. 60, fig. 61, fig. 62, fig. 63, fig. 64, fig. 65, fig. 66, fig. 67, fig. 68, and fig. 69 are the results of cytotoxicity tests of compounds of the present invention, i.e., i.q.2, i.e., i.q.3, i.e., i.q.4, i.e., i.q.5, i.e., i.q.v., i.6, i.e., i.q.v., 7, i.e., 8, i.e., i.q.v., 9, i.q.v., 10, i.q.v., 11, i.q.v., 12, i.q.v., 13, i.q.v., 14, i.q.e., 15, i.q.16, and i.q.v., 17, on mouse macrophage line J774.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the accompanying drawings and the detailed description.
This example provides a method for synthesizing a compound, i.e., iquisvir 1, comprising the following steps (the synthetic route is shown in fig. 1):
(1) In an ice bath at 0 ℃, 3eq of triethylamine is added to a dichloromethane (2 mL) solution of 3-aminopyridine (0.25mmol, 1eq), then 0.5mL of triphosgene (0.5 eq) dichloromethane solution is added dropwise to the mixed system, the mixture is stirred and reacted for 45min in the ice bath at 0 ℃, then 0.2mmol of 1-amino-3- (2-chlorophenyl) cyclobutane-1-carboxylic acid methyl ester is added to the reaction system, and the mixture is stirred and reacted at room temperature overnight;
(2) Diluting with 15mL of dichloromethane and washing with saturated brine, drying the organic layer over anhydrous sodium sulfate, filtering and concentrating to obtain crude methyl 3- (2-chlorophenyl) -1- (3- (pyridin-3-yl) ureido) cyclobutane-1-carboxylate;
(3) Dissolving the crude product obtained in the step (2) in 2mL of methanol, adding 2eq of sodium hydroxide in an ice bath at 0 ℃, stirring for reacting for 20min, monitoring ester bond hydrolysis reaction by using LC-MS, adding trifluoroacetic acid into a reaction system after complete hydrolysis for neutralizing the reaction, and then concentrating to dryness;
(4) Dissolving the product obtained in the step (3) in 2mL of trifluoroacetic acid, heating to 60 ℃, reacting overnight, then cooling and concentrating the reaction liquid to dryness, finally dissolving the obtained product in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 98.37%, and RT =1.222min; ESI-MS: m/z =328.0[ 2 ] M + H] + (ii) a The HPLC and MS spectra are shown in FIG. 2 and FIG. 3, respectively.
The structural formula of the compound is determined by HPLC and MS spectrogram as follows:
designated as eqilsivir 1 (aegivir 1).
This example provides a synthesis of the compound, eqilsivir 2, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-5-methylpyridine.
Dissolving the product of the reaction in DMSO and purifying using a high performance liquid chromatography system to give a yellow solid with a purity of about 91.44%, RT =1.024min; ESI-MS: m/z =342.2[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 4 and FIG. 5, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
is named as the Aiquassivir 2 (Aegivir 2).
EXAMPLE 3 Synthesis and characterization of Aegisvir 3
This example provides a synthesis of the compound, eqilsivir 3, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-4-methylpyridine.
Will reactThe resulting product was dissolved in DMSO and purified using a high performance liquid chromatography system to give a yellow solid with a purity of about 100%, RT =1.237min; ESI-MS: m/z =342.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 6 and FIG. 7, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
is named as the Aiquisvir 3 (Aegivir 3).
EXAMPLE 4 Synthesis and characterization of Aegisvir 4
This example provides a synthesis of the compound, eqilsivir 4, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 2-fluoro-3-aminopyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 100%, wherein RT =1.292min; ESI-MS: m/z =346.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 8 and FIG. 9, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 4 (aegivir 4).
Example 5 Synthesis and characterization of Aegisivir 5
This example provides a synthesis of the compound, eqilsvir 5, which is essentially the same as in example 1, except that: 3-aminopyridine was replaced with 3-amino-6-methylpyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 100%, wherein RT =1.169min; ESI-MS: m/z =342.1[ 2 ], [ M + H ]] + . The HPLC and MS spectra are shown in FIG. 10 and FIG. 11, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 5 (aegivir 5).
Example 6 Synthesis and characterization of Aegisivir 6
This example provides a synthesis of the compound, eqilsvir 6, which is essentially the same as in example 1, except that: replacement of 3-aminopyridine by N 3 ,N 3 -lutidine-3, 5-diaminepyridine.
Dissolving the product obtained from the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a brown solid with the purity of about 100%, and RT =1.155min; ESI-MS: m/z =371.1[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 12 and FIG. 13, respectively.
The structural formula of the compound is determined by HPLC and MS spectrogram as follows:
is named as eqisivir 6 (Aegiivir 6).
Example 7 Synthesis and characterization of Aegiivir 7
This example provides a synthesis of the compound, eqilsivir 7, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-5-fluoropyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 96.28 percent and RT =1.303min; ESI-MS: m/z =346.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 14 and FIG. 15, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 7 (aegivir 7).
Example 8 Synthesis and characterization of Aegisvir 8
This example provides a synthesis of the compound, eqilsivir 8, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-5-chloropyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 90.31 percent and RT =1.427min; ESI-MS: m/z =362.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 16 and FIG. 17, respectively.
The structural formula of the compound is determined by HPLC and MS spectrogram as follows:
is named as eqisivir 8 (Aegiivir 8).
This example provides a synthesis of the compound imiquivir 8, which is essentially the same as example 1, except that: 3-aminopyridine was replaced with 3-amino-6-fluoropyridine.
Dissolving the product obtained from the reaction in DMSO and purifying using a high performance liquid chromatography system to obtain a brown solid with a purity of about 95.64%, RT =1.304min; ESI-MS: m/z =346.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 18 and FIG. 19, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 9 (aegivir 9).
Example 10 Synthesis and characterization of Aegisvir 10
This example provides a synthesis of the compound, eqilsivir 10, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 2-methyl-3-aminopyridine.
Dissolving the product obtained from the reaction in DMSO and purifying using a high performance liquid chromatography system to obtain a white solid with a purity of about 100%, RT =1.195min; ESI-MS: m/z =342.2[ 2 ], [ M + H ]] + . The HPLC and MS spectra are shown in FIG. 20 and FIG. 21, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqisivir 10 (Aegiivir 10).
This example provides a synthesis of the compound, eqilsivir 11, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-4- (1-methyl-1H-pyrazol-4-yl) pyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 98.60 percent and RT =1.160min; ESI-MS: m/z =408.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 22 and FIG. 23, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 11 (aegivir 11).
This example provides a synthesis of the compound, eqilsivir 12, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-4-ethylpyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a yellow solid with the purity of about 100%, wherein RT =1.327min; ESI-MS: m/z =356.1[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 24 and FIG. 25, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
is named as the Aiquassivir 12 (Aegivir 12).
This example provides a synthesis of the compound, eqilsvir 13, which is essentially the same as in example 1, except that: 3-aminopyridine was replaced with 3-amino-4-isopropylpyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 100%, wherein RT =1.343min; ESI-MS: m/z =370.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 26 and FIG. 27, respectively.
The structural formula of the compound is determined by HPLC and MS spectrogram as follows:
designated as eqisivir 13 (Aegisivir 13).
This example provides a synthesis of the compound, eqilsivir 14, which is essentially the same as in example 1, except that: 3-aminopyridine was replaced with 3-amino-4-methyl-5-chloropyridine.
Dissolving the product obtained in the reaction in DMSO, and purifying by using high performance liquid chromatography system to obtain light brown solid with purity of about 98.49%, RT =1.387min；ESI-MS:m/z＝376.0[M+H] + . The HPLC and MS spectra are shown in FIG. 28 and FIG. 29, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 14 (aegivir 14).
This example provides a synthesis of the compound, eqilsivir 15, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-4- (1H-pyrazol-1-yl) pyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 100 percent and RT =1.290min; ESI-MS: m/z =394.0[ m + H ]] + . The HPLC and MS spectra are shown in FIG. 30 and FIG. 31, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 15 (aegivir 15).
This example provides a synthesis of the compound, eqilsivir 16, which is essentially the same as in example 1, except that: the 3-aminopyridine was replaced with 3-amino-4- (4-methyl-1H-pyrazol-1-yl) pyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a light brown solid with the purity of about 93.10% and RT =1.285min; ESI-MS: m/z =408.0[ 2 ] M + H] + . The HPLC and MS spectra are shown in FIG. 32 and FIG. 33, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqilsivir 16 (aegivir 16).
This example provides a synthesis of the compound, eqilsivir 17, which is essentially the same as in example 1, except that:
the 3-aminopyridine was replaced with 3-amino-4- (1H-1, 2, 3-triazol-1-yl) pyridine.
Dissolving the product obtained by the reaction in DMSO, and purifying by using a high performance liquid chromatography system to obtain a yellow solid with the purity of about 97.73 percent and RT =1.280min; ESI-MS: m/z =395.0[ m + H ], [] + . The HPLC and MS spectra are shown in FIG. 34 and FIG. 35, respectively.
The structural formula of the compound is determined according to HPLC and MS spectrums as follows:
designated as eqisivir 17 (Aegisivir 17).
Example 18 assay of inhibitory Activity of Equisetvir series Compounds on coronavirus Main protease
In this example, the inhibitory activity of the ehiquivir series compounds synthesized in examples 1 to 17 on the coronavirus main protease was tested using the novel coronavirus main protease as a test target, and the test method was as follows:
adding main protease into a 96-well plate to enable the final concentration of the main protease to be 100nM, adding an Iquasivir series compound with a series concentration gradient (50-0 muM, 4-fold dilution and 11 concentrations), adding 1 muL of fluorescent polypeptide substrate with the concentration of 1mM into each well after incubating for 10min at 37 ℃, placing the wells in a thermostat at 37 ℃ for incubating for 30min, setting excitation waves to be 340nM and emission waves to be 490nM in a microplate reader, and detecting the fluorescence value (RFU) of each well, wherein the higher the RFU represents that the enzyme catalytic activity is stronger; and the inhibitory activity of the compounds of the Iquasivir series on the main protease is quantified by the following formula:
suppression ratio (%) = (RFU) Control well -RFU Experiment hole )/(RFU Control well -RFU Solvent background pores )；
In the formula, the control well refers to a well containing only buffer, main protease and substrate, but no drug; the experimental wells are wells containing buffer, main protease, substrate and drug; solvent background wells refer to wells containing only buffer and substrate.
The test results are shown in fig. 36 to 52 in sequence.
As can be seen from fig. 36 to 52, other compounds of the genus ehyclidine, except for the ehyclidine 5, all showed excellent inhibitory activity against the novel coronavirus main protease. Wherein, IC of the iquassivir 10 to the novel coronavirus main protease 50 IC of iQuisvir 9 for the novel coronavirus main protease at 22.0. Mu.M 50 IC of iQuisvir 6 for novel coronavirus main protease at 7.12. Mu.M 50 IC of 1.90 μ M for iCalicir 1, iquasivir 3, iquasivir 7, iquasivir 15 and Iquasivir 16 against the novel coronavirus main protease 50 All reach 10 -1 IC of novel coronavirus main proteases on μ M scale, IC of imiqivir 2, imiqivir 4, imiqivir 8, imiqivir 12, imiqivir 13, imiqivir 14 and imiqivir 16 50 All reach 10 -2 IC of uM grade, eqisivir 11, on novel coronavirus main protease 50 Up to 10 -3 μ M scale.
Example 19 cytotoxicity assays for compounds of the Iuquivir series
In this example, the cytotoxicity of the compounds of the series of iqus viruses synthesized in examples 1 to 17 was tested by taking J774 cells as an example, and the test method was as follows:
resuscitating and culturing mouse macrophage line J774 at 3X 10 4 Cell density per well J774 cells were seeded into clear 96-well plates; after culturing for 24h adherence at 37 ℃, adding the drugs to be detected with different concentrations; simultaneously setting a negative control hole and a zero setting hole, wherein the negative control holeThe hole is a hole which only contains cells without adding drugs, and the zero setting hole is a hole which only contains culture medium; the plate was incubated for 8h in a 37 ℃ incubator; finally, 10 mul of WST reagent is respectively added into each hole, after incubation for 60min at 37 ℃, the plate is placed in a microplate reader, the OD value is detected under the wavelength of 460nm, the higher the OD value is, the more surviving cells are, and the cell survival rate is calculated according to the following formula:
cell viability (%) = (OD) Experiment hole -OD Zero setting hole )/(OD Negative control well -OD Zero setting hole )。
The test results are shown in fig. 53 to 69 in this order.
As can be seen from FIGS. 53 to 69, CC of J774 cells by 17 eQuisvir compounds of the present invention 50 Are all larger than 100 mu M. And IC of novel coronavirus main protease by other eqisivir compounds except for eqisivir 5 50 Are all lower than 25 mu M; indicating that the ehquinivir compound is substantially non-cytotoxic to the host cells over an effective concentration range.
Claims (10)
1. A compound, namely, the Iquassivir, is characterized in that the structural formula is shown as a formula (I):
in the formula (I), X is an electron-withdrawing group;
the A ring is selected from saturated quadricyclic group or saturated pentacyclic group which is unsubstituted or has substituent;
R 1 selected from unsubstituted or substituted aromatic nitrogen heterocycles, R 2 Is selected from-H, -OH, -CH 3 、-CH 2 CH 3 Or an electron withdrawing group;
R 3 and R 4 Independently selected from O or S.
2. The compound, iquisvir, of claim 1, wherein in formula (I), X is selected from the group consisting of halogen and halomethyl.
3. The compound imiquivir according to claim 1, wherein in formula (i), the a ring is selected from the group consisting of unsubstituted or substituted saturated quaternary ring groups; the substituent comprises halogen or-CN.
4. The compound, iquisvir, of claim 1, wherein in formula (I), R is 1 Is selected from
Wherein Y and Z are each-H, -OH, -CH 3 、-CH 2 CH 3 、-C(CH 3 ) 2 Five-membered nitrogen heterocycles or electron withdrawing groups.
5. The compound iUquisvir according to claim 4, wherein said five-membered azacyclic ring is selected from unsubstituted or substituted
6. The compound agent iquisvir according to claim 1 or 4, wherein the electron-withdrawing group is selected from the group consisting of halogen, halomethyl, -CN, and-N (CH) 3 ) 2 。
7. The compound, iUquisvir, of claim 1, having a structural formula as shown in at least one of the following formulas (1) to (17):
8. the compound, eqilsvir, of claim 1 having the formula (i) shown in at least one of formulas (1), (2), (3), (4), (6), (7), (8), (11), (12), (13), (14), (15), (16) and (17).
9. Use of the compound of iquisitein according to any one of claims 1-8 for the preparation of coronavirus main protease inhibitors.
10. Use of the compound of iquisitein according to any one of claims 1-8 for the preparation of a medicament against novel coronary viruses.
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| WO2024017178A1 (en) * | 2022-07-18 | 2024-01-25 | Avitar Biosciences, Inc. | Substituted hydantoin compounds, pharmaceutical compositions, and therapeutic applications |
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
| US12030904B2 (en) | 2020-08-24 | 2024-07-09 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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| US12030904B2 (en) | 2020-08-24 | 2024-07-09 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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