CN116041349A - Xanthine compound, preparation method thereof and application thereof in preparation of novel coronavirus 3CL protease inhibitor - Google Patents
Xanthine compound, preparation method thereof and application thereof in preparation of novel coronavirus 3CL protease inhibitor Download PDFInfo
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Abstract
The invention discloses a xanthine compound, a preparation method thereof and application thereof in preparing a novel coronavirus 3CL protease inhibitor, wherein the xanthine compound is prepared from xanthine serving as a raw material through 6 steps of reactions, and has good inhibitory activity on novel coronavirus 3CL protease.
Description
Technical Field
The invention relates to the technical field of chemical drug development, in particular to a xanthine compound, a preparation method thereof and application thereof in preparing a novel coronavirus 3CL protease inhibitor.
Background
At present, the novel coronavirus is mainly prevented by vaccination, so that the probability of the patient to be moderately affected by severe disease is greatly reduced. However, the existing novel coronavaccine does not provide optimal protective effects and the high variability of viruses also poses challenges for vaccine development. In addition, small molecule drugs against new coronaviruses are also gradually introduced into the market, including new coronavirus polymerase inhibitors of adefovir, alzvudine, mo Nupi, and main protease (3 CL) inhibitors of nemaltevir tablet/ritonavir, entecavir, etc., which can effectively inhibit the replication of viruses in vivo to a certain extent, accelerate the nucleic acid negative transfer time and reduce the risk of hospitalization. Among them, the combination of Nemacrpevir tablet/ritonavir is required because Nemacrpevir is easily metabolized in vivo by cytochrome oxidase CYP3A4 in vivo, resulting in reduced efficacy, whereas ritonavir (an already clinically used HIV-1 protease inhibitor, which itself is inactive against new crown 3CL protease) increases its plasma concentration by inhibiting CYP 3A-mediated metabolism. However, this can greatly affect its scope of administration, even creating safety hazards to the patient due to interactions between the drugs and increasing the cost of administration. Entecavir is another 3CL protease inhibitor recently marketed in Japan, and has a structure different from that of the traditional peptidomimetic inhibitors (such as Nemactetavir), and does not need to be used together with a cytochrome oxidase inhibitor (ritonavir), so that the cost of administration is reduced, the compliance is good, and the medicine also needs to be subjected to clinical examination for a longer time. Along with the long-term use of the medicine, the virus drug resistance condition is unavoidable, so that the development of anti-new crown medicines with different targets or new structures is urgent. In addition, the complex yang condition of the new crown patients after the nucleic acid turns negative also makes epidemic prevention and control and drug research and development face great challenges.
The 3CL protease plays an important role in the replication and transcription of the novel coronavirus, and cleavage of viral precursor proteins results in a variety of active enzymes, such as RNA polymerase and helicase involved in transcription and replication of viral RNA. Therefore, inhibiting the 3CL protease function of the virus can effectively destroy the replication of the virus in human body, and is an important choice for developing anti-SARS-CoV-2 drugs.
Disclosure of Invention
The invention aims to provide a xanthine compound which can effectively inhibit 3CL protease and can provide a basis for development of anti-new crown drugs.
Another object of the present invention is to provide a process for producing the xanthine compound. It is a further object of the present invention to provide the use of the xanthine.
The technical scheme of the invention is as follows:
in a first aspect, the present invention provides a xanthine compound having the general structural formula:
wherein R is 1 Selected from F, cl, br, CN, C 1-3 Alkyl or C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3F;
m is selected from 1,2 or 3;
R 2 selected from H or C 1-3 An alkyl group;
R 3 selected from H or C 1-3 An alkyl group;
x is selected from C or N;
R 4 selected from H, C 1-3 Alkyl or acyl; wherein the acyl is selected from formyl, acetyl or substituted aromatic heterocyclic acyl; the aromatic heterocyclic structure in the aromatic heterocyclic acyl is selected from benzene ring, pyridine ring or pyrimidine ring; the substituent is selected from a monosubstituted, disubstituted or trisubstituted aromatic ring structure; wherein the substituent species is selected from F, cl, br, CN, C 1-8 Alkyl or a 3-8 long connecting chain optionally substituted with one or more heteroatoms, including O, S, N.
In one embodiment of the present invention, the xanthine compound has the following structural formula:
in a second aspect, the invention provides a preparation method of the xanthine compound, which comprises the following steps:
(1) Xanthine is added with solvent water, bromine is added, the reaction is carried out for 4 hours at 100 ℃ to obtain a solid product, the solid product is washed by water and diethyl ether in sequence after the reaction is finished to obtain a compound 1a,
(2) Adding solvent N, N-dimethylformamide into the compound 1a, then adding DIPEA, adding p-methoxybenzyl chloride under stirring, reacting and concentrating at room temperature to obtain a first crude product, purifying the first crude product to obtain a compound 1b,
(3) Adding solvent N, N-dimethylformamide into the compound 1b, then adding DIPEA, adding 3,4, 5-trifluorobromobenzyl under stirring, reacting and concentrating at room temperature to obtain a second crude product, purifying the second crude product to obtain a compound 1c,
(4) Mixing the compound 1c, anhydrous potassium carbonate, 3-chloromethyl-1-methyl-1H-1, 2, 4-triazole hydrochloride, sodium iodide and solvent N, N-dimethylformamide, reacting at room temperature, adding water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a third crude product, purifying the third crude product to obtain a compound 1d,
(5) Compound 1d, 1- (2-tetrahydropyranyl) -1H-pyrazole-5-boronic acid pinacol ester, pd 2 (dba) 3 XPhos, KOAc, and THF/H is added 2 O, after ventilation, reacting at 90 ℃, cooling to room temperature after the reaction is finished, adding saturated saline, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a fourth crude product, purifying the fourth crude product to obtain a compound 1e,
(6) Adding trifluoroacetic acid, anisole and concentrated sulfuric acid into the compound 1e, refluxing at 90 ℃ for 24 reaction, cooling to room temperature after the reaction is finished, adding saturated sodium bicarbonate solution for neutralizing acid, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a fifth crude product, purifying the fifth crude product to obtain the compound 1,
the overall synthetic route is as follows:
in one embodiment of the present invention, the purification in the above preparation method steps (2) to (6) is performed by silica gel column chromatography.
In a third aspect, the present invention provides the use of a xanthine compound as described above, or a pharmaceutically acceptable salt thereof, for the preparation of a novel coronavirus 3CL protease inhibitor.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a xanthine as described above, or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the above-mentioned medicine further comprises pharmaceutically acceptable auxiliary materials, auxiliary agents or carriers; the xanthine compound or pharmaceutically acceptable salt thereof is contained in an effective therapeutic dose.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The term "therapeutically effective amount" refers to an amount of a compound of formula (la) sufficient to be therapeutically effective when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the particular activity of the therapeutic agent used, the age of the patient, the physiological condition, the presence of other disease states, and the nutritional condition. In addition, other medications that a patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered.
The term "treatment" means any treatment for a disease in a mammal, including: (i) Preventing the disease, i.e. causing no development of clinical symptoms of the disease; (ii) inhibiting the disease, i.e., arresting the development of clinical symptoms; and/or (iii) alleviating the disease, i.e., causing regression of the clinical symptoms.
The term "pharmaceutically acceptable adjuvants, adjuvants or vehicles" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Such media and agents are well known in the art for use with pharmaceutically active substances. The use thereof in therapeutic compositions is contemplated, except that any conventional medium or agent is incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the compositions.
Compared with the prior art, the invention has the following beneficial effects:
the xanthine compound is a non-peptide compound, does not have the risks of potential toxic and side effects such as nucleoside analogues and the like, has a brand-new skeleton compared with the molecular structure of the existing novel coronavirus drug, can enrich the molecular types of the existing anti-novel coronavirus drug, and slows down the generation of virus drug resistance.
The xanthine compound is prepared from the xanthine which is a cheap and easily available raw material through a 6-step reaction, and the whole process flow is simple, and special equipment and process conditions are not needed.
Experiments show that the xanthine compound has better inhibition activity of the novel coronavirus 3CL protease and can provide a basis for development of anti-novel coronavirus medicaments.
Detailed Description
The following detailed description of the invention is of preferred embodiments, but it should be understood that the invention is not limited to the specific embodiments.
Example 1: preparation of xanthines of formula 1
The general synthetic route for 1- (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -8- (1H-pyrazol-5-yl) -3- (2, 4, 5-trifluorobenzyl) -3, 7-dihydro-1H-purine-2, 6-dione (compound 1) is shown below:
step 1: synthesis of compound 1 a:
xanthine (5 g,0.033mol,1 eq) and solvent water (32.5 mL) were added to the tube, followed by bromine (3.6 mL,2.1 eq) and reacted at 100℃for 4 hours. After the reaction was completed, the solid was washed with water and diethyl ether in this order to obtain compound 1a.
1 H NMR(400MHz,DMSO-d 6 )δ14.11(s,1H),11.66(s,1H),11.01–10.85(m,1H)。
Step 2: synthesis of Compound 1 b:
in a double flask were added compound 1a (3.7 g,0.016mol,1 eq) and solvent N, N-dimethylformamide (50 mL), followed by DIPEA (8.1 mL,3 eq), p-methoxybenzyl chloride (2.16 mL,1 eq) was added with stirring at room temperature, and the reaction was carried out at room temperature for 24 hours. After the reaction, concentrating to obtain a crude product. The crude product was purified by silica gel column chromatography to give compound 1b.
1 H NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),11.11–11.01(m,1H),7.24(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),5.36(s,2H),3.73(s,3H)。
Step 3: synthesis of Compound 1 c:
in a double flask was added compound 1b (1 g,0.014mol,1 eq) and solvent N, N-dimethylformamide (20 mL), followed by DIPEA (1.44 mL,0.0085mol,3 eq), and 3,4, 5-trifluorobromobenzyl (0.35 mL,0.0028mol,1 eq) with stirring at room temperature, and reacted at room temperature for 3 hours. After the reaction, concentrating to obtain a crude product. The crude product was purified by silica gel column chromatography to give compound 1c.
1 H NMR(400MHz,DMSO-d 6 )δ11.47(s,1H),7.40–7.18(m,4H),6.92(d,J＝8.7Hz,2H),5.40(s,2H),5.04(s,2H),3.73(s,3H)。
Step 4: synthesis of Compound 1 d:
in a double flask were charged compound 1c (400 mg,0.003mol,1 eq), anhydrous potassium carbonate (669 g,0.0048mol,5 eq), 3-chloromethyl-1-methyl-1H-1, 2, 4-triazole hydrochloride (3411 mg,0.0016mol,1.5 eq), sodium iodide (24 mg,0.16mmol,0.2 eq) and solvent N, N-dimethylformamide (20 mL) and reacted at room temperature for 24 hours. After the reaction, water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give compound 1d.
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H),7.34(d,J＝8.1Hz,4H),6.98(d,J＝8.3Hz,2H),5.50(s,2H),5.22(s,2H),5.17(s,2H),3.84(s,3H),3.79(s,3H)。
Step 5: synthesis of Compound 1 e:
into a tube was sealed was added compound 1d (10 mg,0.0169mmol,1 eq), 1- (2-tetrahydropyranyl) -1H-pyrazole-5-boronic acid pinacol ester (7 mg,0.0252mmol,1.5 eq), pd 2 (dba) 3 (1 mg,0.001mmol,0.05 eq), XPhos (1 mg,0.0021mmol,0.1 eq), KOAc (5 mg,0.051mmol,3 eq) and THF/H were added 2 O(0.9mL,THF/H 2 O=0.6/0.3), after aeration, the reaction was carried out at 90 ℃ for 24 hours. After cooling to room temperature, saturated brine was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give compound 1e.
Step 6: synthesis of Compound 1:
to the tube was added compound 1e (80 mg,0.12mmol,1 eq), trifluoroacetic acid (1 mL), anisole (17 mg,0.157mmol,1.3 eq) and concentrated sulfuric acid (1-2 drops), and the mixture was refluxed at 90℃for 24 hours. Cooling to room temperature, adding saturated sodium bicarbonate solution to neutralize acid, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain crude product. The crude product was purified by silica gel column chromatography to give compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.78(s,3H),7.30(dd,J＝8.8,6.7Hz,2H),6.80(s,1H),5.22(s,2H),5.11(s,2H),3.76(s,3H)。
Example 2: xanthine compound experiment on 3CL protease inhibition activity
Experimental materials and instruments
| Name of the name | Manufacturer' s |
| 3CL protein | BPS Bioscience |
| 3CL protease assay buffer | BPS Bioscience |
| Dabcyl-KE-14-NH2 | GL Biochem |
| DTT(DL-Dithiothreitol) | Sigma |
| 384 well plate | Perkin Elmer |
| Enzyme label instrument | Perkin Elmer |
| Centrifugal machine | Eppendorf |
Experimental procedure
Test compound: xanthines of formula 1 prepared in example 1.
1. Before use, 0.5M DTT was diluted to a concentration of 1mM in 3CL protease assay buffer.
2. The 3CL protease is diluted at 1.5 ng/. Mu.L (15 ng per reaction) in buffer.
3. Diluted 3CL protease 10 μl was added to the positive control and test compound wells. 10. Mu.L of buffer was added to the blank wells.
4. Test compounds were diluted in DMSO to appropriate concentrations, serially diluted 1:3, with two replicates per concentration and 2.5 μl of test compound added to each well.
5. 2.5. Mu.L DMSO was added to the blank wells and positive control wells.
6. Pre-incubation was performed at room temperature for 30 min with slow shaking.
7. mu.L of 3CL protease substrate (10 mM) was diluted in 3.12mL of assay buffer to give a solution of 80. Mu.M.
8. The reaction was started by adding 12.5. Mu.L of substrate solution to all wells. In a 25. Mu.L reaction, the final concentration of 3CL protease substrate is 40. Mu.M.
9. Slowly shake at room temperature for 4 hours.
10. The excitation light is 360nm, and the fluorescence intensity is detected at the 460nm position of the emission light.
And (3) data processing:
1. mean data and Standard Deviation (SD) of DMSO and positive controls were calculated as High control and Low control for each plate.
2. Percent inhibition of compound wells (% inh) =100 x (ave High control-compound wells)/(ave High control-ave Low control).
3. Detection robustness check was performed using High control and Low control:
S/B＝ave High control/ave Low control，
CV％(Low control)＝100*(SD Low control/ave Low control)，
CV％(High control)＝100*(SD High control/ave High control)，
Z'＝1-3*(SD Low control+SD High control)/(ave High control–ave Low control)。
4. fitting compound IC in nonlinear regression equation by XLfit 5.3.1 50
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))，
X: the number of pairs of concentration of the compound,
y: percent inhibition (% inh),
Top/Bottom: the upper/lower limit value of the Y-axis,
hillslope: slope at the midpoint of the curves Top and Bottom.
The 3CL protease inhibitory activity results for xanthine compounds are shown in table 1 below:
TABLE 1 3CL protease inhibitory Activity of Compound 1
| Numbering of compounds | IC 50 (μM) |
| 1 | 2.5 |
The experimental results show that: the compound 1 has better inhibition activity of the novel coronavirus 3CL protease and can be further developed as a potential lead compound.
The foregoing descriptions of specific exemplary embodiments of the present invention are presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (7)
1. A xanthine compound is characterized by having the following structural general formula:
wherein R is 1 Selected from F, cl, br, CN, C 1-3 Alkyl or C 1-3 Alkoxy group, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1,2 or 3F;
m is selected from 1,2 or 3;
R 2 selected from H or C 1-3 An alkyl group;
R 3 selected from H or C 1-3 An alkyl group;
x is selected from C or N;
R 4 selected from H, C 1-3 Alkyl or acyl; wherein the acyl is selected from formyl, acetyl or substituted aromatic heterocyclic acyl; the aromatic heterocyclic structure in the aromatic heterocyclic acyl is selected from benzene ring, pyridine ring or pyrimidine ring; the substituent is selected from a monosubstituted, disubstituted or trisubstituted aromatic ring structure; wherein the substituent species is selected from F, cl, br, CN, C 1-8 Alkyl or a 3-8 long connecting chain optionally substituted with one or more heteroatoms, including O, S, N.
2. Xanthine compound according to claim 1, characterized by the following structural formula:
3. the method for preparing xanthine compound according to claim 2, comprising the steps of:
(1) Xanthine is added with solvent water, bromine is added, the reaction is carried out for 4 hours at 100 ℃ to obtain a solid product, the solid product is washed by water and diethyl ether in sequence after the reaction is finished to obtain a compound 1a,
(2) Adding solvent N, N-dimethylformamide into the compound 1a, then adding DIPEA, adding p-methoxybenzyl chloride under stirring, reacting and concentrating at room temperature to obtain a first crude product, purifying the first crude product to obtain a compound 1b,
(3) Adding solvent N, N-dimethylformamide into the compound 1b, then adding DIPEA, adding 3,4, 5-trifluorobromobenzyl under stirring, reacting and concentrating at room temperature to obtain a second crude product, purifying the second crude product to obtain a compound 1c,
(4) Mixing the compound 1c, anhydrous potassium carbonate, 3-chloromethyl-1-methyl-1H-1, 2, 4-triazole hydrochloride, sodium iodide and solvent N, N-dimethylformamide, reacting at room temperature, adding water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a third crude product, purifying the third crude product to obtain a compound 1d,
(5) Compound 1d, 1- (2-tetrahydropyranyl) -1H-pyrazole-5-boronic acid pinacol ester, pd 2 (dba) 3 XPhos, KOAc, and THF/H is added 2 O, ventilating, reacting at 90deg.C, cooling to room temperature, adding saturated saline, and adding ethanolExtracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a fourth crude product, purifying the fourth crude product to obtain a compound 1e,
(6) Adding trifluoroacetic acid, anisole and concentrated sulfuric acid into the compound 1e, refluxing at 90 ℃ for 24 reaction, cooling to room temperature after the reaction is finished, adding saturated sodium bicarbonate solution for neutralizing acid, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a fifth crude product, purifying the fifth crude product to obtain the compound 1,
4. the method according to claim 3, wherein the purification in steps (2) to (6) is performed by silica gel column chromatography.
5. Use of xanthines or pharmaceutically acceptable salts thereof according to claim 1 or 2, for the preparation of novel coronavirus 3CL protease inhibitors.
6. A medicament comprising the xanthine compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.
7. The medicament according to claim 6, further comprising pharmaceutically acceptable excipients, adjuvants or carriers; the xanthine compound or pharmaceutically acceptable salt thereof is contained in an effective therapeutic dose.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12091420B2 (en) | 2022-08-05 | 2024-09-17 | Gilead Sciences, Inc. | SARS-COV2 main protease inhibitors |
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| CN116041349B (en) | 2023-10-20 |
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