CN116655606A - Novel deuterated triazine compound, preparation method, composition and application thereof - Google Patents

Novel deuterated triazine compound, preparation method, composition and application thereof Download PDF

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Publication number
CN116655606A
CN116655606A CN202210148597.9A CN202210148597A CN116655606A CN 116655606 A CN116655606 A CN 116655606A CN 202210148597 A CN202210148597 A CN 202210148597A CN 116655606 A CN116655606 A CN 116655606A
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compound
preparation
deuterium
coronavirus
pharmaceutical composition
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黄才古
孙辉
曾维霖
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Guangzhou Anovent Pharmaceutical Co Ltd
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Guangzhou Anovent Pharmaceutical Co Ltd
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Priority to CN202210148597.9A priority Critical patent/CN116655606A/en
Priority to PCT/CN2022/097499 priority patent/WO2023155337A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a deuterated triazine compound shown in a formula I, or pharmaceutically acceptable salt, isomer, prodrug or eutectic thereof. Also discloses a preparation method, a composition and application of the deuterated compound. The compound is used as a 3CL protease inhibitor, realizes better pharmacokinetic property and therapeutic effect on the basis of equivalent virus inhibition activity, and has better patentability. The structural formula of formula I is as follows:

Description

Novel deuterated triazine compound, preparation method, composition and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel deuterated triazine compound, a preparation method, a composition and application thereof.
Background
Coronaviruses in humans were isolated in the uk the earliest 1960 s, and the viruses were named for their surface crown-like projections. SARS viruses belong to the order of the family of the mantle viridae, the genus coronavirus, and are subgroup B coronaviruses of the genus β. The virus particles are round, have a capsule, have fibers arrayed in a crown shape on the periphery, are distributed in the cytoplasm, are round, and have a virus diameter of 80-120 nm. SARS is an infectious disease that is urgent, rapidly transmitted, and has a high rate of mortality, and most of the patients who are infected come into direct or indirect contact with the patient, or live in epidemic areas. MERS virus is a subgroup C coronavirus of the β genus, known as the middle east respiratory syndrome coronavirus (Middle East Respiratory Syndrome Coronavirus, MERS-CoV for short), which causes the middle east respiratory syndrome after infection. MERS-CoV was found in sauter at earliest 9 in 2012, and was also known as 6 th human coronavirus, the 3 rd isolated in the last 10 years, at an early stage because of its similarity to the clinical symptoms of SARS, the name "SARS-like virus". The novel coronavirus is a novel strain of coronavirus which has never been found in human body before, and variant strains such as Alipha, beta, gamma, delta, omicron appear.
Common signs of a person infected with coronavirus are respiratory symptoms, fever, cough, shortness of breath, dyspnea, and the like. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, renal failure, and even death. There is no specific treatment for the disease caused by the novel coronavirus.
Sho Konno et al reported that peptidomimetic 3CL protease inhibitors have anti-SARS-CoV viral activity, biorg. Med. Chem.2013,21,412-424; the inhibitory effect of a series of dipeptidyl homotarget compounds as 3CL protease inhibitors on SARS-CoV was reported in eur.j. Med. Chem.2013,68, 372-384.
Yuto U.et al systems research and high throughput screening (antiviral activity) of salt field company (Shionogi) at month 2022, found that lead triazine compound 1, and through structure-activity relationship and structure optimization research, non-peptide, non-covalent compound 3, S-217622, was obtained. The general name of the medicine is indene fumarate (Ensitrelvir Fumarate), and the chemical name is: (E) -6- ((6-chloro-2-methyl-2H-indazol-5-yl) imine) -3- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazole-2, 4-dione fumaric acid co-crystal (IUPAC) having the following structural formula:
the medicine has better patentability, pharmacological activity and safety, and clinical I-IIa stage researches initially show that the medicine has clinical value, namely oral effectiveness and safety. The clinical indication is treatment of light to moderate new coronaries pneumonia, and single drug administration (without PK enhancer) is expected to be realized. However, the absolute bioavailability of the drug in dogs is low (64.7%), and the drug is probably oxidatively metabolized in vivo with the methyl segment in the molecular structure P1-P1' due to the first pass effect. The clinical pharmacokinetic properties and metabolic safety of the drug are to be improved.
Therefore, there is still a need in the art to develop novel 3CL protease inhibitors with better inhibitory activity or pharmacokinetic properties, and the present invention designs and discloses novel deuterated triazines, which achieve better pharmacokinetic properties and therapeutic effects than S-217622 on the basis of equivalent viral inhibitory activity, and have better patentability. Meanwhile, the preparation method, the pharmaceutical composition and the application of the medicine are disclosed, so that the production and the amplification of the medicine can be realized, the quality is controllable, and the medicine has good clinical value.
Disclosure of Invention
The invention relates to novel deuterated triazine compounds, a preparation method, a pharmaceutical composition and application thereof.
In certain embodiments, the present invention relates to a deuterated triazine compound represented by formula I, or a pharmaceutically acceptable salt, isomer, prodrug, or co-crystal thereof:
wherein: r is R 1 ～R 3 Each independently hydrogen or deuterium; r is R 4 ～R 7 Each independently hydrogen or deuterium; r is R 8 ～R 10 Each independently hydrogen or deuterium; with the proviso that R1-R 10 At least one of which is deuterium.
The invention discloses the above compound, which is characterized in that R 1 ～R 3 2-3 deuterium; r is R 4 ～R 7 2-4 deuterium; r is R 8 ～R 10 2-3 deuterium.
The above compound disclosed in the present invention is characterized in that the compound is a compound selected from the group consisting of:
the invention discloses a preparation method of the compound shown in the formula I, which comprises the following steps: (1) In an organic solvent, carrying out substitution reaction on a compound I-G with a general formula and a compound I-F under the action of alkali to prepare an intermediate I-E; (2) In an organic solvent, carrying out deprotection reaction (tert-butyl removal) on the intermediate I-E under the action of acid to prepare an intermediate I-D; (3) In an organic solvent, carrying out substitution reaction on a general formula compound I-D and a general formula compound I-C under the action of alkali to prepare a general formula intermediate I-B; (4) In an organic solvent, the intermediate I-B in the general formula and the compound I-A are subjected to condensation reaction under the action of alkali to prepare the deuterated triazine compound in the general formula I.
The invention discloses a pharmaceutical composition, which is characterized by comprising a pharmaceutically acceptable carrier and the compound, or pharmaceutically acceptable salts, isomers, prodrugs or eutectic substances thereof. The pharmaceutical composition is characterized in that it comprises an additional therapeutic agent, said additional therapeutic agent being an antiviral agent.
The application of the compound shown in the invention in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition is characterized in that the compound is used for preparing a 3CL protease inhibitor pharmaceutical composition.
The invention discloses application of the pharmaceutical composition, which is characterized in that the pharmaceutical composition is used for preparing medicines for treating and preventing viral infection. Preferably, wherein the viral infection is human coronavirus, novel coronavirus (SARS-CoV-2), SARS coronavirus and MERS coronavirus.
In various embodiments, the compounds preferably have one of the structures shown in table 1 below.
TABLE 1 representative deuterated triazines
In certain embodiments, the invention contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In certain embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, or aqueous buffer, such as saline or phosphate buffer.
In certain embodiments, the disclosed pharmaceutical compositions may comprise a compound disclosed herein and a propellant. In certain embodiments, the propellant is an aerosolized propellant, such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, a Hydrofluoroalkane (HFA), 1, 2-tetrafluoroethane, l,1, l,2, 3-heptafluoropropane, or a combination thereof.
In certain embodiments, the present invention contemplates pressurized containers or non-pressurized containers comprising a compound or pharmaceutical composition described herein. In certain embodiments, the container is a manual pump sprayer, inhaler, metered dose inhaler, dry powder inhaler, nebulizer, vibrating screen nebulizer, jet nebulizer, or ultrasonic nebulizer.
In certain embodiments, the compound or pharmaceutical composition is administered orally, intravenously, or by pulmonary, i.e., pulmonary, administration.
In certain embodiments, the invention relates to the use of a compound described herein in the manufacture of a medicament for the treatment or prophylaxis of viral infections, such as human coronavirus, novel coronavirus (SARS-CoV-2), SARS coronavirus and MERS coronavirus infections.
In certain embodiments, the present invention relates to methods of preparing a compound by mixing starting materials and reagents disclosed herein under conditions that form the compound disclosed herein.
The invention designs and discloses novel deuterated triazine compounds, which realize better pharmacokinetic properties and therapeutic effects than S-217622 on the basis of equivalent virus inhibition activity, and have better patentability. Meanwhile, the preparation method, the pharmaceutical composition and the application of the medicine are disclosed, so that the production and the amplification of the medicine can be realized, the quality is controllable, and the medicine has good clinical value.
The following detailed description is exemplary and explanatory only and is not restrictive.
All solvents and reagents used in the following examples are commercially available and used as such unless otherwise indicated.
The procedure described below can be used to synthesize compounds 1-11.
The following abbreviations are used herein:
LHMDS (lithium hexamethyldisilazide)
ACN: acetonitrile
THF: tetrahydrofuran (THF)
DMF: n, N-dimethylformamide
LiAlD 4 : lithium tetradeuterium aluminum
PBr 3 : phosphorus tribromide
EtOAc: acetic acid ethyl ester
PE: petroleum ether
CD 3 I: deuterated iodomethane
K 2 CO 3 : potassium carbonate
Detailed Description
Preparation example
Preparation example
Example 1: synthesis of Compound I-F
1) Synthesis of Compound I-F-1
To a 250ml three necked flask were added the starting material I-F-2 (10 g,52.6 mmol) and 100ml of tetrahydrofuran, cooled to-10℃and lithium aluminum tetradeuterium (6.3 g,157.8 mmol) was added in 4 portions, and the mixture was warmed to room temperature of 25℃and stirred for 4 hours. TLC monitoring end point, cooling to 0 ℃, slowly adding dropwise water (6 g), 15% sodium hydroxide solution (6 g) and water (18 g), heating to room temperature, stirring for 1h, filtering, washing, concentrating the filtrate under reduced pressure to obtain a yellow oily crude product. Purification by column chromatography (PE: etoac=1:1) afforded compound I-F-1 (6.5 g, 75% yield) as a pale yellow oil.
2) Synthesis of Compound I-F-a
To a 500ml three-necked flask were added raw material I-F-1 (6.5 g,39.4 mmol) and 150ml of tetrahydrofuran, cooled to 0℃and a solution of phosphorus tribromide in THF (21.3 g,78.8mmol,60 ml) was slowly added dropwise, and the mixture was stirred for 4 hours after the addition was completed, and the temperature was raised to 40 ℃. TLC was used for monitoring the end point, the mixture was cooled to room temperature, water (100 g) was slowly added dropwise, ethyl acetate (200 ml) was added, the organic phase was washed with water, sodium hydrogencarbonate solution and brine, and the organic phase was concentrated under reduced pressure to give a crude yellow oily product. Purification by column chromatography (PE: etoac=2:1) afforded compound I-F-a (7.3 g, 82% yield) as a pale yellow oil.
Summary of the structural formulae of Compounds I-F:
the preparation method of the compound I-F-b is the same as that of I-F-a (using lithium aluminum hydride as a reducing agent).
Example 2: synthesis of Compound I-C
1) Synthesis of Compound I-C-1
To a 250ml three necked flask were added raw material I-C-2 (10 g,70.9 mmol) and 100ml tetrahydrofuran, cooled to-10℃and lithium aluminum tetradeuterium (8.5 g,212.7 mmol) was added in 4 portions, and the mixture was warmed to room temperature of 25℃and stirred for 4 hours. TLC monitoring end point, cooling to 0 ℃, slowly dropwise adding water (8.5 g), 15% sodium hydroxide solution (8.5 g) and water (26 g), heating to room temperature, stirring for 1h, filtering, washing, and concentrating the filtrate under reduced pressure to obtain a light yellow oily crude product. Purification by column chromatography (PE: etoac=1:1) afforded compound I-C-1 (6.4 g, 78% yield) as an off-white solid.
2) Synthesis of Compound I-C-b
To a 500ml three-necked flask were added raw material I-C-1 (6.4 g,55.3 mmol) and 150ml of tetrahydrofuran, cooled to 0℃and a solution of phosphorus tribromide in THF (29.9 g,110.6mmol,60 ml) was slowly added dropwise, and the mixture was stirred for 6 hours after the addition was completed, and the temperature was raised to 40 ℃. TLC monitoring end point, cooling to room temperature, slowly adding dropwise water (100 g), adding ethyl acetate (200 ml), washing the organic phase by water, sodium bicarbonate solution and saline solution respectively, concentrating the organic phase under reduced pressure to obtain a light yellow solid crude product. Purification by column chromatography (PE: etoac=2:1) afforded compound I-C-b (7.8 g, 79% yield) as a white solid.
Summary of the structural formulae of Compounds I-C:
the preparation method of the compounds I-C-a, I-C-C and I-C-d is the same as that of the compound I-C-b (using lithium aluminum hydride as a reducing agent).
Example 3: synthesis of Compound I-A
1) Synthesis of Compound I-A-1
To a 250ml three-necked flask were added raw material I-A-2 (10 g,50.6 mmol), DMF80ml and potassium carbonate (20.9 g, 151.8 mmol), and deuterated iodomethane (14.7 g,101.2 mmol) was added dropwise at room temperature, and the mixture was stirred for 8 hours after the addition was completed, and the temperature was raised to 60 ℃. After TLC monitoring the end point, ethyl acetate (300 ml) was added at room temperature, the organic phase was washed with water, brine and the organic phase was concentrated under reduced pressure to give a crude yellow oil. Purification by column chromatography (PE: etoac=3:1) afforded compound I-a-1 (7.8 g, yield 72%) as a pale yellow solid.
2) Synthesis of Compound I-A-a
To a 200ml three-necked flask were added raw material I-A-1 (7.8 g,36.4 mmol), methanol 100ml and palladium on carbon 10% (0.39 g), and ammonium formate (9.2 g,145.6 mmol) was added at room temperature, and the mixture was stirred for 6 hours after the addition was completed, and the temperature was raised to 60 ℃. TLC monitoring the end point, filtering, washing, concentrating the filtrate under reduced pressure to obtain a yellow solid crude product. Purification by column chromatography (PE: etoac=2:1) afforded compound I-a (5.4 g, 80% yield) as a pale yellow solid.
Summary of the structural formula of compound I-A:
the preparation method of the compound I-A-b is the same as that of the compound I-A-a (methyl iodide is used as an alkylating agent).
Example 4: synthesis of Compounds I-E
Synthesis of Compound I-E-a
To a 50ml three-necked flask, I-G (1.0G, 4.3 mmol), I-F-b (1.0G, 4.7 mmol), DMF10ml and potassium carbonate (1.8G, 12.9 mmol) were charged at room temperature, and the mixture was stirred for 4 hours after the charging was completed, and the temperature was raised to 80 ℃. After TLC monitoring the end point, ethyl acetate (30 ml) was added at room temperature, the organic phase was washed with water, brine and the organic phase was concentrated under reduced pressure to give a crude yellow oil. Purification by column chromatography (PE: etoac=3:1) afforded compound I-E-a (1.1 g, 71% yield) as a pale yellow oil.
The preparation method of the compound I-E-b is the same as that of the compound I-E-a.
Example 5: synthesis of Compound I-D
Synthesis of Compound I-D-a
To a 20ml reaction flask were added raw material I-E-a (1.0 g,2.7 mmol) and trifluoroacetic acid (2.5 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. After TLC monitoring the end point, the reaction solution was concentrated under reduced pressure, and the crude product was slurried with toluene+isopropyl ether, filtered, washed, and dried to give Compound I-D-a (0.8 g, yield 92%) as an off-white solid.
The preparation method of the compound I-D-b is the same as that of the compound I-D-a.
Example 6: synthesis of Compound I-B
Synthesis of Compound I-B-a
To a 20ml reaction flask was added the starting material I-D-a (0.6 g,1.9 mmol), I-C-a (0.4 g, 2.3 mmol), DMF5ml and potassium carbonate (0.8 g,5.7 mmol) at room temperature, and after the addition, the temperature was raised to 65℃and stirred for 4h. After TLC monitoring the end point, ethyl acetate (20 ml) was added at room temperature, the organic phase was washed with water, brine, and the organic phase was concentrated under reduced pressure to give a crude yellow solid. Purification by column chromatography (PE: etoac=2:1) afforded compound I-B-a (0.47 g, 60% yield) as a white solid.
The preparation method of the compounds I-B-B, I-B-c, I-B-d, I-B-e and I-B-f is the same as that of the compound I-B-a.
Example 7: synthesis of Compound I
Synthesis of Compound I-1
To a 20ml reaction flask, raw material I-B-a (0.3 g,0.72 mmol), I-A-B (0.17 g, 0.94 mmol) and THF6ml were added at room temperature, LHMDS (1M, 1.46 mmol) was added dropwise at 0℃and stirred at 0℃for 2 hours after the addition, and then stirred at room temperature for 1 hour. TLC monitoring end point, dropping saturated ammonium chloride for quenching, adding ethyl acetate (20 ml), washing the organic phase by water and saline solution, decompressing and concentrating the organic phase to obtain a light yellow solid crude product. Purification by column chromatography (DCM: meoh=10:1) afforded compound I-1 (0.18 g, 46% yield) as a white solid.
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.36(s,1H),8.43(s,1H),7.75(s, 1H),7.51-7.66(m,2H),7.42(m,1H),5.27(s,2H),5.02(s,2H),4.17(s,3H)。 MS(ESI):536([M+H] + )。
Synthesis of Compound I-2
The preparation of compound I-2 was carried out in the same manner as I-1 (using the reaction starting materials I-B-f and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.33(s,1H),8.38(s,1H),7.70(s, 1H),7.52-7.67(m,2H),7.45(m,1H),5.23(s,2H),5.07(s,2H),3.95(s,3H)。 MS(ESI):536([M+H] + )。
Synthesis of Compound I-3
The preparation of compound I-3 was carried out in the same manner as I-1 (using the reaction starting materials I-B-a and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.31(s,1H),8.41(s,1H),7.72(s, 1H),7.51-7.67(m,2H),7.46(m,1H),5.24(s,2H),5.06(s,2H)。MS(ESI): 539([M+H] + )。
Synthesis of Compound I-4
The preparation of compound I-4 was carried out in the same manner as I-1 (using the reaction starting materials I-B-B and I-A-B).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.35(s,1H),8.39(s,1H),7.72(s, 1H),7.51-7.66(m,2H),7.43(m,1H),5.25(s,2H),4.14(s,3H),3.96(s,3H)。 MS(ESI):535([M+H] + )。
Synthesis of Compound I-5
The preparation of compound I-5 was carried out in the same manner as I-1 (using the reaction starting materials I-B-e and I-A-B).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.36(s,1H),8.38(s,1H),7.74(s, 1H),7.53-7.66(m,2H),7.41(m,1H),5.07(s,2H),4.16(s,3H),3.95(s,3H)。 MS(ESI):535([M+H] + )。
Synthesis of Compound I-6
The preparation of compound I-6 was carried out in the same manner as I-1 (using the reaction starting materials I-B-c and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.37(s,1H),8.39(s,1H),7.76(s, 1H),7.52-7.65(m,2H),7.43(m,1H),5.28(s,2H)。MS(ESI):541([M+H] + )。
Synthesis of Compound I-7
The preparation of compound I-7 was carried out in the same manner as I-1 (using the reaction starting materials I-B-d and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.38(s,1H),8.39(s,1H),7.75(s, 1H),7.52-7.64(m,2H),7.42(m,1H),5.08(s,2H)。MS(ESI):541([M+H] + )。
Synthesis of Compound I-8
The preparation of compound I-8 was carried out in the same manner as I-1 (using the reaction starting materials I-B-c and I-A-B).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.35(s,1H),8.41(s,1H),7.76(s, 1H),7.52-7.62(m,2H),7.43(m,1H),5.25(s,2H),4.16(s,3H)。MS(ESI): 538([M+H] + )。
Synthesis of Compound I-9
The preparation of compound I-9 was carried out in the same manner as I-1 (using the reaction starting materials I-B-d and I-A-B).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.38(s,1H),8.40(s,1H),7.75(s, 1H),7.55-7.62(m,2H),7.44(m,1H),5.07(s,2H),4.15(s,3H)。MS(ESI): 538([M+H] + )。
Synthesis of Compound I-10
The preparation of compound I-10 was carried out in the same manner as I-1 (using the reaction starting materials I-B-B and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.39(s,1H),8.41(s,1H),7.75(s, 1H),7.53-7.64(m,2H),7.43(m,1H),5.26(s,2H),3.95(s,3H)。MS(ESI): 538([M+H] + )。
Synthesis of Compound I-11
The preparation of compound I-11 was carried out in the same manner as I-1 (using the reaction starting materials I-B-e and I-A-a).
1 H NMR(400MHz,DMSO-d6)δH(ppm):9.38(s,1H),8.39(s,1H),7.74(s, 1H),7.55-7.64(m,2H),7.44(m,1H),5.08(s,2H),3.96(s,3H)。MS(ESI): 538([M+H] + )。
Example 8:
this example is the antiviral activity of compound S-217622, compound I-1, compound I-2, compound I-4 and compound I-5 against SARS coronavirus, MERS coronavirus and HCoV human coronavirus.
The antiviral activity of compound S-217622, compound I-1, compound I-2, compound I-4 and compound I-5 against SARS coronavirus, MERS coronavirus and HCoV human coronavirus was studied on Vero E6, vero76 cell lines. Virus-induced and compound-induced cytopathic inhibition (CPE) was determined using neutral red assay and EC of compounds was counted 50 、CC 50 Values. Neutral Red assay test compounds were dissolved in DMSO at a concentration of 10mg/mL and serially diluted with 8 semilog diluents with a maximum test concentration of 50 μg/mL (86. Mu.M). Each diluent was added to 5 wells in 96-well plates containing 80-100% confluence Vero E6 or Vero76 cells. 3 wells of each dilution were virus infected and 2 wells were uninfected as a toxicity control. 6 wells were untreated and infected as virus controls. For SARS, MERS and HCoV human coronaviruses, the viruses were diluted to MOI per cell of 0.003, 0.002, 0.001 and 0.03% cell culture infectious dose, respectively. Plates were incubated in an incubator containing 5% CO2 at 37 ℃. On day 5 (HCoV) or day 7 (SARS, MERS) post infection, when the untreated virus control wells reached maximum CPE, the plates were stained with neutral red dye for about 2 hours. The supernatant dye was removed, each well was rinsed with phosphate buffer PBS and mixed with a 1:1 ratio of citric acid buffer and ethanolThe dye was washed for 30 minutes. The optical density values at 540nm were read on a spectrophotometer and converted to percent of control. Antiviral CPE 50% (EC) 50 ) And resulted in 50% cell death in the absence of virus (CC 50 ) The desired concentration of test compound.
Effect examples
Example 9:
this example is directed to SARS-CoV-2 Virus M Pro Protease activity inhibition assay
Detection principle 3-chymotrypsin-like Protease (3-chymatorypsin-like Protease), the main Protease (M) Pro Also known as 3CL Pro ) The ORF1 coding (located in nsp 5) is located in the central region of the replicase gene and is a key protein for the replication of novel coronavirus RNA. The mechanism of action is that after the new coronavirus invades the cells, the host cells are utilized to synthesize two ultra-long replicase polypeptides (ppla and pplab) necessary for self replication. Replicase polypeptides are further cleaved into multiple proteins (e.g., rdRp, helicase, etc.) that are further assembled into the replication transcription machinery necessary for the virus to initiate replication of its own genetic material. M is M Pro There are at least 11 cleavage sites on the replicase polypeptide, and only when these sites on the replicase polypeptide are normally cleaved, they assemble into a replication transcription machinery, which initiates viral replication. In view of M Pro Proteases are critical in the viral replication process and there are no similar proteins in humans, so the main protease M Pro Becomes a potential key drug target for resisting the new coronavirus. Assessment of SARS-CoV-2-M by using fluorescence resonance energy transfer method Pro Inhibitory Activity of proteases.
The specific detection method is that the volume of the whole enzymatic reaction system is 120 mu L, the final concentration of protease is 30 nM, the final concentration of substrate is 20 mu M, and the buffer solution of the reaction system comprises 50mM Tris and pH 7.3 1mM EDTA. SARS-CoV-2-M was added to 96-well plates Pro Protease and different concentrationsIs incubated at 30 ℃ for 10min, and the substrate is added and rapidly placed into an enzyme-labeled instrument for reading. The excitation light and the emission light were 340nm and 405nm, respectively. The test time was 10min, and fluorescence values were read every 30 s. The final results were fit to the reaction rate by taking readings of the first 2min and comparing with the control (DMSO) to calculate the inhibition. Calculation of the corresponding time point IC for anti-SARS-CoV-2 Virus compound by plotting Graghpad prism 7 50 The values, specific values are shown in Table 3.
Table 3: SARS-CoV-2-M Pro IC of protease 50 Value of
Compounds of formula (I) IC 50 (μΜ)
Compound I-1 0.022±0.007μΜ
Compound I-2 0.025±0.008μΜ
S-217622 0.018±0.005μΜ
Example 10:
this example is a pharmacokinetic study of the compound in rats
At 7-10 weeks of age, male Wistar-Hannover rats were subjected to pharmacokinetic studies. During pharmacokinetic studies, all animals were kept individually. Food and water were freely ingested (animals were dosed in the fed state). Animals were fasted overnight and fed 4 hours after dosing. Blood samples were collected by jugular catheterization at predetermined time points following intragastric administration (30 mg/kg). At the completion of the study, animals were euthanized by excessive inhalation anesthesia followed by exsanguination. Collect blood sample to K 2 EDTA tubes and stored on ice until centrifugation to obtain plasma, which was stored in-20℃refrigerator.
LC-MS/MS analysis of plasma samples: plasma samples were treated using protein precipitation using acetonitrile: methanol containing 500:50, and Propranolol (50 ng/ml) as an internal standard, and then quantified according to standard curves (0.1-2500 ng/ml) prepared in blank plasma. Analytes in plasma samples were quantified using LC-MS/MS. Briefly, a Waters acquisition ultra-high performance liquid chromatography system was used in conjunction with a Sciex 6500 triple quadrupole mass spectrometer. Chromatographic separation was accomplished using a Waters Acquity UPLC BEH C18 column (1.7 m,2.1 50 mm). The mobile phase is optimized to achieve good separation between analytes. Typically, solvent A consists of a water/acetonitrile solution of 0.025% formic acid and 1mM ammonium acetate (95:5 v/v), and solvent B consists of a water/acetonitrile solution of 0.025% formic acid and 1mM ammonium acetate (5:95 v/v). The gradient generally starts from 3-30% b up to about 1.2 minutes, then increases to 50-65% b to 1.6 minutes, then decreases to 10-30% b up to about 1.7-1.9 minutes. Analyst 1.7 software was used for peak integration and standard curve regression.
Pharmacokinetic analysis: pharmacokinetic parameters were calculated using non-atrioventricular analysis (Watson v.7.5, thermo Scientific). As shown in Table 4, from the results, it is seen that compound I-1 and compound I-2 have better half-lives and thus better therapeutic effects in animals.
Table 4: pharmacokinetic parameters of Compounds
Application examples
Example 11:
preparation of oral tablets for deuterated Compounds (exemplified by Compound I-1)
The pharmaceutical carriers used for oral tablets include conditioning agents, fillers, binders, disintegrants, additives, glidants, lubricants, film-coating materials, plasticizers, colorants, and the like.
Component (A) Action Content (mg/tablet)
Compound I-1 Active ingredient 200
Starch Filler and disintegrant 100
Dibasic calcium phosphate Filler (B) 20
Pregelatinized starch Filler (B) 40
Citric acid Modulators 2
Sodium bisulfite Additive agent 0.5
10% starch slurry Adhesive agent Proper amount of
Magnesium stearate Lubricant 1.5
White opard Coating premix About 4
Water, ethanol Solvent(s) Proper amount of
The operation method comprises the following steps:
the compound I-1 is respectively milled and sieved according to the formula, then is uniformly mixed with the filler, the disintegrating agent, the regulator and the additive which are milled and sieved, 10 percent of starch slurry is added into the mixture to prepare a soft material in a stirrer, the soft material is prepared into wet granules on a swinging machine, and the wet granules are dried in an oven, are uniformly mixed with the lubricant, and are pressed into tablet cores. The tablet core is coated with Opadry to obtain film coated tablet.
Preparation method of capsule for deuterated compound (taking compound I-1 as an example)
The medicinal carrier used in the capsule comprises filler, binder, disintegrating agent, additive, lubricant, etc.
Component (A) Action Content (mg/grain)
Compound I-1 Active ingredient 200
Lactose monohydrate Filler (B) 82
Pregelatinized starch Filler, binder 38
Sodium carboxymethyl starch Disintegrating agent 12.5
Magnesium stearate Lubricant 1.5
The operation method comprises the following steps:
the compound I-1 and auxiliary materials are respectively ground and sieved according to the formula, uniformly mixed with filler, adhesive, disintegrating agent and the like according to a certain proportion, added into a dry granulator to be pressed into strips, and crushed into particles by a crusher. The granules are mixed with a proper amount of lubricant and disintegrating agent uniformly and then filled into capsules.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the disclosure. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (11)

1. A deuterated triazine compound according to formula I or a pharmaceutically acceptable salt, isomer, prodrug or co-crystal thereof:
wherein:
R 1 ～R 3 each independently hydrogen or deuterium;
R 4 ～R 7 each independently hydrogen or deuterium;
R 8 ～R 10 each independently hydrogen or deuterium;
with the proviso that R 1 ～R 10 At least one of which is deuterium.
2. A compound according to claim 1, wherein R 1 ～R 3 2-3 deuterium.
3. A compound according to claim 1, wherein R 4 ～R 7 2-4 deuterium.
4. A compound according to claim 1, wherein R 8 ～R 10 2-3 deuterium.
5. The compound of claim 1, wherein the compound is a compound selected from the group consisting of:
6. a process for the preparation of a compound of formula I according to any one of claims 1 to 5, comprising the steps of:
(1) In an organic solvent, carrying out substitution reaction on a compound I-G with a general formula and a compound I-F under the action of alkali to prepare an intermediate I-E;
(2) In an organic solvent, carrying out deprotection reaction on the intermediate I-E under the action of acid to obtain an intermediate I-D;
(3) In an organic solvent, carrying out substitution reaction on a general formula compound I-D and a general formula compound I-C under the action of alkali to prepare a general formula intermediate I-B;
(4) In an organic solvent, the intermediate I-B in the general formula and the compound I-A are subjected to condensation reaction under the action of alkali to prepare the deuterated triazine compound in the formula I.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-5, or a pharmaceutically acceptable salt, isomer, prodrug or co-crystal thereof.
8. The pharmaceutical composition according to claim 7, characterized in that it comprises a further therapeutic agent, said further therapeutic agent being an antiviral agent.
9. Use of a compound according to claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the preparation of a 3CL protease inhibitor class pharmaceutical composition.
10. The use according to claim 9, wherein the pharmaceutical composition is for the preparation of a medicament for the treatment and prevention of viral infections.
11. The use according to claim 10, wherein the viral infection is human coronavirus, novel coronavirus SARS-CoV-2, SARS coronavirus and MERS coronavirus.
CN202210148597.9A 2022-02-18 2022-02-18 Novel deuterated triazine compound, preparation method, composition and application thereof Pending CN116655606A (en)

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