CN117430616A - Pyrimido ring compound containing deuterated methyl, preparation method and application thereof - Google Patents

Pyrimido ring compound containing deuterated methyl, preparation method and application thereof Download PDF

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CN117430616A
CN117430616A CN202311263935.4A CN202311263935A CN117430616A CN 117430616 A CN117430616 A CN 117430616A CN 202311263935 A CN202311263935 A CN 202311263935A CN 117430616 A CN117430616 A CN 117430616A
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compound
deuterated methyl
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oxides
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陈芬儿
王帅
张坤
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • 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 belongs to the technical field of medicines, and particularly relates to a pyrimido-ring compound containing deuterated methyl, a preparation method and application thereof. The structure of the compound is shown as a general formula I, and the compound also comprises pharmaceutically acceptable salts, hydrates and solvates thereof, polycrystal or eutectic crystals thereof, and precursors and derivatives with the same biological functions; the compound or the composition thereof can be used for preparing related medicaments for preventing or treating AIDS and the like. The in vitro cell level anti-HIV-1 activity experiment result shows that,the small molecules have stronger anti-HIV-1 biological activity, obviously inhibit the virus replication in MT-4 cells infected by HIV-1 virus, and have lower cytotoxicity;

Description

Pyrimido ring compound containing deuterated methyl, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pyrimido-ring compound containing deuterated methyl, and a preparation method and application thereof.
Background
Human Immunodeficiency Virus (HIV) is the leading culprit for aids (acquired immunodeficiency syndrome). HIV attacks human T lymphocytes, disrupting cellular and humoral immune processes, disabling the immune system. According to 2019 data of the United nations AIDS planning agency, 3790 thousands of people are infected with HIV worldwide, wherein the newly increased infection number in 2018 is 170 ten thousand, and the death number in 2018 due to AIDS is 77 ten thousand.
The life cycle of the HIV virus comprises the following 5 steps: (1) Adsorbing and gradually fusing with host T lymphocyte to release genome RNA into host cell; (2) reverse transcribing the RNA into DNA by reverse transcriptase; (3) integration of viral DNA into the genome of the host; (4) Synthesizing genome and protein required by virus by means of transcription and translation of enzymes and substances in host cells; (5) Assembly is completed within the host and released outside the host cell. These viruses continue to infect new host cells, thereby disrupting the host immune system. There are several key enzymes throughout the life cycle: fusion enzyme, reverse transcriptase, protease, integrase. Among them, reverse Transcriptase (RT) plays an important role, and is also an important target for designing anti-HIV-1 drugs, and currently there are 14 reverse transcriptase inhibitors on the market.
RT inhibitors can be classified as Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside reverse transcriptase inhibitors and substrates act on RT active sites in a competitive manner, and have the defects of poor selectivity, high toxicity and the like. Non-nucleoside reverse transcriptase inhibitors bind in a non-competitive manner to the reverse transcriptase active siteThe allosteric binding pocket, i.e. the non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP), is distant. NNRTIs have the characteristics of high selectivity, high activity and the like, and the NNRTIs used clinically at present are mainly second generation inhibitors: diaryl pyrimidines, rilpivirine (RPV) and itravirin (Etrav)irine,ETR)。
However, the poor water solubility (ETR,<<1 μg/mL; RPV,20 ng/ml), low patient response rate (ETR, 36.5%; RPV, 27.3%), and the production of drug-resistant strains in long-term administration greatly reduced the efficacy of the drug. In addition, toxic side effects (such as cardiotoxicity of ETR (hERG toxicity, IC) 50 =0.5 μΜ), RPV inhibition of CYP enzymes) limit their clinical use. Therefore, the development of novel high-efficiency low-toxicity non-nucleoside reverse transcriptase inhibitors with broad-spectrum drug resistance is one of the hot spots of research by pharmaceutical chemists.
The invention aims to optimize the structure of RPV and ETR, improve the safety and the patentability of the compound by introducing deuterated methyl and pyrimido-ring skeletons, enhance the interaction between the compound and amino acid on the inner wall of NNIBP, and improve the biological activity of the compound against drug-resistant virus strains.
Disclosure of Invention
The invention aims to provide a pyrimido-ring compound containing deuterated methyl structure, which has stronger anti-HIV-1 biological activity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 virus, has lower cytotoxicity and obvious safety, and a preparation method and application thereof.
The invention provides a pyrimido ring compound containing a deuterated methyl structure, which has the following structural formula:
wherein R is 1 Selected from hydrogen, methyl, deuterated methyl;
R 2 selected from the group consisting of substituted or unsubstituted benzene rings, pyridines, pyrimidines, oxazines and oxides thereof, thiophenes (pyrans) (sulfoxides and sulfones), (iso) thiazoles and oxides thereof, pyrroles and oxides thereof, pyrazoles (pyrans) and oxides thereof, imidazoles and oxides thereof, (iso) oxazoles and oxides thereof, pyrazolones, furans, cyclopentadienes, dihydrothiophenes and other episulfides (sulfoxides and sulfones), dihydrofurans and other epoxy compounds, cycloalkanes;
R 3 is SO 2 NH 2 ,CONH 2 ,SO 2 CH 3 ,COOH,B(OH) 2 ,CN,CF 3 ,OCF 3 ,CH 3 ,OCH 3 ,N(CH 3 ) 2 ,NO 2 ,F,Cl,Br,I,SO 2 NHR, CONHR, CONHR and COOR.
In the compound of the invention, deuterated methyl (D) is introduced on the benzene ring of the left wing 3 C) The aim is to improve the patentability and safety of the compound by blocking the methyl and the metabolic site of the related enzyme in the body. While substitution of deuterated methyl groups maintains the binding conformation of the compound to the target protein such that interaction with the target protein is maintained.
The compound is HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), and has stronger biological activity, smaller cytotoxicity and higher selection coefficient.
The compounds of the present invention also include pharmaceutically acceptable salts, stereochemically isomeric forms, hydrates or solvates of the derivatives.
In the present invention, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, formate, mesylate, triflate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate salt.
The invention also provides a preparation method of the pyrimido cyclic compound containing deuterated methyl, which comprises the following specific steps:
in a solvent, 2, 4-dichloropyrimidine derivatives II and 2-deuterated methyl-4-cyanophenol and derivatives thereof are used as raw materials to react under the action of alkali to obtain a compound III; then, the compound III obtained by separation reacts with 1-Boc-4-aminopiperidine under the corresponding solvent and alkaline conditions to obtain a compound IV; removing Boc protecting groups in a mixed solvent of trifluoroacetic acid and dichloromethane after separating the compound IV to obtain a compound V; finally, the compound V reacts with corresponding benzyl bromide or benzyl chloride under the catalysis of alkali in a solvent to obtain the pyrimido ring compound I containing deuterated methyl, wherein the reaction general formula is as follows:
the solvent used in the compounds II to III and the compounds III to IV is one or more of acetone, acetonitrile, toluene, methylene dichloride, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-butanol and isobutanol, and N, N-dimethylformamide is the most preferred; the bases used were the following: one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide, preferably potassium carbonate; the reaction mole ratio of the compound II, the 2-deuterated methyl-4-cyanophenol and the derivative thereof to the alkali is 1:1:1-1:2:3 (1-2): 1-3), and the optimal ratio is 1:1.1:1.2; the mol ratio of the compound III to the 1-Boc-4-aminopiperidine to the alkali is 1:1:1-1:2:3 (1-2): (1-3)), and the optimal ratio is 1:1.5:2; the reaction temperature is 15-150 ℃; the reaction time is 0.5-5 h.
The volume ratio of trifluoroacetic acid to dichloromethane in the compounds IV to V is 1:1-1:10, and the optimal ratio is 1:2; the dosage ratio of the compound IV (ammol) to the trifluoroacetic acid (b ml) is a:b=1:10-10:1, the optimal reaction temperature is room temperature, and the reaction time is 0.5-5 h.
The solvent used in the compounds V to I is one or more of acetone, acetonitrile, toluene, methylene dichloride, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-butanol and isobutanol, and N, N-dimethylformamide is the most preferred; the bases used were the following: one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide, preferably potassium carbonate; the mol ratio of the compound V, benzyl bromide or benzyl chloride to the alkali is 1:1:1-1:2:3 (1-2): 1-3), and 1:1.2:1.5 is the best; the reaction temperature is 15-150 ℃; the reaction time is 0.5-5 h.
The invention also provides a pharmaceutical composition comprising an effective amount of the above compound and an associated pharmaceutically acceptable carrier.
The invention also provides application of the compound or the composition in preparing medicines for preventing and treating AIDS.
The invention is based on the combination mode of diaryl pyrimidine compounds and HIV reverse transcriptase, combines with the design of computer-aided drugs, introduces deuterated methyl on the benzene ring of the left wing, and aims to enhance the safety and stability of the compounds in the body and improve the drug property by closing the methyl on the benzene ring and the metabolic site of related enzymes in the body. While substitution of deuterated methyl groups maintains the binding conformation of the compound to the target protein such that interaction with the target protein is maintained. Experimental results show that the series of compounds have more remarkable anti-HIV-1 activity, lower cytotoxicity and higher selectivity.
Detailed Description
The present invention will be better understood by the following examples of embodiments, but is not limited thereto.
Example 1: synthesis of end product Ia
(1) 500mg of 2, 4-dichlorothieno [3,2-D ] pyrimidine was added to a 50mL eggplant-shaped bottle at room temperature, followed by 374mg of 2, 6-dideugenomethyl-4-cyanophenol, 404mg of potassium carbonate and 15mL of N, N-dimethylformamide. After the completion of the addition, the mixture was stirred at room temperature for 2 hours, and the completion of the reaction was monitored. The reaction was stopped, ethyl acetate was extracted with water, the organic layer was taken, dried over anhydrous sodium sulfate, and subjected to column chromatography (elution with petroleum ether and ethyl acetate) to give 700mg of a white solid in 89% yield, designated IIa.
(2) 670mg of Compound IIa was added to a 50mL eggplant-shaped bottle at room temperature, followed by 625mg of 1-Boc-4-aminopiperidine, 574mg of potassium carbonate and 15mL of N, N-dimethylformamide. After the completion of the addition, the reaction was monitored by stirring at 120℃for 2 hours under heating. The reaction was stopped, ethyl acetate was extracted with water, the organic layer was taken, dried over anhydrous sodium sulfate, and subjected to column chromatography (elution with petroleum ether and ethyl acetate) to give 856mg of a white solid in 85% yield, designated IIIa.
(3) 856mg of Compound IIIa was added to a 25mL eggplant-shaped bottle at room temperature, 3.5mL of methylene chloride was added, and 1.7mL of trifluoroacetic acid was added dropwise with stirring. After the completion of the addition, the mixture was stirred at room temperature for 2 hours, and the completion of the reaction was monitored. Saturated sodium bicarbonate is added dropwise into the reaction system until the system is alkaline, a proper amount of dichloromethane and water are added for extraction, an organic layer is taken, dried by anhydrous sodium sulfate and spin-dried, and the white solid is obtained by column chromatography separation (dichloromethane and methanol are eluted), wherein the yield is 60 percent and is recorded as IVa.
(4) 300mg of compound IVa was added to a 25mL eggplant-shaped bottle at room temperature, and 176mg of 4-bromomethylbenzenesulfonamide, 161mg of potassium carbonate and 5mL of N, N-dimethylformamide were sequentially added. After the completion of the addition, the mixture was stirred at room temperature for 1 hour, and the completion of the reaction was monitored. The reaction was stopped, ethyl acetate was extracted with water, the organic layer was taken, dried over anhydrous sodium sulfate, and subjected to column chromatography (elution with methylene chloride and methanol) to obtain 45mg of a white solid in 10% yield, which was designated Ia.
White powder solid, yield:10%. 1 H NMR(400MHz,DMSO-d 6 )δ8.20(d,J＝5.4Hz,1H),7.79(d,J＝7.9Hz,2H),7.73(s,2H),7.48(d,J＝7.9Hz,2H),7.34(s,2H),7.27(s,1H),6.91(s,1H),3.74(s,1H),3.50(s,2H),2.71(d,J＝23.6Hz,2H),2.00(s,1H),1.79(s,2H),1.64(s,1H),1.46(s,2H).HRMS(ESI)m/z C 27 H 22 D 6 N 6 O 3 S 2 :calcd 554.2041,found 555.2106[M+H] + 。
Example 2: synthesis of end product Ib
The procedure of example 1 was followed to give a white powder solid, yield:28%. 1 H NMR(400MHz,DMSO-d 6 )δ8.20(d,J＝5.4Hz,1H),7.95(s,1H),7.83(d,J＝7.8Hz,2H),7.73(s,2H),7.37(s,1H),7.34(s,2H),7.26(s,1H),6.91(s,1H),3.57(s,2H),2.72(d,J＝28.9Hz,2H),2.15–1.95(m,1H),1.79(s,2H),1.37(d,J＝67.4Hz,4H).HRMS(ESI)m/z C 28 H 22 D 6 N 6 O 2 S:calcd 518.2371,found 519.2445[M+H] + 。
Example 3: synthesis of end product ic
The procedure of example 1 was followed to give a white powder solid, yield:28%. 1 H NMR(400MHz,DMSO-d 6 )δ8.20(d,J＝5.4Hz,1H),7.79(d,J＝8.4Hz,2H),7.73(s,2H),7.47(d,J＝8.1Hz,2H),7.34(s,2H),7.31–7.21(m,1H),3.74(s,1H),3.49(s,2H),2.80–2.59(m,2H),2.11(s,3H),2.02(s,1H),1.95–1.83(m,1H),1.78(s,1H),1.68–1.55(m,1H),1.45(s,2H).HRMS(ESI)m/z C 27 H 25 D 3 N 6 O 3 S 2 :calcd551.1853,found 552.1933[M+H] + 。
Example 4: synthesis of end product Id
The procedure of example 1 was followed to give a white powder solid, yield:43%. 1 H NMR(400MHz,DMSO-d 6 )δ8.21(t,J＝8.0Hz,1H),8.17(d,J＝5.4Hz,1H),7.95(d,J＝5.7Hz,1H),7.83(dd,J＝9.6,7.2Hz,3H),7.73(s,1H),7.39(d,J＝7.9Hz,2H),7.34(q,J＝5.4,4.9Hz,3H),4.11–3.94(m,1H),3.54(s,2H),2.85(d,J＝11.4Hz,2H),2.11(s,3H),1.93–1.81(m,2H),1.64(t,J＝10.0Hz,2H),1.39(s,2H).HRMS(ESI)m/z C 28 H 25 D 3 N 6 O 2 S:calcd 515.2183,found 516.2252[M+H] + 。
Example 5: synthesis of end product ie
The procedure of example 1 was followed to give a white powder solid, yield:19%. 1 H NMR(400MHz,DMSO-d 6 )δ7.78(d,J＝8.2Hz,2H),7.72(s,2H),7.47(d,J＝8.0Hz,2H),7.36(d,J＝6.0Hz,2H),7.34(s,1H),7.27(d,J＝6.0Hz,1H),7.12(s,1H),3.71(s,1H),3.56–3.42(m,2H),2.70(d,J＝33.1Hz,2H),2.11–
2.00(m,1H),1.77(s,1H),1.61(s,1H),1.43(d,J＝34.8Hz,2H),1.30(s,1H).HRMS(ESI)m/zC 27 H 22 D 6 N 6 O 3 S 2 :calcd 554.2041,found 555.2102[M+H] + 。
Example 6: synthesis of end product if
The procedure of example 1 was followed to give a white powder solid, yield:35%. 1 H NMR(400MHz,DMSO-d 6 )δ7.78(d,J＝8.3Hz,2H),7.72(s,2H),7.47(d,J＝8.0Hz,2H),7.36(d,J＝6.0Hz,1H),7.34(s,2H),7.27(d,J＝5.9Hz,1H),7.12(s,1H),3.71(s,1H),3.50(s,2H),2.74(s,2H),2.65(s,1H),2.11(s,3H),1.78(d,J＝11.9Hz,1H),1.61(s,1H),1.44(d,J＝30.9Hz,2H),1.32(d,J＝16.2Hz,1H).HRMS(ESI)m/z C 27 H 25 D 3 N 6 O 3 S 2 :calcd 551.1853,found 552.1916[M+H] + 。
Example 7: synthesis of end product Ig
The procedure of example 1 was followed to give a white powder solid, yield:24%. 1 H NMR(400MHz,DMSO-d 6 )δ7.94(s,1H),7.82(d,J＝7.9Hz,2H),7.72(d,J＝0.9Hz,2H),7.40–7.30(m,4H),7.27(d,J＝6.0Hz,1H),7.10(s,1H),3.70(s,1H),3.47(s,2H),2.82(d,J＝60.3Hz,2H),2.67(t,J＝1.9Hz,1H),2.10(s,3H),2.04–1.92(m,1H),1.76(s,1H),1.53(d,J＝50.4Hz,3H),1.26(d,J＝20.4Hz,1H).HRMS(ESI)m/z C 28 H 25 D 3 N 6 O 2 S:calcd 515.2183,found 516.2256[M+H] + 。
Example 8: synthesis of the end product ih
The procedure of example 1 was followed to give a white powder solid, yield:71%. 1 H NMR(400MHz,DMSO-d 6 )δ8.17–8.02(m,1H),7.78(d,J＝7.4Hz,2H),7.74(s,2H),7.58–7.38(m,3H),7.33(s,2H),7.25(s,1H),7.11–6.91(m,1H),3.81(s,1H),3.52(s,2H),2.76(s,2H),2.67(s,1H),2.12(s,3H),1.99(s,1H),1.80(s,1H),1.44(d,J＝33.5Hz,2H),1.27(d,J＝28.9Hz,1H).HRMS(ESI)m/zC 29 H 27 D 3 N 6 O 3 S:calcd 545.2288,found 546.2369[M+H] + 。
Example 9: synthesis of end product ii
The procedure of example 1 was followed to give a white powder solid, yield:63%. 1 H NMR(400MHz,DMSO-d 6 )δ8.10(s,1H),7.94(s,1H),7.82(d,J＝7.9Hz,2H),7.74(s,2H),7.62(s,1H),7.46(s,2H),7.36–7.29(m,2H),7.25(s,1H),6.99(s,1H),3.80(s,1H),3.53(d,J＝24.1Hz,2H),2.83(d,J＝47.7Hz,2H),2.67(s,1H),2.12(s,3H),2.03(s,1H),1.80(s,2H),1.48(s,2H).HRMS(ESI)m/z C 30 H 27 D 3 N 6 O 2 :calcd 509.2619,found 510.2697[M+H] + 。
Example 10: synthesis of end product Ij
The procedure of example 1 was followed to give a white powder solid, yield:56%。 1 H NMR(400MHz,DMSO-d 6 )δ8.27(d,J＝8.1Hz,1H),8.22(d,J＝7.0Hz,1H),7.97(s,1H),7.86(d,J＝8.1Hz,2H),7.73(d,J＝9.0Hz,1H),7.66(s,2H),7.42(s,1H),7.40–7.29(m,4H),3.71(s,1H),3.50(s,2H),2.86–2.71(m,2H),1.94–1.72(m,4H),1.65–1.48(m,2H).HRMS(ESI)m/z C 30 H 24 D 6 N 6 O 2 :calcd 512.2807,found513.2879[M+H]+。
Example 11: anti-HIV biological Activity test
The anti-HIV viral activity at the cellular level in vitro was determined by the Rega drug study at university of Katholleke belgium and mainly comprises: inhibitory Activity and cytotoxicity against HIV-infected MT-4 cells. The method comprises the following steps: the protection of HIV-mutagenized cytopathy by the drug was assayed by MTT method in HIV-infected MT-4 cells at various times during HIV infection, and the half-effective concentration EC was calculated at the concentration required to protect 50% of the cells from HIV-induced cytopathy 50 Toxicity assays were performed in parallel with anti-HIV activity assays, also in MT-4 cell culture, using MTT to determine the concentration of cytopathic 50% of uninfected cells (CC 50 ) And calculates a selectivity index si=cc 50 /EC 50 。
Materials and methods:
the anti-HIV activity of each compound is monitored by the efficiency of the drug's inhibition of HIV-induced cytopathic effects in the cells. Cell culture was performed using MT-4 cells. The virus strains used were: HIV-1 strain IIIB and HIV-2 strain ROD.
The specific operation is as follows: dissolving the compound in DMSO or water, diluting with phosphate buffer saline solution, and concentrating 3×10 5 MT-4 cells were pre-incubated with 100. Mu.L of each compound at various concentrations for 1h at 37℃and then 100. Mu.L of the appropriate viral dilutions were added to the compounds and the cells were incubated for 1h at 37 ℃. After three washes, the cells were resuspended in culture medium with or without compound, respectively. The cells were then exposed to 5% CO 2 The culture was continued for another 7 days at 37℃in the atmosphere, and the supplementary medium was replaced with medium with or without compound on the third day after infection. Each cultureThe liquid conditions were repeated twice. Cytopathic effects on viruses were monitored daily with a reverse optical microscope. Typically, the viral dilutions used in this experiment often lead to cytopathic effects the fifth day after viral infection. The drug inhibitory concentration was such that the drug produced 50% inhibition of viral cytopathic effect while not directly toxic to cells (CC 50 ) And (3) representing. It is emphasized that when compounds are poorly water soluble and DMSO is required to be dissolved, the specific DMSO concentration is typically less than 10% relative to water (DMSO final concentration in MT-4 cell culture medium is less than 2%). Because DMSO can affect the antiviral activity of the test compounds, antiviral activity in solutions containing the same concentration of DMSO should also be run in parallel versus blank experiments. In addition, the final DMSO concentration (1/1000) was far lower than that required for HIV-1 replication in T cells.
The results of the inhibitory activity of some target compounds on HIV-1 IIIb strains are shown in Table 1 using marketed drugs Nevirapine (NVP), efavirenz (EFV) and ETR as controls.
TABLE 1
a EC 50 An effective concentration to protect 50% of cells from viral infection; b RES056 represents the K103N/Y181C double mutant;
c a represents a compound having an EC50 value of between 1 and 10 nM.

Claims (7)

1. A pyrimido cyclic compound containing deuterated methyl groups, which is characterized by the following structural formula:
wherein R is 1 Selected from hydrogen, methyl, deuterated methyl;
R 2 selected from the group consisting of substituted or unsubstituted benzene rings, pyridines, pyrimidines, oxazines and oxides thereof, thiophenes (pyrans) (sulfoxides and sulfones), (iso) thiazoles and oxides thereof, pyrroles and oxides thereof, pyrazoles (pyrans) and oxides thereof, imidazoles and oxides thereof, (iso) oxazoles and oxides thereof, pyrazolones, furans, cyclopentadienes, dihydrothiophenes and other episulfides (sulfoxides and sulfones), dihydrofurans and other epoxy compounds, cycloalkanes;
R 3 is SO 2 NH 2 ,CONH 2 ,SO 2 CH 3 ,COOH,B(OH) 2 ,CN,CF 3 ,OCF 3 ,CH 3 ,OCH 3 ,N(CH 3 ) 2 ,NO 2 ,F,Cl,Br,I,SO 2 NHR, CONHR, CONHR and COOR.
2. The method for preparing a deuterated methyl-containing pyrimido cyclic compound according to claim 1 wherein the reaction formula is as follows:
the method comprises the following specific steps:
in a solvent, 2, 4-dichloropyrimidine derivatives II and 2-deuterated methyl-4-cyanophenol and derivatives thereof are used as raw materials to react under the action of alkali to obtain a compound III; then, the compound III obtained by separation reacts with 1-Boc-4-aminopiperidine under the corresponding solvent and alkaline conditions to obtain a compound IV; removing Boc protecting groups in a mixed solvent of trifluoroacetic acid and dichloromethane after separating the compound IV to obtain a compound V; finally, the compound V reacts with corresponding benzyl bromide or benzyl chloride under the catalysis of alkali in a solvent to obtain a pyrimido-ring compound I containing deuterated methyl;
the reaction mole ratio of the compound II, the 2-deuterated methyl-4-cyanophenol and the derivative thereof to the alkali is 1:1:1-1:2:3; the reaction mole ratio of the compound III, the 1-Boc-4-aminopiperidine and the alkali is 1:1:1-1:2:3; the reaction temperature is 15-150 ℃; the reaction time is 0.5-5 h;
the volume ratio of trifluoroacetic acid to dichloromethane in the compounds IV to V is 1:1-1:10; the dosage ratio of the compound IV (a mmol) to the trifluoroacetic acid (b ml) is a:b=1:10-10:1, the reaction temperature is room temperature, and the reaction time is 0.5-5 h;
the reaction mole ratio of the compound V, benzyl bromide or benzyl chloride to the alkali is 1:1:1-1:2:3; the reaction temperature is 15-150 ℃; the reaction time is 0.5-5 h.
3. The preparation method according to claim 2, wherein the solvent used in the compounds II to III and the compounds III to IV is one or more of acetone, acetonitrile, toluene, methylene chloride, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-butanol and isobutanol; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide and sodium tert-butoxide.
4. The preparation method according to claim 2, wherein the solvent used in the compounds V to I is one or more of acetone, acetonitrile, toluene, methylene chloride, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-butanol, and isobutanol; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide and sodium tert-butoxide.
5. A pharmaceutical composition comprising an effective amount of any of the compounds of claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutically acceptable salt of a pyrimido-ring compound having a deuterated methyl structure as defined in claim 1 comprising a hydrochloride, hydrobromide, formate, mesylate, triflate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate salt, and pharmaceutically acceptable prodrugs and derivatives.
7. The use of a pyrimidine-fused ring compound having a deuterated methyl structure according to claim 1 for the preparation of a medicament for the prophylaxis and treatment of aids.
CN202311263935.4A 2023-09-27 2023-09-27 Pyrimido ring compound containing deuterated methyl, preparation method and application thereof Pending CN117430616A (en)

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