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CN-121991072-A - Dihydro pteridine-6 (5H) -ketone framework compound and preparation method and application thereof

CN121991072ACN 121991072 ACN121991072 ACN 121991072ACN-121991072-A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a dihydropteridine-6 (5H) -ketone skeleton compound, and a preparation method and application thereof. The dihydro pteridine-6 (5H) -ketone skeleton compound is HIV-1 non-nucleoside reverse transcriptase inhibitor, and the invention also includes its medicinal salt, hydrate and solvate, its polycrystal or eutectic, its precursor and derivative with the same biological function, and its preparation process and the application of the composition containing one or several of these compounds in preparing medicine for treating AIDS. The in vitro cell level anti-HIV-1 activity experiment result shows that the small molecules have stronger anti-HIV-1 biological activity, can obviously inhibit the virus replication in MT-4 cells infected by HIV-1 virus, and have lower cytotoxicity.

Inventors

  • CHEN FENER
  • WANG SHUAI
  • ZHANG YINXIANG

Assignees

  • 复旦大学

Dates

Publication Date
20260508
Application Date
20260113

Claims (8)

  1. 1. A dihydropteridin-6 (5H) -one backbone compound characterized by the following structural formula: ; wherein R 1 is selected from cyano, cyanovinyl, various substituted or unsubstituted benzene rings, pyridines, pyrimidines, oxazines and their oxides, thiophenes (pyrans) (sulfoxides and sulfones), (iso) thiazoles and their oxides, pyrroles and their oxides, pyrazoles (pyrans) and their oxides, imidazoles and their oxides, (iso) oxazoles and their oxides, pyrazolones, furans, cyclopentadiene, dihydrothiophenes and their episulfides (sulfoxides and sulfones), dihydrofurans and their epoxy compounds, cycloalkanes; R 2 is selected from H,CN,NO 2 ,OH,CH 2 OH,CF 3 ,F,Cl,Br,CH 3 ,COOMe,COOH,SO 2 CH 3 ,SONH 2 ,CONH 2 and a series of sulfonyl (derivative) and amide (derivative) with hydrophilic or lipophilic terminal, and the substituent is o-, m-, p-monosubstituted or polysubstituted; X is-H-, -N-, -CH-, -S-, -one of the linking groups S (O) -and-S (O) 2 -.
  2. 2. The dihydropteridin-6 (5H) -one backbone compound of claim 1 further comprising a salt, stereochemical isomer, hydrate or solvate of said compound.
  3. 3. The dihydropteridin-6 (5H) -one backbone compound of claim 2, wherein the salt is a sodium salt, hydrochloride, hydrobromide, sulfate, formate, acetate, phosphate tartrate or citrate, succinate, maleate, triflate, p-methylbenzenesulfonate, methylsulfonate, fumarate, or malate.
  4. 4. The method for preparing a dihydropteridin-6 (5H) -one backbone compound according to claim 1, wherein the reaction formula is: ; The preparation method comprises the following specific steps: (i) In a solvent, taking 2, 6-dimethyl-4-bromoaniline (A) and 2, 4-dichloro-5-nitro-pyrimidine (B) as raw materials, capturing hydrogen under the action of alkali, and reacting with ethyl bromoacetate to obtain a compound C; (ii) Then the compound C reacts with N-Boc-4-aminopiperidine under the corresponding solvent and alkaline conditions to obtain a compound D; (iii) After separation, the compound D is subjected to ring closure reaction under the condition of reduced iron powder and ammonium chloride aqueous solution to obtain a compound E; (iv) Removing Boc protecting groups from the compound E in a mixed solvent of trifluoroacetic acid and dichloromethane to obtain a compound F; (v) The compound F reacts with benzyl bromide or benzyl chloride substituted by different functional groups under the catalysis of alkali in a solvent to obtain a compound II; (vi) And then carrying out metal coupling reaction on the compound II and aromatic boric acid or ester to obtain a target product, namely the dihydropteridine-6 (5H) -ketone skeleton compound I.
  5. 5. The method of claim 4, wherein; The solvent used in the whole reaction is one or more of N, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, acetone, acetonitrile, toluene, methylene dichloride, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol and isobutanol or no solvent; The base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide and sodium tert-butoxide; the acid is one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, acetic acid and ammonium chloride water solution.
  6. 6. The method of claim 4, wherein; The reaction mole ratio of the compound A, B to the bromoacetic acid ethyl ester to the alkali is 1:1:1.5:1-1.2:5:1.5, the reaction temperature is 0-60 ℃, and the reaction time is 12-36 h; the reaction molar ratio of the compound C, N-Boc-4-aminopiperidine to the alkali is 1:1.2:1.2-1:2:4, the reaction temperature is 100-120 ℃, and the reaction time is 6-24 hours; the reaction molar ratio of the compound D to the iron powder to the ammonium chloride is 1:2:2-1:10:10, the reaction temperature is 60-85 ℃, and the reaction time is 8-24 hours; The reaction molar ratio of the compound E to the trifluoroacetic acid is 1:2-1:10, the reaction temperature is 0-25 ℃, and the reaction time is 4-10 h; The reaction mole ratio of the compound F to the substituted benzyl chloride/benzyl bromide to the alkali is 1:1.1:1.2-1:1.3:2, the reaction temperature is 25-45 ℃, and the reaction time is 4-24 hours; The reaction molar ratio of the compound II to the aromatic boric acid/ester to Pd (dppf) Cl 2 to the alkali is 1:1.1:0.01:1.2-1:1.5:0.05:2, the reaction temperature is 100-120 ℃, and the reaction time is 12-24 hours.
  7. 7. A pharmaceutical composition comprising an effective amount of a dihydropteridin-6 (5H) -one backbone compound according to claim 1, or a salt thereof, or a stereochemically isomeric form thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
  8. 8. The use of the dihydropteridin-6 (5H) -one skeleton-containing compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereochemical isomer thereof, or a hydrate or solvate thereof, for the preparation of a medicament for the prophylaxis and treatment of aids.

Description

Dihydro pteridine-6 (5H) -ketone framework compound and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a preparation method and application of diaryl pyrimido ring compounds of biaryl fragments. Background AIDS (acquired immunodeficiency syndrome) is caused by Human Immunodeficiency Virus (HIV). HIV destroys human T lymphocytes, blocks cellular and humoral immune processes, and causes paralysis of the immune system. The united nations aids planning agency 2025 reports that by the end of 2024, there are 4080 tens of thousands of people worldwide who are infected with HIV, about 130 tens of thousands of HIV-infected people in the same year, about 63 tens of thousands of people die from aids-related diseases, and on average, every minute of people die from aids. The life cycle of the HIV virus can be summarized as (1) adsorption to and gradual fusion with T lymphocytes of the host to release genomic RNA into the host cells, (2) formation of DNA by reverse transcription and integration into the genome of the host, (3) transcription and translation by enzymes and substances in the host cells to synthesize the genome and proteins required by the virus, and (4) completion of assembly in the host and release to the outside of the host cells. These viruses continue to infect new host cells, thereby disrupting the host immune system. There are some key enzymes in the whole life cycle, fusion enzymes, reverse transcriptases, proteases, integrases. Wherein reverse transcriptase (REVERSE TRANSCRIPTASE, RT) plays an important role and is also an important target for designing anti-HIV-1 drugs. RT inhibitors can be categorized as nucleoside reverse transcriptase inhibitors (Nucleoside REVERSE TRANSCRIPTASE inhibitors, NRTIs) and Non-nucleoside reverse transcriptase inhibitors (Non-nucleoside REVERSE TRANSCRIPTASE inhibitors, NNRTIs). NRTIs and substrates competitively act on RT active sites, NNRTIs are allosteric binding pockets which are combined with a distance of about 10A from a reverse transcriptase active site in a Non-competitive mode, and are called Non-nucleoside reverse transcriptase inhibitor binding pockets (Non-nucleoside REVERSE TRANSCRIPTASE inhibitor binding pocket, NNIBP), the synthesis of virus DNA is influenced by interfering with RT catalytic active sites, the replication of the virus is influenced, and the synthesis of normal human DNA is not interfered, so that the NNRTIs have the characteristics of high selectivity, low genotoxicity and the like, do not need to be converted into active substances through host cell metabolism, and have the characteristics of faster in vivo effect and higher stability. NNRTIs currently used clinically are mainly second generation HIV inhibitors, itravirin (ETRAVIRINE, ETR) and rilpivirine (RILPIVIRINE, RPV), which are both diaryl pyrimidine structures. The diaryl pyrimidine structures of ETR and RPV give them a strong flexibility, while enhancing the drug resistance barrier to the mutant strain, also determine their physicochemical properties such as poor water solubility (S (ETR) < < 1 μg/mL; S (RPV) =20 ng/mL), leading to low bioavailability. In addition, the low patient response rate (ETR: 36.5%; RPV: 27.3%), and the side effects that result from long-term administration, also limit their clinical use. In addition, long-term clinical use, amino acid mutation of RT can deactivate the originally effective drug, i.e., generate drug-resistant HIV strains. Therefore, the development of novel high-efficiency 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 ETR and RPV, and enhance the nonpolar interaction between the compound and NNIBP inner wall amino acid through biaryl fragments and pyrimidyl rings so as to improve the biological activity of the series of compounds against drug-resistant virus strains. Disclosure of Invention The invention aims to provide a dihydro pteridine-6 (5H) -ketone skeleton-containing compound which has strong inhibition of HIV-1 bioactivity, 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 structural formula of the dihydro pteridine-6 (5H) -ketone-containing skeleton compound provided by the invention is as follows: ; wherein R 1 is selected from cyano, cyanovinyl, various substituted or unsubstituted benzene rings, pyridines, pyrimidines, oxazines and their oxides, thiophenes (pyrans) (sulfoxides and sulfones), (iso) thiazoles and their oxides, pyrroles and their oxides, pyrazoles (pyrans) and their oxides, imidazoles and their oxides, (iso) oxazoles and their oxides, pyrazolones, furans, cyclopentadiene, dihydrothiophenes and their episulfides (sulfoxides and sulfones), dihy