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Preparation method and use of novel S-DABO HIV-1 reverse transcriptase inhibitor

A technology of HIV-1 and reagents, applied in the medical field, can solve problems such as drug-resistant strains

Inactive Publication Date: 2009-12-09
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The common features of this group of compounds are: they can highly inhibit HIV-1, but do not inhibit HIV-2 and other retroviruses; they are not inhibitors of HIV-1 reverse transcriptase substrate competition, but pass the The hydrophobic region of p66 binds and replaces the catalytic aspartic acid residue of the polymerase binding site, thereby achieving the effect of inhibiting HIV-1 replication; it does not inhibit other DNA polymerases, so the toxicity is very small and the toxicity is very high The antiviral selection index, the shortcoming is that the use in vivo and in vitro can quickly produce drug-resistant strains
This type of drug is prone to drug resistance, only one nucleotide mutation is needed to produce drug resistance, and it can produce cross-resistance with other NNRTIs

Method used

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  • Preparation method and use of novel S-DABO HIV-1 reverse transcriptase inhibitor
  • Preparation method and use of novel S-DABO HIV-1 reverse transcriptase inhibitor
  • Preparation method and use of novel S-DABO HIV-1 reverse transcriptase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Compound 1: Ethyl 3-oxo-4-phenylbutyrate

[0025] Ethyl 3-oxo-4-phenylbutyrate

[0026] The activated Zn powder (18g, was washed with 3N hydrochloric acid, H 2 O, Anhydrous EtOH, Anhydrous Et 2 O washed three times, then vacuum dried), suspended in dry THF (125ml) and heated to reflux, dropwise into 20 drops of BrCH 2 COOEt, after 45 minutes (green substance appears in the solution), add C in one go 6 h 5 CH 2 CN (3.12ml, 27mmol), BrCH was added dropwise 2 COOEt (6.6ml, 60mmol) was added dropwise after 1 hour and then refluxed for 10 minutes. Dilute with THF (125×3ml), add K 2 CO 3 (50%, 54ml) aqueous solution was rapidly stirred for 45 minutes, and the layers were left to stand, and the upper organic solvent was poured out, and the remaining residue was washed with THF (2×100ml), and the combined organic phases were added with hydrochloric acid (10%, 50ml) and stirred at room temperature for 45 minutes with NaHCO 3 Adjust PH≈7 and let it stand for stratificat...

Embodiment 2

[0029] Compound 2: Ethyl 2-methyl-3-oxo-4-phenylbutyrate

[0030] Ethyl-2-methyl-3-oxo-Phenylbutanoate

[0031] The activated Zn powder (13g, with 3N hydrochloric acid, H 2 O, Anhydrous EtOH, Anhydrous Et 2 O washed three times, then vacuum dried), suspended in dry THF (45ml) and heated to reflux, dripped 20 drops of ethyl bromoacetate, and after 45 minutes (the solution appeared green substance) added benzonitrile (1.3 ml, 10mmol), dropwise added BrCH (CH 3 )COOEt (5.5ml, 50mmol), after 1 hour, the dropwise addition was completed and then refluxed for 10 minutes. Dilute with THF (45×3ml), add K 2 CO 3 (50%, 15ml) aqueous solution was stirred rapidly for 45 minutes, and the layers were left to stand, and the upper organic solvent was poured out, and the remaining residue was washed with THF (2×50ml), and the combined organic phases were added with hydrochloric acid (10%, 12ml) and stirred at room temperature for 45 minutes with NaHCO 3 Adjust PH≈7 and let it stand for s...

Embodiment 3

[0034] Compound 3: 6-Benzylthiouracil

[0035] 6-benzyl-2-thioxo-2, 3-dihydropyrimidin-4(1H)-one

[0036] Sodium metal (4g, 174mmol) was dissolved in anhydrous EtOH (90ml), SO(NH 2 ) 2 (9.28g, 120mmol), and compound 1 (1.64g, 8.0mmol), the reaction mixture was heated to reflux for 6 hours. Rotate under reduced pressure at 40-50°C until almost completely dry, and dissolve the residue in water (80ml). Concentrated hydrochloric acid (14ml) was added to precipitate a precipitate, and HOAC was added to adjust until pH ≈ 4. The precipitate was filtered out with a suction funnel, washed with 10% EtOH solution, and dried to obtain 1.53 g of a white solid with a yield of 86.5%.

[0037] MS (ESI) m / z: 219 [M+H] +

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Abstract

The invention relates to a novel S-DABO compound which is designed by taking non-nucleoside HIV-1 reverse transcriptase inhibitor 3,4- dihydro-2-alkoxy-6-benzyl-4- carbonyl pyrimidine (DABO) and 1-[(2- hydroxy ethoxy) methyl]-6- thiophenyl thymine (HEPT) as lead compounds, combining research results of the research team, connecting and merging each structure and activity relationship in a molecule according to a basic principle of reasonable drug design. The novel S-DABO compound is shown in the general formula I, and definition of each group is disclosed as description in an affidavit of claim. In the invention, the C2, C4 and C5 sites of a pyrimidine ring are modified through various different groups to obtain the novel compound which is more beneficial to be combined with HIV-1 reverse transcriptase with the structure. Through HIV RT activity test, the novel S-DABO HIV-1 reverse transcriptase inhibitor has higher activity, wherein the activity of one compound is higher than 23 times of nevirapine currently used in clinic; and the compound can become a novel class of latent drug for resisting AIDS.

Description

technical field [0001] The application relates to non-nucleoside HIV-1 (human immunodeficiency virus-1) reverse transcriptase inhibitor 3,4-dihydro-2-alkoxy-6-benzyluracil (DABO) and 1-[ (2-Hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) is used as a lead substance, and with reference to the substrate conformation of HIV-1 reverse transcriptase (HIV-1RT) that acts on this type of compound, design, A series of novel S-DABO compounds were synthesized and tested for their biological activity. Non-nucleoside HIV-1 type reverse transcriptase inhibitors have been developed into more than 30 compounds with different structures, among which three compounds, nevirapine, delavirdine and efavirenz, have been For clinical use, there are also a variety of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in clinical trials. Among them, DABO compounds have become an important class of non-nucleoside HIV-1 reverse transcriptase inhibitors since they were first discovered in 1992. T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/38A61P31/18
Inventor 覃华刘俊义
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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