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Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase

An alkyl, benzyl technology, applied to diketoacids with nucleobase scaffolds: the target is in the field of anti-HIV replication inhibitors of HIV integrase, which can solve the problem that the 3′-processing step does not show inhibition

Inactive Publication Date: 2008-03-26
UNIV OF GEORGIA RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They inhibit the strand transfer step in the HIV integrase assay, but show no significant inhibition of the 3'-processing step of integrase action

Method used

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  • Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase
  • Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase
  • Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0543] 4-(1,3-Dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoic acid Methyl ester (3a).

[0544]

[0545] Step 1: Preparation of 5-acetyl-1,3-dibenzyluracil (2a).

[0546]

[0547] A suspension of 5-acetyluracil (3.1 g, 20 mmol) and potassium carbonate (6.9 g, 50 mmol) in DMF (75 mL) was stirred for 20 min. Then benzyl bromide (6.0 mL, 50 mmol) was added. The resulting mixture was stirred at room temperature for 8 h. DMF was evaporated in vacuum. The residue was purified by column chromatography (dichloromethane: methanol 40:1). The appropriate fraction was concentrated and crystallized from ethanol to obtain 5.34 g of white solid. The yield was 79.8%. Mp.92-93℃. 1 HNMR(CDCl 3 ): 8.23 ​​(s, 1H), 7.29-7.49 (m, 10H), 5.17 (s, 2H), 5.01 (s, 2H), 2.62 (s, 3H). 13 CNMR(CDCl 3 ): 194.5, 160.7, 151.0, 148.4, 136.2, 134.4, 129.2, 129.0, 128.9, 128.5, 128.2, 127.8, 112.2, 53.4, 44.9, 30.7. FAB-HRMS: [M+H] + Calculated value C 20 H 19 N 2 O 3 335.1396, the ...

Embodiment 2

[0552] 4-(1,3-Dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoic acid (4a)

[0553]

[0554] The 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-ene A solution of methyl acid (3a) (757 mg, 1.8 mmol) in dioxane (100 mL) was refluxed with 1N HCl (60 mL) for 4 h. The solution was evaporated to dryness. The obtained solid was recrystallized with hexane and ethyl acetate (3:1) to obtain 617 mg of pale yellow solid. The yield was 84.2%. Mp.186-188℃. 1 HNMR(DMSO-d 6 ): 8.89 (s, 1H), 7.57 (s, 1H), 7.24-7.36 (m, 10H), 5.16 (s, 2H), 5.02 (s, 2H). 13 CNMR(DMSO-d 6 ): 186.1, 169.0, 163.2, 159.9, 151.1, 150.2, 136.5, 135.8, 128.7, 128.4, 128.0, 127.8, 127.6, 127.3, 107.7, 100.9, 52.8, 44.2. FAB-HRMS: [M+H] + Calculated value C 22 H 19 N 2 O 6 407.1243, the measured value is 407.1248.

Embodiment 3

[0556] 4-[1,3-bis(2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobutane Methyl-2-enoate (3b).

[0557]

[0558] Step 1: Preparation of 1,3-bis(2-fluorobenzyl)-5-acetyluracil (2b)

[0559]

[0560] The title compound of this step was synthesized using a method similar to that described in Step 1 of Example 1, except that 2-fluorobenzyl bromide was used instead of benzyl bromide. The yield was 43.9%. Mp.149-150℃. 1 HNMR(CDCl 3 ): 8.35 (d, 1H, J = 1.0 Hz), 7.36-7.44 (m, 2H), 7.04-7.26 (m, 6H), 5.24 (s, 2H), 5.07 (s, 2H), 2.62 (s, 3H). 13 CNMR(CDCl 3 ): 194.3, 161.1 (d, J = 247.9 Hz), 160.7 (d, J = 247.9 Hz), 160.6, 150.8, 148.8 (d, J = 2.9 Hz), 131.3 (d, J = 3.4 Hz), 130.9 ( d, J = 8.2 Hz), 129.19 (d, J = 8.2 Hz), 129.17 (d, J = 2.9 Hz), 124.7 (d, J = 3.8 Hz), 124.1 (d, J = 3.8 Hz), 123.1 ( d, J = 14.5 Hz), 121.4 (d, J = 14.5 Hz), 115.9 (d, J = 21.6 Hz), 115.5 (d, J = 21.6 Hz), 112.2, 47.8, 38.8, 30.6.

[0561] FAB-HRMS: [M+H] + Calculated value C 20 H...

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Abstract

A new class of diketo acids constructed on nucleobase scaffolds, designed as inhibitors of HIV replication through inhibition of HIV integrase, is described. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.

Description

[0001] Related application [0002] This application claims priority from US Patent Application 11 / 047,229 filed on January 31, 2005, which is hereby incorporated by reference in its entirety. [0003] The cost of patent application work is partly supported by grants from the National Institutes of Health, grant number A143181. The US government may reserve certain invention rights in this invention. Background of the invention [0004] Human immunodeficiency virus, HIV, encodes three key viral enzymes through its reverse transcriptase gene, and these enzymes are crucial for the replication of this virus [Fauci, Science, 239, 617-622 (1988); Katz & Skalka, Annu. Rev. Biochem., 63, 133-173 (1994); Frankel, Annu. Rev. Biochem., 67, 1-25 (1998)]. Therefore, these enzymes of the reverse transcriptase gene have been used as targets for attacking potential sites in the development of HIV antiviral chemotherapeutics [De Clercq, J. Med. Chem. 38, 2491-2517 (1995); Clin. Microbiol Rev., 10,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54A61K31/505A61P31/12C07D473/04C07D473/16A61K31/52A61K31/522
CPCC07D473/30C07F9/65616C07D473/00C07D239/54C07F9/65122C07F9/6512A61P31/12A61P31/18A61P43/00A61K31/505
Inventor 瓦苏·奈尔迟国臣维诺德·R·尤奇尔
Owner UNIV OF GEORGIA RES FOUND INC