Polycyclic pyridone derivative having integrase-inhibiting activity

A compound and fusion technology, applied in the field of anti-HIV drugs, can solve problems such as cross-resistance

Inactive Publication Date: 2014-08-06
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two of reverse transcriptase inhibitors and protease inhibitors are clinically used as anti-HIV drugs, but

Method used

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  • Polycyclic pyridone derivative having integrase-inhibiting activity
  • Polycyclic pyridone derivative having integrase-inhibiting activity
  • Polycyclic pyridone derivative having integrase-inhibiting activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0320] [chemical formula 22]

[0321]

[0322] Step 1 Synthesis of Compound 3

[0323] To a solution of compound 1 (1.00 g, 2.39 mmol) in DMF (5 ml) was added compound 2 (1.72 g, 3.57 mmol) and PdCl under a stream of nitrogen 2 (dppf) (175mg, 0.239mmol) and the reaction mixture was stirred at 110°C for 1 hour. After the obtained reaction liquid was left to cool to room temperature, it was diluted with ethyl acetate (50 ml), and saturated potassium fluoride aqueous solution (50 ml) was added thereto, followed by stirring overnight. After the precipitated insoluble matter was filtered, the liquid was separated, and the aqueous layer was extracted twice with ethyl acetate. After washing the combined organic layers 3 times with water and drying over sodium sulfate, the solvent was evaporated off. The obtained crude product was purified by silica gel column chromatography. First, it was eluted with hexane-ethyl acetate (1:1, v / v), then with ethyl acetate only. The target fr...

Embodiment 2

[0329] The following compounds were synthesized by the same procedure as in Example 1.

[0330] [chemical formula 23]

[0331]

[0332] 1 H-NMR (DMSO-d 6 ) δ: 1.35 (d, J = 7.2 Hz, 3H), 1.55 (d, J = 12.6 Hz, 1H), 1.96-2.07 (m, 1H), 3.88-3.93 (m, 1H), 4.02-4.08 (m , 1H), 4.22 (s, 2H), 4.39 (dd, J = 5.7 Hz, 13.8 Hz, 1H), 4.60 (dd, J = 3.9 Hz, 13.8 Hz), 4.79-4.85 (m, 1H), 5.46- 5.49 (m, 1H), 7.04-7.11 (m, 1H), 7.21-7.28 (m, 1H), 7.46 (dd, J = 8.7 Hz, 15.6 Hz, 1H), 7.66 (s, 1H), 8.74 (s , 1H).

Embodiment 3

[0334] [chemical formula 24]

[0335]

[0336] Step 1 Synthesis of Compound 8

[0337] To a solution of compound 6 (200 mg, 0.52 mmol) in DMF (5 ml) were added triethylamine (263 mg, 2.60 mmol) and ethyl chloroformate (169 mg, 1.56 mmol) under ice-cooling. After stirring at the same temperature for 10 minutes, compound 7 (287 mg, 1.56 mmol) and dimethylaminopyridine (6 mg, 0.05 mmol) were added thereto, and then the reaction mixture was stirred at the same temperature for 1 hour. Water was added to the obtained reaction solution, which was washed three times with ethyl acetate, and the aqueous layer was extracted twice with chloroform. After drying the combined extracts over sodium sulfate, the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography. First, it was eluted with chloroform only, then with chloroform-methanol (3:2, v / v). The target fraction was concentrated to give compound 8 (109 mg, yield 38%).

[0338] 1 H-NM...

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Abstract

The present invention relates to a novel compound having an antiviral effect, more specifically, a pyridone derivative having HIV integrase inhibitory activity, and a medicament containing the same, in particular, an anti-HIV agent. The compound of the present invention has integrase inhibitory activity and/or cell proliferation inhibitory activity against viruses, in particular, HIV and drug-resistant strains thereof. Thus, the compound is useful in preventing or treating various diseases, viral infections (for example, AIDS), and the like in which integrase participates.

Description

technical field [0001] The present invention relates to a new compound with antiviral activity, more specifically to a polycyclic pyridone derivative with HIV integrase inhibitory activity and a medicament containing it, especially an anti-HIV medicament. Background technique [0002] Among viruses, human immunodeficiency virus (hereinafter referred to as HIV), which is a retrovirus, is known to cause acquired immunodeficiency syndrome (hereinafter referred to as AIDS (AIDS)). At present, the therapeutic drugs of AIDS are mainly selected from reverse transcriptase inhibitors (such as AZT, 3TC, etc.) The emergence of sexual viruses and other issues. Therefore, development of an anti-HIV drug having a mechanism of action different from them is required. [0003] On the other hand, at present, multidrug combination therapy is reported to be effective in the treatment of AIDS due to the frequent emergence of drug-resistant viruses. Two of reverse transcriptase inhibitors and ...

Claims

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Application Information

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IPC IPC(8): C07D498/14A61K31/4985A61K31/5365A61P31/18
CPCA61K31/437A61K31/4985C07D471/22C07D498/14A61P31/18A61P43/00
Inventor 秋山俊行
Owner SHIONOGI & CO LTD
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