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Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity

A compound, heteroaryl technology, applied in the field of new compounds

Inactive Publication Date: 2005-08-24
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reverse transcriptase inhibitors and protease inhibitors are clinically used as anti-HIV agents, but drugs with the same mechanism of action often show cross-resistance or only show additional activity

Method used

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  • Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity
  • Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity
  • Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0470] Compound I-1

[0471]

[0472] step 1

[0473] At room temperature, 4-acetylamino-5-chloro-2-methoxy-3-nitrobenzoic acid 1 (20.6 g, 67.9 mmol) in methanol (200 ml) was added 5N hydrochloric acid (60 ml), and the mixture was heated under reflux for 14 hours. The reaction solution was neutralized with 2N sodium hydroxide solution under ice-cooling, and then water (100 ml) was added, followed by stirring for 30 minutes. Precipitated crystals were collected and washed with water (100 ml) to obtain Compound 2 (11.9 g) as wet yellow crystals.

[0474] step 2

[0475] The suspension of compound 2 (11.9g), ammonium chloride (1.22g, 22.8mmol) and iron (10.2g, 183mmol) obtained in step 1 in ethanol (450ml)-water (90ml) was heated to reflux for 3 hours. The reaction mixture was filtered through celite, and the remaining residue was washed with chloroform-methanol (1:1 v / v, 500 ml). The filtrate was concentrated under reduced pressure, then water (100 ml) was added to the r...

Embodiment 2

[0521] Compound I-6

[0522]

[0523] step 1

[0524] Under ice cooling, sodium hydride (60%, 0.42g, 10.5mmol) was added to a solution of compound 1 (3.03g, 10.0mmol) in DMF (40ml) over 5 minutes, and the mixture was stirred at room temperature for 1 hour , and then added methyl iodide (0.685ml, 11.0mmol) under ice-cooling, and stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH 3 with 10% hydrochloric acid under ice-cooling. Water (50ml) was added and extracted with ethyl acetate. The organic layer was washed with water (50ml) and brine (50ml), dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford crude compound 6 as a dark brown oil.

[0525] step 2

[0526] Sodium methoxide (28% methanol solution, 3 ml) was added to a methanol (3 ml) solution of the crude compound 6 obtained in step 1, and the mixture was heated to reflux for 2 hours. Under ice-cooling, the reaction mixture was poured into 1N hydrochlori...

Embodiment 3

[0558] Compound I-10

[0559]

[0560] Steps 1-4

[0561] Compound I-10 was synthesized in the same manner as in Step 1 of Example 2 and Steps 2, 4, and 5 of Example 1.

[0562] Melting point: 168-170°C Recrystallization solvent: methanol-isopropanol

[0563] Elemental Analysis: C 17 h 14 ClFN 2 o 3

[0564] Calculated (%): C, 58.55; H, 4.05; N, 8.03; Cl, ​​10.17; F, 5.45.

[0565] Found value (%): C, 58.47; H, 3.97; N, 8.08; Cl, ​​9.90; F, 5.19.

[0566] NMR (DMSO-d 6 )δ: 2.49 (3H, s), 3.90 (3H, s), 5.74 (2H, s), 7.05 (2H, m), 7.18 (2H, m), 7.54 (1H, s), 11.10 (1H, brs ).

[0567] IR (KBr): 3417, 1699cm -1 .

[0568] Compound I-11 was synthesized in the same manner as in Example 3.

[0569]

[0570] Compound I-11

[0571] Melting point: 185-187°C Recrystallization solvent: ethyl acetate-hexane

[0572] Elemental Analysis: C 18 h 16 ClFN 2 o 3

[0573] Calculated (%): C, 59.59; H, 4.45; N, 7.72; Cl, ​​9.77; F, 5.24.

[0574] Found value (%): C, 59.59...

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Abstract

A compound of the formula (I) wherein Z<4>, Z<5> and Z<9> each is independently carbon atom or nitrogen atom; Y is hydroxy, mercapto or amino; R is a group of the formula (II) (wherein C ring is nitrogen-containing heteroaryl) has an inhibitory activity against integrase.

Description

technical field [0001] The present invention relates to a novel compound with antiviral activity, in particular to a nitrogen-containing heteroaryl compound with inhibitory effect on HIV integrase and a pharmaceutical composition containing the compound, especially an anti-HIV agent. Background technique [0002] Among viruses, human immunodeficiency virus (HIV), which is a retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic drugs for AIDS are mainly selected from reverse transcriptase inhibitors (such as AZT, 3TC) and protease inhibitors (such as indinavir), but they are confirmed to be accompanied by side effects such as kidney disease and emergence of drug-resistant viruses. Therefore, there is a need to develop anti-HIV drugs with other mechanisms of action. [0003] On the other hand, Balzarini, J et al reported in Proc. Natl. Acad. Sci. USA 1996, 93, pp. 13152-13157 that combined therapy is effective in treating AIDS due to the fre...

Claims

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Application Information

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IPC IPC(8): C07D215/48A61K31/4184A61K31/4196A61K31/422A61K31/4245A61K31/427A61K31/428A61K31/433A61K31/4355A61K31/437A61K31/47A61K31/4709A61K31/498A61K31/506A61K31/519A61K45/00A61P31/12A61P31/18A61P43/00C07D215/26C07D215/28C07D235/06C07D235/08C07D235/10C07D235/18C07D277/62C07D277/64C07D401/04C07D401/12C07D403/04C07D403/06C07D405/04C07D405/06C07D409/06C07D413/04C07D413/14C07D417/04C07D417/06C07D417/12C07D471/04C07D487/04C07D491/04C07D491/048C07D513/04
CPCC07D417/06C07D235/06C07D471/04A61K31/437C07D417/04C07D413/14C07D235/08C07D403/04C07D513/04C07D235/10C07D215/26C07D277/64C07D215/48C07D405/06C07D401/12C07D413/04C07D473/04C07D491/04C07D235/18C07D215/28C07D417/12C07D487/04C07D403/06C07D401/04A61P31/00A61P31/12A61P31/18A61P37/04A61P43/00
Inventor 富士雅弘三神山秀勋村井均
Owner SHIONOGI & CO LTD
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