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Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis

A compound and drug technology, applied in the field of compounds and analog peptides

Inactive Publication Date: 2002-10-02
AGOURON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Until now, there is no effective treatment for the common cold on the market, and the treatment is only to relieve symptoms

Method used

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  • Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] TMEDA (0.81 mL, 5.37 mmol) and dimethyl sulfide (0.49 mL, 6.67 mmol) were added to n-butyllithium (1.58 M in hexane, 3.4 mL, 5.37 mmol) at 0 °C under argon atmosphere ), the mixture was stirred for 5 hours while raising the temperature to 23°C, the reaction mixture was cooled to -40°C, and Cbz-L-Leu-L-Phe-L-(Tr-Gln)-N(CH 3 )OCH 3 (prepared as described in WIPO International Publication No. WO97 / 43305) (0.85 g, 1.03 mmol) in 9 mL of THF, the mixture was washed with 15 mL of 2N AcOH was quenched at -40 °C and extracted with excess EtOAc, the pH of the aqueous phase was measured with solid Na 2 CO 3 Adjusted to basic, extracted with EtOAc, combined the organic layers, and washed continuously with saturated NaHCO 3 and brine wash with MgSO 4 Drying, filtration and concentration in vacuo, column chromatography of the residue (45% EtOAc / Hexanes) provided the product as a white solid in 60% yield.

Embodiment 2

[0124] 1 H NMR (CDCl 3 )δ0.86(m, 6H), 1.31(m, 1H), 1.53(m, 2H), 1.75(m, 1H), 2.00(s, 3H), 2.27(m, 3H), 3.06(m, 2H ), 3.15(m, 2H), 3.93(m, 1H), 4.54(m, 1H), 4.70(m, 1H), 4.90(m, 2H), 6.50(m, 1H), 6.95(d, 1H, J=7.0), 7.14-7.41 (m, 27H).HRMSC 49 h 54 N 4 o 6 Calculated value of S (M+Cs). Measured value, (C 49 h 54 N 4 o 6 S·0.50H 2 O) Elemental Analysis C, H, N. Embodiment 2: Cbz-L-Leu-L-Phe-L-(Gln)-CH 2 SCH 3

[0125] Cbz-L-Leu-L-Phe-L-(Tr-Gln)-CH 2 SCH 3(0.30 g, 0.363 mmol) was added to 1:1 CH at 0 °C 2 Cl 2 and TFA and stirred for 45 min, the reaction mixture was concentrated in vacuo and extracted with excess EtOAc, the solution was washed with saturated NaHCO 3 and washed twice with brine, MgSO 4 dried, filtered and concentrated in vacuo, the residue was washed with Et 2 O Trituration yielded 0.15 g (71% yield) of the product as a white solid. 1 H NMR (DMSO-d 6 )δ0.80(d, 3H, J=6.6), 0.83(d, 3H, J=7.0), 1.33(m, 3H), 1.47(m, 1H), 1.72(m, 1H), 1.98(s, 3H...

Embodiment 3

[0125] Cbz-L-Leu-L-Phe-L-(Tr-Gln)-CH 2 SCH 3(0.30 g, 0.363 mmol) was added to 1:1 CH at 0 °C 2 Cl 2 and TFA and stirred for 45 min, the reaction mixture was concentrated in vacuo and extracted with excess EtOAc, the solution was washed with saturated NaHCO 3 and washed twice with brine, MgSO 4 dried, filtered and concentrated in vacuo, the residue was washed with Et 2 O Trituration yielded 0.15 g (71% yield) of the product as a white solid. 1 H NMR (DMSO-d 6 )δ0.80(d, 3H, J=6.6), 0.83(d, 3H, J=7.0), 1.33(m, 3H), 1.47(m, 1H), 1.72(m, 1H), 1.98(s, 3H), 2.05(m, 2H), 2.83(dd, 1H, J=14.0, 8.0), 3.05(dd, 1H, J=14.0, 4.4), 3.27(m, 2H), 3.98(m, 1H), 4.38(m, 1H), 4.52(m, 1H), 5.02(m, 2H), 6.78(s, 1H), 7.14-7.35(m, 11H), 7.42(d, 1H, J=7.7), 8.03( d, 1H, J=7.7), 8.42(d, 1H, J=7.4).HRMSC 30 h 40 N 4 o 6 Calculated value of S (M+H), 585.2747; measured value, 585.2720. (C 30 h 40 N 4 o 6 S) Elemental analysis C, H, N. Example 3: Cbz-L-Leu-L-Phe-L-(N-Ac-amino-Ala)-CH 2 O C(O...

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Abstract

Compounds of formula (I), wherein the variables of the formula are as defined in this disclosure, can advantageously inhibit or block the biological activity of picornavirus 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are suitable for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for the preparation of such compounds are also described.

Description

field of invention [0001] The present invention relates to certain peptidomimetic and peptidomimetic compounds which advantageously inhibit the enzymatic activity of picornavirus 3C proteases, in particular rhinovirus 3C proteases, and retard virus growth in cell culture. The invention also relates to the use of these compounds in pharmaceutical compositions and the therapeutic treatment of rhinovirus infections. The invention further relates to methods of synthesizing these compounds and compounds useful in these syntheses. Background of the invention [0002] Picornaviruses are a class of tiny, non-enveloped viruses containing positive-sense RNA that infect humans and other animals. These viruses include human rhinovirus, human poliovirus, human Cossack virus, human enterocytopathic virus, human and bovine enterovirus, encephalomyocarditis virus, meningitis virus, foot-and-mouth virus, hepatitis A virus, and others . Human rhinoviruses are the leading cause of the commo...

Claims

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Application Information

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IPC IPC(8): C12N9/99A61K31/381A61K31/4015A61K31/426A61K31/428A61K31/44A61K31/445A61K38/00A61K38/06A61P31/12A61P31/14A61P31/16A61P43/00C07D207/26C07D417/06C07K5/00C07K5/02C07K5/06C07K5/08C07K5/083C07K5/097
CPCA61K38/00C07K5/06043C07K5/06191C07K5/0821C07K5/0827A61P31/12A61P31/14A61P31/16A61P43/00Y02A50/30C07K5/02
Inventor P·S·德拉格维奇周茹S·E·韦伯T·J·普林斯S·H·莱希S·E·凯法特芮元金
Owner AGOURON PHARMA INC
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