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

a technology of antipicornaviral and composition, applied in the field of antipicornaviral, can solve the problems of no effective treatment of the common cold on the market, and achieve the effect of high-efficiency treatment of maladies

Inactive Publication Date: 2006-03-02
AGOURON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about finding small-molecule compounds that can treat maladies caused by infections with picornaviruses, such as the common cold. The compounds discovered have strong antiviral activity and can specifically target the protease enzyme that these viruses need to replicate. The invention also includes methods for making these compounds and pharmaceutical compositions containing them. The compounds have been found to have high rhinoviral-protease-inhibiting activity, and can be used as prodrugs or pharmaceutically active metabolites.

Problems solved by technology

To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Comparison Compound #1: 5-(3′-(Cbz-L-Leu-L-Phe-L-Gln)-E-Propene)-isoxazole

[0183]

Preparation of Intermediate Cbz-L-(Tr-Gln)-OMe

[0184] Cbz-L-(Tr-Gln) (0.26 g, 0.50 mmol, 1 equiv.) was added to a solution of acetyl chloride (0.25 mL, 3.52 mmol, 7.0 equiv.) in CH3OH (5 mL), and stirring was continued at 23° C. for 1 h (hour). The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (100 mL) and washed with water (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over Na2SO4 and was concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to afford Cbz-L-(Tr-Gln)-OMe (0.23 g, 84% yield) as a white solid: mp=139-140° C.; IR (cm−1) 1742, 1207; 1H NMR (DMSO-d6) δ 1.16 (t, 1H, J=7.0), 1.77 (m, 1H), 1.97 (m, 1H), 3.61 (s, 3H), 4.99 (m, 1H), 5.03 (s, 2H), 7.02-7.55 (m, 20H), 7.69 (d, 1H, J=7.7), 8.59 (s, 1H); Anal. (C33H32N2O5) C, H, N.

Preparation of Intermediate Cbz-L-(Tr-Glu...

example 2

Preparation of Compound A-1: Ethyl-3-((5′-Methylisoxazole-3′-carbonyl)-L-Leu-L-Phe-L-Gin)-E-Propenoate

[0191]

Preparation of Intermediate Boc-L-(Tr-Gln)-N(OMe)Me

[0192] Isobutyl chloroformate (4.77 mL, 36.8 mmol, 1.0 equiv.) was added to a solution of Boc-L-(Tr-Gln)-OH (18.7 g, 36.7 mmol, 1 equiv.) and 4-methylmorpholine (8.08 mL, 73.5 mmol, 2.0 equiv.) in CH2Cl2 (250 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. (minutes), then N,O-dimethylhydroxylamine hydrochloride (3.60 g, 36.7 mmol, 1.0 equiv.) was added. The resulting solution was stirred at 0° C. for 20 min. and at 23° C. for 2 hours (h), and then was partitioned between water (150 mL) and CH2Cl2 (2×150 mL). The combined organic layers were dried over Na2SO4, and were concentrated. Purification of the residue by flash column chromatography (gradient elution, 40-20% hexanes in EtOAc) provided Boc-L-(Tr-Gln)-N(OMe)Me (16.1 g, 82% yield) as a white foam: IR (cm−1) 3411, 3329, 3062, 1701, 1659; 1H NMR (CDCl3) ...

example 3

Preparation of Compound A-2: Ethyl-3-((Isoxazole-5′-carbonyl)-L-Leu-L-Phe-L-Gln)-E-Propenoate

[0199]

Preparation of Intermediate Ethyl-3-((Isoxazole-5′-carbonyl)-L-Leu-L-Phe-L-(Tr-Gln))-E-Propenoate

[0200] This compound was prepared from ethyl-3-(Boc-L-Leu-L-Phe-L-(Tr-Gln))-E-propenoate and isoxazole-5-carbonyl chloride using the procedure described above (Example 2) for the preparation of ethyl-3-((5′-methylisoxazole-3′-carbonyl)-L-Leu-L-Phe-L-(Tr-Gln))-E-propenoate: IR (cm−1) 3282, 1643, 1530; 1H NMR (CDCl3) δ 0.87 (t, 6H, J=6.6), 1.29 (t, 3H, J=7.2), 1.49-1.64 (m, 3H), 1.69-1.80 (m, 1H), 1.90-1.96 (m, 1H), 2.30 (t, 2H, J=7.2), 2.92-2.96 (m, 1H), 3.02-3.09 (m, 1H), 4.17 (q, 2H, J=7.2), 4.42-4.48 (m, 3H), 5.69 (d, 1H, J=15.3), 6.65 (s, br, 1H), 6.66 (dd, 1H, J=15.9, 5.4), 6.76-6.79 (m, 2H), 7.00-7.31 (m, 22H), 8.24 (s, 1H); Anal. (C47H51N5O7.0.75H2O)C, H, N.

Preparation of Ethyl-3-((Isoxazole-5′-carbonyl)-L-Leu-L-Phe-L-Gln)-E-Propenoate

[0201] The title compound was prepared from et...

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Abstract

Peptido and peptidomimetic compounds of the formula: wherein the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is related to U.S. Provisional Application No. 60 / 098,358, filed Aug. 28, 1998, and U.S. Provisional Application No. 60 / 083,828, filed Apr. 30, 1998.FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION [0002] The invention pertains to peptide-like and peptidomimetic compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and compounds useful in such syntheses. BACKGROUND OF THE INVENTION [0003] The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruse...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/04C07K5/04A61K31/433A61K31/4245A61K31/40C07D211/76A61K31/42A61K31/422A61K31/4412A61K31/454A61K38/00A61K38/05A61P31/12C07D207/26C07D207/27C07D261/18C07D413/12C07D413/14C07K5/02C07K5/027
CPCA61K38/00C07D207/26C07K5/0205C07D413/12C07D261/18A61P31/12A61P31/16C07K5/02Y02A50/30
Inventor DRAGOVICH, PETER SCOTTWEBBER, STEPHEN EVANPRINS, THOMAS JAYZHOU, RUMARAKOVITS, JOSEPH TIMOTHYJOHNSON, THEODORE O. JR.
Owner AGOURON PHARMA INC
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