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Carbamate aspartic acid specific cysteine proteinase inhibitors and uses thereof

A cysteine ​​protease, specific technology, applied in the direction of non-central analgesics, anti-inflammatory agents, antiviral agents, etc., can solve the problems of poor oral absorption, rapid metabolism, poor stability, etc., and achieve good cell penetration sexual effect

Inactive Publication Date: 2007-07-11
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this potency is not always reflected in cellular models of apoptosis
Additionally, peptide inhibitors often have undesirable pharmacological properties, such as poor oral absorption, poor stability, and rapid metabolism

Method used

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  • Carbamate aspartic acid specific cysteine proteinase inhibitors and uses thereof
  • Carbamate aspartic acid specific cysteine proteinase inhibitors and uses thereof
  • Carbamate aspartic acid specific cysteine proteinase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] [3S / R]-5-fluoro-4-oxo-3-[(S)-3-methyl-2-(carbazole-carbamoyloxy-butane Amido)-pentanoic acid

[0139]

[0140] Method A:

[0141] (S)-2-(Chlorocarbamoyloxy)-3-methylbutanoic acid, tert-butyl ester

[0142]

[0143] To a solution of diphosgene (4.55 g) in THF (34 ml) was added dropwise (S)-tert-butyl 2-hydroxy-3-methylbutyrate (for the preparation see Tetrahedron. Lett. (Tetrahedron Letters, (1993), 7409) (4.0 g) and pyridine (1.82 g) in THF (34 ml).

[0144] The resulting mixture was allowed to warm to room temperature over 4 hours. The mixture was then filtered through celite and the filtrate was concentrated under reduced pressure. The residue was redissolved in diethyl ether (200ml) and filtered again through celite. The filtrate was concentrated under reduced pressure to afford the subtitle compound as a pale yellow oil (5.27 g): 1 HNMR (400MHz, CDCl 3 )δ0.98-1.10(6H, m), 1.55(9H, s), 2.30(1H, m), 4.83(1H, m).

[0145] Method B:

[0146] (S...

Embodiment 1A

[0162] [3S / R]-5-fluoro-4-oxo-3-[(S)-3-methyl-2-(carbazole)-carbamoyloxy- Butyrylamino]-valeric acid

[0163]

[0164] It was prepared using a method similar to Method C above. The product was isolated as a white solid (88% last step): IR (solid) 1721.2, 1695.6, 1664.9, 1449.8, 1378.1, 1198.9, 1040.1, 758.5 ​​cm -1 ; 1 H NMR (400MHz, d 6 -DMSO) δ1.10 (6H, brm), 2.41 (1H, m), 2.54-3.04 (2H, m), 4.31-4.82 (1.6H, m, CH2F), 5.10-5.41 (2.4H, m), 7.45(2H, m), 7.57(2H, m), 8.22(2H, m), 8.30(2H, m), 8.51-8.99(1H, brm), 12.60(1H, brs); 13 C NMR (100MHz, d 6 -DMSO) δ19.0, 19.1, 19.3, 30.4, 30.5, 30.6, 32.9, 34.5, 34.7, 47.3, 47.4, 52.0, 52.3, 80.4, 80.8, 83.2, 83.4, 83.4, 85.1, 85.2, 116.2, 116.3, 124.1 , 125.7, 125.9, 137.9, 151.7, 151.9, 152.0, 168.8, 169.0, 169.2, 172.0, 172.1, 173.1, 173.2, 202.2, 202.4, 202.5, 202.6; 19 F NMR (376MHz, d 6 -DMSO) -226.6(t), -226.8(t), -230.5(t), -230.9(t), -232.9(t), -233.0(t); MS(ESI+ve) 443(M+H ).

Embodiment 2

[0166] [3S / R]-5-fluoro-4-oxo-3-[(S)-3-methyl-2-(3-chlorocarbazole)-carbamoyloxy yl-butyrylamino]-pentanoic acid

[0167]

[0168]It was prepared using methods similar to Methods A-E above. The product was isolated as a white solid (99% last step): IR (solid) 1721.2, 1690.5, 1664.9, 1444.7, 1367.9, 1209.1, 1040.1 cm -1 ; 1 H NMR (400MHz, d 6 -DMSO) δ1.02-1.13 (6H, m), 2.40 (1H, m), 2.50-2.99 (2H, m), 4.30-4.85 (1.6H, m), 5.09-5.48 (2.4H, m), 7.48(1H, m), 7.56-7.66(2H, m), 8.20-8.32(3H, m), 8.39(1H, m), 8.55-8.99(1H, brm), 12.5(1H, br); 13 CNMR (100MHz, d 6 -DMSO) δ18.1, 18.9, 19.1, 30.4, 30.5, 33.0, 34.5, 34.7, 47.4, 52.0, 52.3, 80.6, 80.9, 81.1, 83.4, 83.43, 85.1, 85.2, 103.8, 104.0, 117.0, 119.3, 121.3 ( ); 19 F NMR (376MHz, d 6 -DMSO) -226.6(t), -226.8(t) -230.4(t), -230.9(t), -231.0(t), -232.8(t), -232.84(t), -232.9(t); MS(ESI+ve)477(M+H).

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Abstract

This invention provides caspase inhibitors of formula (I): wherein Z is oxygen or sulfur; R<1> is hydrogen, -CHN2,R, CH2OR, CH2SR, or -CH2Y; Y is an electronegative leaving group; R<2> is CO2H, CH2CO2H, or esters, amides or isosteres thereof; R<3> is a group capable of fitting into the S2 subsite of a caspase enzyme; R<4> and R<5> are taken together with the intervening nitrogen to form heterocyclic ring and R is as described in the specification. The compounds are effective inhibitors of apoptosis and IL-1 beta secretion.

Description

[0001] related application [0002] This application is a divisional application of Chinese invention patent application 01807578.9, the filing date of which is March 29, 2001, and the title of the invention is "carbamate aspartic acid specific cysteine ​​protease inhibitor and its use". [0003] This application claims priority to US Provisional Patent Application 60 / 192,826, filed March 29,2000. field of invention [0004] The invention belongs to the field of medicinal chemistry, and relates to novel compounds and pharmaceutical compositions thereof, which inhibit aspartic acid-specific cysteine ​​proteases mediating programmed cell death and inflammation. The present invention also relates to methods of treating diseases involving caspase activity using the compounds and pharmaceutical compositions of the present invention. Background of the invention [0005] Apoptosis, or programmed cell death, is the primary mechanism by which organisms eliminate unwanted cells. De...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/403A61K31/404A61K31/54A61K31/473A61K31/55A61K31/58C07D209/08C07D209/86C07D221/12C07D223/26C07D223/28C07D279/30C07D403/12A61P43/00A61K31/496A61K31/5415A61K31/575A61P9/00A61P19/02A61P19/08A61P25/32A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06C07D209/04C07D209/82C07D223/22C07D279/36C07J9/00
CPCC07D209/86C07D223/26C07D223/28C07D209/08C07D403/12C07D279/30C07D221/12A61P1/04A61P1/16A61P1/18A61P11/06A61P13/12A61P17/14A61P19/00A61P19/02A61P19/04A61P19/08A61P19/10A61P21/00A61P25/08A61P25/14A61P25/16A61P25/28A61P25/30A61P25/32A61P27/00A61P29/00A61P31/04A61P31/06A61P31/12A61P31/14A61P31/18A61P31/20A61P35/00A61P35/02A61P37/02A61P37/04A61P37/06A61P43/00A61P7/04A61P7/06A61P9/00A61P9/10A61P3/10A61K31/55
Inventor D·比宾格顿J-D·查里尔D·凯R·克尼格泰尔J·戈莱克M·默蒂摩尔J·斯图德雷
Owner VERTEX PHARMA INC
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