Imidazole and benzimiddzole caspase inhibitors and uses thereof

A technology of benzimidazole ring and application, applied in the field of medicinal chemistry, can solve problems such as unclear appropriate pharmacological properties, and achieve the effects of improving cell penetration, pharmacokinetic properties, and improving efficacy

Inactive Publication Date: 2007-02-07
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] Although many caspase inhibitors have been disclosed, it is unclear whether they have suitable pharmacological properties for use in therapy

Method used

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  • Imidazole and benzimiddzole caspase inhibitors and uses thereof
  • Imidazole and benzimiddzole caspase inhibitors and uses thereof
  • Imidazole and benzimiddzole caspase inhibitors and uses thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0071] The compounds of the present invention can generally be prepared according to the description of the following Basic Reaction Scheme I and by way of the Preparative Examples below, using methods known to those skilled in the art for the preparation of analogous compounds.

[0072] Reaction Diagram I

[0073]

[0074] Reagents: (a) EDC, diisopropylethylamine, HOBt, 2; (b) hydrolysis or TFA / DCM; (c) DMAP, EDC, diisopropylethylamine, HOBt, 4; (d) Dess- Martin periodinane

[0075] Reaction Scheme I shows a general route for the preparation of compounds of the invention. The following abbreviations are used: EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HOBT is 1-hydroxybenzotriazole; TFA is trifluoroacetic acid; DCM is dichloro Methane; DMAP is 4-dimethylaminopyridine. Reaction of known imidazole-2-carboxylic acid or known benzimidazole-2-carboxylic acid (represented by general formula 1) with amino ester derivative 2 gives amide 3. If ester 3 is a tert-butyl...

Embodiment 1

[0078] [3S / R, (2S)]-5-fluoro-3-{2-[(1H-imidazole-2-carbonyl)-amino]-propionylamino]-4-oxo-pentanoic acid trifluoroacetate (compound 1)

[0079]

[0080] Method A:

[0081] (2S)-2-[(1H-Imidazole-2-carbonyl)-amino]-propionic acid tert-butyl ester

[0082]

[0083] To a solution of 1H-imidazole-2-carboxylic acid (0.17g) in N,N-dimethylformamide (DMF) (3mL) was added tert-butyl alanine hydrochloride (0.22g), diisopropylethyl Amine (0.27 mL) and HOBT (0.41 g) were then cooled to 0°C and the reaction mixture was treated with EDC.HCl (0.32 g). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate, washed with water and brine, and dried (MgSO 4 ), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the title compound (0.263 g, 73%) as a colorless oil, 1 H NMR 400MHz CDCl 3 1.50 (9H, s), 1.51 (3H, d, J 7.2), 3.70...

Embodiment 2

[0098] [3S / R, (2S)]-3-{2-[(1H-benzimidazole-2-carbonyl)-amino]-propionylamino}-5-fluoro-4-oxo-pentanoic acid trifluoroethyl salt (compound 2)

[0099]

[0100] Using a method similar to the above A-D, the title compound (142 mg, 90% yield in the last step) was obtained from 1H-benzimidazole-2-carboxylic acid: (isolated compound as TFA salt) yellow-white solid; IR ( solid, cm 1)3277.9, 1654.6, 1526.6, 1188.6, 1142.5, 1050.4, 927.5, 748.2, 712.4; 1 H NMR (DMSO-D 6 )1.42 (3H, d), 2.51-2.95 (2H, m), 4.21-4.75 (2H, m), 4.76-5.60 (3H, brm), 7.41 (2H, m), 7.65 (2H, m), 8.21 -9.05(2H,m); 13 C NMR (DMSO-D 6 ) 18.0, 18.7, 18.8 (Ala CH 3 ), 37.2, 34.6, 34.7 (Asp CH 2 ), 47.6, 48.8, 48.85, 49.1 (Asp CH), 52.0, 52.5 (Ala CH), 83.5, 85.2, 85.3, 103.8, 106.0 (CH 2 F), 116.6, 123.9 (Aryl CH), 145.3, 145.4, (Aryl C), 158.4, 158.7, 158.8, 172.1, 172.2, 172.4, 172.5, 172.6, 172.7, 173.2 (NC=O), 202.6, 202.7, 202.8 , 202.9 (C=O); M + Measured: 364.1177, C 16 h 17 FN 4 o 5 m + T...

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Abstract

The present invention provides the aspartic acid specific cysteine ​​protease inhibitor of formula I: wherein, R 1 is CO 2 H, CH 2 CO 2 H or its ester, amide or isostere; R 2 and R 3 each independently selected from hydrogen or optionally substituted C 1 -C 6 Aliphatic group; R 4 and R 5 each independently selected from hydrogen, optionally substituted C 1 -C 6 aliphatic, or R 4 and R 5 Together with the ring they are attached to form an optionally substituted bicyclic ring. The caspase inhibitors are useful in the treatment of various diseases such as cancer, acute inflammation, autoimmune diseases, ischemic diseases and certain neurodegenerative diseases.

Description

[0001] Cross-references to related applications [0002] This application claims priority to US Provisional Patent Application 60 / 252,252, filed November 21,2000. field of invention [0003] The present invention belongs to the field of medicinal chemistry and relates to a new compound capable of inhibiting aspartic acid-specific cysteine ​​protease mediating programmed cell apoptosis and inflammation and its pharmaceutical composition. The present invention also relates to methods of treating diseases associated with caspase activity using the compounds and pharmaceutical compositions of the present invention. Background of the invention [0004] Apoptosis, or programmed cell death, is an important process by which organisms eliminate unwanted cells. Unregulation of apoptosis (hyperapoptosis or apoptosis regression) is associated with many diseases such as cancer, acute inflammatory and autoimmune diseases, ischemic d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/90C07D235/24C07D473/00C07D471/04C07K5/02A61K31/4164A61P29/00C07D233/28A61K31/4184A61K38/00A61K45/00A61P1/04A61P1/16A61P1/18A61P3/10A61P5/14A61P7/04A61P7/06A61P7/08A61P9/04A61P9/10A61P11/00A61P11/06A61P13/12A61P17/00A61P17/02A61P17/06A61P17/14A61P19/02A61P19/10A61P21/00A61P21/04A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P25/32A61P27/02A61P31/00A61P31/04A61P31/06A61P31/12A61P31/18A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00C07D233/00C07K5/078
CPCC07K5/0202C07K5/0205C07K5/06139C07D235/24A61K38/00C07D233/90A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P13/12A61P17/00A61P17/02A61P17/06A61P17/14A61P19/02A61P19/08A61P19/10A61P21/00A61P21/02A61P21/04A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P25/32A61P27/02A61P29/00A61P31/00A61P31/04A61P31/06A61P31/12A61P31/14A61P31/18A61P31/20A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00A61P5/14A61P7/04A61P7/06A61P7/08A61P9/00A61P9/04A61P9/10A61P3/10Y02A50/30
Inventor D·凯J·戈雷克
Owner VERTEX PHARMA INC
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