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Novel imaging agents comprising caspase-3 inhibitors

A cysteine ​​aspartic acid, protease technology, applied in the directions of in vivo radioactive preparations, antiviral agents, preparations for in vivo experiments, etc.

Inactive Publication Date: 2007-01-31
GE HEALTHCARE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This means that the optimal imaging time is between 10 and 15 hours after injection [Reutelingsperger et al., J. Immunol. Meth., 265 (1-2), 123-32(2002)], making this method unsuitable for the clinical judgment of patients with acute coronary syndrome

Method used

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  • Novel imaging agents comprising caspase-3 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Embodiment 1: 1,1, the synthesis of 1-three (2-aminoethyl) methane

[0264] (Step a): Dimethyl 3-(methoxycarbonylmethylene)glutarate

[0265] Carbomethoxymethylenetriphenylphosphorane (167g, 0.5mol) in toluene (600ml) was treated with dimethyl 3-oxoglutarate (87g, 0.5mol) and the reaction was heated to 100°C in an oil bath. °C, heated at 120 °C for 36 hours under a nitrogen atmosphere. The reaction was then concentrated in vacuo and the oily residue was triturated with 40 / 60 petroleum ether / diethyl ether (1:1, 600ml). Triphenylphosphine oxide precipitates out and the supernatant is decanted / filtered off. The vacuum evaporated residue was subjected to Kugelrohr distillation under high vacuum Bpt (oven temperature 180-200°C, 0.2 torr) to give dimethyl 3-(methoxycarbonylmethylene)glutarate (89.08 g, 53% ).

[0266] NMR 1 H(CDCl 3 ): δ3.31 (2H, s, CH 2 ), 3.7 (9H, s, 3xOCH 3 ), 3.87 (2H, s, CH 2 ), 5.79 (1H, s, =CH,) ppm.

[0267] NMR 13 C(CDCl 3 ), δ36.56, CH ...

Embodiment 2

[0292] Embodiment 2: Another preparation method of 1,1,1-three (2-aminoethyl) methane

[0293] (Step a): Amidation of trimethyl ester with p-methoxy-benzylamine

[0294] Tris(methoxycarbonylmethyl)methane [2 g, 8.4 mmol; prepared according to Step 1(b) above] was dissolved in p-methoxy-benzylamine (25 g, 178.6 mmol). Install a distillation apparatus and heat to 120° C. for 24 hours under nitrogen flow. The progress of the reaction was monitored by the amount of methanol collected. The reaction mixture was cooled to room temperature, 30 mL of ethyl acetate was added, and the precipitated triamide product was stirred for 30 minutes. The triamide was isolated by filtration and the filter cake was washed several times with sufficient ethyl acetate to remove excess p-methoxy-benzylamine. After drying, a white powder (4.6 g, 100%) was obtained. The essentially insoluble product was used directly in the next step without further purification or characterization.

[0295] (Step b...

Embodiment 3

[0301] Embodiment 3: Preparation of 3-chloro-3-methyl-2-nitrosobutane

[0302] A mixture of 2-methylbut-2-ene (147ml, 1.4mol) and isoamyl nitrite (156ml, 1.16mol) was cooled to -30°C with a cardice / methanol bath, stirred vigorously with an overhead air stirrer, Concentrated hydrochloric acid (140ml, 1.68mol) was added dropwise at a rate such that the temperature was kept below -20°C. This takes about 1 hour and care must be taken to prevent overheating due to the large heat release. Ethanol (100 ml) was added to reduce the viscosity of the slurry (formed at the end of the addition) and the reaction was stirred at -20°C to -10°C for 2 hours to complete the reaction. The precipitate was collected by vacuum filtration, washed with 4 x 30 ml of cold (-20°C) ethanol and 100 ml of ice-cold water, then dried in vacuo to give 3-chloro-3-methyl-2-nitrosobutane as a white solid. The ethanol filtrate and washings were combined, diluted with water (200ml) and cooled, and allowed to stan...

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Abstract

The present invention relates to diagnostic imaging agents for in vivo imaging. Such imaging agents comprise synthetic caspase 3 inhibitors labeled with an imaging moiety suitable for in vivo diagnostic imaging. The invention also provides a pharmaceutical composition and a radiopharmaceutical composition comprising the imaging agent, and a kit for preparing the radiopharmaceutical composition. The present invention also provides chelator conjugates of caspase 3 inhibitors which are suitable for use in the preparation of imaging agents comprising radioactive or paramagnetic metal ions. Imaging agents of the invention are useful in vivo for diagnostic imaging and / or therapeutic monitoring in various disease states involving caspase 3.

Description

field of invention [0001] The present invention relates to diagnostic imaging agents for in vivo imaging. Such imaging agents comprise synthetic caspase-3 inhibitors labeled with an imaging moiety suitable for in vivo diagnostic imaging. Background of the invention [0002] Programmed cell death (apoptosis) is a complex process involving many cellular processes involving multilevel regulation. Apoptosis is initiated by one of two pathways. The first is an extrinsic pathway initiated by cell surface death receptors, and the second is an intrinsic pathway initiated by endogenous initiators such as DNA damage induced by UV radiation. These two pathways culminate in energy-demanding co-ordinated cell death, which, unlike necrotic cell death, does not involve an inflammatory response. Apoptotic cells send out "eat me" signals on their cell surface, which induce other cells to destroy them through phagocytosis. [0003] Apoptosis is essential for many processes in the body. F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/00A61K49/00A61K49/06A61K49/08A61K49/10A61K49/12A61K49/14A61K51/02A61K51/04A61K51/06A61K51/08
CPCA61K51/0455A61K51/0446A61K51/088A61K51/0431A61K51/0459Y02P20/582A61P1/16A61P13/08A61P13/10A61P19/02A61P21/00A61P25/00A61P25/14A61P25/16A61P25/28A61P31/04A61P31/18A61P35/00A61P35/02A61P37/04A61P37/06A61P43/00A61P9/10A61P3/10A61K51/04A61K51/08
Inventor D·希斯科克B·牛顿B·吉伯特
Owner GE HEALTHCARE LTD
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