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Phenobarbital derivatives useful in immunoassay

A phenobarbital, medium phenobarbital technology, applied in the field of phenobarbital derivatives that can be used in immunoassays, can solve problems such as not pointing out barbiturate cross-reactivity

Active Publication Date: 2010-09-01
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The last cited patent also describes an enzyme immunoassay for barbiturates, but only phenobarbital and its derivatives are exemplified in this assay without indication of cross-reactivity with other barbiturates

Method used

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  • Phenobarbital derivatives useful in immunoassay
  • Phenobarbital derivatives useful in immunoassay
  • Phenobarbital derivatives useful in immunoassay

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] The synthesis of embodiment 1. compound (1)

[0086] At room temperature, to 101 mg (0.259 mmol) of compound (1) [a] Krausz, L.M.; Hitz, J.B.; Buckler, R.T. and Burd, J.F. Therapeutic Drug Monitoring, 1980, 2, 261-272; b] Castro, A. ; Chung, A. and Monji, N. Research Communications in Chemical Pathology and Pharmacology, 1980, 28, 309-317.] In a stirred solution in 15 mL of dry THF containing 76 μL (0.55 mmol; 2.1 equivalents) of triethylamine 47 mg (0.41 mmol; 1.6 equiv) of glutaric anhydride were added. After stirring briefly at room temperature, the reaction was boiled at reflux (90° C. oil bath) under argon. After 1 hour, analysis by RP-HPLC indicated that the reaction was complete with only one major product peak. The reaction was evaporated to dryness under reduced pressure (rotary evaporator). The residue was redissolved in about 2.5 mL of 1:1 MeCN / water, filtered (0.45 μ) and purified using preparative RP-HPLC [column I] using 5% (0 min) → 100% (20 min) → 100...

Embodiment 2

[0087] Embodiment 2. the synthesis of compound (3)

[0088] 16.1 mg (0.140 mmol) of N-hydroxysuccinimide (NHS) and 38.1 mg (0.199 mmol) of 3-ethyl-1-dimethylaminopropylcarbodiimide hydrochloride were mixed under argon (EDC.HCl) was added to a stirred solution of 54.1 mg (0.139 mmol) of compound (2) in 4 mL of dry DMF and the solution was stirred at room temperature under argon for about 3 h. LC / MS indicated partial NHS ester formation. A further 32.3 mg (0.281 mmol; total addition = 0.421 mmol, 3 eq) of NHS and 55.3 mg (0.288 mmol; total addition = 0.487 mmol, 3.5 eq) of EDC.HCl were added and the reaction was heated at room temperature under argon Stir overnight. LC / MS indicated essentially complete conversion to the desired NHS ester (3). LC / MS: t R ~10.0 min [5% (0 min) → 88% (17.5 min) of 0.1% TFA / MeCN in 0.1% TFA / water]; found M+H 487.1. The entire product mixture / solution was used as such in the next step [see Example 3] without further purification.

Embodiment 3

[0089] Embodiment 3. the synthesis of compound (4)

[0090] The entire reaction / product mixture (~4 mL) containing (3) (from Example 2; transferred via syringe to a small addition funnel) was added dropwise to 81.2 μL (~0.554 mmol; ~0.554 mmol; ~ 4 equivalents) of 2,2'-(ethylenedioxy)-diethylamine [Fluka 03739] (DADOO) in 4 mL of dry THF and 2 mL of dry DMF [using a pipette] while continuing Stir effectively. The flask and addition funnel from Example 2 were washed with 4 mL of dry THF and the washing was added dropwise to the reaction over ~15 min. Analysis of the reactants after ~0.5 h showed the disappearance of the NHS ester (3) and formation of the desired product (4) (t R ~8.25min), which contains a small amount of dimer. The reaction was evaporated under reduced pressure to remove THF, then under high vacuum (high vacuum rotary evaporator) to remove DMF. The residue was redissolved in 1:1 MeCN / water, filtered (0.45 μ) and purified using preparative RP-HPLC with 5% (...

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Abstract

Phenobarbital derivatives synthesized out of the alkyl chain at the 5-position, particularly with hydrophilic properties, and carrying an active ester at the end, allow formation of aminodextran conjugates that give curves in the desired range of the assay in the ONLINE TDM microparticle assay format when matched against the Roche FPIA antibody specific for phenobarbital (''an antibody specific for phenobarbital'').

Description

[0001] related application [0002] This application claims priority to US Provisional Application Serial No. 60 / 981,202, filed October 19, 2007. field of invention [0003] The present invention relates to the field of therapeutic drug monitoring and in particular phenobarbital derivatives and analytical methods using the derivatives for the determination of phenobarbital in patient samples. Background of the invention [0004] The problem overcome by the present invention is the development of an improved non-isotopic homogeneous microparticle agglutination immunoassay specific for the therapeutic drug phenobarbital, based on the kinetic interaction of microparticles (KIMS). (barbiturates) have no cross-reactivity with other substances. [0005] Other non-isotopic immunoassays specific for phenobarbital have employed different techniques such as fluorescence polarization immunoassay (FPIA), as in US 4,614,823 to Kirkemo et al; immunoassays using enzyme-mediated signal gen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/62G01N33/94
CPCC07D239/62Y10T436/13
Inventor R·许
Owner F HOFFMANN LA ROCHE & CO AG
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