Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-01-31
1992-01-21
Robinson, Allen J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546 62, 546 72, C07D491147
Patent
active
050829424
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel markers usable for marking organic compounds having --NH--, --NH.sub.2, --CHO, --COOH or --CO--groups, with a view to the detection of these compounds by chemiluminescence or fluorescence in determination processes such as liquid chromatography.
It is known that the determination by liquid chromatography of amines, aldehydes, ketones or acids not having spectral properties requires, in order to achieve a high sensitivity, the transformation of these compounds with the aid of marking reagents in order to give them absorption, fluorescence or chemiluminescence properties.
The use of markers of this type for the detection of carboxylic derivatives or amines is in particular described by H. Cisse, R. Farinotti, S. Kirkiacharian and A. Dauphin in Journal of Chromatography, 225, 1981, pp.509-515; by M. Tsitini Tsamis, A. M. Mange, R. Farinotti and G. Mahuzier in Journal of Chromatography, 277, 1983, pp.61-69; by N. Kubab, R. Farinotti and G. Mahuzier in Analysis, 1986, v.14, no.3, pp.125-130; and by D. Amir and E. Haas in Int. J. Peptide Protein Res., 26, 1986, pp.7-17.
In liquid chromatography determination processes, in particular chemiluminescent markers are sought, because analysis by chemiluminescence is subject to a large amount of development and makes it possible to improve the sensitivity of the determination. Thus, chemiluminescence methods make it possible to obtain a detection limit of approximately 1 femtomole, whereas in spectrofluorimetric methods, the detection limit currently reached is a few hundred femtomoles.
A detection method of chemiluminescence in liquid chromatography is in particular described by M. Tod, R. Farinotti and G. Mahuzier in Analysis, 1986, v.14, no.6, pp.271-280.
The presently used chemiluminescent markers such as orthophthalaldehyde, fluorescamine and anthracene and dansylated derivatives suffer from certain disadvantages. Thus, orthophthalaldehyde and fluorescamine are not very sensitive. Anthrazcene derivatives are inhibited by dissolved oxygen and dansylated derivatives are inhibited by certain excitation reaction products. Moreover, certain chemiluminescent markers have a by no means negligible toxicity, which is in particular the case with anthracene and dansylated derivatives.
As a result of recent research, it has been found that coumarin nuclei were of a certain interest, because they have an equivalent sensitivity to the highest performance products, which have neither toxicity, nor sensitivity with respect to the conventional inhibitors, such as dissolved oxygen, halide and nitro derivatives. In addition, they are easy to use under varied excitation and chromatography conditions.
The present invention specifically relates to novel doumarin derivatives in the form of derivatives of tetrahydro-2,3,6,7,1H,5H,11H-(1)benzopyrano(6,7,8 ij)quanolizinone-11 complying with the formula: ##STR3## in which R.sup.1 represents the radical of formula: ##STR4## in which m is equal to 0 or 1 and n is equal to 0 or an integer between 1 and 12, provided that n is equal to 0 when m is equal to 0, or the radical of formula:
In these novel derivatives, the use of the coumar in nucleus of formula: ##STR5## makes it possible to obtain improved fluorescence and chemiluminescence properties. Moreover, the choice of an appropriate --CO--R.sup.1 group fixed to this coumarin nucleus makes it possible to obtain markers which can be used for a large number of organic compounds.
Thus, the novel derivatives according to the invention have the advantage of a good sensitivity, the capacity of being used as markers for different compounds, of being usable in the normal or reverse phase, of not being inhibited by the conventional quenchers such as dissolved oxygen, halides and nitrates, of having under no toxicity and of rapidly reacting with the compounds to be marked under relatively gentle conditions.
According to a first embodiment of the invention, the radical R.sup.1 represents the radical: ##STR6##
This derivative is tetrahydro-2,3,6,7,1H,5H, 11H(1)-benzo-pyrano(
REFERENCES:
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Makuzier, G. et al. CA 113:23889n (1990).
Tod, M. et al., CA 112:151038a (1990).
Optics Communications, vol. 15, No. 3, Drexhage et al., "Water-Soluble Coumarin Dyes for Flashlamp-Pumped Dye Lasters", pp. 399-403.
Journal of Chromotography, vol. 225, 1981, Elsevier Scientific Publishing Co., Cisse et al. "Dosage de l'Acide Dipropylacetique dans le Plasma par Chromatographie en Phase Liquide et Detection Spectrofluorimetrique", pp. 509 -515.
Chalom Joseph
Farinotti Robert
Mahuzier Georges
Tod Michel
Laboratories Eurobio
Robinson Allen J.
Treanor Susan P.
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