Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-10-14
2002-05-21
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000, C536S120000, C536S122000
Reexamination Certificate
active
06391862
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to single-isomer chiral resolving agents for separation stereoisomers and, more particularly, to functionalized single-isomer charged cyclodextrins for separations of stereoisomers.
BACKGROUND OF THE INVENTION
The separation of stereoisomers (e.g., enantiomers) is generally considered to be one of the more difficult tasks in analytical chemistry since chiral compounds exhibit identical physical properties in non-chiral environments. As a result, conventional separation techniques such as gas chromatography (GC), high pressure liquid chromatography (HPLC) and capillary electrophoresis (CE) have been modified to provide a chiral environment to facilitate enantiomer separation.
One such approach in providing a chiral environment has been through the use of chiral resolving agents, such as cyclodextrins. In fact, electrophoresis has become established as a powerful method for the separation of enantiomers (St. Claire, R. L.,
Anal. Chem
. 1996, 68, 569R) due in part to the versatility of various cyclodextrins as resolving agents in both acidic and alkaline background electrolytes (BE). Although significant improvements in enantiomeric separations have been achieved with native as well as derivatized neutral cyclodextrins, as recently reviewed in Fanali, S.,
J. Chromatogr. A
, 1996, 735, 77, the analysis of noncharged enantiomers only became possible when charged cyclodextrins entered the stage (Terabe,
S., Trends Anal. Chem
. 1989, 8, 129).
However, charged cyclodextrins used so far are complex mixtures that contain a large number of isomers differing both in their degree of substitution (the number of charges per cyclodextrin molecule) and the loci of substitution. As a result, the use of these resolving agent mixtures is fraught with at least four distinct problems in any given separation. First, the number and loci of substituents on the cyclodextrin greatly effect the chiral selectivity of the system, in which the direction and magnitude of these changes cannot be predicted a priori (Weseloh, et al.,
J. Microcolumn Sep
. 1995, 7, 355). As a result, when mixtures of different isomers of substituted cyclodextrins are used, the overall separation selectivity of the system can be reduced or eliminated (Weseloch, et al.,
J. Microcolumn Sep
. 1995, 7, 355; Szeman, et al.,
J. Chromatogr. A
1996, 728, 423; Stalcup, et al.,
Anal. Chem
. 1995, 67, 19). Mixtures of charged cyclodextrins also present the problem of kinetic band broadening when the finite complexation rates of the different cyclodextrin isomers are slightly different, which unavoidably decreases separation efficiency. Likewise, fundamental molecular level studies through nuclear magnetic resonance (NMR) spectroscopy (Endresz, et al.,
J. Chromatogr., A
, 1996, 732, 132) or crystallographic analysis (Harata, et al.,
Carbohydr. Research
1991, 222, 37) or molecular modeling (Lipkowitz, et al.,
J. Am. Chem. Soc
., 1997,114, 15540), which are aimed at improving the level of understanding of the chiral recognition process, are rendered impossible with mixtures of resolving agent. Finally, resolving agent mixtures (commercial or otherwise) often differ between batches and thus compromise the reproducibility of difficult separations.
Accordingly, there is a need in the art for resolving agents that do not exhibit the deficiencies associated with charged cyclodextrin mixtures.
It is, therefore, an object of the present invention to provide alternative resolving agents for use in chiral separations, inter alia, that do not exhibit the deficiencies commonly associated with charged cyclodextrin mixtures.
SUMMARY OF THE INVENTION
The present invention provides a single-isomer cyclodextrin composition of substantially pure cyclodextrin derivatives having the formula:
where “n” is 6-12, and at least one of Y
1
, Y
2
and Y
3
is SO
3
−
, and where Y
1
, Y
2
and Y
3
, being other than SO
3
−
, are independently hydrogen, a C
1
-C
12
alkyl group, a C
2
-C
8
hydroxyalkyl group, a C
2
-C
12
acyl group, an aryl group, a carbamate group, a thiocarbamate group or a combination thereof Preferably, the cyclodextrin composition has an isomeric purity of at least 80 mole %, with an isomeric purity of at least 90 mole % being more preferable, and an isomeric purity of at least 95 mole % being even more preferable.
In one embodiment, a single-isomer cyclodextrin composition is provided with Y
1
being SO
3
−
, and Y
2
and Y
3
being preferably H, CH
3
, CH
2
CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
. Examples of these single-isomer cyclodextrin derivatives are hepta-6-sulfato-&bgr;-cyclodextrin, heptakis-(2,3-diacetyl-6-sulfato)-&bgr;-cyclodextrin, heptakis-(2,3-dimethyl-6-sulfato)-&bgr;-cyclodextrin, octa-6-sulfato-&ggr;-cyclodextrin, octakis-(2,3-diacetyl-6-sulfato)-&ggr;-cyclodextrin, and octakis-(2,3-dimethyl-6-sulfato)-&ggr;-cyclodextrin.
In another embodiment, a single-isomer cyclodextrin composition is provided with Y
2
being SO
3
−
, and Y
1
and Y
3
being preferably H, CH
3
, CH
2
CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
. In other embodiments, the present invention provides single-isomer cyclodextrin compositions with: Y
3
being SO
3
−
and Y
1
and Y
2
being preferably H, CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
; Y
1
and Y
2
being SO
3
−
and Y
3
being H, CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
; Y
1
and Y
3
being SO
3
−
and Y
2
being preferably H, CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
; Y
2
and Y
3
being SO
3
−
and Y
1
being preferably H, CH
3
, CH
2
CHOHCH
3
, CH
2
CN, or OCCH
3
.
The present invention also provides a method for electrophorectically separating stereoisomers of a chiral analyte using the above-described single-isomer cyclodextrin compositions. The chiral analyte is separated into its respective stereoisomers by first introducing into an electrophoretic separation chamber a sample of the chiral analyte and of a background electrolyte containing at least one single-isomer cyclodextrin composition and thereafter applying an electric potential across the electrophoretic separation chamber thereby inducing differential migration of the stereoisomers of the chiral analyte.
The present invention provides a method for chromatographically separating stereoisomers of a chiral analyte using the above-described single-isomer cyclodextrin compositions. The chiral analyte is separated into its respective stereoisomers by first introducing into a chromatographic separation chamber the chiral analyte, and a mobile phase containing at least one single-isomer cyclodextrin composition and thereafter applying pressure across the separation chamber thereby inducing differential displacement of the stereoisomers of the chiral analyte.
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Cavitron® product literature, published by Cerestar USA, Inc., Aug. 1996.*
Wenz, Gerhard. “Cyclodextrins as Building Blocks for Supramolecular Structures and Functional Units”, Angew. Chem. Int. Ed. Engl., vol. 33: 802-822, 1994.*
Duchene et al. “Pharmaceutical and Medical Applications of Cyclodextrins”, Chapter 19 of Polysaccharides in Medicinal Applications, publ. by Marcel Dekker, Inc., pp. 575-602, 1996.*
T. Christians et al., “New single-isomer chiral selector for capillary electrophoresis: the highly water-solubleheptakis(2-N,N-dimethylcarbamoyl)-&bgr;-—cyclodextrin”, J. Chromatogr. A, 911 pp.249-257, (2001).
W. Zhu et al., “A Family of Single-Isomer, Sulfated &ggr;-Cyclodextrin Chiral Resolving Agents for Capillary Electrophoresis. 1. Octakis(2,3-diacetyl-6-sulfato)-&ggr;-cyclodextrin”, Anal
Baker & Botts L.L.P.
Maier Leigh C.
The Texas A&M University System
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