Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-12-29
2002-01-29
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S832000
Reexamination Certificate
active
06342645
ABSTRACT:
STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
REFERENCE TO MICROFICHE APPENDIX/SEQUENCE LISTING/TABLE/COMPUTER PROGRAM LISTING APPENDIX Submitted on a Compact Disc and an Incorporation-by-reference of the Material on the Compact Disc
Not applicable.
BACKGROUND OF THE INVENTION
D-chiro-inositol (DCI) is a rare isomer of inositol that, in recent years, has been implicated as having, a role in the activity of insulin on the body. Recent clinical trials have brought forth its potential pharmacological value for the treatment of diseases of insulin resistance.
For example, in a recent Phase II clinical study with 44 women afflicted with polycystic ovary syndrome (PCOS), administration of DCI (1200 mg/day for 6-8 weeks) resulted in ovulation by 86% of the patients, contrasted to ovulation in only 27% of the control (placebo) subjects (Nestler et al., N. Engl. J. Med. 340:1314-1320 (1999)). Similarly, in a clinical study of subjects with impaired glucose tolerance, administration of DCI (1200 mg/day for 2 weeks) restored glucose tolerance and insulin secretion to normal levels (Kessler et al., Diabetes Abst. 58th Scientific Sessions, #1385, A358 (1998)).
An excellent source of DCI is the aminoglycoside kasugamycin, a fermentation product of Streptomyces kasugaspinus and Streptomyces kasugaensis, which contains a molecule of DCI bound through a glycosidic linkage to the aminosugar kasugamine. Treatment of kasugamycin with strong acid cleaves this glycosidic linkage, liberating DCI and kasugamine, along with various other nitrogen-containing side products (FIG.
1
).
The methods currently used to hydrolyze kasugamycin and liberate DCI require large volumes of strongly acidic aqueous solutions (Kennington et al., U.S. Pat. No. 5,091,596) or large quantities of strongly acidic ion exchange resin (Sato et al., U.S. Pat. No. 5,714,643). In addition, prolonged reaction times and high temperatures and/or high pressures are required to complete the hydrolysis.
Moreover, for the production of meaningful quantities of DCI, these methods require the use of large volumes of high-boiling aqueous solutions. Purification of DCI from such a hydrolysis mixture requires processing through similarly large volumes of expensive anionic and cationic ion exchange resins, much of which are spent neutralizing the acids.
An alternative method for the production of DCI from kasugamycin is acetolysis. An advantage of this process is that it eliminates the need for ion exchange chromatography. Disadvantages, however, include the difficulties in removing the acetylating reagent and the production of side products. Extensive processing of the reaction mixture is generally required to remove these side products and so isolate pure DCI. (Riley et al., U.S. Pat. Nos. 5,463,142; 5,932,774).
In view of its high therapeutic potential and the ongoing studies involving treatment with DCI, there remains a need in the art for simple and efficient methods of preparing and/or isolating pure DCI without any of the disadvantages of present methods.
FIELD OF THE INVENTION
The present invention relates to methods for the production and isolation of D-chiro-inositol (DCI) from kasugamycin. More specifically, the present invention relates to a method of producing DCI by hydrolysis of kasugamycin with aqueous tritluoroacetic acid in the presence of a strongly acidic ion exchange resin. The present invention further relates to methods of isolating DCI from an aqueous mixture such as a hydrolysis mixture, either directly or by forming an organic derivative of DCI.
BACKGROUND ART
Not applicable.
BRIEF SUMMARY OF THE INVENTION
Accordingly, a first embodiment of the present invention relates to a method for producing DCI from kasugamycin, which comprises hydrolyzing kasugamycin in an aqueous solution of trifluoroacetic acid (TFA) in the presence of a strongly acidic ion exchange resin and then isolating DCI from the product mixture.
A second embodiment of the present invention relates to a method for solating DCI from a product mixture resulting from an acid hydrolysis of kasugamycin, which comprises contacting an aqueous solution of the reaction mixture sequentially with: (i) a not more than 12-fold excess of a basic (or ionic) ion exchange resin; and (ii) a not more than 6-fold excess of an acidic or cationic) ion exchange resin.
A third embodiment of the present invention relates to a second method for isolating DCI from a product mixture resulting from an acid hydrolysis of kasugamycin, which comprises preparing, an organic derivative of DCI and then isolating the derivatized DCI using an organic solvent extraction.
A fourth embodiment of the present invention relates to the pharmaceutical uses of DCI prepared and/or isolated according to any of the methods of the present invention.
REFERENCES:
patent: 5091596 (1992-02-01), Kennington et al.
patent: 5714643 (1998-02-01), Sato et al.
Longo Rachel K.
Plourde, Jr. Robert
Sleevi Mark C.
Insmed Pharmaceuticals, Inc.
Price Elvis O.
Richter Johann
Sterne Kessler Goldstein & Fox PLLC
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