Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1991-11-06
1993-08-24
Bernhardt, Emily
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544251, 544257, C07D49822, C07D48714, C07D47504, A61K 31505
Patent
active
052390748
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel method of preparing diastereoisomeric compounds derived from tetrahydrofolic acid. These compounds include, by way of industrial products, (i) a mixture of the 6P and 6Q diastereoisomers as defined below (and probably having formulae III and respectively IV given below), in a molar ratio 6P/6Q of about 7/3, (ii) the pure 6P diastereoisomer and (iii) the pure 6Q diastereoisomer.
The invention further relates to the use of said 6P and 6Q diastereoisomers in the synthesis of the 6S and 6R diastereoisomers of reduced folates, such as the following acids in particular:
ABBREVIATIONS
For convenience, the following abbreviations have been used in the present description:
a) the reduced folates (6RS)-folinic acid) factor of Leuconostoc citrovorum), belonging to the series of so-called "natural" configuration, the calcium salt of this acid being known as "Calcium Leucovorin" of so-called "unnatural" configuration series of so-called "natural" configuration series of so-called "unnatural" configuration -methenyl-5,6,7,8-tetrahydrahydrofolic acid (or "anhydroLeucovorin") with the anion X.sup.- -methenyl-5,6,7,8-tetrahydrofolic acid with the anion X.sup.-, belonging to the series of so-called "natural" configuration -methenyl-5,6,7,8-tetrahydrofolic acid with the anion X.sup.-, belonging to the series of so-called "unnatural" configuration -methenyl-5,6,7,8-tetrahydrofolic acid with the anion X.sup.- and the acid HX -methenyl-5,6,7,8-tetrahydrofolic acid with the anion X.sup.- and the acid HX -methylene-5,6,7,8-tetrahydrofolic acid -methylene-5,6,7,8-tetrahydrofolic acid, belonging to the series of so-called "natural" configuration -methylene-5,6,7,8-tetrahydrofolic acid, belonging to the series of so-called "unnatural" configuration
b) the other abbreviations
PRIOR ART
Commercial folinic acid [or 5-CHO-(6RS)-THF], which has the nomenclatures (6RS)-5-formyl-5,6,7,8-tetrahydrofolic acid and (6RS)-5-formyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid and which is prepared in particular, with its calcium salt, from folic acid or from N.sup.5,N.sup.10 -methenyl-5,6,7,8-tetrahydrofolic acid [see, for example, patent documents CH-A-496 012 and GB-A-1 560 372], is known to be a 1/1 molar mixture of two diastereoisomers which differ from one another by their configuration at C.sup.6 (the carbon atom in the 6 position of the pteridinyl ring).
It is known that patent document GB-A-1 560 372 envisages in its description (see page 2, lines 4-6) the use of a complex - internal salt or zwitterion - of anhydro-Leucovorin (the compound of the formula [5,10-CH.sup.+ -(6RS)-THF]X.sup.-) in which one of the carboxylate ions, COO.sup.-, of the R-p-benzoyl-(L)-glutamic acid residue has reacted with the positive charge delocalized over the N.sup.5, C.sup.11 and N.sup.10 atoms, as a starting material in the synthesis of (6RS)-folinic acid and its calcium salt.
It is known from the article by J. C. FONTECILLA-CAMPS et al., J. Am. Chem. Soc., 101, 6114 (1979), that the biologically active diastereoisomer of folinic acid has the 6S configuration. It is pointed out that this diastereoisomer has in the past been called on the one hand the "natural isomer" by way of convenience because of its biological activity, and on the other hand "(1,L)-folinic acid", where the term "1" refers to the configuration at C.sup.6 and the term "L" refers to the configuration of the glutamic acid side-chain.
(6RS)-Folinic acid, 5-CHO-(6RS)-THF, is generally and commonly used, with its calcium salt, as a therapeutic means of "relief" in patients undergoing anticancer chemotherapy based on methotrexate, and as a means of increasing the inhibition of thymidylate synthetase by anticancer agents such as 5-fluorouracil and 5-fluoro-2'-deoxyuridine.
The 6R diastereoisomer of folinic acid, called the "unnatural isomer" (as opposed to the biologically active 6S) by way of convenience, was long thought to be inactive; however, it has been indicated [see F. M. SIROTNAK et al., Biochem. Pharm., 28, 2993 (1979)
REFERENCES:
patent: 5006655 (1991-04-01), Muller et al.
L. Rees, et al., "A simple and effective method for preparation of the 6(R)- and 6(S)-diasteroisomers of 5-formyltetrahydrofolate (Leucovorin)", Journal of the Chemical Society, Chemical Communications, 1987, pp. 470-472.
S. B. Horowitz, et all, "Diastereoisomers of formaldehyde derivatives of tetrahydrofolic acid and tetrahydroaminopterin", Journal of Medicinal Chemistry, vol. 12, No. 1, Jan. 1969, pp. 49-51.
C. Temple, Jr., et al., "Preparation and purification of L-(+)-5-formyl-5,6,7,8-tetrahydrofolic acid", Journal of Medicinal Chemistry, vol. 22, No. 6, Jun. 1979.
D. B. Cosulich, et al., "Diastereoisomers of Leucovorin", Journal of the American Chemical Society, vol. 74, No. 16, Aug. 20, 1952.
M. May et al., J. Am. Chem. Soc., 73, 3067-3075, (1951).
J. C. Fontecilla-Camps et al., J. Am. Chem. Soc., 101, 6114-6115, (1979) (see p. 4, lines 25-26).
J. C. Fontecilla-Camps et al., "Deveopments in Biochemistry", vol. 4, pp. 235-240, (1979).
R. Kalbermatten et al., Helv. Chim. Acta, 64, 2627-2635 (1981).
C. M. Tatum et al., Biochemistry, 16, 1093-1102, (1977).
Marazza Fabrizio
Melera Attilio
Viterbo Rene
Bernhardt Emily
Sapec S.A.
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