Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-01-14
2002-05-21
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S398000, C514S252100
Reexamination Certificate
active
06392042
ABSTRACT:
The present invention relates to medicaments comprising, as active principle, at least one compound of general formula:
in their stereoisomeric forms or their salts with an inorganic or organic acid, to novel compounds of formula (I) or their salts with an inorganic or organic acid, and to their preparation.
In the general formula (I):
R
1
represents the stereoisomeric forms of the chain
—(CHOH)
3
—CH
2
OH (II)
and
either R
2
represents a hydrogen atom and R
3
represents the stereoisomeric forms of the chain
—CH
2
—(CHOH)
2
—CH
2
OH (III)
or R
2
represents the stereoisomeric forms of the chains
—(CHOH)
3
—CH
2
OH (II)
or
—CH
2
—(CHOH)
2
—CH
2
OH (III)
and R
3
represents a hydrogen atom with the exception of
fructosazine of formula
deoxyfructosazine of formula
and the compound of formula
The medicaments according to the invention thus comprise at least one stereoisomer of the following compounds:
or a salt of such a compound with an organic or inorganic acid, with the exception of fructosazine, deoxyfructosazine and the compound of formula (VI).
The medicaments according to the invention are preferably those which comprise, as active principle, at least one compound of formula (I) chosen from the following compounds:
1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[5-(1R,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol
1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[5-(1S,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol
1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol
1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol
1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol
1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol
1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol
1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol
or a salt of such a compound with an inorganic or organic acid,
and, more advantageously still, those which comprise, as active principle, at least one compound of formula (I) chosen from the following compounds:
1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol
1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol
or a salt of such a compound with an inorganic or organic acid.
The following compounds are known:
fructosazine, deoxyfructozasine and the compound of formula (VI) are described (Patent JP 43-13469, Ann., 644, 122-127 (1961); Agr. Biol. Chem., 39 (5), 1143-1148 (1975)),
the stereoisomers of general formula (VIa), (VIb), (VIc) and (VId) mentioned hereinbelow have been described (Patent JP 43-13469, Carbohyd. Res., 26(2), 377-84 (1973), J. Anal. Appl. Pyrolysis, 13, 191-198(1988))
the compounds of general formulae (VII), (VIII) and (IX) resulting from glucose, fructose, mannose and galactose have been described in Japanese Patent JP 53-90401.
However, their use as medicament has not been mentioned and this is the subject matter of the present invention.
The compounds of formula (I) or their salts with an inorganic or organic acid, with the exception of the following compounds:
are novel and, as such, form part of the invention.
The preferred compounds of formula (I) are the following:
1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[5-(1S, 2R, 3R, 4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[5- (1S, 2S,3S, 4-tetrahydroxybutyl)pyrazin-2-yl butane-1S,2S,3S,4-tetraol
1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol
1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol
1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
or a salt of such a compound with an inorganic or organic acid,
advantageously
1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol
1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol
1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
or a salt of such a compound with an inorganic or organic acid,
and, more advantageously still, the following compound:
1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol
or a salt of such a compound with an inorganic or organic acid.
The stereoisomeric forms of the compounds of general formula (I) are obtained from the stereoisomeric forms of the reactants hereinbelow used by the preparation process according to the invention.
The stereoisomers of the compounds of formula (I) in which R
1
represents the stereoisomeric forms of the —(CHOH)
3
—CH
2
OH chain (II), R
2
represents a hydrogen atom and R
3
represents the stereoisomeric forms of the —CH
2
—(CHOH)
2
—CH
2
OH chain (III), that is to say the compounds represented by the general formula (VII), can be obtained by reaction of ammonium formate with an aldose, or a mixture of 2 aldoses, of the dextrorotatory or laevorotatory series, of general formula:
CHO—CHOH—R
1
(X)
in which R
1
has the same meaning as in the formula (I).
This reaction can preferably be carried out at a temperature of between 15° C. and 100° C., preferably in aqueous medium.
The aldoses are commercially available or can be obtained from:
a) commercially available aldoses:
by epimerization reactions, by application or adaptation of the methods described in Adv. Carbohydr. Chem., 13, 63, (1958), in particular in basic medium by means of a dilute aqueous sodium hydroxide solution (0.03 to 0.05%), at a temperature of between 20 and 40° C.,
by chain-extension reactions, by application or adaptation of the methods described in “The Carbohydrates”, edited by W. Pigman and D. Horton, Academic Press, New York, Volume IA, 133 (1972), and in particular by forming the cyanohydrin of the starting aldose (for example, by reaction with sodium cyanide in aqueous solution, at a temperature of between 10 and 30° C. and in the presence of sodium hydroxide, at a pH in the region of 9), then hydrolysis of the nitrile functional group thus formed to the corresponding acid by application or adaptation of the methods described in Organic Synthesis, Volume I, page 436 and Volume III, page 85 (for example, using concentrated sulphuric acid or hydrochloric acid, in aqueous solution, at a temperature of between 20° C. and the reflux temperature of the reaction mixture), and then reduction of the carboxylic acid funct
Bashiardes Georges
Carry Jean-Christophe
Evers Michel
Filoche Bruno
Mignani Serge
Aventis Pharma S.A.
Newman Irving
Patel Sudhaker B.
Raymond Richard L.
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