Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-11
2002-06-18
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S336000
Reexamination Certificate
active
06407110
ABSTRACT:
The present invention relates to medicaments comprising, as active principle, at least one compound of formula (I):
or one of its stereoisomers or one of its salts with an inorganic or organic acid, to novel compounds of formula (I), to their stereoisomers, to their salts with an inorganic or organic acid and to their preparation.
In the formula (I) either R
2
represents a —CH
2
—(CHOH)
2
—CH
3
chain and R
3
represents a hydrogen atom or R
2
represents a hydrogen atom and R
3
represents a —CH
2
—(CHOH)
2
—CH
3
chain.
The compounds of formula (I) comprising several asymmetric carbons exhibit stereoisomeric forms. These various stereoisomers form part of the invention.
The preferred medicaments according to the invention are those which comprise, as active ingredient, at least one compound of formula (I) chosen from:
1-[5-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S-triol
1-[5-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1S,3S,3R-triol
1-[5-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S-triol
1-[5-(2S,3R-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R-triol
1-[5-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S-triol
1-[5-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R-triol
1-[5-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S-triol
1-[5-(2S,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2R, 3R-triol
1-[6-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S-triol
1-[6-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R-triol
1-[6-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S-triol
1-[6-(2S,3R-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R-triol
1-[6-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S-triol
1-[6-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R-triol
1-[6-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S-triol
1-[6-(2S,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R-triol
and their salts with an inorganic or organic acid.
The particularly preferred medicaments are those which comprise, as active principle, at least one compound of formula (I) chosen from the following:
1-[6-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S-triol
1-[6-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R-triol
1-[6-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S-triol
1-[5-(2R,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S-triol
and their salts with an inorganic or organic acid.
It has been reported in the literature that the compounds of following formula (I) can be made by the reaction of rhamnose and ammonia or ammonium salt of organic acid (Patent JP78-90401):
No pharmacological activity is described for any of these derivatives.
The other compounds of formula (I), their stereoisomers and their salts with an inorganic or organic acid are novel and also form part of the invention.
The preferred compounds of formula (I) are the following compounds:
1-[6-(2S,3S-dihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S-triol
1-[6-(2R,3R-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R-triol
and their salts with an inorganic or organic acid.
The compounds of formula (I) can be prepared by reaction of ammonium formate with one or two aldoses of formula (II):
H
3
C—(CHOH)
3
—CHOH—CHO (II)
or one of its stereoisomers.
This reaction is generally carried out in aqueous medium, at a temperature of between 20° C. and 100° C.
The aldoses H
3
C—(CHOH)
3
—CHOH—CHO and their stereoisomers are commercially available or can be prepared 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 boiling temperature of the reaction mixture), and then reduction of the carboxylic acid functional group to the corresponding aldehyde by application or adaptation of the methods described in J. Am. Chem. Soc., 71, 122 (1949), in particular using an alkali metal borohydride (for example, sodium borohydride), in aqueous solution, at a temperature of between 20° C. and the boiling temperature of the reaction mixture, by chain-shortening reactions, by application or adaptation of the methods described in “The Carbohydrates”, edited by W. Pigman and D. Horton, Academic Press, New York, Volume IB, 1980, page 929 or Chem. Ber., 83, 559 (1950) and in particular by converting the aldehyde functional group of the aldose to the corresponding hydroxylamine by application or adaptation of the methods described in Organic Synthesis, Volume II, page 314 (for example, using hydroxylamine hydrochloride, in aqueous solution and in the presence of a base, such as sodium carbonate, at a temperature of between 20 and 50° C.), and then reaction with 3,4-dinitrofluorobenzene in the presence of carbon dioxide and a base, such as sodium hydrogencarbonate, in aqueous solution, and an aliphatic alcohol (for example, isopropyl alcohol), at a temperature of between 50 and 80° C.,
by deoxygenation reactions, by application or adaptation of the methods described in Carbohydr. Res., 36, 392 (1974) and 28D, 357 (1996), in particular by converting an alcohol functional group of the aldose to the corresponding sulfonate by application or adaptation of the methods described in Carbohydr. Res., 54, 105 (1977) and in J. Carbohydr. Chem., 6, 169 (1987) and 6, 537 (1987), for example using methanesulfonyl or p-toluenesulfonyl chloride in the presence of a base, and then the action of sodium borohydride or of lithium aluminium hydride in a solvent, such as respectively dimethyl sulfoxide, on the one hand, or benzene and diethyl ether, on the other hand, at a temperature of between 20° C. and the boiling temperature of the reaction mixture,
b) corresponding allyl alcohols, by application or adaptation of the methods described in Science, 220, 949 (1983) and in particular using tert-butyl hydroperoxide in the presence of a titanium(IV) complex, such as the titanium(IV) isopropoxide and optically pure dialkyl tartrate (for example, diethyl tartrate) complex, followed by successive reaction with sodium thiophenolate, para-chloroperbenzoic acid in acetic anhydride, and diisopropylaluminum hydride.
The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, chromatography or crystallisation, for example) or chemical (formation of salts, for example) methods.
The compounds of formula (I) can optionally be converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent, such as an alcohol, a ketone, an ether or a chlorinated solvent.
These salts also form part of the invention. Mention may be made, as examples of pharmaceutically acceptable salts, of the addition salts with inorganic or organic acids, such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllineacetate, salicylate, methylenebis-(-hydroxynaphthoate), hydrochloride, sulphate, nitrate and phosphate.
REFERENCES:
patent: 53-90401 (1978-08-01), None
patent:
Bashiardes Georges
Carry Jean-Christophe
Evers Michel
Filoche Bruno
Mignani Serge
Aventis Pharma S.A.
Bernhardt Emily
Gupta Balaram
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