Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-14
2002-03-26
Raymond, Richard L. (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
06362185
ABSTRACT:
The present invention relates to medicaments comprising, as active principle, at least one compound of formula:
or one of their stereoisomers or their salts with an inorganic or organic acid, to novel compounds of formula (I) and to their preparation.
In the formula (I), either R
1
represents a —CH(Ra)—CHOH—CHOH—CH
2
OH chain and
R
2
represents a —CH
2
—CHOH—CHOH—CH
2
OH chain,
or R
1
represents a —CHOH—CHF—CHOH—CH
2
OH chain and R
2
represents a —CH
2
—CHF—CHOH—CH
2
OH chain,
or R
1
represents a —CHOH—CHOH—CHOH—Rb chain and R
2
represents a —CH
2
—CHOH—CHOH—Rb chain,
or R
1
represents a —CH
2
—CHOH—CHOH—CH
2
OH chain and R
2
represents a —CH
2
—CHOH—CHOH—CH
2
OH chain,
or R
1
and R
2
are identical and each represent a —(CHOH)n—CH
2
OH chain in which n is equal to 1, 2, 3 or 4,
Ra represents an alkoxy radical (1-6 C in a straight or branched chain) or a fluorine atom,
Rb represents a carboxyl, —CO—NH
2
or —CH
2
—NH
2
radical.
As the compounds of formula (I) comprise several asymmetric carbons, [lacuna] exhibit stereoisomeric forms. These various stereoisomers form part of the invention.
The compound of formula:
is described in Nippon Shokuhin Kogyo Gakkaishi, 37 (2), 154 (1990), Agric. Biol. Chem., 44 (5), 1189 (1980), Carbohydr. Res., 67 (2), 549 (1978).
The compound of formula:
is described in Dev. Food Sci., 13, 85 (1986).
No pharmacological activity is described for these derivatives.
The other compounds of formula (I) are novel and, as such, form part of the present invention.
The preferred medicaments are those which comprise, as active principle, at least one of the following compounds:
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-methoxy-butane-1,2,3-triol,
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-fluorobutane-1,2,3-triol,
-1-[6-(2-Fluoro-3,4-dihydroxybutyl)pyrazin-2-yl]-2-fluorobutane-1,3,4-triol,
-1-[6-(2,3-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1,2,3-triol,
-4-[6-(2,3-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanoic acid,
-4-[6-(2,3-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanamide,
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2,3-triol,
1-[6-(1,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1,2-diol,
1-[6-(1,2,3-Trihydroxypropyl)pyrazin-2-yl]propane-1,2,3-triol,
1-[6-(1,2,3,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1,2,3,4-tetraol,
1-[6-(1,2,3,4,5-Pentahydroxypentyl)pyrazin-2-yl]-pentane-1,2,3,4S,5-pentaol,
their stereoisomers and their salts with a pharmaceutically acceptable inorganic or organic acid.
The particularly preferred medicaments are those which comprise a compound chosen from the following compounds:
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,
-1-[6-(2S-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,
-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,
-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,
-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoic acid,
-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoic acid,
-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,
1-[6-(1R,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1R,2-diol,
1-[6-(1S,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1S,2-diol,
1-[6-(1R,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1R,2S,3-triol,
1-[6-(1S,2R,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2R,3-triol,
1-[6-(1S,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2S,3-triol,
1-[6-(1R,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol,
1-[6-(1R,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,
1-[6-(1R,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol,
1-[6-(1R,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,
1-[6-(1S,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol,
1-[6-(1S,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol,
1-[6-(1S,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,
1-[6-(1S,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,
1-[6-(1R,2R,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4S,5-pentaol,
1-[6-(1R,2S,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3S,4R,5-pentaol,
1-[6-(1R,2S,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4S,5-pentaol,
1-[6-(1R,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4R,5-pentaol,
1-[6-(1R,2S,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4R,5-pentaol,
1-[6-(1S,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3R,4R,5-pentaol,
1-[6-(1S,2R,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3S,4R,5-pentaol,
and their salts with a pharmaceutically acceptable inorganic or organic acid.
The even more particularly preferred medicaments are those which comprise a compound chosen from the following compounds:
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,
-1-[6-(2s-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,
-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,
-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,
-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoic acid,
-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoic acid,
-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,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 derivatives of formula:
OHC—CHOH—Rc (II)
in which Rc represents a —CH(Ra)—CHOH—CHOH—CH
2
OH, —CHOH—CHF—CHOH—CH
2
OH, —CHOH—CHOH—CHOH—Rb, CH
2
—CHOH—CHOH—CH
2
OH or —(CHOH)n—CH
2
OH chain in which n is equal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C as a straight or branched chain) or a fluorine atom and Rb represents a carboxyl, —CO—NH
2
or —CH
2
—NH
2
radical, 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 derivatives of formula (II) and their stereoisomers 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”,
Bashiardes Georges
Carry Jean-Christophe
Evers Michel
Filoche Bruno
Mignani Serge
Aventis Pharma S.A.
Balasubrasubramanian Venkataraman
Newman Irving
Raymond Richard L.
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