Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-11
2004-11-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252120, C544S366000, C544S387000
Reexamination Certificate
active
06818637
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
The present application claims benefit under 35 U.S.C. §365(c) to PCT Application serial number FR00/00026, filed Jan. 7, 2000, which is incorporated herein by reference.
The present invention relates to novel products of general formula (I),
and to their salts with an inorganic or organic acid, to their preparation, to the pharmaceutical compositions which comprise them and to their use as an antidiabetic agent.
Products exhibiting hypoglycemic properties, of general formula:
in which either R
1
represents a hydrogen atom and R
2
represents a chain of formula:
CH
2
—CHOH—CHOH—CH
2
OH (A)
CHOH—CHOH—CHOH—CH
2
OH (B)
or R
1
represents a chain of formula (A) and R
2
represents a hydrogen atom, have been disclosed in Application WO 97/28813.
However, nothing in the prior art allowed it to be anticipated that, because of their structural modifications with respect to these products, the products of general formula (I) according to the invention would exhibit greatly improved properties, both in terms of antiglycemic activity and in terms of bioavailability and/or toxicity.
The present invention relates to the products of general formula (I),
in which:
R
1
represents the stereoisomeric forms of the chain
—(CHOH)
3
—CH
2
—O—COR (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
—O—COR (III)
or R
2
represents the stereoisomeric forms of the chains
—(CHOH )
3
—CH
2
—O—COR (II)
or
CH
2
—(CHOH)
2
—CH
2
—O—COR (III)
and R
3
represents a hydrogen atom
and
R represents an —(Alk)
i
—(Cycloalk) radical,
for which:
Alk denotes an alkyl radical,
Cycloalk denotes a cycloalkyl radical,
i is equal to 0 or 1;
and
to their stereoisomeric forms and to their salts with an inorganic or organic acid.
The term “alkyl” is understood to mean: a saturated straight- or branched-chain hydrocarbonaceous radical comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl.
The term “cycloalkyl” is understood to mean: a saturated cyclic hydrocarbonaceous radical comprising 5 or 6 carbon atoms, such as cyclopentyl or cyclohexyl. The present invention thus relates to the products of general formulae
in which
R represents an —(Alk)
i
—(Cycloalk) radical,
for which:
Alk denotes an alkyl radical,
Cycloalk denotes a cycloalkyl radical,
i is equal to 0 or 1;
and to their stereoisomeric forms or to the salts of such products with an organic or inorganic acid. According to the present invention, preference is given to the products having the following general formulae:
in which
R represents an —(Alk)
i
—(Cycloalk) radical,
for which:
Alk denotes an alkyl radical,
Cycloalk denotes a cycloalkyl radical,
i is equal to 0 or 1;
and to the salts of such products with an organic or inorganic acid.
More preferably still, the present invention relates to the products of general formula (IX)
in which:
R represents an —(Alk)
i
—(Cycloalk) radical,
for which:
Alk denotes an alkyl radical,
Cycloalk denotes a cycloalkyl radical,
i is equal to 0 or 1;
and to the salts of such products with an organic or inorganic acid.
According to an even more advantageous aspect, the present invention relates to the products of general formula (IX) in which:
R represents an —(Alk)
i
—(Cycloalk) radical,
for which:
Alk denotes the methyl radical,
Cycloalk denotes a cyclohexyl radical,
i is equal to 0 or 1;
and to their salts with an organic or inorganic acid.
The products according to the present invention can very advantageously be chosen individually from:
4,4′-O,O-dicyclohexyloyl-2-[(1R,2S,3R)(1,2,3,4-tetra-hydroxylbutyl)]-5-[(2′S,3′R)(2′,3′,4′-trihydroxy-butyl)]pyrazine
4,4′-O,O-di(cyclohexylacetyl)-2-[(1R,2S,3R)-(1,2,3,4-tetrahydroxylbutyl)]-5-[(2′S,3′R)-(2′,3′,4′-trihydroxybutyl)]pyrazine
and their salts with an inorganic or organic acid.
In particular: 4,4′-O,O-dicyclohexyloyl-2-[(1R,2S,3R)(1,2,3,4-tetrahydroxylbutyl)]-5-[(2′S,3′R)(2′,3′,4′-trihydroxybutyl)]pyrazine and its salts with an inorganic or organic acid.
According to the present invention, the products of general formula (I) in which R is defined as above can be obtained from the products of general formula:
in which:
Ri
1
represents the stereoisomeric forms of the chain
—(CHOH)
3
—CH
2
OH (XI)
and
Ri
2
represents a hydrogen atom and Ri
3
represents the stereoisomeric forms of the chain
—CH
2
—(CHOH)
2
—CH
2
OH (XII)
or Ri
2
represents the stereoisomeric forms of the chains
—(CHOH)
3
—CH
2
OH (XI)
or
—CH
2
—(CHOH)
2
—CH
2
OH (XII)
and Ri
3
represents a hydrogen atom,
by reaction with a corresponding acyl halide of formula R—COX, in which R is defined as above and X represents a halogen atom, such as chlorine.
This reaction is carried out in the presence of an organic or inorganic base, preferably pyridine, at temperatures of between 0 and 40° C.
The acyl halide of formula R—COX, in which R is defined as above and X represents a halogen atom, such as chlorine, may be commercially available or optionally can be prepared from the corresponding acid R—COOH according to the usual methods; in particular, the acyl chloride can be prepared from the corresponding acid by reaction with oxalyl chloride in a solvent, such as dichloromethane, N,N-dimethylformamide or a mixture of these two solvents.
The acyl halide can advantageously be prepared in situ. The products of general formula (X) can be prepared in the following way:
The stereoisomeric forms of the products of general formula (X) are obtained from the stereoisomeric forms of the reactants hereinbelow used by the preparation process according to the invention.
The stereoisomers of the products of formula (X) in which Ri
1
represents the stereoisomeric forms of the—(CHOH)
3
—CH
2
OH chain (XI), Ri
2
represents a hydrogen atom and Ri
3
represents the stereoisomeric forms of the —CH
2
—(CHOH)
2
—CH
2
OH chain (XII) can be obtained by reaction of ammonium formate with an aldose, or a mixture of 2 aldoses, of the dextrorotatory or levorotatory series, of general formula:
CHO—CHOH—Ri
1
(XIII)
in which Ri
1
has the same meaning as in the formula (X)
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 sulfuric 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 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 t
Bouchard Herve
Commercon Alain
Aventis Pharma SA
Parker III Raymond S.
Patel Sudhaker B.
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