Sodium oxamate for the treatment of diabetic conditions

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...

Reexamination Certificate

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C514S561000

Reexamination Certificate

active

06300375

ABSTRACT:

The present invention relates to mixtures which can be isolated from Eugenia Jambolana Lamarck seeds (Myrtaceae family), medicaments containing these mixtures or some of their constituents, the use of these mixtures and constituents for the preparation of an antidiabetic medicament and their preparations.
A plant extract prepared from Eugenia Jambolana seeds or bark containing a polyphenol and sterol mixed complex is described in patent FR 2,465,484.
New mixtures which can be isolated from Eugenia Jambolana Lamarck seeds, and which are free of polyphenol and sterol complex, as well as certain constituents of these mixtures endowed with hypoglycaemic properties, have now been found.
These mixtures are characterized in that they are free of polyphenol and sterol derivatives and can be isolated by grinding Eugenia Jambolana Lamarck seeds, maceration of the powder with a lower aliphatic alcohol with the use of heat, filtration, recovery of the insoluble part no longer containing polyphenol and sterol compounds, treatment of the insoluble part with an ammoniacal solution, treatment of the ammoniacal mixture with a lower aliphatic alcohol with the use of heat, filtration, recovery of the insoluble matter and drying this insoluble matter which constitutes the mixture I, then optionally treatment of the mixture I with a water-lower aliphatic alcohol solution, filtration, partial concentration of the filtrate, purification on nonpolar adsorbent resins, partial concentration, centrifugation, ultrafiltration and isolation of the mixture II.
From the mixture II, there may also be separated sodium oxamate and the compounds of formula:
in which either R
1
represents a hydrogen atom and R
2
represents a chain of formula:
or R
1
represents a chain of formula (A) and R
2
represents a hydrogen atom.
Sodium oxamate has already been described by TOUSSAINT, Ann., 120, 237 (1861).
The compounds of formula (I) have already been described by KUHN et al., Ann., 644, 122-127 (1961); TSUCHIDA et al., Agr. Biol. Chem., 39 (5), 1143-1148 (1975); TSUCHIDA et al., Agr. Biol. Chem., 40 (5), 921-925 (1976); TSUCHIDA et al., Nippon Shokuhin Kogyo Gakkaishi, 37, 154-161 (1990) and AVALOS et al., tetrahedron, 49, 2655-2675 (1993).
The present invention also relates to the process for preparing the mixture I from dried and finely ground Eugenia Jambolana Lamarck seeds.
The powder is screened, preferably with the aid of a normalized screen with holes 0.5 &mgr;m in diameter and then subjected to the following treatment:
a—maceration, with stirring, in a lower aliphatic alcohol, at a temperature of between 40 and 70° C.,
b—filtration under vacuum and recovery of the insoluble matter,
c—maceration, with stirring, of the insoluble matter with a lower aliphatic alcohol at a temperature of between 40 and 70° C.,
d—filtration under vacuum and removal of the alcoholic phases containing mainly the undesirable polyphenols and sterols,
e—taking up the insoluble matter in an anmoniacal solution at a temperature of between 10 and 30° C.,
f—taking up the whole wet ammoniacal mass in a water-lower aliphatic alcohol solution, at a temperature of between 40 and 70° C.,
g—filtration and removal of the alcoholic solution,
h—washing of the insoluble matter with a lower aliphatic alcohol, filtration and removal of the alcoholic solution,
i—recovery of the insoluble matter and drying.
In step a, the procedure is generally carried out by means of 2 to 10 liters of a lower aliphatic alcohol such as methanol or ethanol per 1 kg of screened powder. Preferably, 5 liters of ethanol with a titre of 93-95° Gay Lussac are used at 60° C. for 1 hour.
The filtration of step b is preferably carried out under a vacuum of 40 kPa.
In step c, the procedure is generally carried out by means of 2 to 10 liters of a lower aliphatic alcohol such as methanol or ethanol per 1 kg of starting screened powder. Preferably, 4 liters of ethanol with a titre of 93-95° Gay Lussac are used at a temperature of 60° C. for 1 hour.
The filtration of step d is preferably carried out under a vacuum of 40 kPa.
In step e, per 1 kg of starting screened powder, 750 to 1250 ml of an aqueous ammoniacal solution preferably containing 350 ml of 28% ammonium hydroxide per 1000 ml are generally used. It is particularly advantageous to use 1 liter of the aqueous ammoniacal solution and to carry out the procedure for 10 to 30 hours and, preferably, 20 hours at a temperature close to 20° C.
In step f, the wet ammoniacal mass obtained from 1 kg of starting screened powder is generally taken up, with stirring, in 2 to 10 liters of a lower aliphatic alcohol-water mixture (methanol or ethanol for example) (70/30 to 80/20 by volume) and, preferably, in 5 liters of an ethanol-water mixture (75/25 by volume), at 60° C. for 1 hour.
In step g, the filtration is preferably carried out on a cotton cloth and under a vacuum of about 80 kPa.
In step h, the washing is generally carried out with 500 to 1500 ml of a lower aliphatic alcohol (methanol or ethanol for example) per 1 kg of starting screened powder and, preferably, with 1 liter of ethanol and the filtration is carried out on a cotton cloth and under a vacuum of about 80 kPa.
In step i, the drying is preferably carried out in the open air and protected from light.
The present invention also relates to the process for preparing the mixture II.
The mixture I obtained above is subjected to the following operations:
j—treatment of the mixture I by means of a water-lower aliphatic alcohol solution,
k—decantation and then, on the one hand, drawing off the top phase which is filtered to give the filtrate 1 and, on the other hand, treating the bottom phase with water and filtration to give the filtrate 2, pooling of the filtrates 1 and 2 and concentration to aqueous phase,
l—treatment with a nonpolar adsorbent resin and then filtration,
m—concentration of the filtrate, filtration and then ultrafiltration,
n—freeze-drying and isolation of the extract II.
In step j, 10 to 25 liters of the water-lower aliphatic alcohol solution (methanol or ethanol for example) (95/5 to 90/10 by volume) are generally used per 1 kg of the mixture I. It is preferable to carry out the procedure in 18 liters of a water-ethanol solution (17.7-0.93 by volume).
In step k, it is preferable to filter the top phase on a cotton cloth. It is advantageous to add, per 1 kg of the mixture I, 10 to 25 liters of water to the bottom phase and in particular 10 liters and to filter on sintered glass.
In step k, the concentration is generally carried out in a thermosiphon concentrator at a temperature of 35° C. under a vacuum of 0.4 kPa.
In step l, S861 resin or XAD-type resins marketed by Rhom and Hass are preferably used and the mixture is filtered on sintered glass.
In step m, the concentration is generally carried out in a thermosiphon concentrator at a temperature of 35° C. under a vacuum of 0.4 kPa. It is also advantageous to carry out 3 successive ultrafiltrations on 10 kd, 3 kd and 1 kd cartridges.
The present invention also relates to the process for preparing sodium oxamate and the compounds of formula (I).
The said process consists in subjecting the mixture II to the following operations:
o—chromatography of the mixture II on an infusorial earth column, recovery of the fractions containing the 4 products and pooling of these fractions into a single fraction,
p—chromatography of the fraction previously obtained on a Sephadex® column in order to obtain sodium oxamate, the compound of formula (I) for which R
1
represents a hydrogen atom and R
2
represents a residue (B) and a mixture of the compound of formula (I) for which R
1
represents a hydrogen atom and R
2
represents a residue (A) and of the compound of formula (I) for which R
1
represents a residue (A) and R
2
represents a hydrogen atom,
q—optionally, chromatography of the mixture of the compound of formula (I) for which R
1
represents a hydrogen atom and R
2
represents a residue (A) and of the compound of formula (I) for which R
1
represents a residue (B) and R
2
represents a hydrogen atom by HPLC.
The chromat

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