Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-01-04
1994-07-05
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
540453, 540456, A61K 3142, C07D49816
Patent
active
053267826
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel salts of 26-[(2-dialkylaminoalkyl)sulphonyl ]pristinamycin II.sub.B.
26-[(2-Dialkylaminoalkyl)sulphonyl ]pristinamycin II.sub.B of formula ##STR1## in which Alk represents a linear or branched alkylene radical and R represents linear or branched alkyl radicals, these radicals containing 1 to 10 carbon atoms, are products known for their antibacterial activity and their synergistic action on the antibacterial activity of pristinamycin I.sub.A and its derivatives as has been described in European Patent 191 662.
BACKGROUND OF THE INVENTION
However, the oxidation processes which lead to this sulphone are not always totally satisfactory given that they often lead to an impure product. It is necessary to carry out subsequent purifications, in particular by chromatography, in order to arrive at a product of satisfactory quality.
Moreover, a limited choice of solvents may be used for treating these products. The salts hitherto prepared were soluble in chlorinated solvents or ketones, solvents normally employed for the treatment of pristinamycin II.sub.B sulphones. No acid has allowed until now the preparation of salts which precipitate in the solvents employed.
DESCRIPTION OF THE INVENTION
It has now been found that salts derived from tartaric acid such as di-p-toluoyltartrate, di-t-butylacetyltartrate, dibutyryltartrate and di-i-valeryltartrate of 26-[(2-dialkylaminoalkyl)sulphonyl ]-pristinamycin II.sub.B are salts which are very insoluble in organic solvents and/or which easily precipitate and as a result make it possible to carry out the purification of this sulphone with very good results.
The salts mentioned above are obtained by salification with the corresponding acid.
The reaction is carried out under the conditions normally used, which do not modify the rest of the molecule. It is carried out in a chlorinated solvent, in particular in methylene chloride, dichloroethane, chloroform, trichloroethylene or tetrachloroethane, or in a ketone, in particular methyl ethyl ketone, at a temperature of between 10.degree. and 25.degree. C.
The salts according to the invention may be reconverted the usual methods in order to release the starting base thus purified.
The novel salts according to the invention are particularly useful by virtue of their insolubility which makes it possible to overcome the purification problems which hitherto existed.
In addition, tartaric acid derived salts of 26-[(2-dialkylaminoalkyl)sulphonyl]pristinamycin II.sub.B furthermore exhibit antibacterial properties and synergistic properties on the antibacterial activity of pristinamycin I.sub.A, virginiamycin S and soluble derivatives of pristinamycin I.sub.A and virginiamycin S, previously described in particular in U.S. Pat. Nos. 4,798,827 and 4,618,599.
In vivo, they synergize the antimicrobial activity of pristinamycin I.sub.A in experimental infections of mice with Staphylococcus aureus IP 8203 at a dose of about 75 mg/kg by the oral route (combination 30/70).
Their toxicity is higher than 750 mg/kg by the subcutaneous route.
EXAMPLES
The following examples illustrate the preparation of the products according to the invention.
EXAMPLE 1
A solution of 10.861 g of di-p-toluyltartaric acid (26.05 mmol) in 180 cm.sup.3 of dichloromethane is cooled at 15.degree. C. in a 500 cm.sup.3 single-necked round-bottomed flask. A solution of 24 g of crude 26-[(2-diethylaminoethyl)sulphonyl]pristinamycin II.sub.B (26S) (sulphone assay=74.3%) is introduced over 22 minutes into 180 cm.sup.3 of dichloromethane while stirring the mixture which becomes cloudy after addition of 60% of this solution and becomes completely clear again at the end of the addition. The mixture of these two solutions is slightly exothermic. 10 minutes after the end of the addition, the salt begins to crystallize. After 3 hours, it is filtered, washed with 3 times 20 cm.sup.3 of dichloromethane and dried under reduced pressure.
23.37 g of salt assaying at 100%, or an actual yield of 82.6%, are thus obtained
REFERENCES:
patent: 4775753 (1985-10-01), Barriere et al.
patent: 4866172 (1989-09-01), Chatterjee et al.
patent: 4931557 (1990-06-01), Brennan et al.
Barriere Jean-Claude
Corbet Jean-Pierre
Paris Jean-Marc
Radisson Xavier
Bond Robert T.
Rhone-Poulenc Rorer S.A.
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