Streptogramin derivatives, their preparation and pharmaceutical

Details Streptogramin derivatives, their preparation and pharmaceutical Streptogramin derivatives, their preparation and pharmaceutical

1997-01-31

1998-07-28

Hill, Jr., Robert J.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

514 9, 514 11, A61K 3812, C07K 500, C07K 700, C07K 1700

Patent

active

057864497

DESCRIPTION:

BRIEF SUMMARY
This application is a national stage application filed under 35 U.S.C. .sctn. 371 and claims priority of International application number PCT/FR95/01025, filed Jul. 31, 1995.
The present invention relates to streptogramin derivatives of general formula: ##STR2## in which the radical R.sub.1 denotes a methyl or ethyl radical, alkenyl radical containing 3 to 5 carbon atoms if R.sub.3 and R.sub.4 are methyl radicals and radical and, the other, a methyl radical.
Soluble derivatives belonging to the group B of streptogramins were described previously in European Patent Applications EP 133 097 and EP 248 703. However, by themselves or used in combination with a synergizing component of group A, these derivatives are active only by injectable route and are not, or not very, active orally.
The derivatives of the general formula (I) which are defined above thus open the way to new streptogramins intended for an oral treatment.
According to the invention the streptogramins of general formula (I) in the case of which R.sub.2 is a chlorine or bromine atom can be obtained by the action of the corresponding N-halosuccinimide derivative on pristinamycin I in the case of which R.sub.2 is a hydrogen atom.
The reaction is performed by means of N-chloro- or N-bromosuccinimide in an organic solvent like, for example, a chlorinated solvent (dichloromethane, dichloroethane, chloroform) or a nitrile (acetonitrile), at a temperature of between 20 and the reflux temperature of the solvent employed.
According to the invention the streptogramins of general formula (I) in the case of which R.sub.2 is an alkenyl radical containing 3 to 5 carbon atoms can be obtained by rearrangement in a slightly basic medium of a salt derived from 4-N-alkenylammonio pristinamycin IA of general formula: ##STR3## in which R.sub.1 is defined as above, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are a hydrogen atom or a methyl radical, provided that at least 2 of them are hydrogen atoms, and X.sup..THETA. denotes an anion, to give the derivative of general formula: ##STR4## in the case of which R.sub.1, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are defined as above.
The reaction is performed by heating at a temperature of between 80.degree. and 100.degree. C. in an aqueous or two-phase medium (for example in ethyl acetate/water medium) in the presence of sodium acetate or of sodium or potassium bicarbonate. A halide of 4-N-alkenylammonio pristinamycin IA is advantageously employed.
The halide of 4-N-alkenylammonio pristinamycin IA can be obtained by the action of an alkenyl halide of general formula: ##STR5## in the case of which R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are defined as above and Hal denotes a halogen atom, on a pristinamycin derivative of general formula: ##STR6## in which R.sub.1 is defined as above.
The reaction is advantageously performed in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform) or an alcohol (for example ethanol) or in a mixture, at a temperature of between 20.degree. C. and the reflux temperature of the reaction mixture. Preferably, a product of general formula (IV) in the case of which Hal is a chlorine or bromine atom is reacted.
The products of general formula (V) are known products, which are described by J. Preud'Homme, P. Tarridec, and A. Belloc, Bull. Soc. Chim. Fr., 2, 585 (1968).
The new streptogramin derivatives of general formula (I) can be purified, if appropriate, by physical methods such as crystallization or chromatography.
The streptogramin derivatives according to the present invention exhibit antibacterial properties and properties of synergizing the antibacterial activity of the derivatives of pristinamycin II.
In vivo, it has been shown that they synergize the antimicrobial activity of pristinamycin II.sub.B on the experimental infections of the mouse with Staphylococcus aureus IP 8203 in doses of between 30 and 150 mg/kg orally (30/70 combination).
Their toxicity (LD50) is higher than 1000 mg/kg orally.
The following examples illustrate the preparation of th

REFERENCES:
patent: 4617290 (1986-10-01), Corbet et al.
Preud'Homme et al., "Pristinamycine Isolement, Caracterisation et identification des Constituants," Bulletin de la Societe Chimique de France, No. 2, pp. 585-591.
Certified English Translation of above-listed article by Preud'Homme et al., "Pristinamycin: Isolation, Characterization and Identification of the Constituents".

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