Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1993-01-04
1994-05-10
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D47114, A61K 31395
Patent
active
053109007
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
Streptogramins are known products mentioned, in particular, by J. Preud'homme et al., Bull. Soc. Chim. Fr., 2, 585-91 (1968) or by C. Cocito, Antibiotics, 296 (1983).
In U.S. Pat. No. 4,618,599 and U.S. Pat. No. 4,798,827, soluble derivatives of pristinamycin I.sub.A and of virginiamycin S have been described.
The present invention relates to the preparation of streptogramin derivatives of general formula: ##STR2## and to their salts, their preparation [sic] and their use.
BACKGROUND OF THE INVENTION
In the general formula (I), the symbol R represents a methyl or ethyl radical and the symbol Y represents a hydrogen atom or a methylamino or dimethylamino radical or a radical of structure: ##STR3## in which R' is an amino-protecting radical.
As an example, R' may advantageously be selected from trifluoroacetyl, benzyloxycarbonyl, 2-propenyloxycarbonyl, nitrobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or o-nitrobenzyloxyacetyl.
DESCRIPTION OF THE INVENTION
According to the invention, the streptogramin derivatives of general formula (I) may be obtained by reductive cleavage of a streptogramin of general formula: ##STR4## in which Y and R are defined as above.
The reductive cleavage is carried out by treatment in an acid medium in the presence of a reducing metal.
The reaction is performed in a strong acid medium, at a pH below 2, in the presence of a reducing metal whose redox potential is less than -0.94 V (s.c.e.). The procedure is carried out in an aqueous medium, or in an aqueous-alcoholic medium (for example in a water/methanol or water/ethanol mixture), at a temperature of between -10.degree. and 60.degree. C. The acid may be selected from sulphuric, hydrochloric, hydrobromic, trifluoroacetic or methanesulphonic acid.
As an example, the reducing metal may be advantageously selected from zinc, magnesium, aluminium or sodium amalgam. It is preferable to work under nitrogen.
According to the invention, the streptogramin derivatives of general formula (I) may also be prepared by electrochemical reduction in an acid medium of a streptogramin derivative of general formula (II).
Controlled-potential electrolysis is carried out in aqueous or aqueous-alcoholic acid solution containing up to 50% of alcohol (for example methanol or ethanol), at a temperature of between 0.degree. and 60.degree. C., with constant stirring and under a nitrogen atmosphere, in an electrolysis cell in which the cathode consists of a bed of mercury. The potential of the working electrode E is such that -0.9>E>-1.1 V (s.c.e.).
The acid is advantageously selected from hydrochloric, hydrobromic or sulphuric acid.
The products obtained by the process according to the invention are especially advantageous as intermediates for the preparation of biologically active streptogramin derivatives.
More specifically, they serve as intermediates for obtaining new streptogramin derivatives of general formula: ##STR5## in which Y and R are defined as above and R.sub.1 represents a phenyl or pyridyl radical monosubstituted with a linear or branched alkyl radical containing 2 to 6 carbon atoms or with a trifluoromethyl radical, or represents a phenyl radical disubstituted with linear or branched alkyl radicals containing 1 to 6 carbon atoms or with nitro radicals, or represents a naphthyl radical or a quinolyl radical substituted with a halogen atom, which enable the resistance of tumors to anticancer substances to be eliminated, and are especially advantageous as agents associated with cancer treatment.
The products of general formula (III) may be obtained by the action of an acid of general formula: acid, on a product of general formula (I).
When a reactive derivative is reacted, the latter may be selected from the anhydride, a mixed anhydride, an acid halide or a reactive ester.
The reaction is performed in an organic medium, optionally in the presence of an acid-acceptor such as a nitrogenous organic base (for, example a trialkylamine, a pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazab
Barriere Jean-Claude
Dubroueucq Marie-Christine
Fleury Maurice
Largeron Martine
Paris Jean-Marc
Bond Robert T.
Rhone-Poulenc Rorer S.A.
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