Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

• Streptogramins are known products and mentioned in particular by J. Preud 'Appel et al., Bull. Soc. Chim. Fr., 2, 585-91 (1968) or by C. Cocito, Antibiotics, 296 (1983).
• the present invention relates to the preparation of streptogramin derivatives of general formula:
• R represents a methyl or ethyl radical and the symbol Y represents a hydrogen atom or a methylamino, dimethylamino radical or a radical of structure:
• R ' is a protective amino radical
• R ′ can advantageously be chosen from, trifluoroacetyl, benzyloxycarbonyl, propene-2 yloxycarbonyl, nitrobenzyloxycarbonyl, fluorenyl-9 methyloxycarbonyl or o.nitrobenzyloxyacetyl.
• the streptogramin derivatives of general formula (I) can be obtained by reductive cleavage of a streptogramin of general formula:
• the reductive cleavage is implemented by treatment in an acid medium, in the presence of a reducing metal.
• the reaction is carried out in a strong acid medium, at a pH of less than 2, in the presence of a reducing metal whose redox potential is less than -0.94V (e.c.s.).
• the operation is carried out in an aqueous medium, or in an alcoholic medium (for example in a water-methanol or water-ethanol mixture), at a temperature between -10 and 60 ° C.
• the acid can be chosen from sulfuric, hydrochloric, hydrobromic, trifluoroacetic or methanesulphonic acids.
• the reducing metal can be advantageously chosen from zinc, magnesium, aluminum or sodium amalgam. Preferably one operates under nitrogen.
• the streptogramin derivatives of general formula (I) can also be prepared by electrochemical reduction in acid medium of a strepf ⁇ gramine derivative of general formula (II).
• Electrolysis with controlled potential is carried out in aqueous or hydroalcoholic acid solution containing up to 50% alcohol (methanol or ethanol for example) at a temperature between 0 and 60 ° C, with constant stirring and under a nitrogen atmosphere , in an electrolysis cell in which the cathode consists of a sheet of mercury.
• the potential of the working electrode E is such that -0.9> E> -1.1 V (e.c.s).
• the acid is advantageously chosen from hydrochloric, hydrobromic or sulfuric acids.
• the products obtained by the process according to the invention are particularly advantageous as intermediates for the preparation of biologically active streptogramin derivatives.
• R 1 represents a phenyl or pyridyl radical monosubstituted by a straight or branched alkyl radical containing 2 to 6 carbon atoms or by a radical trifluoromethyl, or represents a phenyl radical disubstituted by straight or branched alkyl radicals containing 1 to 6 carbon or nitro atoms, or represents a naphthalenyl radical or a quinolyl radical substituted by a halogen atom, which make it possible to suppress the resistance of tumors anticancer substances, and are particularly interesting as agents associated with cancer treatments.
• the products of general formula (III) can be obtained by the action of an acid of general formula: R 1 -COOH (IV) in which R 1 is defined as above, or of a reactive derivative of this acid, on a product of general formula (I).
• the latter can be chosen from anhydride, a mixed anhydride, an acid halide or a reactive ester.
• the reaction is carried out in an organic medium, optionally in the presence of an acid acceptor such as an organic nitrogenous base (a trialkylamine, a pyridine, N-methylmorpholine, 1,8-diaza bicyclo [5.4.0] undecene-7, diaza-1,5 bicyclo [4.3.0] nonene-5 for example) in your organic solvent such as a chlorinated solvent (methylene chloride, dichlorethane, chloroform for example), an amide (dimethylformamide for example ), an oxide (dimethyl sulfoxide for example), a ketone (acetone for example) or an ether (tetrahydrofuran for example), at a temperature between -20 and 60 ° C.
• an acid acceptor such as an organic nitrogenous base (a trialkylamine, a pyridine, N-methylmorpholine, 1,8-diaza bicyclo [5.4.0] undecene-7, diaza-1,5 bicyclo [4.3.0] nonene-5 for example)
• a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide, ethyl-1 hydrochloride (3-dimethylamino-propyl) -3 carbodiimide for example) and optionally in the presence of a catalyst such as hydroxybenzotriazole, in a solvent mentioned above, or in the presence of a carbonate or a bicarbonate of alkali or alkaline earth metal at the temperature defined above.
• a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide, ethyl-1 hydrochloride (3-dimethylamino-propyl) -3 carbodiimide for example)
• a catalyst such as hydroxybenzotriazole
• the salts can be addition salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or with organic acids such as acetates, propionates, succinates, maleates, fumarates, methanesulfonates, tartrate, camphosulfonate or substitution derivatives of these compounds.
• mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or with organic acids such as acetates, propionates, succinates, maleates, fumarates, methanesulfonates, tartrate, camphosulfonate or substitution derivatives of these compounds.
• the products of general formula (III) prepared from the products according to the invention are agents capable of maintaining the chemosensitivity of tumors, or of restoring the chemosensitivity of tumors which have become resistant.
• RPMI 1640 containing 10% fetal calf serum The tubes are incubated with the products to be tested, at different concentrations and at
• the results are expressed by the IC 50 ( ⁇ M).
• the IC 50 corresponds to the concentration of product making it possible to obtain 50% of cytotoxicity due to doxorubicin, that is to say to a concentration of non-cytotoxic product by itself.
• the products of general formula (III) have been shown to be active at concentrations of between 0.2 and 2 ⁇ M.
• streptogramin derivatives are slightly toxic: they have generally been shown to be non-toxic at doses of 200 mg / kg subcutaneously in mice.
• the pH of the reaction mixture is adjusted to a value close to 4 by slow addition of 110 cm 3 of a 10N aqueous solution of sodium hydroxide.
• the organic phase is decanted, the aqueous phase is extracted with 500 cm of dichloromethane then the combined organic phases are filtered through a bed of Supercel.
• the filtrate is washed with 3 times 100 cm 3 of distilled water, dried over sodium sulfate, filtered and then concentrated to a volume of 500 cm under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C.
• the solution obtained is deposited on a column of 7 kg of silica gel (diameter: 15 cm, height: 92 cm).
• the column is eluted with a dichloromethane / methanol mixture (97/3 by volume), making fractions of 1.5 liters.
• the fractions 7 to 13 are concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C, the residue obtained is triturated for 2 hours in 400 cm 3 of pentane, filtered and then dried under reduced pressure ( 0.27 kPa) at a temperature in the region of 20 ° C.
• 66 g of dice (3-hydroxy-picolinoyl) pristinamycin IA are thus obtained in the form of a white powder melting at around 206 ° C.
• EXAMPLE 2 To a solution of 10 g of virginiamycin S1 in your mixture of 200 cm 3 of methanol and 50 cm of a 5N aqueous solution of hydrochloric acid, maintained under a nitrogen atmosphere, 5 g of zinc is added. powder. The gray suspension obtained is stirred for 1 hour at a temperature in the region of 20 ° C. The pH of the reaction mixture is then 1.2, it is then adjusted to 5 by adding 100 cm 3 of a 1N aqueous solution of sodium hydroxide. The mixture is extracted with 3 times 300 cm of dichloromethane; the combined organic phases are dried over sodium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C.
• the electrolysis is carried out by means of a 3-electrode assembly.
• the electrolysis cell consists of a set of ground glassware, the anode and cathode compartments being concentric and separated by a wall of sintered glass of porosity 7.
• Tacussel IG5 N complete the circuit.
• the working electrode is a sheet of mercury whose area is equal to 60 cm 2 .
• the auxiliary electrode is a platinum blade.
• the reference electrode is a calomel electrode with saturated potassium chloride solution (e.c.s.).
• Example 7 By operating as described above in Example 3, but on a sheet of mercury whose potential is fixed at -0.9 V DHW, we proceed to the electrolysis of 0.35 g of pristinamycin I A in 200 cm 3 d hydrochloric acid 1N. 0.09 g of dice (3-hydroxy-picolinoyl) pristinamycin IA is obtained, the characteristics of which are identical to those of the product obtained in Example 1.
• Example 7
• Dice (3-hydroxy-picolinoyl) pristinamycin I can be obtained as described in Example 1, but starting from 1 g pristinamycin I C , 25 cm 3 of a 1N aqueous solution of hydrochloric acid and 0.5 g zinc powder. 0.8 g of a residue is thus obtained which is purified by flash chromatography (eluent: methylene chloride, methanol 98/2 by volume), collecting 10 cm 3 fractions. Fractions 19 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 0.3 g of dice (3-hydroxy-picolinoyl) is thus obtained pristinamycin I in the form of a white powder.
• the dice (3-hydroxy-picolinoyl) pristinamycin I can be obtained as described in Example 1 but from 1 g of pristinamycin I B , 25 cm 3 of a 1N aqueous solution of hydrochloric acid and 0.5 g zinc powder. 0.8 g of a residue is thus obtained which is purified by flash chromatography (eluent: methylene chloride, methanol 98/2 by volume), collecting 10 cm 3 fractions. Fractions 18 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. Aaiinnssii 00 is obtained,, 22 gg of dedees ((hhyytdroxy-3 picolinoyl) pristinamycin I in the form of a white powder.
• Dice (3-hydroxy-picolinoyl) trifluoroacetyl-4N pristinamycin I B can be obtained as described in Example 2 but from 0.68 g of trifluoroacetyl-4N pristinamycin I B , 2.8 cm 3 of an aqueous solution 5N hydrochloric acid in 14 cm 3 of methanol and 0.34 g of zinc powder in 14 cm 3 of methanol.
• Trifluoroacetyl-4N pristinamycin I B is obtained in the following manner:
• 0.43 cm of chloride is added simultaneously to a solution of 1.5 g of dice (3-hydroxy picolinoyl) pristinamycin IA in 25 cm of methylene chloride maintained at 5 ° C. 4-tert-butyl benzoyl dissolved in 5 cm 3 of methylene chloride and 0.34 cm 3 of triethylamine.
• the reaction mixture is then stirred for 2 hours at a temperature in the region of 20oC, then 20 cm 3 of distilled water are added.
• the organic phase is decanted, the aqueous phase is extracted twice with 25 cm 3 of methylene chloride, the combined organic phases are washed with 20 cm 3 of distilled water and then dried over magnesium sulfate.
• 4-T-butyl benzoyl chloride can be prepared according to the method described by F. Bell and R.D. Wilson, J. Chem. Soc. 2340 (1956). Usage example 2
• the organic phase is decanted, the aqueous phase is extracted twice with 20 cm 3 of methylene chloride, the combined organic phases are washed with 20 cm 3 of distilled water and then dried over sodium sulfate. After filtration and then concentration to dryness under reduced pressure (2.7 kPa) at 30 ° C of the organic phases, 2.07 g of a residue is obtained which is purified by flash chromatography (eluent: ethyl acetate) by collecting fractions of 10 cm 3 . Fractions 61 to 131 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. 1.25 g of
• the organic phase is decanted and washed with 50 cm 3 of a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, filtration then concentration to dryness under reduced pressure (2.7 kPa) at a temperature close to 30 ° C., 1.8 g of residue are obtained which is purified by flash chromatography (eluent: 1.2 dichloroethane / methanol 97/3 by volume), collecting 60 cm 3 fractions. The residue obtained after dry concentration under reduced pressure (2.7 kPa) at a temperature in the region of 30 ° C of fractions 12 to 16 is triturated in a mixture of 50 cm 3 of ethyl ether and 100 cm 3 of pentane.
• the solid is filtered and dried at a temperature in the region of 20 ° C, thus obtaining 0.75 g of (5-butyl picolinoyl) -1 from (3-hydroxy picolinoyl) pristinamycin IA in the form of a white powder melting at 165 ° C.
• Example of use 6 By operating in a manner analogous to that described in Example 1, but starting from 1.5 g from (3-hydroxy picolinoyl) pristinamycin IA, 0.63 cm 3 of triethylamine and 0 , 91 g of 2-chloro-quinolinecarboxylic acid-4 chloride and after purification by flash chromatography (eluent: dichloromethane / methanol 98/2 by volume), collecting 30 cm 3 fractions and concentration to dryness under reduced pressure (2 , 7 kPa) fractions 10 to 15 at a temperature close to 30oC, 1.02 g of (2-chloro-quinolyl-4) carbonyl-1 is obtained from (3-hydroxy-picolinoyl) pristinamycin IA in the form of a white powder melting at a temperature above 260 ° C.
• the chloride of 2-chloro-quinolinecarboxylic-4 acid can be prepared according to the method described by B. Mulert, Chem. Ber., 39, 1901 (1906).
• Example of use 9 By operating in a manner analogous to that described in Example 1, but from 1 g from (3-hydroxy-picolinoyl) virginiamycin S1, 0.31 cm 3 of triethylamine and 0.64 g of 2-chloro-quinolinecarboxylic acid-4 chloride and after purification by flash chromatography (eluent: dichloromethane / methanol 98/2 by volume), collecting fractions of 10 cm 3 and dry concentration under reduced pressure (2.7 kPa) of fractions 15 to 35 at a temperature in the region of 30 ° C, 0.85 g of (2-chloro-4-quinolyl) carbonyl-1 is obtained from (hydroxy -3 picolinoyl) virginiamycin S1 in the form of a white powder melting at a temperature above 260 ° C.

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• Preparation Of Compounds By Using Micro-Organisms (AREA)
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• 1990
  • 1990-07-19 FR FR9009235A patent/FR2664894A1/fr active Granted
• 1991
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  • 1991-07-18 CA CA002087535A patent/CA2087535A1/fr not_active Abandoned
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  • 1991-07-18 DK DK91913610.1T patent/DK0539486T3/da active
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  • 1991-07-18 JP JP3512352A patent/JPH05509091A/ja active Pending
  • 1991-07-18 WO PCT/FR1991/000590 patent/WO1992001691A1/fr not_active Ceased
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