Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-11-19
1998-05-05
Ketter, James
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435120, 435127, 530338, 540456, 540460, 540461, 540472, 549200, C07D26722, C07D24504
Patent
active
057473030
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new compounds of formula: ##STR2## to their salts, to their preparation and to their use.
In the formula (I), R represents a hydroxyl, alkyloxy, phenylalkyloxy or --NH--CH.sub.2 --COOH radical, R' and R" are identical and each represent a hydroxyl or methoxy radical and R'" represents a hydrogen, bromine, chlorine or iodine atom or a nitro radical.
In the preceding and following definitions, the alkyl and alkyloxy radicals and portions contain 1 to 4 carbon atoms in a straight or branched chain, Arg means arginine, Lys means lysine, Pro means proline, Fmoc means 9-fluorenylmethoxycarbonyl, Pmc means 2,2,5,7,8-pentamethylchroman-6-sulphonyl and Boc means tert-butoxycarbonyl.
The compound of formula (I) in which R, R' and R" represent a hydroxyl radical and R'" represents a hydrogen atom can be prepared by fermentation of A9738 actinomycetes (CBS 162.94) and isolation of the product.
The fermentation is carried out according to conventional fermentation processes. A medium comprising peptone, a yeast extract, a meat extract, glucose, calcium carbonate, sodium chloride and agar is preferably used as culture medium. This fermentation is preferably carried out at a temperature of between 25.degree. and 30.degree. C. The broth is then extracted and the aqueous phase ultrafiltered and chromatographed a number of times.
The compounds of formula (I) in which R represents an alkyloxy or phenylalkyloxy radical can be prepared by esterification of a corresponding compound of formula (I) in which R represents a hydroxyl radical.
This esterification is preferably carried out by reaction of an alcohol R--OH, in which R represents an alkyl or phenylalkyl radical, either in the presence of thionyl chloride, according to the method described by M. E. Jung et al., Tetrahedron Letters, 30(32), 4211-4 (1989), or in the presence of sulphuric acid or gaseous hydrochloric acid, at a temperature of between 0.degree. and 25.degree. C., or when R represents a benzyloxy radical, in the presence of para-toluenesulphonic acid, according to the method described by T. E. Walker et al., J. Org. Chem., 51, 1175-9 (1986). The tert-butyl ester can also be obtained by reaction with isobutene according to the process described in U.S. Pat. No. 3,496,219.
The compounds of formula (I) in which R represents an --NH--CH.sub.2 --COOH radical can be prepared by reaction with glycine of a corresponding compound of formula (I) in which R represents a hydroxyl radical.
It is particularly advantageous to use the compound of formula (I) in the activated form. Mention may be made, as activated form, of the reaction product of the compound of formula (I) with N-hydroxysuccinimide, H-benzotriazol-1-yl!-1,1,3,3-tetramethyluronium hexafluoromethylphosphate, which can be prepared in an inert solvent, such as an amide such as dimethylformamide or N-methyl-2-pyrrolidone, a chlorinated solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran or a mixture of these solvents, at a temperature of between 15.degree. and 60.degree. C., in the presence of 4 .ANG. molecular sieve or of a coupling agent such as dicyclohexylcarbodiimide or alternatively a pentafluorophenyl ester which can be prepared according to the method described by L. Kisfaludy et al., Synthesis, 325-327 (1983).
The condensation is generally carried out under the same temperature and reaction mixture conditions as those described above for the preparation of the activated form of the compound of formula (I), optionally in the presence of pyridine or of an amine such as diisopropylethylamine. These reactions can be carried out without isolating the activated product.
The compounds of formula (I) in which R' and R" represent methoxy radicals can be prepared by reaction with trimethylsilyldiazomethane of a corresponding compound of formula (I) in which R' and R" represent hydroxyl radicals. When R represents an unprotected hydroxyl radical, a compound of formula (I) is obtained in which R, R' and R" are methoxy radicals.
This reaction is carried
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Debernard Jean-Jacques
Dubertret Catherine
Helynck Gerard
Leboul Jean
Martin Jean-Paul
Ketter James
Martin Michael B.
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Savitzky Martin F.
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