Patent EA-005199-B1 (EA)
Title: Streptogramin derivatives, preparation and compositions containing them
Inventor: ACHARD DANIEL
IPC: C07K5/078
Filed: 2000-06-29
Abstract: 1. Group A streptogramin derivative of the formula: in which R1 represents a halogen atom or an azido or thiocyanato radical, R2 represents a hydrogen atom or a methyl or ethyl radical, R3 represents a hydrogen atom, or a radical R'3-CO- for which R'3 is phenyl or phenylalkyl which are unsubstituted or which are substituted on the phenyl radical [with one or more radicals chosen from alkyl, optionally carrying a radical NR'R'' in which the radicals R' and R'', which are identical or different, may be hydrogen atoms or alkyl radicals which can form together with the nitrogen atom to which they are attached a 3- to 8-membered saturated or unsaturated heterocyclyl radical optionally comprising another heteroatom chosen from oxygen, sulfur or nitrogen, it being possible for the said heterocycle itself to be substituted with one or more radicals (alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, phenyl, aryl, heterocyclyl, heterocyclylalkyl, which are saturated or unsaturated and have 3 to 8 members, or -CH2-CO-NR'R''), or alternatively R' and/or R'' may be a hydroxyalkyl radical, a phenyl radical, a 3- to 8-membered saturated or unsaturated heterocyclylalkyl radical, a radical -CO-NR'R'' for which NR'R'' is as defined above, or alkyl or acyl radicals which are substituted with NR'R'' which is as defined above], or alternatively R'3 may be chosen from phenyl or phenylalkyl radicals which are substituted on the phenyl radical with one or more radicals [chosen from alkyl, which may be substituted with an alkyloxy or alkylthio radical optionally carrying themselves a carboxyl radical or a radical NR'R'' as defined above, or chosen from acyloxy which may be substituted with NR'R'' as defined above], or alternatively R'3 may be chosen from alkyl or cycloalkyl radicals which are optionally substituted [with a carboxyl radical, a carboxyalkyldisulfanyl radical or with a radical NR'R'', -CH2-NR'R'', or -CO-NR'R'', or with an alkyloxycarbonyl, alkyloxy or alkyldisulfanyl radical which are optionally substituted with NR'R'' or -CO-NR'R'' for which NR'R'' is as defined above], or alternatively R'3 may be chosen from 3- to 8-membered saturated or unsaturated heterocyclyl radicals which are optionally substituted [with alkyl or acyl which are themselves optionally substituted with NR'R'']; provided that alkyl and aryl radicals or alkyl or acyl parts of radicals are linear or branched and contain 1-12 carbon atoms; the bond ---- represents a single bond (stereochemistry 27R) or a double bond, as well as its salts when they exist. 2. Group A streptogramin derivative according to claim 1, in which R1 represents a fluorine, chlorine, bromine or iodine atom or an azido or thiocyanato radical, R2 represents methyl radical; R3 represents a hydrogen atom, or a radical R'3-CO- for which R'3 is phenyl or phenylalkyl which are unsubstituted or which are substituted on the phenyl radical [with one or more radicals chosen from alkyl, optionally carrying a radical NR'R'' in which the radicals R' and R'', which are identical or different, may be hydrogen atoms or alkyl radicals which can form together with the nitrogen atom to which they are attached a 3- to 8-membered saturated or unsaturated heterocyclyl radical optionally comprising another heteroatom chosen from oxygen, sulfur or nitrogen, it being possible for the said heterocycle itself to be substituted with one or more radicals (alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, phenyl, aryl, heterocyclyl, heterocyclylalkyl, which are saturated or unsaturated and have 3 to 8 members, or -CH2-CO-NR'R''), or alternatively R' and/or R'' may be a hydroxyalkyl radical, a phenyl radical, a 3- to 8-membered saturated or unsaturated heterocyclylalkyl radical, a radical -CO-NR'R'' for which NR'R'' is as defined above, or alkyl or acyl radicals which are substituted with NR'R'' which is as defined above], or alternatively R'3 may be chosen from phenyl or phenylalkyl radicals which are substituted on the phenyl radical with one or more radicals [chosen from alkyl, which may be substituted with an alkyloxy or alkylthio radical optionally carrying themselves a carboxyl radical or a radical NR'R'' as defined above, or chosen from acyloxy which may be substituted with NR'R'' as defined above], or alternatively R'3 may be chosen from alkyl or cycloalkyl radicals which are optionally substituted [with a carboxyl radical, a carboxyalkyldisulfanyl radical or with a radical NR'R'', -CH2-NR'R'', or -CO-NR'R'', or with an alkyloxycarbonyl, alkyloxy or alkyldisulfanyl radical which are optionally substituted with NR'R'' or -CO-NR'R'' for which NR'R'' is as defined above], or alternatively R'3 may be chosen from 3- to 8-membered saturated or unsaturated heterocyclyl radicals which are optionally substituted [with alkyl or acyl which are themselves optionally substituted with NR'R''], it being understood that the heterocycles are chosen from pyrrolidinyl, imidazolyl, pyridyl, piperidinyl, piperazinyl or morpholinyl, and the bond ---- represents a single bond (stereochemistry 27R) or a double bond, as well as their salts when they exist. 3. Group A streptogramin derivative according to one of claims 1 to 2, characterized in that it is (16R)-16-deoxo-16-fluoropristinamycin IIB. 4. Group A streptogramin derivative according to one of claims 1 to 2, characterized in that it is (16R)-16-deoxo-16-thiocyanatopristinamycin IIB. 5. Group A streptogramin derivative according to one of claims 1 to 2, characterized in that it is (16R)-16-deoxo-16-chloropristinamycin IIB. 6. Group A streptogramin derivative according to one of claims 1 to 2, characterized in that it is (16R)-16-azido-16-deoxopristinamycin IIB. 7. Group A streptogramin derivative according to one of claims 1 to 2, characterized in that it is (16R)-16-deoxo-16-fluoropristinamycin IIA. 8. Process for preparing a group A streptogramin derivative according to claim 1, characterized in that there is halogenated, in that there is converted to an azide or in that there is converted to a thiocyanate, a streptogramin derivative of general formula: in which R2 is as defined above, the bond ---- represents a single bond (stereochemistry 27R) or a double bond, and in which the hydroxyl function at the 14-position has been previously protected, followed by the removal of the protecting radical and where appropriate, in order to obtain a group A streptogramin derivative according to claim 1 or 2, for which R3 is other than a hydrogen atom, introduction of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester residue which may be substituted (R3), and optionally conversion to a salt when they exist. 9. Process according to claim 8, characterized in that the procedure is carried out in the presence of an aminosulfur trifluoride or in the presence of sulfur tetrafluoride, by means of a reagent such as a tetraalkylammonium, trialkylbenzylammonium or trialkylphenylammonium halide, azide or thiocyanate or by means of an alkali metal halide, azide or thiocyanate optionally supplemented with a crown ether. 10. Process according to claim 8, characterized in that the procedure is carried out, for the fluorination, by the action of a fluorinating agent chosen from a sulfur fluoride, hexafluoropropyldiethylamine or N-(2chloro-1,1,2-trifluoro-ethyl)diethylamine. 11. Process according to one of claims 8, 9 or 10, characterized in that, where appropriate, the esterification is carried out by any known method which does not alter the rest of the molecule. 12. Process according to one of claims 8, 9 or 10, characterized in that the aminosulfur trifluoride may be chosen from diethylaminosulfur trifluoride, bis-(2-methoxyethyl)aminosulfur trifluoride or morpholinosulfur trifluoride. 13. Pharmaceutical composition comprising a group A streptogramin derivative according to claim 1, in the pure state or in the form of a combination with at least one group B streptogramin derivative, where appropriate in the form of a salt, and/or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. 14. Pharmaceutical composition according to claim 14, characterized in that the group B streptogramin derivative is chosen from the natural components: pristinamycin IA, pristinamycin IB, pristinamycin IC, pristinamycin ID, pristinamycin IE, pristinamycin IF, pristinamycin IG, virginiamycin S1, S3 or S4, vemamycin B or C, etamycin or from the semisynthetic derivatives of general formula: in which: 1) Rb, Rc, Re and Rf are hydrogen atoms, Rd is a hydrogen atom or a dimethylamino radical, and Ra is a radical of structure -CH2R'a for which R'a is 3-pyrrolidinylthio or 3- or 4-piperidylthio which may be substituted with alkyl, or alkylthio substituted with 1 or 2 hydroxysulfonyl, alkylamino, dialkylamino (itself optionally substituted with mercapto or dialkylamino), or substituted with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or alternatively Ra is a radical of structure -CHR'a for which R'a is 3-pyrrolidinylamino, 3- or 4-piperidylamino, 3-pyrrolidinyloxy, 3- or 4-piperidyloxy, 3-pyrrolidinylthio, 3- or 4-piperidylthio which may be substituted with alkyl, or R'a is alkylamino, alkyloxy or alkylthio substituted with 1 or 2 hydroxysulfonyl, alkylamino, dialkylamino (itself optionally substituted with dialkylamino), or with trialkylammonio, 4- or 5-imidazolyl, or with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or Ra is a 3- or 4quinuclidinylthiomethyl radical, or alternatively 2) Ra is a hydrogen atom and a) either Rb, Re and Rf are hydrogen atoms, Rd is a radical -NHCH3 or -N(CH3)2 and Rc is a chlorine or bromin