Patent EA-004297-B1 (EA)
Title: Streptogramin derivatives, production thereof and compositions containing the same
Inventor: BACQUE ERIC
IPC: C07D498/18
Filed: 2000-07-26
Abstract: 1. A group B streptogramin derivative of general formula: wherein: R is chosen from -NR1R2 and -SR3, wherein R1 and R2, which may be identical or different, are an hydrogen atom, the radical C1-C8-alkyl, which is unsubstituted or substituted with hydroxyl; C3-C8-alkenyl; C3-C8-cycloalkyl; C1-C8-alkyloxy; dialkylamino; phenylalkyl, which is optionally substituted with [one or more halogen atoms or radicals chosen from alkyl hydroxyalkyl, alkyloxy, and dialkylamino], saturated and unsaturated 3- to 8-membered heterocyclylalkyl containing one or more heteroatoms chosen from nitrogen, sulphur and oxygen; or dialkylaminoalkyl; or, alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a ring chosen from 3- to 12-membered, saturated, partially saturated, and unsaturated, monocyclic and polycyclic heterocycles optionally containing at least one additional heteroatom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted [with one or more radicals chosen from hydroxyl; alkyl; phenyl, which is unsubstituted or substituted with a halogen atom; phenylalkyl; phenylalkenyl, (the alkenyl portion having from 2 to 4 carbons), hydroxyalkyl; acyl; alkyloxycarbonyl; and heterocyclyl or heterocyclylcarbonyl, wherein the heterocyclyl portion is 4- to 6-membered, saturated or unsaturated, and contains one or more heteroatoms chosen from oxygen, sulphur, and nitrogen], R3 is C1-C8 -alkyl or C1-C8-cycloalkyl radical, substituted with a radical-NR1R2, wherein R1 and R2, which may be identical or different, are hydrogen and alkyl radical, or form, together with the nitrogen atom to which they are attached, a heterocycle as defined above; or, alternatively, R3 is 3- to 7-membered, saturated and unsaturated, monocyclic and polycyclic, heterocyclyl or heterocyclylmethyl radical, and optionally one more heteroatom, chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with alkyl radical; is an unsaturated ring residue which is unsubstituted at 5gamma or a saturated ring residue which is substituted at 5gamma with a fluoro ; Ra is chosen from methyl and ethyl radicals; and Rb, Rc, and Rd have one of the definitions below: 1) Rb and Rc are both hydrogen; and Rd is hydrogen and methylamino and dimethylamino radical; 2) Rb is hydrogen; Rc is hydrogen, chlorine, and bromine atom, and C3-C5-alkenyl radical; and Rd is a radical -NMe-R''', wherein R''' is chosen from the radicals: alkyl, hydroxy-C2-C4-alkyl, and C2-C8-alkenyl, which are unsubstituted or substituted with phenyl; cycloC3-C6-alkylmethyl; benzyl; and substituted benzyl, which is substituted [with one or more halogen atoms, and hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino and dialkylamino radicals]; and heterocyclylmethyl or heterocyclylethyl, wherein the heterocyclyl portion is saturated or unsaturated and 5- or 6-membered and contains 1 or 2 heteroatoms chosen from sulphur, oxygen, and nitrogen, and which are unsubstituted or substituted with [alkyl radical, C2-C8-alkenyl, cycloalkyl-C3-C6, saturated and unsaturated 4- to 6-membered heterocyclyl, phenyl, substituted phenyl as defined above for the definition of R1, or benzyl radicals]; or, alternatively, R''' is cyanomethyl or carboxymethyl, or -CORe or -CH2CORe, wherein Re is -OR'e, and wherein R'e is C1-C6-alkyl; C2-C6-alkenyl; benzyl; phenyl; tolyl; and heterocyclylmethyl, wherein the heterocyclyl portion is 5- or 6-membered and contains 1 or 2 heteroatoms chosen from sulphur, oxygen and nitrogen; or, alternatively, Re is alkylamino; alkylmethylamino; and heterocyclylamino or heterocyclyl(methyl)amino radicals, wherein the heterocyclyl portion is saturated and 5- or 6-membered and contains 1 or 2 heteroatoms chosen from sulphur, oxygen, and nitrogen, and which are unsubstituted or substituted with a radical chosen from alkyl, benzyl, and alkyloxycarbonyl radicals; 3) Rb is hydrogen; Rd is -NHCH3 and -N(CH3)2 radicals; and Rc is chlorine and bromine atoms, or C3-C5-alkenyl radical [when Rd is -N(CH3)2]; 4) Rb and Rd are both hydrogen; and Rc is halogen atom and alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, C1-C6-alkyl, and trihalomethyl; 5) Rb and Rc are both hydrogen; and Rd is halogen atoms, or ethylamino, diethylamino or methylethylamino, alkyloxy or trifluoromethoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, C1-C6-alkyl, phenyl, and trihalomethyl; 6) Rb is hydrogen; Rc is halogen atom and alkylamino, dialkylamino, alkyloxy or trifluoromethoxy, and thioalkyl radicals, and C1-C3-alkyl; and Rd is halogen atom and amino, alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, C1-C6-alkyl, and trihalomethyl; or 7) Rc is hydrogen; and Rb and Rd are both methyl radicals; with the proviso that, unless specifically defined, the alkyl and acyl radicals are straight or branched and contain from 1 to 4 carbon atoms and that the alkenyl radicals also have a straight or branched chain and contain from 2 to 4 carbon atoms; or a salt thereof. 2. A group B streptogramin derivative according to claim 1, characterized in that R is -NR1R2 or -SR3, wherein: R1 and R2, which may be identical or different, are hydrogen, C1-C8-alkyl, which is unsubstituted or substituted with hydroxyl; C3-C8 alkenyl; C3-C8 cycloalkyl; C1-C8-alkyloxy; dialkylamino; phenylalkyl, which is unsubstituted or substituted [with one or more halogen atoms or alkyl, hydroxyalkyl, alkyloxy, or dialkylamino]; saturated and unsaturated 3- to 8-membered heterocyclylalkyl containing one or more heteroatoms chosen from nitrogen, sulphur and oxygen; or dialkylaminoalkyl; or, alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a ring chosen from 3- to 12-membered, saturated, partially saturated, and unsaturated, monocyclic and polycyclic heterocycles optionally containing at least one additional heteroatom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted [with one or more radicals of hydroxyl; alkyl; phenyl, which is unsubstituted or substituted with a halogen atom; phenylalkyl; hydroxyalkyl; acyl; alkyloxycarbonyl; or heterocyclyl and heterocyclylcarbonyl, wherein the heterocyclyl portion is 4- to 6-membered, saturated or unsaturated, and contains one or more hetero atoms chosen from oxygen, sulphur, and nitrogen]; R3 is C1-C8-alkyl radical, which are substituted with a radical -NR1R2, wherein R1 and R2, which may be identical or different, alkyl radicals or, together with the nitrogen atom to which they are attached, forms a geterocycle, as defined above or R3 is 3-7-membered saturated or unsaturated, monocyclic and polycyclic heterocyclyl or heterocyclylmethyl optionally containing at least one additional heteroatom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with alkyl radical; is an unsubstituted ring residue which is unsubstituted at 5gamma or a saturated ring residue which is substituted at 5gamma with a fluoro ; Ra is an ethyl radical; and Rb, Rc, and Rd have one of the definitions below: 1) Rb and Rc are both hydrogen atoms and Rd is methylamino or dimethylamino radicals; 2) Rb is a hydrogen atom, Rc is hydrogen and chlorine atoms, and Rd is a radical -NMe-R''', wherein R''' is C2-C8-alkenyl and heterocyclylmethyl or -COOR'e, wherein R'e is C1-C6-alkyl, C1-C6-alkenyl, phenyl, and tolyl; 3) Rb is a hydrogen atom, Rd is -NHCH3 and -N(CH3)2 radicals, and Rc is a chlorine atom; or a salt thereof. 3. A group B streptogramin derivative according to claim 1, characterized in that said derivative is 5delta-(1-morpholino)methyl-5delta,5gamma-dehydropristinamycin IE; 4. A group B streptogramin derivative according to claim 1, characterized in that said derivative is 5delta-[N-methyl-N-2-(1,3-dioxolanyl)methyl]aminomethyl-5delta,5gamma-dehydropristinamycin IE. 5. A group B streptogramin derivative according to claim 1, characterized in that said derivative is 5delta-morpholinomethyl-4xi-methylamino-4xi-de(dimethylamino)-5delta,5gamma-dehydropristinamycin IE. 6. A group B streptogramin derivative according to claim 1, characterized in that said derivative is 5delta-morpholinomethyl-4xi-methylamino-4xi-dedimethylamino-5delta,5gamma-dehydro-4epsilon-chloropristinamycin IE. 7. A group B streptogramin derivative according to claim 1, characterized in that said derivative is 5delta-[bis(2-methoxyethyl)aminomethyl]-5gamma,5gamma-dehydropristinamycin IE. 8. A process of producing of group B streptogramin derivatives according to claim 1, characterized by acting with fluorinating agent on group B streptogramin derivative of general formula: wherein R, Ra, Rb, Rc, and Rd are defined as above, and subsequently separating out a fluorinated derivative or derivative unsaturated at 5gamma,5delta, and if necessary of converting of received streptogramin derivative in salt. 9. A process according to claim 8, characterized in that, separating out a fluorinated derivative or derivative unsaturated at 5gamma,5delta is performed by chromatography or by crystallization. 10. A process of producing of group B streptogramin derivatives according to claim 1, wherein symbol means characterized by acting with thionylhalogenide in presence of nitrogen-containing base on sinergistine derivative of group B of general formula: wherein R, Ra, Rb, Rc, and Rd are defined as for claim 1, with subsequently converting, if needed, of received streptogramin derivative in salt. 11. A process of producing of group B streptogramin derivatives according to claim 1, wherein symbol means characterized by acting with an amine HNR1R2 or a thiol HS-R3 with a halogenated compound of general formula: wherein Ra, Rb, Rc, and Rd are defined as for claim 1 and Hal represents a halogen atom, with following converting of received streptogramin derivative in salt. 12. Streptogramin derivatives of general formula: wherein R, Ra, Rb, Rc, and Rd are defined as fo