GB2206879A - Novel pristinamycin IIB derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Novel pristinamycin IIB derivatives, their preparation and pharmaceutical compositions containing them Download PDF

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GB2206879A
GB2206879A GB08715966A GB8715966A GB2206879A GB 2206879 A GB2206879 A GB 2206879A GB 08715966 A GB08715966 A GB 08715966A GB 8715966 A GB8715966 A GB 8715966A GB 2206879 A GB2206879 A GB 2206879A
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iib
radical
isomer
deoxy
hydroxypristinamycin
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GB8715966D0 (en
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Devnandan Chatterjee
Neil Victor Harris
Trevor Parker
Christopher Smith
Peter James Warren
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May and Baker Ltd
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May and Baker Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Abstract

Novel pristinamycin IIB derivatives have the formula: <IMAGE> in which R1 denotes a substituted alkylthio radical, a radical of formula Het-S-, a dialkylamino radical, a radical of formula <IMAGE> where R2 is a substituted alkyl radical or a heterocyclic radical and n is 1 or 2 or an alkylamino radical. These compounds have useful antibacterial activity.

Description

"NEW COMPOSITIONS OF MATTER" This invention relates to pristinamycin IIB derivatives, their preparation, and compositions containing them.
The present invention provides new pristinamycin II derivatives, of the formula:
in which R1 denotes 1. an alkylthio radical containing 1 to 5 carbon atoms, substituted i) with one or two aLkyLamino or dialkylamino radicals in which the alkyl portions, which contain 1 to 5 carbon atoms, can optionally form, together with the nitrogen atom to which they are linked, a saturated heterocyclic radical chosen from 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted with an alkyl radical containing 1 to 5 carbon atoms), or alternatively ii) with a 2- or 3-pyrrolidinyl, 2-, 3- or 4piperidyl, 2- or 3-azetidinyl or 2-, 3- or 4-azepinyl radical, 2. a radical of general formula:: Het-S- (11) in which Het denotes a 3-pyrrolidinyl, 3- or 4-piperidyl, 3-azetidinyl or 3- or 4-azepinyl radical, optionally substituted with an alkyl radical containing 1 to 5 carbon atoms, 3. a dialkylamino radical in which the alkyl portions, which contain 1 to 5 carbon atoms, can optionally form, together with the nitrogen atom to which they are linked, a saturated heterocyclic radical chosen from 1-pyrrol idinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted with an alkyl radical containing 1 to 5 carbon atoms), 4. a radical of general formula::
in which R2 denotes i) either a 4- to 7-membered nitrogen-containing heterocyclic radical optionally containing one or more other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, and optionally substituted with an alkyl radical, ii) or an alkyl chain containing 2 to 4 carbon atoms and substituted with 1 or 2 radicals chosen from phenyl, cycloalkylamino or N-alkyl-N-cycloalkylamino con tainin 3 to 6 r= ato-ssalkylaminow dialkylamino or dialkylcarbamoyloxy, the alkyl portions of these last 2 radicals optionally being able to form, with the nitrogen atom to which they are attached, a 4- to 7-membered saturusted or tssnsaturated heterocyrlic radical optionally con taining another hetero atom chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, ond optionally substituted with an alkyl radical), or substituted with one or more 4- to 7-membered nitrogen-containing heterocyclic radicals optionally containing 1 or 2 other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphate, these heteroeyclic radicals optionally being substituted with an alkyl radical, the said heterocyclic radicals being attached to the chain which bears them via a carbon atom, with the proviso that at least one of the substituents borne by the above alkyl chain is a nitrogen-containing substituent capable of fording salts, or [(S)-1-methyl-2-pyrrolidinyl]methyl, and the symbol n equals 1 or 2, 5. an alkylamino radical which is optionally substituted by a hydroxy (e.g. the 2-hydroxyethylamino radical) or alkylamino or dialkylamino, the alkyl portions of this last radical optionally being able to form, with the nitrogen atom to which they are attached, a 4- to 7-membered saturated or unsaturated heterocyclic radical optionally containing another hetero atom chosen from nitrogen, oxygen or suLphur in the state of sulphoxide or sulphone, and optionally substituted with an alkyl radical), or substituted with one or more 4- to 7-membered nitrogen-containing heterocyclic radicals optionally containing 1 or 2 other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphate, these heterocyclic radicals optionally being substituted with an alkyl radical, the said heterocyclic radicals being attached to the chain which bears them via a carbon atom, with the proviso that the alkyl radicals and potions mentioned above are linear or branched and contain, except where otherwise stated, 1 to 10 carbon atoms.
The pristinamycin IIB derivatives of general formula (I) have isomeric forms and their isomers and their mixtures are included within the scope of the present invention.
The wavy line wy indicates that the hydroxy group, in the 16-position may be above (beta) or below (alpha) the plane of the ring system.
In the definition of the general formula (I), section 4., when R2 denotes a heterocyclic radical, this radical can be chosen, by way of example, from 3-azetidinyl, 3-pyrrolidinyl, 3- or 4-piperidyl or 3- or 4-azepinyl, when R2 denotes an alkyl radical substituted with a heterocyclic radical, the he te rocyc I ic radical can be chosen, by way of example, from the radicals mentioned above or a 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2 azepinyL, piperazinyl, 4-alkylpiperazinyl, quinolyl, isoquinolyl or imidazolyl radical, when R2 contains a dialkylamino or dialkylcarbamoyloxy radical in which the alkyl portions form a heterocyclic radical with the nitrogen atom to which they are attached, this ring can be chosen, for example, from: 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepinyl, morpholino, thiomorpholino in the form of sulphoxide or sulphone, 1-piperazinyl, 4-alkyl-1-piperazinyl, N-alkyl1-homopiperazinyl, or l-imidazolyl.
The following compounds of general formula (I) can be mentioned, in particular, by way of example : 16-alcohols of - 26-(3-azetidinyl) sulphinylpristinamycin IIB - 26-(1-methyl-3-azetidinyl)sulphinylpristinamycin IIB - 26-(1-ethyl-3-azetidinyl)sulphinylpristinamycin Ilg - 26-(1-isopropyl-3-azetidinyl)sulphinylpristinamycin IIB - 26-(3-pyrrolidinyl)sulphinylpristinamycin IIB - 26-(1-methyl-3-pyrrolidinyl)sulphinylpristinamycin IIg - 26-(1-ethyl-3-pyrrolidinyl)sulphinylpristinamycin IIg - 26-(1-isopropyl-3-pyrrolidinyl)sulphinylpristinamycin II - 26-(3-piperidyl)sulphinylpristinamycin IIB - 26-(1-methyl-3-piperidyl)sulphinylpristinamycin IIB - 26-(1-ethyl-3-piperidyl)sulphinylpristinamycin IIB - 26-(4-piperidyl)sulphinylpristinamycin IIB - 26-(1-methyl-4-piperidyl)sulphinylpristinamycin IIB - 26-(1-ethyl-4-piperidyl)sulphinylpristinamycin IIB - 26-(3-azepinyl)sulphinylpristinamycin IIB - 26-(4-azepinyl)sulphinylpristinamycin IIB - 26-(2-cyclopropylaminoethyl)sulphinylpristinamycin IIB - 26-(2-cyclobutyLaminoethyl)sulphinylpristinamycin IIE - 26-(2-cyclopentylaminoethyl)sulphinylpristinamycin IIB - . (@-cyclohexylaminoethyl)sulphinylpristinamycin ::' - 26-(N-cyclohexyl-N-methyl-2-aminoethyl )sulph inylpr ist ina- mycin IIB - 26-(2-methylaminoethyl)sulphinylpristinamycin IIB - 26-(2-ethylaminoethyl)sulphinylpristinamycin IIB - 26-(2-propylaminoethyl)sulphinylpristinamycin IIB - 26-(2-isopropylaminoethyl)sulphinylpristinamycin IIB - 26-(2-butylaminoethyl)sulphinylpristinamycin IIB - 26-(2-isobutylaminoethyl)sulphinylpristinamycin IIB - 26-(2--n-decylaminoethyl)sulphinylpristinamycin IIB - 26-(2-dimethylaminoethyl)sulphinylpristinamycin IIB - 26-(2-diethylaminoethyl)sulphinylpristinamycin IIB - 26-(2-dipropylaminoethyl)sulphinylpristinamycin IIB - 26-(2-diisopropylaminoethyl)sulphinylpristinamycin IIB - 26-(2-dibutylaminoethyl)sulphinylpristinamycin 1Ig - 26-(2-diisobutylaminoethyl)sulphinylpristinamycin IIB - 26-(N-ethyl-N-methyl-2-aminoethyl)sulphinylpristina nyc in Ilg - 26-t2-(1-azetidinyl)ethyl3sulphinylpristinamycin II6 - 26-(2-(1-pyrrolidinyl)ethyl]sulphinylpristinamycin IIB - 26-(2-piperidinoethyl)sulphinylpristinamycin IIB - 26-[2-(1-azepinyl)ethyl]sulphinylpristinamycin IIB - 26-(2-morpholinoethyl)sulphinylpristinamycin IIB - 26-[2-(1-piperazinyl)ethyl]sulphinylpristinamycin IIB - Z6-t2-(4-methyl-1-piperazinyl)ethylAsulphinylpristina- mycin IIB - 26-[2-(4-methyl-1-homopiperazinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(1-imidazolyl)ethyl]sulphinylpristinamycin IIB - 26-(2-dimethylaminocarbamoyloxyethyl )sulph inylpr ist ina- mycin IIB - 26-(2-diethylaminocarbamoyloxrethyl)sulphinylpristina- mycin IIB - 26-(2-diisopropylaminocarbamoyloxyethyl)sulphinylpristinamycin II8 - 26-E2-(4-methyL-1-piperazinyl )carbamoyloxyethyL)sulphinyl- pristinamycin IIB - 26-[2-(2-azetidinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(3-azetidinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(2-pyrrolidinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(3-pyrrolidinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(2-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(3-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(4-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(2-azepinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(3-azepinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(4-azepinyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(3-quinolyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(4-quinolyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(1,2,3,4-tetrahydro-2-isoquinotyl)ethyl]sulphinylpristinamycin IIB - 26-[2-(1-isoquinolyl)ethyl]sulphinylpristinamycin IIB - 26-(2-imidazolylethyl)sulphinylpristinamycin IIB - 26-t2-cyclopropylamino-1-methylethyl)sulphinyLpristinz- mycin IIB - 26-(2-cyclobutylamino-1-methylethyl)sulphinylpristinamycin IIs - 26-(2-cyclopentylamino-1-methylethyl )sulphinylpristina- tyein tis - 26-(cyclohexylamino-1-methylethyl)sulphinytpristinamycin IZB - 26-[2-(N-cyclohexy-N-methylamino)-1-methylethyl]sulphinylpristinamycin I I - 26-(2-methylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-ethylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-C1-methyl-2-propylaminoethyl)sulphinylpristinatnycin IIB - 26-(2-isopropylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-butylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-isobutylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(1-methyl-2-n-decylaminoethyl)sulphinylpristinamycin IIB - 26-(2-dimethylamino-1-methylethyl)sulphinylpristina- mycin IIB - 26-(2-diethylamino-1-methylethyl)sulphinylpristinamycin IIg - 26-(2-dipropylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-diisopropylamino-1-methylethyl)sulphi ylpristina- mycin IIB - 26-(2-2-dibutylamino-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-diisobutylamino-1-ethylethyl)sulphinylpristina- mycin IIB - 26-(2-(N-ethyl-N-methylamino)-1-methYlethyL )sulph inyl- pristinamycin IIB - 26-E2-( 1-azetidinyl )-1-methylethyl )sulphinylpristina- mycin IIB - 26-[1-methyl-2-(1-pyrrolidinyl)ethyl]sulphinylpristinamycin IIB - 26-(1-methyl-2-piperidinoethyl)sulphinylpristinamycin IIB - 26-[2-(1-azepinyl)-1-methylethyl]sulphinylpristinamycin IIB - 26-(1-methyl-2-morpholinoethyl)sulphinylpristinamycin IIB - 26-E 1-methyL-2-Cl-piperaz inyl )ethyl)sulphinylpristina- mycin IIB - 26-(2-C4-methyl-1-piperazinyl )-1-methylethyl)sulphinyL- pristinamycin IIB - 26-[2-(4-methyl-1-homopiperazinyl)-1-methylethyl]sulphinylpristinamycin IIB - 26-[2-(1-imidazolyl)-1-methylethyl]sulphinylpristina mycin IIB - 26-(2-dimethylaminocarbamoyloxy-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-diethylaminocarbamoyloxy-1-methylethyl)sulphinylpristinamycin IIB - 26-(2-diisopropylaminocarbamoyloxy-1-methylethyl-)- sulphinylpristinamycin IIB - 26-[2-(4-methyl-1-piperazinyl)carbamoyloxy-1-methylethyl]sulphinyloristinamycin IIB - 26-[2-(2-azetidinyl)-1-methylethyl]sulphinylpristinamycin IIg - 26-[2-(3-azetidinyl)-1-methylethyl]sulphinylpristinamycin II6 - 26-t1-methyl-2-(2-pyrrolidinyl)ethyl)sulphinylpristina- mycin II6 - 26-C1-methyl-2-(3-pyrrolidinyl)ethylJsuLphinylpristina- mycin IIB - 26-[1-methyl-2-(2-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[1-methyl-2-(3-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[1-methyl-2-(4-piperidyl)ethyl]sulphinylpristinamycin Ilg - 26-[2-(2-azepinyl)-1-methylethyl]sulphinylpristinamycin IIB - 26-52-(3-azepinyl)-1-methylethyl]sutphinylpristir.a- mycin IIB - 26-(2-(4-azepinyl )-1-methylethyl)sulphinylpristinamycin IIB - 26-[1-methyl-2-(3-quinolyl)ethyl]sulphinylpristinamycin IIB - 26-[1-methyl-2-(4-quinolyl)ethyl]sulphinylpristinamycin 118 - 26-t1-methyl-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethylu- sulphinylpristinamycin IIB - 26-t2-(I-isoquinolyl )-1-methylethyl)sulphinyLpristina- mycin IIB - 26-(2-imidazolyl-1-methylethyl)sulphinylpristinamycin I IB - 26-(2-cyclopropylamino-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-cyclobutylamino-2-methylethyl)sulphinylpristina- mycin IIB - 26-(2-cyclopentylamino-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-cyclohexylamino-2-methylethyl)sulphinylpristina- mycin IIg - 26-[2-(N-cyclohexyl-N-methylamino)-2-methylethyl]sulphinylpristinamycin IIB - 26-(2-methylamino-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-ethylamino-2-methylethyl)sulphinylpristinamycin 11B - 26-(2-methyl-2-propylaminoethyl)sulphinylpristinamy - 26-(2-isopropylamino-2-methylethyl )sulph inylpr ist ina- mycin IIB - 26-(2-butylamino-2-methylethyl )sulphinyLpristinamyc in IIB - 26-(2-isobutylamino-2-methylethyl)sulphinyLprist-ina- mycin IIB - 26-(2-methyl-2-n-decylaminoethyl )sulph inylpr ist ina- mycin IIB - 26-(2-dimethylamino-2-methylethyl)sulphinylpristina- mycin IIB - 26-(2-diethylamino-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-dipropylamino-2-methylethyl)sulphinylpristina- mycin IIB - 26-(2-diisopropylamino-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-dibutylamino-2-methylethyl)sulphinylpristina- mycin IIB - 26-(2-diisobutylamino-2-methylethyl)sulphinylpristina- mycin IIB - 26-t2-(N-ethyl-N-methylamino)-2-methylethyl]sulphinyl- pristinamycin IIB - 26-t2-(1-azetidinyl)-2-methylethyl]sulphinylpristina- nyc in IIg - 26-[2-methyl-2-(1-pyrrolidinyl)ethyl]sulphinylpristina mycin IIB -- 26-(2-methyl-2-piperidinoethyl)sulphinylpristinar.r @@ ::18 - 26-[2-(1-azepinyl)-2-methylethyl]sulphinylpristinamycin IIB - 26-(2-methyl-2-morPholinoethyl)sulphinylpristinamycin IIB - 26-E2-methyl-2-( 1-piperaz inyl )ethyl )sulph inyLpr-ist ina- mycin IIB - 26-(2-(4-methyl )-1-piperazinyl)-2-methylethyl)sulphinyL- pristinamycin IIB - 26-E2-(4-methyl-1-homopiperazinyl)-2-methylethyl]sulphinyl- pristinamycin IIB - 26-E2-C 1-imidazoLyl)-2-methyLethyl)sulphinylpristina- mycin IIB - 26-(2-dimethylaminocarbamoyloxy-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-diethylaminocarbamoyloxy-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-diisopropylaminocarbamoyloxy-2-methylethyl)sulphinylpristinamycin IIg - 26-[2-(4-methyl-1-piperazinyl)carbamoyloxy-2-methyl ethylJsulphinylpristinamycin IIB - 26-[2-(2-azetidinyl)-2-methylethyl]sulphinylpristinamycin IIB - 26-[2-(3-azetidinyl)-2-methylethyl]sulphinylpristinamycin IIB - 26-[2-methyl-2-(2-pyrrolidinyl)ethyl]sulphinylpristinamycin IIB - 26-(2-inethyl-2-(3-pyrrolidinyl)ethyl)sulphinylpristina- mycin IIB - 26-[2-methyl-2-(2-piperidyl)ethyl]sulphinylpristinamycin IIB - 26-[2-methyl-2-(3-piperidyl)ethyl]sulphinylpristinamycin .IB - 26-[2-methyl-2-(4-piperidyl)ethyl]sulphinylpristinamycin IIIB - 26-[2-(2-azepinyl)-2-methylethyl]sulphinylpristinamycin Ilg - 26-[2-(3-azepinyl)-2-methylethyl]sulphinylpristinamycin IIB - 26-[2-(4-azepinyl)-2-methylethyl]sulphinylpristinamycin IIB - 26-[2-methyl-2-(3-quinolyl)ethyl]sulphinylpristinamycin IIB - 26-[2-methyl-2-(4-quinolyl)ethyl]sulphinylpristinamycin Ilg - 26-[2-methyl-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]sulphinylpristinamycin IIB - 26-E2-(1-isoquinolyl)-2-methylethyl)suLphinytpristina- mycin IIB - 26-(imitazolyl-2-methylethyl)sulphinylpristinamycin IIB - 26-(2-dimethylamino-3-phenylpropyl)sulphinylpristina- inamycin IIB - 26-(2-dimethylaminobutyl)sulphinylpristinamycin - 26-(3-azetidinyl)sulphonylpristinamycin IIB - 26-(1-methyl-3-azetidinyl)sulphonylpristinamycin IIB - 26-(1-ethyl-3-azetidinyl)sulphonylpristinamycin IIB - 26-(1-isopropyl-3-azetidinyl)sulphonylpristinamycin IIB - 26-(3-pyrrolidinyl)sulphonylpristinamycin IIB - 26-(1-methyl-3-pyrrolidinyl)sulphonylpristinamycin IIB - 26-(1-ethyl-3-pyrrolidinyl)sulphonylpristinamycin IIB - 26-(1-isopropyl-3-pyrrolidinyl)sulphonylpristinamycin IIs - 26-(3-piperidyl)sulphonylpristinamycin Ilg - 26-(1-methyl-3-piperidyl)sulphonylpristinamycin IIB - 26-(1-ethyl-3-piperidyl)sulphonylpristinamycin IlB - 26-(4-piperidyl)sulphonylpristinamycin IIB - 26-(1-methyl-4-piperidyl)sulphonylpristinamycin IIB - 26-(1-ethyl-4-piperidyl)sulphonylpristinamycin IIs - 26-(3-azepinyl)sulphonylpristinamycin IIB - 26-(4-azepinyl)sulphonylpristinamycin IIB - 26-(2-cyclopropylaminoethyl)sulphonylpristinamycin IIB - 26-(2-cyclobutylaminoethyl)sulphonylpristinamycin Ilg - 26-(2-cyclopentylaminoethyl)sulphonylpristinamycin IIB - 26-(2-cyclohexylaminoethyl)sulphonylpristinamycin IIB - 26-(N-cycichexyl-N-methyl-2-aminoethyl)sulphonyLpris- tinamycin 118 - 26-(2-methylaminoethyl)sulphonylpristinamycin IIB - 26-(2-ethylaminoethyl)sulphonylpristinamycin IIB - 26-(2-propylaminoethyl)sulphonylpristinamycin IIB - 26-(2-isopropylaminoethyl)sulphonylpristinamycin IIB - 26-(2-butylaminoethyl)sulphonylpristinamycin IIB - 26-(2-isobutylaminoethyl)sulphonylpristinamycin IIB - 26-(2-n-decylaminoethyl)sulphonylpristinamycin IIB - 26-(2-dimethylaminoethyl)sulphonylpristinamycin IIB - 26-(2-diethylaminoethyl)sulphonylpristinamycin IIB - 26-(2-dipropylaminoethyll)sulphonylpristinamycin IIB - 26-(2-diisopropylaminoethyl)sulphonylpristinamycin IIB - 26-(2-dibutylaminoethyl)sulphonylpristinamycin IIB - 26-(2-diisobutylaminoethyl)sulphonylpristinamycin IIg - 26-(N-ethyl-N-methyl-2-aminoethyl)sulphonylpristinamycin IIB - 26-E2-(1-azetidinyl)ethyl]sulphonylpristinamycin IIg - 26-[2-(1-pyrrolidinyl)ethyl]sulphonylpristinamycin IIB - 26-(2-piperidinoethyl)sulphonylpristinamycin IIB - 26-[2-(1-azepinyl)ethyl]sulphonylpristinamycin IIB - 26-(2-morpholinoethyl)sulphonylpristinamycin IIB - 26-[2-(1-piperazinyl)ethyl]sulphonylpristinamycin IIB - 26-(2-(4-methyl-1-piperazinyl )ethyl)sulphonylprist ina- mycin Ilg - 26-E2-(4-methyl-1-homopiperazinyl)ethyl]sulphonylpris- tinamycin IIB - 26-t2-(1-imidazolyl)ethyl]sulphonylpristinamycin I16 - 26-(2-dimethylaminocarbamoyloxyethyl)sulphonylpristina- mycin IIB - 26-(2-diethylaminocarbamoyloxyethyl)sulphonylpr,stina- mycin IIB - 26-(2-diisopropylaminocarbamoyloxyethyl)sulphonylpristinamycin IIB - 26-t2-(4-methyL-1-piperazinyl)carbamoyloxyethylusulpho- nylpristinamycin IIB - 26-[2-(2-azetidinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(3-azetidinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(2-pyrrolidinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(3-pyrrolidinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(2-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(3-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(4-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(2-azepinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(3-azepinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(4-azepinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(3-quinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(4-quinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(1-isoquinolyl)ethyl]sulphonylpristinamycin IIB - 26-(2-imidaszolylethyl)sulphonylpristinamycin IIB - 26-(2-cyclopropylamino-1-methylethyl)sulphonylpristina- mycin 118 - 26-(2-cyclobutylamino-1-methylethyl)sulphonylpristina- mycin IIB - 26-(2-cyclopentylamino-1-methylethyl)sulphonyLDristina- mycin IIB - 26-(2-cyclohexylamino-1-methylethyl)sulphonylpristinamycin IIB - 26-[2-(N-cyclohexyl-N-methylamino)-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-methylamino-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-ethylamino-1-methylethyl)sulphonylpristinamycin IIB - 26-(1-methyl-2-propylaminoethyl)sulphonylpristinamycin IIB - 26-(Z-isopropylamino-1-methylethyl)sulphonylpristina- mycin IIB - 26-(2-butylamino-1-methylethy()sulphonylpristinamycin IIB - 26-(2-isobutylamino-1-methylethyl)sulphonylpristina- mycin IIB - 26-(1-methyl-2-n-decylaminoethyl)sulphonylpristina- mycin IIg - 26-(2-dimethylamino-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-diethylamino-1-methylethyl)suLphonylPristina- mycin IIB - 26-(2-dipropylamino-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-diisopropylamino-1-methylethyl)sulphonylpristina- mycin IIB - 26-(2-dibutylamino-1-methylethyl)sulphonylpristina mycin IIB - 26-(2-diisobutylamino-1-methylethyl)sulphonylpristina- mycin IIB - 26-C2-(N-ethyl-N-methylamino)-l-methylethylZsulphonyl- pristinamycin IIB - 26--t2-(1-(azetidinyl)-1-methylethylJsulphonylpristina- mycin IIB - 26-[1-methyl-2-(1-pyrrolidinyl)ethyl]sulphonylpristinamycin Ilg - 26-(1-methyl-2-piperidinoethyl)sulphonylpristinamXcin IIB - 26-[2-(1-azepinyl)-1-methylethyl]sulphonylpristinainamycin IIB - 26-(1-methyL-2-morpholinoethyl)sulphonylpristinamycin I I B - 26-[1-methyl-2-(1-piperazinyl)ethyl]sulphonylpristinamycin IIB - 26-(2-C4-methyl-1-piperazinyl)-1-methylethyl )sulphonyl- pristinamycin IIs - 26-[2-(4-methyl-1-homopiperazinyl)-1-methylethyl]sulphonylpristinamycin IIB - 26-[2-(1-imidazolyl)-1-methylethyl]sulphonylpristinamycin IIB - 26-(2-dimethylaminocarbamoyloxy-1-methylethyl)sulphonylpristinamycin 118 - 26-(2-diethylaminocarbamoyLoxy)-1-metr,ylethyl)-sulPhonyl- pristinamycin IIB - 26-(2-diisopropylaminocarbamoyloxy-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-(4-methyl-1-piperazinyl )carbamoyloxy-1-methyl- ethyl]sulphonylpristinamycin IIB - 26-t2-(2-azetidinyl)-1-methylethylZsulphonylpristina- mycin IIB - 26-tZ-(3-azetidinyl)-1-methylethylZsulphonyl-pristina- mycin IIB - 26-C1-methyl-2-(2-pyrrolidinyl)ethyl3sulphonylpristinamycin IIB - 26-C1-methyl-2-(3-pyrrolidinyl)ethytZsulphonylpristina- mycin IIB - 26-[1-methyl-2-(2-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[1-methyl-2-(3-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-t1-methyl-2-(4-piperidyl)ethylZsulphonylpristina- mycin IIB - 26-[2-(2-azepinyl)-1-methylethyl]sulphonylpristinamycin Ilg - 26-[2-(3-azepinyl)-1-methylethyl]sulphonylpristina mycin IIB - 26-t2-(4-azepinyl )-1-nethylethyl]sulphonylpristina- mycin IIB - 26-[1-methyl-2-(3-quinolyl)ethyl]sulphonylpristina mycin Ilg - 26-[1-methyl-2-(4-quinolyl)ethyl]sulphonylpristinamycin IIB - 26-[1-methyl-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]sulphonylpristinamycin IIB - 26-(2-Cl-isoquinolyl )-1-methylethyl)sulphonytpristina- mycin 11B - 26-(2-imidazolyl-1-methylethyl)sulphonylpristinamycin IIB - 26-(2-cyclopropylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-cyclobutylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-cyclopentylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-cyclohexylamino-2-methylethylEsulphonylpristina- mycin IIB - 26-[2-(N-cyclohexyl-N-methylamino)-2-methylethyl]sulphonylpristinamycin IIB - 26-(2-methylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-ethylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-methyl-2-propylaminoethyl)sulphonylpristinamycin IIB - 26-(Z-isopropylamino-2-methylethyl)suLphonytpristina- mycin IIB - 26-(2-butylamino-2-methyLethyl)sulphonylpristinamycin IIB - 26-(2-isobutylamino-2-methylethyl)sulphonyLpristina- mycin IIB - 26-(2-methyl-2-n-decylaminoethyl)sulphonylpristinamycin IIB - 26-(2-dimethylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-diethylamino-2-methyiethyl)sulphonylpristinamycin IIB - 26-(2-dipropylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-diisopropylamino-2-methylethyl)sulphonylpristinamycin II8 - 26-(2-dibutylamino-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-diisobutylamino-2-methylethyL)sulphonylpristinamycin IIB - 26-[2-(N-ethyl-N-methylamino)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-(1-azetidinyl)-2-methylethyl]sulphonylpristinamycin Ilg - 26-[2-methyl-2-(1-pyrrolidinyl)ethyl]sulphonylpristinamycin IIg - 26-(2-methyl-2-piperidinoethyl)sulphonylpristinamycin IIB - 26-[2-(1-azepinyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-(2-methyl-2-morpholinoethyl)sulphonylpristinamycin IIB - 26-[2-methyl-2-(1-piperazinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(4-methyl-1-piperazinyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-(4-methyl-1-homopiperazinyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-(1-imidazolyl)-2-methylethyl]sulphonylpristinamycin IIg - 26-(2-dimethylaminocarbamoyloxy-2-methylethyl)sulphonylpristinamycin IIB - 26-(2-diethylaminocarbamoyloxy-2-methylethyl )suLphonyl- pristinamycin IIg - 26-(2-diisopropylaminocarbamoyloxy-2-methylethyl)- sulphonylpristinamycin IIg - 26-[2-(4-methyl-1-piperazinyl)carbamoyloxy-2-methylethyl]sulphonylpristinamycin IIB - 26-C2-(2-azetidinyl)-2-methylethyl)sulphonylpristina- mycin Ilg - 26-[2-(3-azetidinyl)-2-methylethyl]sulphonylpristinamycin IIg - 26-[2-methyl-2-(2-pyrrolidinyl)ethyl]sulphonylpristinamycin IIg - 26-[2-methyl-2-(3-pyrrolidinyl)ethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(2-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(3-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(4-piperidyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(2-azepinyl-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-(3-azepinyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-(4-azepinyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(3-quinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(4-quinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-methyl-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]sulphonylpristinamycin IIB - 26-[2-(1-isoquinolyl)-2-methylethyl]sulphonylpristinamycin IIB - 26-[2-imidazolyl-2-methylethyl]sulphonylpristinamycin IIB - 26-(2-dimethylamino-3-phenyLpropyl)sulphonylpristina- mycin Ilg - 26-(2-dimethylaminobutyl)sulphonylpristinamycin IIB and the 26-thio analogues thereof e.g. 16-alcohols of 26-(1-diethylaminoprop-2-yl)thio- pristinamycin IIB, as well as 16-alcohols of 26-(2-hydroxyethylamino)- and 26-(4-methylpiperazin-l-yl)- pristinamycin IIB and especially Compound No.
1. 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16alpha- hydroxypristinamycin IIB (isomer A) 2. 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16beta- hydroxypristinamycin IIB (isomer A) 3. 16-deoxy-26-(2-diisopropylaminoethyl)thio-16alpha hydroxypristinamycin IIB (isomer A) 4. 16-deoxy-26-(2-diisopropylaminoethyl)thio-16beta hydroxypristinamycin IB (isomer A) 5. 16-deoxy-26-(2-diisopropylaminoethyl)sulphinyl 16alpha-hydroxypristinamycin IIB (isomer A2) 6. 16-deoxy-26-(2-diisopropylaminoethyl)sulphinyl 16beta-hydroxypristinamycin 11B (isomer A2) 7. 16-deoxy-26-(2-diethylaminoethyl)thio-16beta-hydroxy pristinamycin 11B (isomer A) 8. 16-deoxy-26-(2-diethylaminoethyl)thio-16alpha hydroxypristinamycin IIB (isomer A) 9. 16-deoxy-26-(2-diethylaminoethyl)sulphinyl-16alpha- hydroxypristinamycin IIB (isomer A2) 10. 16-deOxy-26-(2-diethylaminoethyl)sulphinyl-16alpha- hydroxypristinamycin IIB (isomers A1 + A2) 11. 16-deoxy-26-(2-diethylaminoethyl)sulphinyl-16beta- hydroxypristinamycin (isomer A2) 12. 16-deoxy-26-ethylamino-l6beta-hydroxypristinamycin IIB (isomer A) 13. 16-deOxy-26-ethylamino-16alpha-hydroxypristinamycin 11B isomer A) 14. 16-deoxy-26-(2-diethylaminoethyl)amino-16alpha hydroxypristinamycin IIB 15. 16-deoxy-26-(2-diethylaminoethyl)amino-16beta hydroxypristinamycin IIB and isomers and salts thereof.
The numbers 1 to 15 are assigned to the compounds for easy reference, later in the specification, for example in the Examples.
The compounds of general formula (I) may be prepared by the application or adaptation of known methods (i.e.- methods heretofore used or described in the chemical literature).
According to the present invention, the products of general formula (I) may be prepared by reduction of a compound of the general formula:
where R1 is as hereinbefore defined.
The reaction may be carried out using sodium borohydride in an inert organic solvent, e.g. an alcohol, for example methanol, at ambient temperature.
According to a further feature of the present invention the products of general formula (I) in which R1 does not represent a radical of general formula (III) may be prepared by the reaction of a product of general formula: R1 -H (7) in which Rt is defined as above for R1 with the proviso that it does not represent R2-S(O) - with a product of formula:
that is to say a pristinamycin 1,A 16-alcohol, described by Le Goffic.
The reaction may be carried out in a similar manner to that described in European Patent Publication EP 135410 in an organic solvent such as an alcohol such as methanol or athenolp or a chlorinated solvent such ss; methylene chloride, 1,2-dichloroethane or chloroform, or in a mixture of these solvents (for example methylene chloride/methanol) at a temperature between -30 and 500C, optionally under nitrogen or argon.When R1 js a sub.stituted thio radicalitis preferred to carry out the reaction in alcohol in presence of an alkali metal alkoxide Occasionally it may be advantageous to operate in the presence of a tertiary amine, for example triethylamine, or of an ethanolamine (for example dimethylethanolamine).
A person skilled in the art will understand that, when R1 denotes a radical containing a secondary amine group capable of interfering with the reaction, this group will need to be protected beforehand, before the product of general formula (V) is reacted with the product of formula (VI). Any usual means which enables a secondary amine function to be blocked in the form of a labile radical can be used for this purpose. It is especially advantageous to use the trifluoroacetyl radical as a blocking radical which can be removed as described below. In such a case, however, it is not absolutely essential to remove the protective radical, and the protected derivative can be used directly in the oxidation reaction.
According to a further feature of the present invention, the products of general formula (I) in which R1 represents a radical of general formula (III) where n - 1 may be prepared by oxidation of a derivative of pristinamycin 115 (some of which are compounds of general formula (I) ), of its salt or of a protected derivative, of general formula:
in which Rtis defined as above, it being understood that in the cases where contains r sulphur-containing hetero cyclic ring, the sulphur atos can be in the for. of a sulphide, sulphoxide or sulphate.
The reaction is generally carried out by means of an oxidizing agent, optionally prepared in situ, in an aqueous edius or in an organic solvent, preferably a chlorinated solvent (.ethylene chloride, 1,2-dichloroethane or chlorofora, for example or an alcohol (methanol or tert-butanol, for example) or a fixture of these solvents. Optionally the operation can be carried out under nitrogen.
Along the oxidizing agents which are suitable for preparing a product of general formula (I) in which n = 1, it is possible to mention organic peracids: percarboxylic or persulphonic acids (for example peracetic, pertrifluoroacetic, perforeic, perbenzoic, -chloroper- benzoic, p-nitroperbenzoic, perealeic, monoperphthalic, percaephoric or p-toluenepersulphonic acids). or inorganic peracids (for example periodic or persulphuric acid) or potassium peroxymonosulphate.
The compounds of general formula (IV) in which R1 represents a radical of general formula (III) may be prepared by oxidation of a derivative of pristinamycin IIB, of its salt or of a protected derivative, of general formula:
in which R2 is defined as above, it being understood that in the cases where contains a sulphur-containing hetero cyclic ring, the sulphur atom can be in the form of a sulphide, sulphoxide or sulphate.
The reaction is generally carried out by means of an oxidizing agent, optionally prepared in situ, in an aqueous medium or in an organic solvent, preferabLy a chlorinated solvent (methylene chloride, 1,2-dichloroethane or chloroform, for example) or an alcohol (methanol or tert-butanol, for example) or a mixture of these solvents. Optionally the operation can be carried out under nitrogen.
Among the oxidizing agents which are suitable for preparing a product of general formula (IV)in which n = 1, it is possible to mention organic peracids: percarboxylic or persulphonic acids (for example peracetic, pertrifluoroacetic, performic, perbenzoic, m-chloroperbenzoic, p-nitroperbenzoic, permaleic, monoperphthalic, percamphoric or p-toluenepersulphonic acids). or inorganic peracids (for example periodic or persulphuric acid).
When the intention is to prepare a product of general formula (IV) in which n = 2, the operation is advantageously carried out in the presence of selenium dioxide and hydrogen peroxide, using the salt of the product of general formula (VIII), or in the presence of a peracid such as those referred to above, especially pertrifluoroacetic acid, or m-chloroperbenzoic acid.
When the derivative of pristinamycin IIg of general formula (vTiT) is used in the form of a salt, use is made of the salts formed with organic or inorganic acids, preferably with trifluoroacetic, tartaric, acetic, benzoic or hydrochloric acids.
When the product of general formula (viii) is used in the form of a salt or of a protected derivative, the react ion is advantageously carried out at a temperature between -40 and 500C.
When it is intended to prepare a product of general formula (IV) in which n = 1, it is also advantageous to operate by starting from the derivative of pristinamycin IIB of general formula (viii) in the presence of an alkali metal bicarbonate (for example sodium bicarbonate) at a temperature between -60 and -4C0C.
When R2 contains an alkylamino or cycloalkylamino substituent, it is also possible to utilize a protected derivative of the product of general formula (VIII). The latter can be protected by any amine-protective group whose introduction and removal do not affect the remainder of the molecule; use is advantageously made of the trifluoroacetyl group which can be removed after the react ion by treatment it h an alkali metal bicarbonate (sodium or potassium bicarbonate) in an aqueous solution.
Yhe products of general formula (VIII) can be prepared by the reaction of a product of general formula: $2-SH (IX) in which R is defined as above, with the product of formula:
that is to say pristinamycin IIA.
The reaction is usually carried out in an organic solvent such as an alcohol such as methanol or ethanol, or a chlorinated solvent such as methylene chloride, ,2- dichloroethane or chloroform, or in a mixture of these solvents (for example methylene chloride/methanol) at a temperature between -30 and 500C.
Occasionally it may be advantageous to operate in the presence of a tertiary amine, for example triethylamine, or of an ethanolamine (for example dimethylethanolam.-e) A person skilled in the art will understand that, when R denotes a radical containing a secondary amine group capable of interfering vith the reaction, this group will need to be protected beforehand, before the product of generaL formula (IX) is reacted with the product of formula (X) Any usual means which enables a secondary amine function to be blocked in the form of a labile radical can be used for this purpose. It is especially advantageous to use the trifluoroacetyl radical as a blocking radical which can be removed as described above.In such a case, however, it is not absolutely essential to remove the protective radical, and the protected derivative can be used directLy in the oxidation reaction.
The products of general formula (n) in which n is equal to 2 can also be prepared by the oxidation of a product of general formula (iv) in which n is equal to 1.
The reaction is carried out under conditions which are similar to the conditions described above for preparing a product of general formula (iv) in which n = 2 starting from a pristinamycin IIB derivative of general formula (-i )e The new products of general formula (I) can be purified by known methods, for example by crystallization, chromatography or successive extractions in an acidic or basic medium.For the person skilled in the art who is aware of the sensitivity of synergistins in an alkaline medium, a "basic medium is understood to mean a tedium which is just alkaline enough to Liberate the parent substance from its salt of addition with on acid, that is to say a medium whose pH does not exceed 80 It is welt known that the synergistins obtained by fermentation constitute products which are greatly sought after by medical prartitioners for the treatment of many complaints due to Gram-positive bacteria (of the Staphylococci, Streptococci, pneumococci or enterococci type) and Gram-negative bacteria (of the Haemophilus, gonococci, meningococci type).However, these products have the disadvantage of being insoluble in an aqueous medium dnd consequently can be administered only by oral route, generally in the for. of gelatine capsules, coated pills or tablets. In view of this insolubility, it has hitherto been impossible to use the known syner-gistins when the patient is unable to swallow; this is the case, in particular, in paediatrics and in reanimation, while the activity spectrum of these products would render them a valuable indication in many circumstances, for example in cases of comatose septicaemias.
The new products according to the invention have the considerable advantage of being capable of being dissolved in water, usually in the form of salts, in usable therapeutic doses, and of enhancing, via a synergism phenomenon, the antibacterial action of pristinamycin IA, virginiamycin S or of soluble synergistin derivatives of general formula:
in which Y denotes a hydrogen atom or a dimethylamino radical and 1) either
denotes a single bond, Z and R3 denote a hydrogen atom and X denotes a radical of general formula:
in which: : - either R denotes a hydrogen atom and R5 denotes a hydroxy or alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkylamino radical whose alkyl radicals can form, with the nitrogen atom to which they are attached, a 4 to 7-membered hetero-cyclic ring chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl rings, or R9 denotes a cycloalkyl radical containing 3 to 7 carbon atoms or a saturated 4 to 7-membered heterocyclic ring chosen from the azetidine, pyrrolidine, piperidine and azepine rings, these heterocyclic rings being option-ally capable of being substituted by n alkyl radical on the nitrogen atom, - or RA denotes a formyl or alkylcarbonyl radical and denotes an alkyl radical substituted by a carboxy, alkyl amino or dialkylamino radical whose I alkyl radicals can form, with the nitrogen atom to which they are attached a 4 to 7-membered heterocyclic ring chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl or azepinyl ring, or Rr denotes a 4 to 7-membered heterocyclic ring chosen from the azetidine, pyrrolidine, piperidine and azepine rings, these heterocyclic rings being capable of being substituted by an alkyl radical on the nitrogen atom, - or Rfl and Rg, which are identical or different, denote an alkyl radical optionally substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dialkyl-amino radical whose alkyl radicals optionally form, with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring chosen from azetidinyl, pyrrolidinyl, piperi- dinyl, piperazinyl, N-alkylpiperazinyl or azepinyl - or R2 and R5 form, together with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring chosen from the azetidine, pyrrolidine, piperidine, morpholine and piperazine rings, optionally substituted by an alkyl radical, 2) or
denotes a double bond, X denotes an oxygen atom and Z denotes a radical of general formula:
defined as follows: a) either R and R each denote a hydrogen atom and denotes a 3-pyrrolidinylthio or 3- or 4-piperidylthio radical (these radicals being optionally substituted by an alkyl radical) or Rg denotes an alkylthio radical substituted by one or two hydroxysulphonyl, alkylamino, or dialkylamino (optionally substituted by a mercapto or dialkylamino radical) radicals, or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl radical) morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl and 2-or 3-pyrrolidinyl radicals (the latter two rings being optionally substituted by an alkyl radical on the nitrogen atom), b) or Ry and R7 together form a valency bond and R6 denotes a 3-pyrrotidinylamino, 3- or 4-piperidylamino, 3-pyrrolidinyloxy, 3- or 4-piperidyloxy, 3-pyrrolidinylthio or 3- or 4-piperidylthio radical (these radicals being optionally substituted by an alkyl radical on the ni nitrogen atom in the ring), or Rs denotes an alkylamino, alkyloxy or alkylthio radical substituted by one or two hydroxy-sulphonyl, alkylamino, dialkylamino (optionally substitu-ted by a dialkylamino radical), trialkylammonio or 4- or 5-imidazlyl radicals or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercapto alkyl radical), morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidinyl and 2or 3-pyrro-lidinyl radical (the last two rings being optionally sub-stituted by an alkyl radical on the nitrogen atom), it being understood that the alkyl radicals and alkyl moieties referring to the symbols of the general formula (XZ) contain 1 to 5 carbon atoms and form a Linear or branched chain, or derivatives of the general formula:
in which the symbol Y denotes a hydrogen atom or a dimethylamino radical and the symbol R8 denotes a F or 4-quinuclidinyl radicals or salts thereof.
Some of the derivatives of synergistins of formulae (Xl) and (XIV) can have isomeric forms. It is to be under stood that these isomeric forms as well as their mixtures can be advantageously associated with the products of general formula (I).
The products of general formula (XI) defined as above under 1), with the exception of those in which R4 denotes a formyl or alkylcarbonyl radical, can be prepared by the action of an amine of general formula:
in which R4 and R5 are defined as above, on a synergistin of general formula:
in which Y denotes a hydrogen atom (virginiamycin S) or the dimethylamino radical (pristinamycin IA) in the presence of an alkali metal cyanoborohydride.
The operation is generally carried out with an excess of amine of general formula (XV) in the presence of an alkali metal cyanoborohydride such as sodium cyanoborohydride, in an organic solvent such as an alcohol containing dissolved gaseous hydrogen chloride (methanolic hydrogen chloride or ethanolic hydrogen chloride) at a temperature between OOC and the reflux temperature of the reaction mixture, preferably at a temperature in the region of 20 C The reaction can be advantageously carried out in the presence of a drying agent such as molecular sieves.
The products of general formula (xT) defined as above under 1) in which Rg denotes a formyl or alkylcarbonyl radical and R; denotes an alkyl radical substituted by a carboxy, alkylamino or dialkylamino radical whose alkyl radicals optionally form, with the nitrogen ato to which they are attached, a 4 to 7-membered heterocyclic ring chosen from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, alkyl-piperazinyl or azepinyl ring, or denotes a saturated 4 to 7-membered heterocyclic ring chosen from the azetidine, pyrrolidine, piperidine and azepine rings, these hetero-cyclic rings being capable of being substituted by an alkyl radical on the nitrogen atom, and Y is defined as above, can be prepared by the action of a product of general formula: : R9 - CO - Q (xvii) in which R9 denotes a hydrogen atom or an alkyl radical and Q denotes a halogen atom or an alkylcarbonyloxy radical, on a product of general formula:
in which Y iS defined as before and R'S has the corres- ponding definition of R5 which is given above.
The reaction is usually carried out in an organic solvent such as pyridine, in a chlorinated solvent (methylene chloride) or an ether (tetrahydrofuran) in the presence of an acid acceptor such as an organic base such as triethylamine or an inorganic base such as an alkali metal carbonate or bicarbonate such as sodium bicarbonate, the operation being carried out at a teaperature between 0 and 800C.
It is to be understood that, when R'5 denotes a radical containing a secondary amine group, the said group must be protected before the product of general formula (X.VTI)is reacted with the product of general formula (rvIIl) The protection is carried out under the conditions des cribed earlier for the preparation of the product of the general formula (VIII).
It is also to be understood that, when R4 and/or R5 in the general formula (XV) denote a radical con taining a secondary amine group, the latter must be pro tected beforehand, before the product of general formula (XV) is reacted with the product of general formula (XVI). The blocking and the deblocking are carried out as described earlier.
The products of general formula(Y.I) defined as before under 2), in which Y is defined as before and the other symbols are defined as before under 2) a) can be prepared by the action of a product of general formula: R'6-H (XIX) in which R' has the definition of R given earlier under 2) a), on the product of general formula:
in which Y is defined as before.
The operation is usually carried out in an organic solvent such as an alcohol such as methanol, or a chlorinated solvent such as chloroform, or a mixture of these solvents, at a temperature between OOC and the reflux temperature of the reaction mixture, preferably at a tempera- ture in the region of 20 0c.
The products of general formula (XX) can be prepared by the action of an alkali metal borohydride such as sodium cyanoborohydride on a product of general formula:
in which Y is defined as before.
The operation is usually carried out in an organic solvent such as an ether such as tetrahydrofuran, or an alcohol, for example isopropanol, in the presence of an acid such as triftuoroacetic acid, at a temperature betueen 0 C and the reflux temperature of the reaction mixture, preferably at a temperature in the region of acoc.
The products of general formula (XXI) can be obtained by the action of a product of formula:
in which either X1 denotes an alkyloxy radical and X2 denotes an alkyloxy or dimethylamino radical, or X1 and X2 both denote a dimethylamino radical, on a product of general formula (XVI).
In practice, it is advantageous to react tertbutoxybis(dimethylamino)methane with the product of general formula (XVI5, the operation being carried out in an organic solvent such as a chlorinated solvent such as 1,2-dichloroethane, or an amide (for example dimethylformamide) at a temperature between 0 and 80 0c, preferably at a temperature in the region of 20 C.
The products of general formula (XXII)can be prepared according to the methods described by H. Bredereck et al., Chem. Ber., 101, 41 and 3058 (1968) and Chem. Ber., 106, 3725 (1973).
The products of general formula (xi) in which Y is defined as before and the other symbols are defined as earlier under 2) b), except for R6 denoting a 3-pyrro Lidinyloxy, 3- or 4-piperidyloxy or alkyloxy radical, optionally substituted as defined under 2) b), can be prepared by the action of a product of general formula: R"6 - H (xxiii) in which R"6 has the definition of R6 given above, on a product of general formula (XXI) in which Y is defined as earlier.
The reaction is carried out in an organic medium in the presence of an acid (for example acetic acid or a mixture of acetic acid with catalytic quantities of trifluoroacetic acid), in the presence or absence of a solvent, at a temperature between 0 and 500C; preferably at a temperature in the region of 20 0C.
Where applicable, the solvent can be chosen from organic solvents such as ethers (tetrahydrofuran), alcohols (ethanol) and chlorinated solvents (methylene chloride or chloroform, for example).
The products of general formula (xi) in which Y is defined as before and the other symbols are defined as earlier under 2) b) can be prepared by the action of a product of general formula: (XXIV) in which R"' is defined as R6 under 2) b), on a product of general formula:
in which r is defined as before and Z1 denotes a tosyloxy, acetyloxy, trimethylsilyloxy or dialkyloxyphosphoryloxy radical whose alkyl moieties contain 1 to 4 carbon atoms forming a linear or branched chain or Z1 denotes a chlorine atom.
The operation is usually carried out in an organic solvent such an ether such as tetrahydrofuran, an alcohol such as ethanol, or a chlorinated solvent (methylene chlo- ride or chloroform, for example) at a temperature in the region of ZOOC. The reaction is carried out in a basic medium, for example in the presence of an alkali metal hydride or an alkali metal alcoholate such as sodium ethoxide or potassium tert-butoxide.
When R"' is different from a substituted alkyloxy or (heterocyclic ring radical)oxy radical, it is also possible to operate either in a neutral medium at a tem peraturebetween 0 and 500C, in one of the solvents mentioned above, or in an acetic medium under conditions identical to those described earlier for the action of a product of general formula (XXIII)on a product of general formula (XXI) The products of general formula (XXV) can be prepared by acid hydrolysis of a product of general formula (XXI) to obtain a product of general formula:
followed: $ ) either by the action of a product of general formula: : X'1-X (XXVII) in which X denotes a halogen atom and Z'1 has the definition given before for Z1, except for denoting a chlorine atom ss ) or by the action of a product of formula: (C6H5)3 P Cl (XXVIII) to obtain a product of general formula (XXV) in which Z1 denotes a chlorine aton.
The hydrolysis of the product of general formula (XXI) to the product of general formula (XXV) is carried out by means of an aqueous solution of an inorganic acid such as a 0.1 N aqueous solution of hydrochloric acid, the operation being carried out at a temperature in the region of 200 C.
The reaction of the product of general formula(XXVII) with the product of general formula (XXVI) is generally carried out in an inorganic solvent such as methylene chloride in the presence of an acid-acceptor such as an organic base such as triethylamine, or an inorganic base such as an alkali metal carbonate or bicarbonate, for example sodium or potassium bicarbonate. The operation is generally carried out at a temperature between -20 and +20 0C.
The reaction of the product of general formula (XXVIII) with the product of general formula GVT) is usually carried out in a chlorinated solvent such as methylene chloride at a temperature between -20 and +200C.
The products of general formula(XIV), in which Y and R#are defined as above, can be prepared by the action of a thiol of general formula: SH (XXIX) in which RShas the definition given above, on a product of general formula:
in which Y is defined as above.
The reaction is generally performed in an organic solvent such as an alcohol, e.g. methanol or a chlorinated solvent, e.g. chloroform, or a mixture of these solvents, at a temperature of between -20 C and the refluxing temperature of the reaction mixture, preferably at a temperature in the region of 20 C.
It is understood that the thiol of (R) or (S) configuration leads to the synergistin derivative of general formula (Xiv) of the corresponding configuration.
The thiol of general formula (XXIX) can be obtained from the thiol ester of general formula: R#-S-COR' (XXXI) in which is defined as above and R' denotes an alkyl radical containing 1 to 4 carbon atoms, preferably a methyl radical, by any known method for obtaining a thiol from a thiol ester tdithout affecting the remainder of the molecule. The reaction is formed, in particular, by alcoholysis in alkaline medium, e.g. in an alcohol such as methanol, in the presence of sodium methylate or sodium hydroxide, at a temperature of between 2OOC and the refluxing temperature of the reaction mixture.
The thiol ester of general formula (XXXI) can be prepared by a method similar to that described by R.P.
Volante, Tet. Let. 22 (33), 3119 (1981), from an alcohol of general formula: RaOH (xxxrni; in which R8is defined as above, and a thiocarboxylic acid of general formula: R' CO SH (XXXIII) in which R' is defined as above, by treatment with a mixture of triphenylphosphine and dialkyl azodicarboxylate, e.g. diisopropyl azodicarboxylate.
The reaction is performed under conditions similar to those described in the above reference.
It is understood that the alcohol of general formula (XXXII) of (R) or (S) form leads, respectively, to the thiol ester of general formula (XXII) of (S) or (R) c figuration.
The alcohol of general formula(XXXII) of (R) or (S) form can be prepared according to the method described by B. Ringdahl et al., Acta. Pharm. Suec., 16, 281 (1979).
The products of general formula (XXX) can be prepared as described in European Patent Publication 133,098.
When the products of general formula (XIV) take the form of a mixture of isomers, it is possible to separate the latter by any known method which does not affect the remainder of the molecule; e.g. by high performance liquid chromatography.
The new products of general formula (XIV)can be purified by the usual known methods, e.g. crystallization, chromatography or successive extractions in acid and basic medium. For those versed in the art who are familiar vith the sensitivity of synergistins in alkaline medium, it is obvious that "basic medium" is understood to mean a medium which is just sufficiently alkaline to liberate the parent substance from its addition salt with an acid, i.e. a medium in which the pH does not excess 7.5 to 8.
The new products of general formula (?Th?) can be converted to an addition salt with acids by the action of an acid in an organic solvent such as an alcohol, ketone, ester or chlorinated solvent. The salt precipitates, after concentration of its solution where appropriate; it is separated by filtration or decantation. The addition salts vith acids can also be obtained in the state of aqueous solutions by adding an aqueous solution of the corresponding acid to the product of general formula (X7).
The products of general formulae (IX), (xv), (XIX), (XXIII) and (XXIV) can be prepared according to, or in a similar manner to, the methods described in the exam- ples below, and especially according to: - G.G. Urquart et al., Org. Synth., 21, 36 (1941) - A.I. Vogel, J. Chem. Soc., 1822 (1948) - J.H. Chapman and LN. Owen, J. Chem. Soc., 579 (1950) - He R. Snyder et al., J. Am. Chem. Soc., 69, 2672 (1947) - D.D. Reynolds et al., J. Org. Chem., 26, 5125 (1961) - J.W. Haeffele et al., Proc. Sci. Toilet Goods Assoc.e 32, 52 (1959) --H. Barrer et al., J. Org. Chem., 27, 641 (1962) - J.H. Biel et al., J. Amer. Chem.Soc., 77, 2250 (1955) when dealing vith a product of general formula (IX), (XIX), (XXIII) or (XXIV) in which R2, R'6, $"6 or R denotes a substituted alkylthio or (heterocyclic ring radical)thio radical, or according to: - A.J.W. Headlee et al., J. Amer. Chem. Soc., 55, 1066 (1933) B.K. Campbell and K.N. Campbell, J. Amer. Chem. Soc., 60, 1372 (1938) - R.C. Elderfield et al., J. Amer. Chem. Soc., 68, 1579 (1946) when dealing with a product of general formula (XXIII) or (XXIV)) in which R"6 or R"'6 denotes a substituted alkyloxy or (heterocyclic ring radical)oxy radical, or according to: - J. Amer. Chem. Soc., 54, 1499 (1932) and - J. Amer. Chem.Soc., 54, 3441 (1932), when dealing with a product of general formula (XV) or or general formula (IX), (XXIII) or (XXIV) in which R2,R"6 or R"'6 are substituted alkylamino radicals, or according to : E.F. Elslager et al., J. Med. Chem., 17, 99 (1974) L.M. Werbel et al., J. Het. Chem., 10, 363 (1973) when dealing with a product of general formula (IX).
(XXIII) or (XXIV) in which R2,R"6 or R"'6 are (heterocyclic ring radical)amino radicals.
It is to be understood that in the above methods, when R2,RA, RR7 R'6, R" or R"'6 contain a secondary amine group capable of interfering with the reaction, this must first be protected by any known method which does not affect the remainder of the molecule. The protective radical is removed after reaction under the conditions described earlier.
Where applicable, the isomers of the products of general formula (I) and/or of the products of general formula (XI) can be separated by chromatography or by high performance liquid chromatography.
The products of general formula GxI) can be purified as mentioned earlier for the products of general formula ( The new products of general formula (XIV) poss ess the considerable advantage that they can be slubi lived in water in the state of salts, at doses which can be used therapeutically, while retaining the general acti vity spectrum of synergistins. They are active, in parti cular, on Staphylococcus aureus Smith in vitro at concen trations of between 1 and 125 pg/ml and in vivo at doses of between 5 and 50 mg/kg subcutaneously in mice.
In addition, they are especially advantageous on account of their low toxicity.
The synergistin derivatives of general formula (XIV) have a synergistic effect on the antibac terial action of pristinamycin IIA on Staphylococcus aureus Smith in vitro at doses of between 0.1 and 10 pg/ cm3 and in vivo in mice at doses of between 10 and 200 mg/kg subcutaneously, when they are combined in propor tions varying between 10:90X and 90:10Z.
The pristinamycin IIB B derivatives of formula(I)and their pharmaceutically acceptable salts exhibit particularly advantageous antibacterial properties in vitro and in vivo.
In vitro, the products of formula (I) have shown themselves to be active towards Staphylococcus aureus Smith In addition, they have a synergistic effect on the antibacterial action of pristinamycin IA.
In vivo, the products of formula (I) have shown themselves to be active in the mouse in experimental infections with Staphylococcus aureus Smith by the subcutaneous route. When they are combined with natural or synthetic pristinamycin IA in proportions from 10-90% to 90-10%, they have a synergistic effect on the antibacterial action by the subcutaneous route.
The ED results are given in Table I which follows.
50 In addition the products of formula (I) are especially advantageous on account of their low toxicity and when n is 2, their non-clastogenicity in vitro.
The products of general formula (I) are more stable in acid conditions than the corresponding 16-oxocompounds either described in EP 135410 or of general formula (IV).
In vitro concentration g/ml In vivo dosage mg/kg s.c.
Compound No. alone with pristinamycin IA alone with pristinamycin IA 8 30 4 > 100 60 7 - 4 > 100 24 3 - 8 - 32 4 - 8 - 11 9 30 0.5 220 5.5 11 8 2 100 14 5 8 4 50 10 6 30 1 120 9 1 60 1 120 6.5 2 8 2 55 10 12 - 8 70 13 13 - 4 - 10 15 - 8 - 30 Compound 2/Compound of reference example 62 - 1 - 17 Compound 1/Compound of refetence example 62 - 1 - 7.5 TABLE I The products of special interest are those of formula (I) in which the symbol \ denotes:: - either a nitrogen-containing 5 or 6-membered heterocyclic ring radical unsubstituted or substituted by an alkyl radical, - or an alkyl chain of 2 to 4 carbon atoms and substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino of 3 to 6 ring atoms, and N-alkyl-N-cycloalkylamino of 3 to 6 ring atoms, alkylamino, dialkylamino, dialkylcarbamoyloxy (the alkyl moieties of these two latter radicals being unjoined or joined to form, with the nitrogen atom to which they are attached, a saturated or unsaturated 5 or 6membered heterocyclic ring which may contain another hetero-atom chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl), or substituted by a nitrogencontaining 5 or 6-membered heterocyclic ring which may contain another hetero atom chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone and unsubstituted or substituted by alkyl, this heterocyclic ring being linked to the alkyl by a carbon atom of the ring, it being understood that t sst one or the oubstituents carried by the above alkyl chain is 8 nitrogen-containing substituent capable of forming salts, and n is 1 or 2; and, among these products, those which are especially active are the products of formula (I) in which R denotes an alkyl chain containing 2 to 4 carbon atoms substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino of 5 to 6 ring atoms, N-alkyl-N-cycloalkylamino of 5 or 6 ring atoms, alkylamino of 1 to 4 carbon atoms, and dialkylamino (in which the alkyl moieties contain 1 to 3 carbon atoms each or form, with the nitrogen atom to which they are attached, a saturated 5 or 6-membered heterocyclic ring), or R denotes a nitrogen-containing 5 or 6-membered heterocyclic ring unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, at least one of the substituents carried by the alkyl chain being a nitrogen-containing substittent capable of forming salts, and at least one of the radicals carried by this chain is placed in 8 1- or 2- position, and n is 1 or 2.
For use in therapy, the compounds of formula (I)can be used as such, that is to say in the form of the base, in combination with already known synergistins, but, since the chief advantage of the products of the invention is their solubility in water, it is especially advantageous to use them in the form of pharmaceutically acceptable salts, in combination with known synergistins or with the synergistins of formula (V), dissolved either in the form of pharmaceutically acceptable salts or, where applicable, in the form of the base when the solubility is sufficient for the solution produced to contain ( in a volume suitable for a single dose) a quantity of active ingredient which is at least equal to the therapeutically active dose.
Both for the products of formula (I' and for the products of formula (V), the pharmaceutically acceptable salts which can be mentioned are the salts of addition with inorganic acids such as hydrochlorides, hydrobromides, sulphates, nitrates, phosphates, or with organic acids, such as acetates, propionates, succinates, maleates, fumarates, methanesulphonates, p-toluenesulphonates, isethionates, or substitution derivatives of these compounds.There can also be mentioned, as pharmaceutically acceptable salts, the salts with alkali metals (such as sodium and potassium salts), with alkaline-earth metals (SUCCi es the ;t), the ammonium salt and salts of addition with nitrogen-containing organic bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dibenzylamine, dicyclohexylbenzylamine, N-benzyl-B -phenethylamine, N,N'-dibenzylethylenediamine, benzhydrylamine, arginine, leucine, lysine or N-methylglucamine).
Quaternary ammonium salts corresponding to the anions listed above can be mentioned as pharmaceutically acceptable salts for the products of general formula (V) in which Z denotes a radical of general formula (VII) in which R4 denotes a trialkylammonio radical.
The following examples, given without implying any limitation, show how the invention can be put into practice. The NMR spectra of the products illustrated in these examples and in the reference examples which follow, show general characteristics which are common to all the products of general formula (I) or of general formula (V) and individual characteristics which are specific to each of the products, depending on the substituents. Only the individual characteristics due to the changeable radicals are mentioned in the examples or reference examples which follow.For the products of general formula (I), all the protons are designated according to the numbering indicated in the following formula:
For the synergistins of general formula (V) all the protons are designated according to the numbering indicated in the general formula (XXIII); this numbering is that recommended by J.O. Anteunis et al., (Eur. J. Biochem., 58, 259 (1975)).
Unless stated otherwise, all the spectra were recorded at 250 MHz in deuterochloroform; the chemical shifts are expressed in ppm relative to the tetramethylsilane signal. The abbreviations used in the following text are as follows: s = singlet d = doublet t = triplet mt = multiplet m = unresolved bands dd = doublet of doublets dt = doublet of triplets ddd = doublet of doublets of doublets dddd = doublet of doublets of doublets of doublets It is to be understood that the various isomers have been classified arbitrarily according to the chemical shifts observed in NMR.
The names isomer A1 and isomer A2 of the products of general formula (I) in which n = 1 are given to the isomers which have the characteristics: approximately 1.7 (s, -CH3 at 33); approximately 3.8 (s, # CH2 et 17) : < 5 (d, -H27) isomer A2 or > 5 (d, -H27) isomer A1; approximately 5.50 (broad d, -H13); approximately 6.20 (d, -H11); approximately 6.6 ( NH at 8); 3 8 (s, -H20).
The names isomer B1 and isomer B2 of the products of general formula (I) in which n = 1 are given to the isomers which have the characteristics: approximately 1.5 (s, -CH3 at 33); approximately 3.7 and 3.9 (2d, > CH2 at 17); approximately 4.8 (mt, -H13); < 5 (d, -H27) isomer 62 or > 5 (d, -H27). isomer B1; approximately 5.70 (borderline AB, -H11 and -H10); approxi mately 7.7 ( > NH at 8); approximately 7.8 (s, -H20).
The name isomer A of the product of general for mula (VII) is given to the isomer which has NMR characteris tics identical to those listed above for the isomers A1 and A2 of the products of general formula (I), it being understood that the H at 27 is characterized by: 4.7 (d, J 4 1 Hz).
The name isomer B of the product of general formula (VII) is given to the isomer which has NMR characteristics identical to those listed above for the isomers B1 and B2 of the products of general formule (I), it being understood that the H at 27 is characterized by: 4.6 (d, J y 2.5 Hz).
In the following examples, the name "flash" chroma tography is given to a purification technique in which a short chromatography column is used and operated under an intermediate pressure (50 kPa) with the use of a silica with a particle size distribution of 40-53 m, according to W.C. Still, M. Kahn and A. Mitra (J. Org. Chem. 43, 2923 (1978).
In the examples described below, unless stated otherwise, all the products can be dissolved at a strength of at least 2%, in the form of hydrochloride.
EXAMPLE 1 Compounds 1 and 2 To a stirred solution of 26-(2-diethylaminoethyl)- sulphonylpristinamycin IIB (isomer A) (7.9g) in methanol (250 cc) at room temperature was added portionwise sodium borohydride (0.47g) over 5 minutes.
After stirring at room temperature for 20 minutes dichloromethane (250 cc) and water (330 cc) were added and the organic phase separated. The aqueous phase was extracted with a further 100 cc of dichloromethane, the combined organic phases were dried over anhydrous magnesium sulphate and evaporated to dryness affording a light yellow solid (7.lg).Partial purification by "flash" chromatography on silica was carried out [eluent: chloroform-methanol (90-10 by volume)] 100 cc fractions being collected, according to the following scheme: Purification Scheme
Batch A (7.lug) "flash" chromatography Batch B (2.3g) Batch C (2.5g) Fractions 3-7 Fractions 10-15 "fast" n "810X" Batch B was combined with a similar batch (B1, 0.6g) [and batch C was combined with a similar batch (C1, l.Og)], produced from treating 3.3g of 26-(2-diethylaminoethyl) sulphonylpristinamycin IIB (isomer A) with sodium borohydride according to the conditions above.
Further purification of the combined batches B+B1 by "flash" chromatography on silica [eluent: ethyl acetate-methanol (90-10 by volume)] 30 cc fractions being collected, was carried out. After concentrating fractions 34 to 39 to dryness under reduced pressure at 40-45"C, dissolving the residue (0.66g) in ethyl acetate (6 cc) and pouring the solution into light petroleum (bp 40-600C) (70 cc), 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16alpha-hydroxypristinamycin 11B (isomer A) ("fast" 16-stereoisomer) was obtained as a colourless solid (0.55g) melting slowly above 104"C. Found: C, 58.4; H, 7.6; N, 7.7; S, 4.47%.
Calculated for C34H52N4OgS: C, 58.9; H, 7.6; N, 8.1; S, 4.63%.
Further purification of the combined batches C+C1 by "flash" chromatography on silica [eluent: ethyl acetate-methanol (85-15 by volume)] 30 cc fractions being collected, was carried out. After concentrating fractions 31 to 39 to dryness under reduced pressure at 40-450C, dissolving the residue (1.0g) in ethyl acetate (7 cc) and pouring the solution into light petroleum (bp 40-600C) (75 cc), 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16beta-hydroxypristinamycin 11B hydrate (isomer A) ("slow" 16-stereoisomer) was obtained as s colourless solid (0.66g) melting slowly above 106 C.
Found: C, 57.7; H, 7.4; N, 7.8; S, 4.53%. Calculated for C34H52N409S.H20: C, 57.4; H, 7.67; N, 7.88; S, 4.51%.
EXAMPLE 2 Compounds 3 and 4 To a stirred solution of 26-(2-diisopropylaminoethyl)thiopristinamycin 11B (isomer A) (4.0g) in methanol (80 cc) at room temperature was added dropwise over 15 minutes a solution of sodium borohydride (0.296g) in water (6 cc), whilst maintaining the reaction temperature at 250C with external cooling.
The resulting clear solution was stirred for a further 75 minutes at room temperature then poured into water (700 cc) and the pH of the solution adjusted to 4 by addition of dilute hydrochloric acid (1M). The pH of the solution was then adjusted to 8 by addition of dilute sodium hydroxide solution (1M) and extracted twice with chloroform (total 400 cc). The aqueous phase was saturated with sodium chloride and further extracted with ethyl acetate (500 cc). The combined chloroform and ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated affording a colourless syrup (4.5g).Two successive purifications by "flash" chromatography on silica were carried out [eluent: chloroform-methanol (90-10 by volume)] 50 cc fractions being collected, according to the following scheme: Purification Scheme
Batch A (4.5g) "flash" "flash" chromatography Batch B (3.5g) Fractions 8-17 Fractions 18-23 "flash" chromatography J Batch D (l.lg) Batch E (1.2g) Fractions 23-28 Fractions 33-48 In all cases, the fractions recovered were concentrated to dryness under reduced pressure at 40-450C.
Batch D was dissolved in ethyl acetate (30 cc), the solution was filtered and poured into hexane (120 cc) affording 16-deoxy-26-(2-diisopropylaminoethyl)thio16alpha-hydroxypristinamycin IIB hydrate (isomer A) ("fast" 16-stereoisomer) as a white powder (0.83g) melting slowly above 115 C. Found: C, 60.4; H, 8.0; N, 7.8; S, 4.58; H20, 2.55%. Calculated for C36H56N407S .H20: C, 61.2, H, 8.27; N, 7.93; S, 4.54; H2Q2.55%.
Batches C and E were combined, dissolved in ethyl acetate (35 cc), the solution was filtered and poured into hexane (150 cc) affording 16-deoxy-26-(2-diisopropylaminoethyl)thio-16beta-hydroxy pristinamycin IIB hydrate (isomer A) ("slow" 16-stereoisomer) as a white powder (0.92g) melting slowly above 120 C Found: C, 60.8; H, 7.9; N, 7.8; S, 4.56; H20, 2.7%: Calculated for C36H56N407S.H20: C, 61.2; H, 8.27; N, 7.93; S, 4.54; H2O, 2.55%.
EXAMPLE 3 Compounds 5 and 6 To a stirred solution of 26-(2-diisopropylaminoethyl)sulphinylpristinamycin IIB (isomer A2) (4.0g) in methanol (100 cc) at room temperature was added portionwise sodium borohydride (0.4g) over l0minutes, whilst maintaining the reaction temperature at 250C with external cooling. The resulting clear solution was stirred for a further 5 minutes at room temperature then poured into water (750 cc). Glacial acetic acid (5 cc) was added to adjust the pH of the solution to 4, followed by addition of solid sodium bicarbonate to bring the pH to 7.5.The mixture was extracted with ethyl acetate (2x29 cc), the extracts were dried over anhydrous magnesium sulphate and evaporated yielding a golden meringue (3.5g), which was purified by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume, followed by 80-20 by volume) 50 cc fractions being collected. Fractions 17 to 24 were combined and concentrated to dryness under reduced pressure at 40-450C to give a white solid (0.9g) which was dissolved in ethyl acetate (20 cc).
After filtering the solution, hexane (100 cc) was added and the precipitate separated off by filtration to give 16-deoxy-26- (2-diisopropylaminoethyl) sulphinyl-l6alpha- hydroxypristinamycin 11B hydrate (isomer A2) ("fast" 16-stereoisomer) as a white powder (0.55g) melting slowly above 1200 C.
Fractions 31 to 40 were combined and concentrated to dryness under reduced pressure at 40-450C to give a white solid (1.3g) which was dissolved in ethyl acetate (20 cc). After filtering the solution, hexane (100 cc) was added and the precipitate separated off by filtration to give 16-deoxy-26-(2-diisopropylaminoethyl)sulphinyl-16beta-hydroxypristinamycin IIB hydrate (isomer A2) ("slow" 16-stereoisomer) as a white powder (0.7g) melting slowly above 120 C. Found: C, 59.0; H, 7.6; N, 7.5; S, 3.9; H20, 3.1%: Calculated for C36H56N4O8S.1.5 H20: C, 59.1; H, 8.13; N, 7.7; S, 4.4; H20, 3.7%.
EXAMPLE 4 Compound 7 To a stirred solution of 2-diethylaminoethanethiol hydrochloride (0.65g) in methanol (40 cc) under nitrogen was added sodium methoxide (0.21g) portionwise followed by 16-deoxy-16beta-hydroxypristinamycin 11A ("slow" 16-stereoisomer) (2g). The pale yellow solution was kept at room temperature for 18 hours, evaporated to low volume and absorbed onto silica then purified by "flash" chromatography on silica [eluent: chloroform-methanol (90-10 by volume)] 40 cc fractions being collected. Fractions 8 to 15 were combined and concentrated to dryness under reduced pressure at 40-45"C. The residue (1.23g) was further purified by "flash" chromatography on silica [eluent: methanol] 7 cc fractions being collected. Fractions 18 to 36 were combined and concentrated to dryness under reduced pressure at 40-450C to give a white solid (0.73g) which was dissolved in ethyl acetate (7 cc). The solution was poured into light petroleum (b.p. 40-60"C) (75 cc) affording 16-deoxy-26-(2-diethylaminoethyl)thio16beta-hydroxypristinamycin IIB hemihydrate (isomer A) as a white powder (0.6g) melting slowly above 105 C to give a complete melt at 125"C. Found: C, 60.6; H, 8.0; , 8.2;S, 4N66; H20, 1.4%.
Calculated for C34H52N407S.0.5H20: C, 60.9; H, 7.98; N, 8.36; S, 4.79; H20, 1.34%.
EXAMPLE 5 Compound 8 To a stirred solution of 16-deoxy-16alpha-hydroxypristinamycin IIA ("fast" 16-stereoisomer) (1.54g) in methanol (40 cc) under argon at 0 C was added 2-diethylaminoethanethiol hydrochloride (0.501g) followed by sodium methoxide (0.162g) portionwise. The resulting pale yellow solution was kept at 5 C for 42 hours, evaporated to 5 cc volume and purified by "flash" chromatography on silica (eluent: methanol) 13 cc fractions being collected. Fractions 12 to 17 @@@@ @@@bined and concentrated to dryness under reduced pressure at 40-45 C to give a white solid (1.2g) which was dissolved in ethyl acetate (3 cc).The solution was poured into light petroleum (b.p. 40-600C) (10 cc) affording 16-deoxy- 26- (2-diethylaminoethyl) thio-l6alpha-hydroxy- pristinamycin IIB (isomer A) as a white powder (l.Og) melting slowly above 112 C to give a complete melt 122-125 C. Found: C, 61.4; H, 8.0; N, 8.2; S, 4.56%.
Calculated for C34H52 N407S: C, 61.8; H, 7.93; N, 8.48; S, 4.85.
EXAMPLE 6 Compounds 9, 10 and 11 To a stirred solution of 16-deoxy-26-(2-diethylaminoethyl)thio-16alpha-hydroxypristinamycin IIB (isomer A) ("fast" 16-stereoisomer) (3.4g) in dichloromethane (250 cc) at 5 C was added trifluoroacetic acid (0.594g) followed by 3-chloroperbenzoic acid (0.892g). After stirring at 50C for 18 hours the reaction mixture was evaporated under reduced pressure at 40-45 C. The residue was purified by "flash" chromatography on silica [eluent: chloroform- methanol (87-13 by volume)] 20 cc fractions being collected.
Fractions 26 to 34 were concentrated to dryness under reduced pressure at 40-450C and the residue further purified by "flash" chromatography as above. Fractions 10 to 16 afforded after concentration to dryness under reduced pressure at 40-450C 16-deoxy-26-(2-diethylaminoethyl)sulphinyl- 16alpha-hydroxypristinamycin IIB (isomer A2) ("fast" 16-stereoisomer) as a white powder (0.6g) m.p. 138-1400C. Found: C, 57.4; H, 7.3; N, 7.6; S, 4.61; C1, 3.61; H20, 1.62. Calculated for C34H52N408S. 0.6H20. 0.25 CHC13: C, 57.3; H, 7.51; N, 7.81; S, 4.47; C1, 3.71; H20, 1.51%.
Fractions 36 to 46 from the first purification step were concentrated to dryness under reduced pressure at 40-450C affording 16-deoxy-26-(2-diethylaminoethyl)sulphinyl-16alpha-hydroxypristinamycin IIB (isomers A1 + A2) ("fast" 16-stereoisomer) as a white solid (0.5g), m.p. 138-140 C. Found: C, 57.7; H, 7.4; N, 7.7; S, 4.52; C1, 3.10; H20, 1.13%. Calculated for C34H52N4O8S. 0.45H20.0.22 CHC13: C, 57.4; H, 7.73; N, 7.88; S, 4.51; C1 3.3; H2O, 1.14%.
By proceeding in a similar manner but using the isomeric Compound 7 prepared in Example 4 there was prepared 16-deoxy-26-(2-diethylaminoethyl)sulphinyl- 16beta-hydroxypristinamycin (isomer A A2).
EXAMPLE 7 Compounds 12 and 13 To a solution of 16-deoxy-16beta-hydroxy pristinamycin II, ("slow" 15-stereoisomer) (1.05g) in ethanol (15 cc) was added ethylamine (5 cc of a 33% w/w solution in ethanol), kept at room temperature for 90 hours and then evaporated to dryness. The resultant pale brown solid was purified by "flash" chromatography on silica [eluent: chloroform-methanol (90-10 by volume)]. The second component eluted, after concentration to dryness under reduced pressure at 40-45 C, was dissolved in ethyl acetate. Addition of light petroleum (b.p. 40-600C), followed by filtration, gave 16-deoxy-26-ethylamino-16beta-hydroxypristinamycin IIB hydrate (isomer A) as a white powder (0.46g), m.p. 135-137 C. Found: C, 60.6; H, 7.5; N, 9.4; H20, 2.1%.Calculated for C30H44N4O7. 0.9H2O : C, 61.18 ; H, 7.84; N, 9.51; H20, 2.75%.
By proceeding in a similar manner but using the isomer 16-deoxy-16alpha-hydroxypristinamycin IIA (0.92g), the isomeric 16-deoxy-26-ethylamino-16alphahydroxypristinamycin IIB hydrate (isomer A) was obtained as a white powder (0.5g) m.p. 131-134 C.
Found: C, 62.8; H, 7.9; N, 9.7; H20, 1.5%.
Calculated for C30H44N407. 0.25H20: C, 62.4; H, 7.77; N, 9.71; H20, 0.78%.
EXAMPLE 8 Compounds 14 and 15 To a solution of 16-deoxy-16alpha-hydroxy- pristinamycin IIA ("fast" 16-stereoisomer) (1.5g) in ethanol (60 cc) was added 2-diethylaminoethylamine (1 cc) and the mixture was stirred at room temperature for 30 hours. After evaporating to dryness under reduced pressure at 40-450C the residual brown solid was purified by "flash" chromatography on silica [eluent: ethyl acetate-methanol (92-8 by volume)] 35 cc fractions being collected. Fractions 15-45 were combined and evaporated to dryness under reduced pressure at 40-450C affording a white solid (0.45g).
This material was combined with a second batch prepared from reacting 1.6g 16-deoxy-16alpha-hydroxypristinamycin IIA ("fast" 16-stereoisomer) in ethanol (70 cc) with 2-diethylaminoethylamine (1.08 cc) as above. The combined batches were further purified by "flash" chromatography on silica [eluent: ethyl acetate-methanol (98-2 by volume)] 30 cc fractions being collected. Fractions 31-59 were combined and concentrated to dryness under reduced pressure at 40-45"C to give a white solid (0.8g) which was dissolved in ethyl acetate. The solution was filtered and light petroleum (b.p. 40-600C) was added. On cooling 16-deoxy-26-(2-diethylaminoethyl)amino-16alphahydroxypristinamycin IIB hemihydrate was obtained as white crystals (0.7g) m.p. 118-1200C. Found: C, 62.1; H, 8.4; N, 10.3; H20, 1.3%. Calculated for C34H53N5O7.0.5H2O : C, 62.6; H, 8.3; N, 10.7; H20, 1.4%.
By proceeding in a similar method but using the i someric 16-deoxy-16beta-hydroxypristinamycin IIA (1.4g), the isomeric 16-deoxy-26-(2-diethylaminoethyl)amino-16-betahydroxypristinamycin IIB hydrate was obtained as white crystals (0.49g) m.p.
123-125 C. Found: C, 59.5; H, 8.0; N, 10.0%.
Calculated for C34H53N5O7.2.5H2O : C, 59.3; H, 8.5; N, 10.2X.
EXAMPLE 9 By using the same method as that described in Example 2 of European Patent Publication No. 191662, but starting from 26-(2-cyclopentylaminoethyl)thiopristinamycin 11B (isomer A)(2.9 g), sodium bicarbonate (0.72 g), and 98% meta-chloroperbenzoic acid (0.75 g) at -30 C, and after purification by "flash" chromatography [eluent : dicliloromethane- methanol (90-10 by volume)], 30 cc fractions being collected, and concentrating fractions 25 to 31 to dryness under reduced pressure (2.7 kPa) at 300C, a yellow solid (0.7 g) is obtained which is re-purified by "flash" chromatography [eluent : dichloromethanemethanol (95 - 5 by volume)], 20 cc fractions being collected.After concentrating fractions 78 to 95 to dryness under reduced pressure (2.7 kPa) at 300C, 26-(2-cyclopentylaminoethyl) sulphinylpristinamycin IIB (isomer A2)(2.3 g) is obtained in the form of a pale yellow solid melting at about 1l40O.
NMR spectrum 1.30 to 2.25 (mt,
of cyclopentyl) 1.76 (s, -CH3 at 33) 2.80 (mt, -H4)
4.81 (d, -H27) 5.53 (d, - 6.19 (d, -H11) 6.30 (mt, zNH at 8) 8.15 (s, -H20) 26-(2-cyclopentylaminoethyl)thiopristinamycin IIB (isomer A) can be prepared by using the same procedure as that described in Example 2 of European Patent Publication No. 191662, but starting from pristinamycin 11A (15 g) and 2-cyclopentylamino- ethanethiol (4.3 g).After stirring for 3 days at -20 C and purification by "flash" chromatography [eluent dichloromethane-methanol (90-10 by volume)], 30 cc fractions being collected, followed by concentration of fractions 69 to 92 to dryness under reduced pressure (2.7 kPa) at 30 C, a yellow solid (5.2 g) is obtained, which is dissolved in a mixture of acetone (45 cc) and diethyl ether (90 cc). The precipitate which forms is separated by filtration and then dried under reduced pressure (90 Pa) at 350C to give 26-(2-cyclopentylaminoethyl)thiopristinamycin IIB (isomer A)(2.9 g) in the form of a pale yellow solid melting at about 144 C.
NMR spectrum: 1.50 to 2 (mt, sCH2 of cyclopentyl) 1.73 (s, -CH3 at 33) 2.78 (mt, -H4) 2.85 to 3.05 (mt, -S-CH2-CH2N#) 2.88 and 3.18 (2d, #CH2 at 15)
3.42 (mt, -H26) 3.82 (s, ,CH2 at 17) 4.70 (d, -H27) 5.48 (d, -H13) 6.18 (d, -Hll 6.82 (mt, )NH at 8) 8.15 (s, -H20) 2-cyclopentylaminoethanethiol can be obtained by a method similar to that described by D.D. Reynolds et al., J.Org.Chem. 26, 5109 (1961).
REFERENCE EXAMPLE 1 3-Mercaptoquinuclidine (2.8 g) is added to a solution of 56-methylenepristinamycin IA (4.4 g) in a mixture of methanol (40 cc) and chloroform (20 cc), and the solu- tion obtained is then stirred for 44 hours at a te.pera- ture in the region of 20 C. The region mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 300C. The residue obtained is suspended in ethyl ether (100 cc) and then separated by filtration. The solid thereby obtained is washed with ethyl ether (3 x 10 cc) and then purified by flash chroeatography (eluant:- methylene thloride/methanol (90:10 by volume)], collecting 100-cc fractions.The fractions 11 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at 300C. The residue is stirred in ethyl ether (120 cc). The solid obtained is separated by fil tration and then purified again by flash chroeatography [eluant : methylene chloride/methanol (85:15 by volume)], collecting 100-cc fractions. Fractions 3 to 7 are col- bined and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. The residue is stirred in ethyl ether (50 cc) and the solid thereby obtained separated by filtration, washed with ethyl ether (3 x 5 cc) and then dried under reduced pressure (27 Pa) at 200C.
5 #-[(3-Quinuclidinyl)thiomethyl]pristinamycin IA (1.7 g) is thereby obtained in the form of a pale yellow solid, m.p. about 200 C.
NMR spectrum Mixture of 4 isomers 2.88 and 2.89 (2s, 4 -N(CH3)z) 3.21 and 3.22 (2s, 4 -CH3) 6.51 and 6.53 (2d, 2 -NH-) 6.57 and 6.58 (2d, 4#) 7.82 and 7.85 (o, the H6 of the 2 preponderant isomers 7.95 (1, the H6 of the 2 minority isomers 8.78 and 8.81 (2d, 6 -NH- of 2 preponderant isomers) 8.98 and 9.0 (2d, 6 -NH- of the 2 minority isomers) A 5 X strength aqueous solution of 5#-[(3-quinucli- dinyl)thiomethyl]pristamycin IA is obtained with: product ............................ 100 mg 0.1N hydrochloric acid.. 0.98 cc distilled water qs 2 cc 3-Mercaptoquinuclidine lay be prepared in the following anner:: Sodium methylate (0.5 g) is added to a solution of 3-(acetylthio)quinuclidine (14.5 g) in methanol (150 cc).
The reaction mixture is then heated under reflux for 1 hour. Sodium aethylate (0.5 g) is added again and the fixture is then heated under reflux for 2 hours. The reaction fixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. Distilled water (40 cc) is added to the residue obtained, followed by acetic acid (approxinately 1 cc) to obtain a pH in the region of 8.
The mixture obtained is extracted with ethylene chloride (3 x 20 cc). The combined organic phases are dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 300C. The brown oiL obtained is distilled under reduced pressure (920 Pa); the fraction distilling at about 94 0C is collected.
3-Mercaptoquinuclidine (2.8 g) is thereby obtained.
3-(Acetylthio)quinuclidine lay be obtained in the following manner: Diisopropyl azodicarboxylate (31.6 cc) is added dropwise in the course of 30 minutes to a solution, ain- tained at 50C under an atmosphere of nitrogen, of triphenylphosphine (42 g) in tetrahydrofuran (300 cc). The suspension obtained is then stirred for 30 minutes at 5 C. A solution of 3-hydroxyquinuclidine (10.2 g) and thiolacetic acid (11.4 cc) in tetrahydrofuran (600 cc) is then added to this suspension, aaintained at 5 C, in the course of 30 minutes. The reaction fixture is then stirred for 20 hours at a temperature in the region of 20 C.
It is then concentrated to dryness under reduced pressure (2.7 kPa) at 4OC. The oil obtained if dissolved in ethyl ether (400 cc), and then washed with hydrochloric acid (3 x 160 cc). The coibined aqueous phases are washed with ethyl ether (100 cc) and then neutralized to a pH in the region of 7 by adding sodiun bicarbonate. The pH of the solution obtained is then adjusted to about 9 by adding a few drops of 10N aqueous sodium hydroxide solution.
The mixture is extracted with methylene chloride (3 x 200 cc). The combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 300C. 3-(Acetylthio)quinuclidine (14.7 g) is thereby obtained in the for. of a brown oil tRf = 0.33; eluant : methylene chloride/methanol (90:10 by volume)).
REFERENCE EXAMPLE 2 Working in a tanner similar to that described in Ref. Ex.1, but starting with 5#-methylenepristinamycin 1A (6.15 g) and (3S)-3-mercaptoquinuclidine (1.1 g) and after two purifications by flash chrosatography, collected ing 50-cc fractions [ist flash chromatography : eluant : methylene chloride/iethanol (90:10 by volume), concentration to dryness of the fractions 12 to 36; 2nd flash chromatography : eluant : methylene chloride/methanol (90:10 by volume), concentration to dryness of the fractions 3 to 203, 5 #-[[(3S)-3-quinuclidinyl]thiomethyl]pristina- glycin IA (2.6 g) is obtained in the form of a pale yellow powder.This product say be obtained in the crystallized state in the following manner 5#-{[(3S)-3-Quinuclidinyl]thiomethyl}pristinamycin IA (2.6 9) is dissolved in methanol (20 cc). A yellow solu tion i obtained. After filtration and drying under reduced pressure (27 Pa) at 30 C, a crystalline precipitate appears after priming by scratching 5#-{[(3S)-3- Quinuclidinyl]thiomethyl}pristinamycin IA (1.2 g) is obtained in the form of white crystals, m.p. about 200 C (product crystallized in combination with ethanol).
NMR spectrum; 1 isomer (traces of the isomer in respect of the 5# carbon) 0.62 (dd, J = 15 and 6, 1H, 5B2)
4.98 (dd, J = 14 and 7.5, IN, 5#) 5.30 m, 2H, 5a and 4) 7.90 (dd, 1H, the Hg) 5#-{[(3S)-3-Quinuclidinyl]thiomethyl}pristina- mycin IA may also be crystallized in the following manner : 5#-{[(3S)-3-Quinuclidinyl]thiomethyl}pristina- mycin IA (17.4 g) is dissolved in acetone (87 cc) which has been brought to reflux beforehand. The solution obtained is filtered and the insoluble arterial is rinsed with acetone (10 cc). After 3 hours at 200C, the crystals obtained are filtered and then dried.Recrystallization of the product (14.8 g) obtained in acetone (75 cc) under the same conditions gives, after filtration followed by drying under reduced pressure (90 Pa) at 200C, white crystals (12.2 g), .p. about 185-1900C.
(3S)-3-Mercaptoquinuclidine may be obtained in the following manner: 10N aqueous sodium hydroxide solution (30 cc) is added slowly to a solution of (3S)-3-(acetylthio)quinu- clidine (29 g) in methanol (30 cc) maintained at approxilately 25 C. The reaction fixture is stirred for 2 hours at a teoperature in the region of 20 C. The pH of the reaction fixture is then brought to a value in the region of 9 by adding acetic acid (approxi.ately 10 cc). The mixture obtained is extracted with ethylene chloride (3 x 100 cc). The combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 300C.The residue obtained is purified by distillation under reduced pressure (970 Pa). (3S)-3-Mercaptoquinuclidine (12 g) is thereby obtained in the for. of white crystals which melt at 46 C and distil at 95 C under 970 Pa (&alpha;D20=-118 , C= 1.1, methanol).
(3S)-3-(Acetylthio)quinuclidine may be obtained in a manner similar to that described in-Rer. Ex. 1, but starting with triphenylphosphine (104.8 g), diisopropyl azodicarboxylate (80.8 g) and (3R)-3-hydroxyquinuclidine (25.7 g). (3S)-3-(Acetylthio)quinuclidine (30 g) is thereby obtained in the for. of a yellow oil [Rf = 0.2; eluant ; methylene chloride/methanol (90:10 by volume)].
According to R.P. Volante, Tet. Let., 22 (33), 3119 (1981) the 3 carbon of (R) configuration is converted to carbon of (S) configuration during the reaction.
(3R)-3-Hydroxyquinuclidine is prepared according to the method described by B. RINGDAHL, B. RESUL and R. DAHLBOM, Acta Phar.a. Suec. 16, 281 (1979).
REFERENCE EXAMPLE 3 Working in a manner similar to that described in Ref. Ex. 1, but starting with 5#-methylenepristinamycin 1A (6.15 g) and (3R)-3-iercaptoquinuclidine (1 g), and after a purification by flash chromatography, collecting 40-cc fractions (eluant: ethylene chloride/methanol (85:15 by volume)), and concentration to dryness of the fractions 20 to 30, 5#-{[(3R)-3-quinuclidinyl]thiomethyl}pristina- mycin IA (2 9) is obtained in the for. of a beige pow der, m.p. about 2000C.
NMR spectrum 0.58 (dd, J = 15 and 5.5, 1H, 562) 1.5 to 2.2 (c,
2.30 (c, 1H, 58) 2.35 (d, J = 15, 1H, 5B1) 2.50 (dd, 1H of -CH2S-) 2.60 (dd, 1H, 5#2)
4.95 (dd, iH, 5#1) 5.28 (c, 2H, 5&alpha; and 4&alpha;) 7.87 (c, 1H x 0.85, the H6 of the 1st isomer) 7.93 (c, 1H x 0.15, the H6 of the 2nd isomer) 5#-{[(3R)-3-Quinuclidinyl]thiomethyl}pristina- glycin 1A lay be recrystallized in the following manner : : 5#-{[(3R)-3-Quinuclidinyl]thiomethyl}pristina- glycin IA (14.15 g) is dissolved in ethanol (75 cc).
Distilled water (4 cc) is added to this solution, which is then left to crystallize at 4 C. The crystals obtained are filtered off and then rinsed with a ethanol/ water (95:5 by volume) mixture (4 x 10 cc). After being dried under reduced pressure (90 Pa) at 420C, white crystals (10.22 g) are obtained, m.p. about 1900C.
(3R)-3-Mercaptoquinuclidine may be obtained in a tanner similar to that described in Ref. Ex.2, but starting with (3R)-3-(acetylthio)quinuclidine (32.5 g) and ION aqueous sodium hydroxide solution (35 ec) (3R)-3 .ercaptoquinuclidine (11.5 g) is obtained in the for. of white crystals which melt at'450t and distil at 900C under 830 Pa (20 = +1210, C = 1.1, ethanol).
0 (3R)-3-(Acetylthio)quinuclidine may be obtained in a manner similar to that described in Ref. Ex. 1, but starting with triphenylphosphine (104.8 g), diisopropyl azodicarboxylate (80.8 g) and (3S) 3-hydroxyquinuclidine (25.7 g). (3R)-3-(Acetylthio)quinuclidine (33.8 g) is thereby obtained in the for. of a pale brown oil (Rf = 0.4; eluant: ethylene chloride/iethanol (80:20 by volume)3.
(3S)-3-Hydroxyquinuclidine is prepared according to the method described by 6. RINGDAHL et al., Acta Pharm.
Suec. 16, 281 (1979).
REFERENCE EXAMPLE 4 Working in a anner similar to that described in Ref. Ex. 1, but starting with 56-.ethylenepristinamycin IA (3.5 g) and 4-iercaptoquinuclidine (0.6 g) and after concentration to dryness, a solid is obtained which is stirred in ethyl ether.After filtration, a beige solid (3.6 g) is isolated, and purified by flash chroiatography, collecting 50-cc fractions teluant: methylene chlorides methanol (85:15 by volume)). After concentration to dryness of fractions 19 to 35, washing with ethyl ether, with tration ad then drying of the resulting solid under reduced pressure (2.7 kPa) at 20 C, 5#-[(4-quinuclidinyl)- thiomethyl]pristinamycin IA (1.2 g) is obtained in the for. of an off-white powder, m.p. about 2000C.
NMR spectrum (2 isomers in respect of the 56 carbon, in the ratio 85:15 approximately): 0.62 (dd, J = 15 and 5.5, 1H, 5B2)
2.20 (c, 1H, 56) 2.28 (c, 1H, -CH2-S-) 2.35 (d, J = 15, 1H, 5ss1) 2.47 (dd, 1H, 5s2)
3.22 (dd, 1H, -CH2-S-) 5.01 (dd, iH, 5#1) 5.29 (broad d, J = 5.5, 50) 7.86 (c, 0.85H, the H6 of the preponderant isomer 7.92 (c, 0.15H, the H6 of the minority isomer) 4-Mercaptoquinuctidine may be obtained according to the method described by A. GROB, Melv. Chim. Acta, 57, 2339 (1974).
REFERENCE EXAMPLE 5 The procedure is similar to that described in Ref. Ex. 1, but starting with 5#-methylenevirginiamycin S (1.2 g) in methanol (20cc) and (3R)-3-mercaptoquinuclidine (0.21 g). After purification by flash chromatography, collecting 10-cc fractions Celuant: methylene chloride/.ethanol (95:5 by volume up to the fraction 35, then methylene chloride/ methanol (80:20 by volume)], concentration to dryness of the fractions 47 to 55 and drying under reduced pressure (2.7 kPa) at 300C, 5#-{[(3R)-3-quinuclidinyl]thiomethyl}- virginiamycin S (0.6 g) is obtained in the form of an offwhite powder, ..p. about 1850C.
NMR spectrum (2 isomers in respect of the 5 6 carbon, in the-ratio 80:20 approximately): 0.4 (dd, J = 15 and 5.5, 1H, 5ss2)
2.34 (d, J = 15, IH, 5ss1) 2.52 (dd, 1H of -CH2S-) 2.63 (dd, lH, 5E2)
4.94 (dd, 1H, 5#1) S Z7 (broad d, J = 5, IH, 50) 7.82 (dd, J = 4 and 1, the H6 of the 1st isomer 7.9 (dd, J = 4 and 1, the H6 of the 2nd isomer) REFERENCE EXAMPLE 6 The procedure is similar to that described in Ref. EX. 1, but starting with 5#-methylenevirginiamycin S(1.1g) in methanol (20 cc) and (3S)-3-mercaptoquinuclidine (0.19 g). Lfter purification by flash chromatography, collecting 10-cc fractions [eluant : ethylene chloride/methanol (90:10 by volume)), concentration to dryness of fractions 19 to 32 and drying under reduced pressure (2.7 kPa) at 300C, 5e- [(3S)-3-quinuclidinyl]thiomethyl virginiamycin S (0.5 g) is obtained in the form of a pale yellow powder, m.p. about 1900C.
NMR spectrum (2 isomers in respect of the 5 carbon, in the ratio 85:15 approximately): 0.39 (dd, J = 15 and 5, 1H, 562)
2.34 (d, J = 15, 1H, 5ss1) 2.52 (dd, 1H of -6H2S-) 2.64 (dd, 1H, 5#2)
5.27 broad d, 1H, 5a) 7.80 (dd, J = 4 and 1, 1H x 0.85, the H6 of the 1st isomer) 7.90 (dd, J = 4 and 1, 1H x 0.15, the H6 of the Znd isomer) REFERENCE EXAMPLE 7 Working in a manner similar to that described in Ref. Ex.2, but starting with (3S)-3-mercaptoquinuclidine (1.62 g) and stirring at -20 C for 20 hours, a beige zeringue-like product (11.4 g) is obtained after concentration to dryness under reduced pressure (2.7 kPa) at 300C, and this is stirred in diethyl ether (100 cc), fil- tered and then rinsed with the same solvent (3 x 20 cc).
This product may be recrystallized in acetone as described in Ref. Ex.2, to give 5#-{[(3S)-3-quinuclidinyl]thiomethyl}- pristinamycin 1A (6.6 g) in the form of white crystals, m.p. about 198-200 0C, the characteristics which are identical to those of the product obtained in Ref, Ex.2, and containing 3 X of minority isomer assayed by HPLC.
REFERENCE EXAMPLE 8 (3S)-3-nercaptoquinuclidine (0.18 g) dissolved in acetone (5 cc) is added at -200C in the course of 1 hour to a solution of 56-nethylenepristinamycin IA (1 g) in acetone (20 cc). After 18 hours' stirring at -20 C, the reaction mixture is filtered and the solid rinsed with acetone (3 x 2 cc).After being dried in the air, 5s- {[(3S)-3-quinuclidinyl]thiomethyl}pristinamycin 1A (0.6 g) is obtained in the form of uhite crystals, m.p. about 1900C, the characteristics of which are identical to those of the product obtained in ef. Ex.2 and containing 3 X of the minority 5#-isomer assayed by HPLC.
REFERENCE EXAMPLE 9 (3S)-3-Mercaptoquinuclidine (0.16 g) dissolved in acetone (5 cc) is added at -780C to a solution of 56methylenepristinamycin IA (1.22 g) in acetone (15 cc), and the solution obtained is stirred under nitrogen for 24 hours at -78 0C. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 300C to give 1.4 g of a cream-white solid containing 5 X of inority isomer assayed by HPLC and having characteristics identical to those of the product obtained in Ref. Ex. 2.
The present invention also provides pharmaceutical compositions comprising a compound of the formula (I), in the free form or, preferably, in the form of an addition salt with a pharmaceutically acceptable acid, optionally in association with a known synergistine or, preferably, a synergistine of the formula (XI) or (XIV) it being possible for the composition or association also to contain any other pharmaceutically compatible product which is inert or physiologically active. The compositions of the invention can he administered by parenteral, oral, rectal or topical route.
Sterile compositions for parenteral administration can be, preferably, aqueous or nonaqueous solutions, suspensions or emulsions. Water, propylene glycol, r poly (ethylene glycol), vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents, can be used as a solvent or vehicle. These compositions can also contain adju- vants, especially vetting agents, isotonizing agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in various ways, for example by an asepticizing filtration, by adding sterilizing agents to the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved in an injectable sterile medium at the time of use.
Tablets, pills, pouders or granules can be employed as solid compositions for oral administration. In these compositions, the active product according to the invention (optionally combined with another pharmaceutically compatible product) is nixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch. These compositions can also comprise substances other than diluents, for example a lubricant such as magnesium stearate.
Pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used as liquid compositions for oral administration. These compositions can also comprise substances other than the diluents, for example wetting agents, sweeteners or flavourings.
Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active substance, excipients such as cocoa butter, semi-synthetic glycerides or poly(ethylene glycols).
Compositions for topical administration aan be, for example, creams, salves, lotions, eye lotions, mouth washes, nasal drops or aerosols.
In general, when the compounds of general formula (I) are associated with known synergistins,or synergistins described in EP 133096 or 133097 or of formula (xI) the ratio is from l0:9O' to 90:10; preferably 50% to 50% wt/wt.
In human therapy, the products according to the invention, which may be combined with known synergistins or preferably with synergistins of general formula (XI) or (XIV) are especially useful in the treatment of infections of a bacterial origin. The dosages depend on the required effect and on the duration of treatment; for an adult, they are generally between 500 and 2000 mg per day by parenteral route, especially by an intravenous route such as a slow perfusion, the dosage of known synergistin or synergistin of general formula (XI) or (XIV) if present itself being between 500 and 2000 mg per day.
As a general rule, the practitioner will determine the dosage which he or she considers the most suitable, depending on the age, weight and all the other individual characteristics of the subject to be treated.
The following examples, given without implying any limitation, illustrates the compositions according to the invention.
EXAMPLE A An injectable solution for perfusion, containing 5 g/l of active product having the following composition is prepared: - 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16alpha- hydroxypristinamycin IIB (isomer A) 5 g - 0.1 N aqueous solution of hydrochloric acid 49 cc - distilled water q.s. 1000 cc EXAMPLE B An injectable solution for perfusion, containing 1 g/l of active mixture having the following composition is prepared:: - 16-deoxy-26-(2-diethylaminoethyl)sulphinyl-16alpha- hydroxypristinamycin IIB (isomer A2) 0.6 g - 5 8 -[2- (4-methyl-l-piperazinyl) ethyl]- thiomethylpristinamycin IA 0.4g - 0.1 N aqueous solution of hydrochloric acid 12.7 cc - distilled water q.s. 1000 cc EXAMPLE C An injectable solution for perfusion, containing 1 g/l of active mixture having the following composition is prepared: - 16-deoxy-26-(2-diethylaminoethyl)sulphinyl-16alpha hydroxypristinamycin IT.B (isomer A2) 0.6 g - 5# -[3(S)-quinuclidinyl thiomethylpristinamycin IA 0.4g - 0.1 N aqueous solution of hydrochloric acid 12.7 cc - distilled water q.s. 1000 cc EXAMPLE D An injectable solution for perfusion, containing 1 g/l of active mixture having the following composition is prepared: : - 16-deoxy-26-(2-diethylaminoethyl)sulphonyl-16alpha hydroxypristinamycin IIB (isomer A ) 0.6 g - 5#-[3(R)-quinuclidinyl- thiomethylpristinamycin IA 0.4g - 0.1 N aqueous solution of hydrochloric acid 12.7 cc - distilled water q.s. 1000 cc EXAMPLE E An injectable solution for perfusion, containing 1 g/l of active mixture having the following composition is prepared: - 16-deoxy-26-(2-diisopropylaminoethyl)thio-16alpha hydroxypristinamycin IIB (isomer A) 0.6 g - 5 S [3-quinuclidinyl thiomethylpristinamycin IA 0.4g - 0.1 N aqueous solution of hydrochloric acid 12.7 cc - distilled water q.s. 1000 cc

Claims (22)

1. A pristinamycin IIB derivative of the formula :
in which R1 denotes 1. an alkylthio radical containing 1 to 5 carbon atoms, substituted i) with one or two alkylamino or dialkylamino radicals in which the alkyl portions, which contain 1 to 5 carbon atoms, can optionally form, together with the nitrogen atom to which they are Linked1 a saturated hetero- cyclic radical chosen from 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepi yl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted with an alkyl radical containing I to 5 carbon atoms), or alternatively ii) with a 2- or 3-pyrrolidinyl, 2-, 3- or 4 piperidyl, 2- or 3-azetidinyl or 2-, 3- or 4-azepinyl radical, 2. a radical of general formula:: Het-S- (11) in which Het denotes e 3-pyrrolidinyl, 3- or 4-piperidyl, 3-azetidinyl or 3- or 4-azepinyL radical, optionally substituted with an alkyl radical containing 1 to 5 carbon atoms, 3. a dialkylamino radical in which the alkyl portions, which contain I to 5 carbon atoms, can optionally form, together with the nitrogen atom to which they are linked, a saturated heteroey lic radical chosen from 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted with an alkyl radical containing 1 to 5 carbon atoms), 4. a radical of general formula::
in which R2 denotes i) either a 4- to 7-membered nitrogen-containing heterocyclic radical optionally containing one or more other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, and optionally substituted with an alkyl radical, ii) or an alkyl chain containing 2 to 4 carbon atoms and substituted with 1 or 2 radicals chosen from phenyl, cycloalkylamino or N-alkyl-N-cycloalkylamino containing 3 to 6 ring atoms, alkylamino, dialkylamino or dialkylcarbamoyloxy1 the alkyl portions of these last 2 radicals optionally being able to for., with the nitrogen atom to which they are attached, a 4- to 7-membered saturated or unsaturated heterocyclic radical optionally containing another hetero atom chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, and optionally substituted with an alkyl radical), or substituted with one or more 4- to 7-membered nitrogen-contin- ing heterocyclic radicals optionally containing 1 or 2 other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, these heterocyclic radicals optionally being substituted with an alkyl radical, the said heterocyclic radicals being attached to the chain which bears them via a carbon atom with the proviso that at least one of the substituents borne by the above alkyl chain is a nitrogen-containing substituent capable of forming salts, or [(S)-1-methyl-2-pyrrolidinyl]methyl, and the symbol n equals 1 or 2,
5. an alkylanino radical which is optionally substituted by a hydroxy (e.g. the 2-hydrozyethylamino radical) or alkylamino or dialkylamino, the alkyl portions of this last radical optionally being able to form, with the nitrogen atom to which they are attached, r 4- to 7-membered saturated or unsaturaced heterocyclic radical optionally con taining another hetero atom chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, ond optionally substituted with an alkyl radical), or substituted with one or ore 4- to 7-membered nitrogen-contain ing heterocyclic radicals optionally containing 1 or 2 other hetero atoms chosen from nitrogen, oxygen or sulphur in the state of sulphoxide or sulphone, these heterocyclic radicals optionally being substituted with an alkyl radical, the said heterocyclic radicals being attached to the chain which bears them via a carbon atom, with the proviso that the alkyl radicals and portions mentioned above are Linear or branched and contain, except where otherwise stated, 1 to 10 carbon atoms, and its isomer forms and their mixtures.
2. 16-deoxy-26-(2-diethylaminoethyl)sulphonyl 16alpha-hydroxypristinamycin IIB (isomer A) and its isomers and salts.
3. 16-deoxy-26-(2-diethylaminoethyl)sulphonyl16beta-hydroxypristinamycin IIB (isomer A) and its isomers and salts.
4. 16-deoxy-26-(2-diisopropylaminoethyl) thio- 16alpha-hydroxypristinamycin IIB (isomer A) and its isomers and salts.
5. 16-deoxy-26-(2-diisopropylaminoethyl) thio16beta-hydroxypristinamycin IIB (isomer A) and its isomers and salts.
6. 16-deoxy-26-(2-diisopropylaminoethyl)sulphinyl-16alpha-hydroxypristinamycin IIB (isomer A2) and its isomers and salts.
7. 16-deoxy-26-(2-diisopropylaminoethyl)sulphinyl-16beta-hydroxypristinamycin IIB (isomer A2) and its isomers and salts.
8. 16-deoxy-26-(2-diethylaminoethyl) thio 16beta-hydroxy-pristinamycin IIB (isomer A) and its isomers and salts.
9. 16-deoxy-26-(2-diethylaminoethyl) thio16alpha-hydroxypristinamycin IIB (isomer A) and its isomers and salts.
10. 16-deoxy-26-(2-diethylaminoethyl)sulphinyl- 16alpha-hydroxypristinamycin IIB (isomer A2) and its isomers and salts.
11. 16-deoxy-26-(2-diethylaminoethyl)sulphinyl 16alpha-hydroxypristinamycin IIB (isomers A1 + A2) and its isomers and salts.
12. 16-deoxy-26-(2-diethylaminoethyl)sulphinyl16beta-hydroxypristinamycin (isomer A2) and its isomers and salts.
13. 16-deoxy-26-ethylamino-16beta-hydroxypristinamycin IIB (isomer A) 'and its isomers and salts.
14. 16-deoxy-26-ethylamino-16alpha-hydroxypristinamycin 11B (isomer A) and its isomers and salts.
15. 16-deoxy-26-(2-diethylaminoethyl)amino 16alpha-hydroxypristinamycin IIB and its isomers and salts.
16. 16-deoxy-26-(2-diethylaminoethyl)amino l6beta-hydroxypristinamycin IIB and its isomers and salts.
17. Process for the preparation of a compound as claimed in claim 1 which comprises reducing a compound of the general formula:
where R1 is as defined in claim 1.
18. Process for the preparation of a compound as claimed in claim 1 in which R1 does not represent a radical of formula III which comprises reacting a product of the formula: R1'-H (V) in which R1' is defined as above for R1 with the proviso that it does not represent R2-S(O)n with a product of formula:
19. Process for the preparation of a compound as claimed in claim 1 in which R1 represents a radical of formula III where n = 1 which comprises oxidizing a pristinamycin derivative or salt or protected derivative thereof of formula:
in which R2 is defined as above, it being understood that there R2 contains a sulphur containing heterocyclic ring the sulphur atom can be in the form of a sulphide, sulehoxide or sulphone.
20. Process for the preparation of a compound as claimed in claim 1 substantially as described in any of the foregoing Examples.
21. A pristinamycin 11B derivative as claimed in claim 1 when prspared by a process as claimed in any one of claims 17 to 20.
22. A pharmaceutical composition comprising a pristinamycin 11B derivative as claimed in any one of claims 1 to 16 and 21 in association with an inert pharmaceutically acceptable carrier or coating and/or pristinamycin IAi virginiamycin S, or a soluble synergistin derivative of general formula XI as hereinbefore defined.
GB08715966A 1987-07-07 1987-07-07 Novel pristinamycin IIB derivatives, their preparation and pharmaceutical compositions containing them Withdrawn GB2206879A (en)

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FR2664598A1 (en) * 1990-07-16 1992-01-17 Rhone Poulenc Rorer Sa PROCESS FOR THE PREPARATION OF SULFINYL PRISTINAMYCIN IIB.
FR2664894A1 (en) * 1990-07-19 1992-01-24 Rhone Poulenc Sante NOVEL STREPTOGRAMIN DERIVATIVES AND THEIR PREPARATION.
FR2766489A1 (en) * 1997-07-28 1999-01-29 Rhone Poulenc Rorer Sa STREPTOGRAMINE DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
WO2002050083A1 (en) * 2000-12-21 2002-06-27 Aventis Pharma S.A. Streptogramin derivatives, preparation thereof and compositions containing same
FR2833954A1 (en) * 2001-12-26 2003-06-27 Aventis Pharma Sa New streptogramin A derivatives useful as antibacterial agents
US6878820B2 (en) 2001-12-26 2005-04-12 Aventis Pharma S. A. Streptogramin derivatives, their preparation and compositions containing them
US6962901B2 (en) * 2000-12-21 2005-11-08 Aventis Pharma S.A. Streptogramin derivatives, their preparation and compositions which contain them
US7232799B2 (en) 2000-12-21 2007-06-19 Aventis Pharma Sa Streptogramin derivatives and compositions thereof
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
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Cited By (17)

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WO1992001693A1 (en) * 1990-07-16 1992-02-06 Rhone-Poulenc Rorer S.A. Method for the preparation of sulphinyl pristinamycin ii¿b?
FR2664598A1 (en) * 1990-07-16 1992-01-17 Rhone Poulenc Rorer Sa PROCESS FOR THE PREPARATION OF SULFINYL PRISTINAMYCIN IIB.
FR2664894A1 (en) * 1990-07-19 1992-01-24 Rhone Poulenc Sante NOVEL STREPTOGRAMIN DERIVATIVES AND THEIR PREPARATION.
WO1992001691A1 (en) * 1990-07-19 1992-02-06 Rhone-Poulenc Rorer S.A. New derivatives of streptogramines and preparation thereof
US6815437B1 (en) 1997-07-28 2004-11-09 Aventis Pharma S.A. Streptogramines, their preparation and compositions containing them
FR2766489A1 (en) * 1997-07-28 1999-01-29 Rhone Poulenc Rorer Sa STREPTOGRAMINE DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
WO1999005165A1 (en) * 1997-07-28 1999-02-04 Rhone-Poulenc Rorer S.A. Streptogramines, their preparation and compositions containing them
US6962901B2 (en) * 2000-12-21 2005-11-08 Aventis Pharma S.A. Streptogramin derivatives, their preparation and compositions which contain them
FR2818644A1 (en) * 2000-12-21 2002-06-28 Aventis Pharma Sa STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM
WO2002050083A1 (en) * 2000-12-21 2002-06-27 Aventis Pharma S.A. Streptogramin derivatives, preparation thereof and compositions containing same
US7232799B2 (en) 2000-12-21 2007-06-19 Aventis Pharma Sa Streptogramin derivatives and compositions thereof
FR2833954A1 (en) * 2001-12-26 2003-06-27 Aventis Pharma Sa New streptogramin A derivatives useful as antibacterial agents
WO2003055891A1 (en) * 2001-12-26 2003-07-10 Aventis Pharma S.A. Streptogramin derivatives, preparation thereof and compositions containing same
US6878820B2 (en) 2001-12-26 2005-04-12 Aventis Pharma S. A. Streptogramin derivatives, their preparation and compositions containing them
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
US11505550B2 (en) 2015-07-02 2022-11-22 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
WO2021239667A1 (en) 2020-05-27 2021-12-02 Università Degli Studi Di Trento New therapy for the treatment of tumors

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