IE60343B1 - Process for the preparation of pristinamycin iiB derivatives - Google Patents

Description

The present invention relates to a new process for the preparation of S-oxides derived fro® pristinaraycin IIB.

European Patent Application No. 191,.662 describes 5 S-oxides derived fro»» pristinaraycin lXg of general formulas in which the symbol R represents either a 4- to 7-membered nitrogen-containing heterocyclic radical,, optionally containing 1 or more other hetero atoms chosen fro® amongst nitrogen, oxygen or sulphur in the sulphoxide or the sulphone form, and optionally substituted with an alkyl radical, or an alkyl chain containing 2 to 4 carbon atoms, IS substituted with 1 or 2 radicals chosen from amongst phenyl, cycloalkylamino or K-alkyl-N-cycloalkylasai.no containing 3 to 6 members, alkylamino, dialkylamino or dialkylcarbamsoyloxy (it being possible for the alkyl parts of these last 2 radicals optionally to form, with the nitrogen atom to which they are attached, a 4- to 7» mesfeered saturated or unsaturated heterocycle optionally containing another hetero atom chosen from amongst nitrogen, oxygen or sulphur in the sulphoxide or the sulphone form, and optionally substituted with an alkyl radical) radicals or substituted with one or more 4- to 7-membered nitrogen-containing heterocycles optionally containing 1 ox 2 other hetero atoms chosen from amongst nitrogen, oxygen or sulphur in the sulphoxide or the sulphone for> and optionally substituted with an alkyl radical, the said heterocycles being attached to the chain which carries them via a carbon ate®, it being understood that at least one of the substituents carried by the alkyl chain above is a nitrogen-containing substituent capable of forming salts, or aa [(S)-l-®ethyl-2~pyrrolidinylJaetfeyl radical, the alkyl radicals mentioned feeing straightchain or branched and containing, unless otherwise stated, 1 to 10 carbon atoms, the isomeric forms thereof or the mixtures thereof and the addition salts thereof with acids and the preparation thereof.

In the general formula (I): where R represents a heterocyclic radical, this radical may be chosen, by way of example, from amongst χ 3-azetidinyl, 3-pyrrolidinyl, 3- or 4-piperidvl or 3- or 4-aaepinyl, when R represents a heterocycle-substituted alkyl radical, the heterocyclic radical may be chosen, by way of example, from amongst the radicals mentioned above or 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2-azepinyl, piperazinyl, 4-alkylpiperazinyl, quinolyl, isoquinolyi or imidazolyl radicals, when R contains a dialkvl amino or dialky lcarbamovloxy radical in which the alkyl parts form, with the nitrogen atom to which they are attached, a heterocycle, the latter may be chosen, by way of example, from amongst: 1-azetidinyl, 1-pyrrol idinyl, piperidino, l-asepinyl, morpholino, thiomorpholino in the stlphoxide or the sulphone fam, l-piperasinyl, 4-alkyl-l-piperasinyl, N-alkyl-l-homopiperazinyl or 1-iaidazolyl.

It has now been found that the products of general formula (Ϊ) may fee obtained by oxidising a pristinamycin XIB derivative, a salt thereof or a protected derivative, of general formulas in which R is defined as above, it feeing understood that in the cases where R contains a sulphur-containing hefcerocvcle, the sulphur atom may he ia the form of sulphide, sulphoxide or sulphone fora, using potassium peroxymonosulphate, and then separating the isomers obtained, if required.

Potassium peroxymonosulphate means a mixture which also contains potassium sulphate and potassium hydrogen sulphate, as defined in US Patent 2,802,722 and marketed under the name Oxone*.

The reaction is carried out in water or in a water/alcohol (e.g. water/methanol) or water/chlorinated solvent (e.g. water/dichloromethane) mixture at temperatures between -60 and 25”C.

When the pristinamycin II8 derivative of general formula (II) is employed in the form of a salt, salts formed with organic or inorganic acids, preferably with trifluoroacetic, tartaric, acetic, benzoic, hydrochloric or sulphuric acids, or with potassium hydrogen sulphate, are used.

When H contains an alkylamino or cycloalkylamino substituent, it is also possible to employ a protected derivative of· the product of general formula (II), the latter may be protected by any amine-protective group, the attachment and the removal of which does not affect the rest of the molecule? the tri fluoroacetyl group, which can be removed after the reaction by treatment with an alkali metal bicarbonate (sodium or potassium bicarbonate) in an aqueous solution, is advantageously used.

The potass i?es peroxymonosulpfeate is prepared according to the method described in US Patent 2,802,722.

The products of general formula (II) say be obtained according to the method described in European Patent Application So. 191,662. It is not absolutely essential to isolate the pristinamycin 2¾ derivative of general formula (II) in order to implement the process according to the invention.

The products of general formula (I) obtained at the end of this process, say be purified by known methods, e.g. by crystallisation, chromatography or successive extractions in an acid or basic medium. Fox the specialist who is aware of the. sensitivity of synergistins in an alkaline medium, basic medium means a medium of which the alkalinity is just sufficient to release the parent substance from its addition salt with 5 an acid, i.e. a medium, of which the pH does not exceed 8.

The isomers of the products of general formula (I) may be separated by any known method. This Is advantageously carried out by chromatography or high per10 formance liquid chromatography.

The products of general formula (1) obtained by the process according to the Invention show an antibacterial activity on gram-positive bacteria (of the Staphylococcus, Streptococcus, Pneumococcus and Sntero15 coccus type) and gram-negative bacteria (of the Haemophilus, Gonococcus and Meningococcus type). Additionally, they have the advantage that they can be solubilised in water generally In the form of salts, at therapeutic doses which can. be used and that they enhance, by a synergistic phenomenon, the antibacterial actios of pristinamycin IA, vlrglnlamycis S or soluble derivatives as described in Suropean Patent Application JSo. 191,652.

Additionally, the products of general formula (I) obtained by the process according to the invention say be useful in the preparation of sulphones derived from prlstinasysin IIS, of general formiulas in which R Is defined as in the case of general formula (2), which are active as antimicrobial agents and also have the property ©£ synergislng the action of group I pristinaucycins.

The preparation of the sulphones derived from pristinamycin XIB of general formula (III) is carried out by oxidising a pristinaxaycin IIB derivative of general formula (1), under the conditions described in European Patent. Application Ho. 191,562.

The process according to the invention has the advantage that it can be implemented easily and that it enables a purer product, which is easier to treat, when appropriate, in the subsequent phase of preparing the corresponding sulphone, to be obtained or that it offers fewer risks of the starting product being degraded and especially fewer risks in carrying out the preparation of th® products of general formula (I).

More especially, th® process according to the invention makes it possible to obtain the products of the general formula (I) for which the symbol R represents an alkyl chain containing 2 to 4 carbon atoms., substituted with 1 or 2 radicals chosen from amongst phenyl, cyclo» alkylamino or H-alkyl-H-cycloalkylamino containing 5 or 6.members, alkylamino containing 1 to 4 carbon atoms, or dialkylamino (in which the alkyl parts contain 1 to 3 carbon atoms or tor», with the nitrogen atom to which they are attached, a 5- or £-membered saturated heterocycle) radicals, or represents a 5« ar 6-membered nitrogen-containing heterocycle optionally substituted with an alkyl radical containing 1 to 4 carbon atoms, it being understood that at least one of the substituents carried by the alkyl chain above is a nitrogen-containing substituent capable of forming salts, and that at least oa@ of the radicals carried by this chain is situated at the i -posit ion or at the 2-pos it ion.

The products of general formula (I) thus obtained may be converted into salts.

As pharsaaceutically acceptable salts, there may be mentioned especially the addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulphates, nitrates and phosphates or with organic acids, such as acetates, propionates, succinates, aaleates, fumarates, methanesulphonates, p-toluenesulphonates, isethionates, citrates and tartrates or substitution derivatives of these compounds.

The following examples, given in a non-limiting way, show how the invention may be put into practice. The not spectra for the products illustrated in these examples have general characteristics which are common to all the products of general formula (I) and particular characteristics which are specific to each of the products depending on the substituents. Only the specific characteristics due to the radicals which vary are mentioned in the examples. For the products of general formula (I), all the protons are denoted according to th® numbering shown in the following formulas Unless otherwise stated, all the spectrum determinations were carried out at 250 MSr ia deuterochloro15 form; the chemical shifts are expressed in ppa relative to the tetramethyl silane signal. The abbreviations used below are as followss ε = singlet d * doublet t triplet m = multiplet c “ complex dd « doublet of doublet dt « doublet of triplet add « doublet of doublet of doublet dddd « doublet of doublet of doublet of doublet It is understood that the different isomers were classified arbitrarily according to the chesaical shifts observed in SMR spectroscopy.

The isomers with the following characteristics are called isomer A, and isomer of the products of general formula (I)s approximately 1.7 (s, -CK3 at 33); approximately 3.8 (s, >CH, at 17) j <5 (d, -¾) isomer A2 or >5 (d, -¾) isomer Ax; approximately 5.50 (broad d, -=1¾) > approximately S.20 (d, -Hu); approximately 5.6 (>NH at 8); a8 (s, -¾).

The isomers with the following characteristics are called isomer 3, and isomer 32 of the products of general formula (I)s approximately 1.5 (s, -CH3 at 33); approximately 3.7 and 3.9 (2d, ^CH, at 17);; approximately 4.8 (m, -Hi3); <5 (d, ~H27) isomer 32 or >5 (d, -¾) isomer Bx; approximately .70 (limiting AS, ~KU and -Hlo); approximately 7.7 0ΝΗ at 8); approximately 7.8 (s, -H20)The isomer which has NMR characteristics identi15 cal to those stated above for the isomers A, and A, of the products of general formula (1) is called isomer A of th® product of general formula (II), it being understood that the a at 27 is characterised toys 4.7 (d, J < 1 Hz).

The isomer which has NKR characteristics identi20 cal to those stated above for the isomers 3X and B, of the products of general formula (I) is called isomer 3 of the product of general formula (II), it being understood that the H at 27 is characterised bys 4.6 (d, J a 2.5 Hz). EXAMPLE 1 2S An aqueous solution (40 cc) of Oxone* (8.1 g) is added, at 0*C, to 26-((2-diethylaminoefhyl)thi®3pristinaraycim IIa (isomer A) (13 g) suspended in distilled water (170 cc), in the course si 15 minutes. The mixture obtained is stirred for 30 minutes at 0’C and KORIT S2 ULTRA charcoal (1.3 g) and a small amount of sodium thiosulphate are added to it. After stirring for 30 minutes at 20*C, the suspension is filtered through Celite and then rinsed with distilled water (50 ce). The solution is adjusted to pa 7 by adding solid sodiusa bicarbonate and then washed with dichloromethane (3 x 100 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 *C to give a light beige-coloured solid (9.9 g) coataining 26-( (2-diethylaminoethyl)sulphinyl jpristinamycin HB (isomer Ag) (85%), isomer (10%) and 26-((2-diethylaminoethyl) sulphonyl J pristinamyc in IIB (5%).

The crystalline form of 26-( (2-diethylaminoethyljsulphinyljpristinamycin IIB aay be obtained by operating as followss A part of the solid obtained above (5 g) is taken up with acetonitrile (13 cc). After dissolving in the heated state, ether (10 cc) is added and crystallisation is initiated by scratching. The crystals are filtered, washed with ether and then dried under reduced pressure (270 Pa) at 20eC. 26-( (2-DiethylaMmoethyl)sulphinyl)pristinamycin XI„ (3.9 g) (isomer A,s 85%, isomer A, χ 15%) is thereby obtained in the form of white crystals, m.p. approximately 116’C.

XXR spectrum (isomer JU) 1.03 (t, -N(CK2CHa)2) 1.75 (s, -CH3 at 33) 2.05 and 2.35 (2m, ^CH2 at 25) 2.45 to 2.70 (®f -NiCH^CHah) 2.70 to 3.10 (a, -SCH2-CH2-) 2.75 (a, H at 4) 2.92 to 3.10 (m, \cH2 at 15) 4.,81 (d, a at 27) .5 (d, H at 13) 6.19 (d, H at 11) .50 (dd, at 8) 6.58 (dd, H at 5) 8.12 (s, S at 20) NMR spectrum (isomer 1.04 {f, -^¾¾) 1.69 (s, -CH3 at 33) to 2.3 (m, \cb2 at 25) to 2.3 (m, ^CBS al 2.60 (a, ^N-Cga-CHa) 2.7 to 2.95 (a, -S(O)-CH2-CS2-HQ 2-7 (ra, H at 4) 2.86 and 3.04 (2dd, at 15) 3.28 (a, H at 26) 3.78 (A3 system, >CH2 at 17) .25 (d, H at 27) S 5.4 (d, H at 13) 6.15 (d, H at 11) 6.60 (dd, H at 5) 6.83 (dd, at 8) 8.08 (s, H at 20) Th® 26-[ (2-diethylaxninoethyl)thio]pristinamycin Ils may bs prepared as described ia US Patent 4,590,004. EXAMPLE 2 An aqueous solution (10 cc) of Oxone* (1.9 g) is added, at -5*0, to 26-[ (2-diethylaminoethyl)thio)15 pristinamycin IIS (isomer A) (3 g) suspended ia a mixture of distilled water (30 cc) and ethanol (6 cc), in the course of 10 minutes. After stirring for 10 minutes, the reaction mixture is washed with dichlorornethane (2 x 20 cc). The aqueous phase is adjusted to pH 7 by adding solid sodium bicarbonate and then extracted with dichlorornethane (4 x 50 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 “C. A white solid (2.4 g) containing 26-((2 -diethylaminoethy1) sulphiny1 'j prist inasayc in I la (isomer 3¼ « 88%, isomer Ax ; 6%) and 26-[(2-diethylaminoethyl)sulphonyl)pristinamycin lls (6%) is thereby obtained. The 2Q£R characteristics of the product obtained are identical to those of the product in Example 1.

BSAMPL1 __3 Oxone* (1.65 g) dissolved in distilled water (32 cc) is added slowly, at -30*C, to 26-Π B (isomer As 87%, Bs 13%) (3.2 g) dissolved in methanol (48 cc). After main35 taining the mixture at -30*C for 30 minutes and then at -40*C for 15 minutes, distilled water (30 cc) followed by BORIT SZ ULTRA charcoal (3 g) are added. The mixture is stirred for 30 minutes at 20 *C, filtered through Celite 1 and then rinsed with distilled water (SO cc). The aqueous phase is washed with ethyl acetate (2 x 100 cc) and then with ethyl ether (50 cc) before being adjusted to pg 7 by adding solid sodium bicarbonate and then extracted with dichloromethane (2 x 250 cc). The organic phases are washed with distilled water (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30C. A very light yellow cake (2.4 g) is obtained, which is stirred in a pentanes diethyl ether (50s50 by volume) mixture (40 cc). After filtration and then drying under reduced pressure (270 Pa) at 20*0, 26-(( (R)-l~diethylamino-2-propyl]sulphinyl>pristinemycin. IIS (isomer A^ 80%) (2.2 g) is obtained in the form of an off-white solid, a.p. approximately 140*C.

KMR spectrum; 1.02 (t, «KfCHg-Cla), S H 1.34 (d,0*- c - ch„ ch3 1.72 (s, »CS3 at 33) 2.01 and 2.55 (2m, Sis, at 25) 2.45 to 2.70 (aa, 1H in -CHg-S(CS2-CH3)2 and -N(C@5-CS3)2S 2.. .90 (a, 1H in 2.75 (s, S at 4) 2.88 aad 3.08 (2dd, ^CB2 at 15) (m, — S»»CS~) o CHS 3.73 (sa, H at 25) 3.80 (s, at 17) 4-92 (broad e, S at 27) .42 (d, S at 13) .6.15 6.55 (dd, E at S) 6.. 70 (dd, ^SS at 8) 8.06 (s, Bat 20) The 26-( [ (R)-l-diethylasiino-2-propyl)thio>pristinamycin IIB say be obtained as follows · (R)«l-Dietfeyla3aiaio-2-propaaethiol (3.2 cc) is 2 added, at -30C, under a nitrogen, atmosphere, to pristinamycin IIA (10.5 g) suspended in «ethanol (200 cc). After stirring for 18 hours at -30*C, methyl acrylate (2 cc) is added and the mixture is stirred for 1 hour.

Distilled water (200 cc) and potassium hydrogen sulphate (amount required to adjust the pH to 4) are then added at -1019C followed by NOR1T 52 ULTRA charcoal (10 g). After stirring for 30 minutes at 0*C, the mixture is filtered through Celite and then washed with distilled water (150 cc). The aqueous phase is washed with ethyl acetate (100 cc) and then with ethyl ether (100 cc) and then adjusted to pH 7 by adding solid sodium bicarbonate. After extracting with dichloromethane (200 cc), the organic phase is washed with water (100 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30*0. The solid obtained is crushed in ethyl ether (100 cc), filtered through sintered glass and then dried under reduced pressure (270 Pa) at 20*C. 2S~{((R)-l-Diethyl20 amino-2-propyl]thio}pristinamycin IIB (isomer As 85%, Isomer Bs 15%) (3.36 g) is thereby obtained in the form of a light beige-coloured solid, m.p. approximately 130C.

HKH spectrum (isomer A) 1.03 (t, -^(CHgCgab) at 25) 1.32 (d, 1.72 (s, -CHj3at 33) 1.88 and 2.10 (2a, 2.55 (sa, -H(i^CH8)ai 2.45 and 2.60 (2m, -C^-H(CHsGHa),i 2.78 (e, H at 4) 2.92 and 3.10 (2dd, at 15) (®, -5-CH-) £5¾ 3.52 (stt, E at 3.82 (s, ^CHa 26) at 17) 3 6.13 6.32 4.79 (broad ε, H at 27) 5.49 (d, H at 13) d, H at 11) c, at 3) 6.52 (dd, H at 5) 8.13 (s, Ξ at 20) (isomer 3) (t, -N(CBA)2) 1.50 (s, -CH3 at 33) 2.05 2.5 ,2», >CH2 « 25, 2.5 (sa, WCB-CHg) 2.44 and 2.55 (2m, »CS2-H(CH2CH3)2) 2.62 (s, H at 4) 2.74 and 3.10 (2dd, at 15) 3.01 -S-CB-) I 3.69 and 3.89 (2d, at 17) 3.74 <3, 15 at 26) 4.01 (d, J » 2.5, E at 27) 4.80 (A3 system, S at 13 'and E af 14) .65 (d, Ξ at 11) 6.60 (dd, B at 5) 7.71 (Ri, at 8) ' 7.80 (e, S at 20) The (E5-l-diethylaaino-2«-pa«»pan©thiol may be prepared as follows ϊ (R)-JS,H-Methyl-2-iBercaptopropionaaide (137.5 g) dissolved is ethyl ether (500 cc) is added dropwise to a suspension of lithium aluminium hydride (34.2 g) in ethyl ether (16G0 cc) in the course of 1 hour and 20 minutes. The reaction mixture is then maintained under reflux for 2 hours and 3 r0 minutes and then cooled to a temperature J. 4 in the vicinity of 0*C. Distilled water (40 cc) is then added so that the temperature of the mixture does sot exceed 20 *C and 5N sodium hydroxide (29.4 cc) followed toy distilled water (133 cc) are then added. The reaction mixture is filtered and the pH of the filtrate is adjusted to 8 by adding acetic acid (70 cc). The mixture obtained is filtered again, rinsed with ethyl ether (3 x 300 cc) and the filtrate is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30*C. A, yellow oil is obtained, which is purified by distillation under reduced pressure (1,3 kPa). (R)-1-Diethylamino~2~propanethiol (101 g) is thereby obtained in the form of a colourless oil « 55-5o*C? (a)g° - -37.1* (C = 4.8, CE3OH) ] .

The (R) -H, N-diethyI - 2 -mere apt opropionamide may be prepared as follows; (R) -N,H-Diethyl-2-acetylthiopropionamide (105 c) in ethyl ether (S00 cc) is added to a 5M sodium hydroxide solution (517 cc) maintained at 20 *C, in the course of 30 minutes. 'The reaction mixture is stirred for 2 hours 30 minutes at a temperature in the vicinity of 20*C. The aqueous phase is separated by decantation.

The pH of the aqueous phase is then adjusted to pH * 5-6 by slowly adding acetic acid (140 cc). The mixture obtained is extracted with diehloromethane (300 ec) asd then with diehloromethane (200 cc), the ccastoined organic phases are dried over sodiw sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30*C.

(R)-H,H-Diethyl-2-mercaptopropionamide (78.6 g) is thereby obtained in the fora of a purplish-blue oil £(«*]“« -21-1 (c « 3.8? CHaOH)3.

The (E,)“S,^-diethyl-2-acetylthiopropio35®ide say be prepared as follows: (S) -N,H-DIethyl-2-chloropropionamide (8S.3 g) dissolved ia ethanol (150 cc) is added to a suspension of the potassium salt of thiolacetie acid (72.6 g) in ethanol (300 cc). The reaction mixture is then heated for hours at a temperature la the vicinity of $0*C and then filtered and concentrated to dryness under reduced pressure (130 Pa) at a temperature in the vicinity of 50 *C. The residue obtained is taken up and stirred in dichloromethane (500 cc) and then washed with distilled water (300 cc), with a 10% aqueous potassium bicarbonate solution (300 cc) and then with distilled water (300 cc). The organic phase is decanted, dried over sodium sulphate and charcoal 3S (1 g) filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30*C. Th® residue obtained is distilled under reduced pressure (17 Pa), (R)-N,N-Diethyl2-acetylthiopropionamide (105.5 g) in the form of a slightly yellow oil (b.p.X7Fa = 105-107*C; [ejp° = +156 (c = 18.1 ; CHC13)3 is thereby obtained.

The (S)-M,M-diethyl-2-chloropropionamide η&γ be obtained as follows: Diethylamine (480 cc) is added to a solution of (S)-2-chloropropionyl chloride (175.2 g) in chloroform (900 cc), which is maintained at C’C, in the course ©f 1 hour. Distilled water (400 cc) and dichloromethane (300 cc) are added to the reaction mixture. The organic phase is decanted and then washed with an aqueous 2H hydrochloric acid solution (300 cc) and then with distilled water (400 cc). The organic phase is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature is. the vicinity of 30 *C„ The residue obtained is distilled under reduced pressure (17 Pa). (SJ-^i^-Diethyl2-chloropropiouamide (151.9 g) in the form of a colourless oil [b.p.a7P, * 83-85C? [β]” = +39.7 (c * 1©.4; CBCla)3 is thereby obtained.

(R)- and (S)-2-chloropropiosxyi chlorides may be prepared according to the method described by S-C.J. FO, S.M. 3ISNBADM and J.P. SRESHST3XH, J. Am. Cham. Soc», 76, 6054 (1954)» EXJWLS 4 An aqueous solution (20 cc) of Oxone* (1.01 g) is added, at -60C, to 26—{[(SJ-l-diethylamiuc-S-propylJ1 β thio}pristinamycin Ils (isomer A) (2 g) dissolved in methanol (30 cc), in the course of 30 minutes. The suspension obtained is stirred for 30 minutes at -60 ”C and then for 16 hours at -20“C. Oxone* (0.2 g) dissolved in water (5 se) is then added and the mixture is stirred for 30 minutes at -20C. The reaction mixture is diluted with water (100 cc), treated with NORIT SX ULTRA charcoal (0.5 g), stirred for 15 minutes, filtered through Celite and then rinsed with water (3 x 5 cc). The aqueous phase is extracted with ethyl acetate (3 x 50 cc), adjusted to pH 7 by adding solid sodium bicarbonate, saturated with sodium chloride and then washed with die hl orome thane (3 x 50 cc).

The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30*C. A white cake is thereby obtained, which is stirred in diethyl ether (20 cc). The resulting solid is filtered and then dried under reduced pressure (270 Pa) at 20*C to give 2S-{ [ (S)-I-diethylaaaino-2«propyl Jsulphinyl^pristinamycin Hg (isomer A^s 90%, isomer A,s 5%) (1.5 g) in the fora of a whitish solid, m.p. approximately 130“C, the RS® characteristics of which are Identical to those of the product obtained ia Example 5 belowThe 25--( [ (5)-1 -diethylamino-2-propyl]this>pristinamycin 1¾ (isomer A) may be obtained as followss (S)-l-Diethylamixso-2-propanethiol (3,2 g) is added, at -20*C, to pristinamycin (10.5 g) dissolved in a methylene chloridesmethanol (50s5© by volume) mixture (200 cc), under a nitrogen atmosphere. After stirring for 70 hours at -20 *C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 3©*C. and then taken up with ethyl acetate (100 cc). The solution obtained Is washed with an aqueous 0.2K potassium hydrogen sulphate solution (100 cc). The aqueous phase Is decanted and then washed with ethyl acetate (3 x 100 cc). The organic phase is washed with distilled water (50 cc) and the aqueous phases are then combined, adjusted to pH 7 by adding solid sodium bicarbonate (2 g) and washed with dichloromethane (100 cc followed by 2 x 50 cc). The latter organic phases are combined, dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30eC- The solid obtained is stirred in ethyl ether (150 cc), filtered and then rinsed with ether (3 x 10 cc). A beige-coloured solid (9.2 g) is thereby obtained, which is recrystallised in acetonitrile (20 cc). After filtration and drying at 20*C under reduced pressure (270 Pa), 2S~{[ (S)- 1-diethylaaino2-propyl)thio}pristinamycin II@ (isomer A) (2.3 g) is obtained in the form of white crystals, m.p. approximately 128*C.

HKR spectrum 1.04 (t, -HtcajCg,)^ 1.73 (s, -CH3 at 33) 1.90 and 2.13 (2m, \ch. at 25) 2.4 to 2.7 (a, -C&-K(CHgCS3)2) 2.78 (Β, E at 4) 2.93 and 3.12 (2dd, at 15) 3.02 (a, -S-Cg-) 3.55 (a, H at 2SJ 3.84 (s, ^CHjt at 17) 4.81 (broad s, Ξ af 27) .49 (d, H at 13) 6.154 (d, E at 11) .30 (c, at 8) S.53 (dd, E at 5) 8.13 (s, S at 20) The (S)-l-diethylamino-2-pxx>panethiol may be prepared as follow© s (S)-H,H-Diethyl-2-aercftptopropiona®ide (171 g) dissolved in ethyl ether (SOO cc) is added drogwise to a suspension of lithium aluminium hydride (42.6 g) in ethyl 8 ether (1500 cc) in the course of 1 hour and 20 minutes.

The reaction mixture is then maintained under reflux for hours and 30 minutes and then cooled to a temperature in the vicinity of 0C. Distilled water (49.8 cc) is then added so that the temperature of the mixture does not exceed 20 aC, and 5N sodium hydroxide (3S.6 cc) and distilled water (166 cc) axe then added. The reaction mixture is filtered, the pH of the filtrate is adjusted to 8 by adding acetic acid (70 cc). The mixture obtained is filtered again, the filtrate is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2-7 kPa) at a temperature in the vicinity of 30°C. A yellow oil is obtained, which is purified by distillation under reduced pressure (1.3 kPa). (S)-1 -Diethylamino-2-propanethiol (100 g) is thereby obtained in the fora of a colourless oil Eb.p-i.3M>. 55 55-56‘C; Ec355° * +39.6’ (c - 5.6, £Ha?H)).

The (S)-N,H-diethyl-2~mercaptopropionamide may ha prepared as follows; (S)-N,H-Diethyl-2-acetylthiopropionamide (223 g) in ethyl ether (1000 cc) is added to a SB sodium hydroxide solution (1100 cc) which is maintained at 20*C, in the course of 30 minutes. The reaction mixture is stirred for 20 hours at a temperature ia the vicinity of 20 *C. The aqueous phase is separated by decantation and then washed with ethyl ether (3 x 250 cc). The pB of the aqueous phase is then adjusted to 5 by slowly adding acetic acid (280 ce). The aixture obtained is extracted with dichlorornethane (500 ce followed hy 2 x 250 cc), the combined organic phases are dried over soditn sulphate in the presence of carbon black, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 3®’C. ($)-N,J3-Diethyl~ 2-mercaptopropionamide (171.7 g) is thereby obtained in the form of a purplish-blue oil “ +20.7“ (e * 3, CHs OB)).

The (S)-H,H-diethyl-2-acetylthiopropionamide may be prepared as followss (R)-S,HI-Diethyl-2-chloropropionamide (20 g) ΐ. s dissolved in ethanol (30 cc) Is added to a suspension of the potassium salt of thiolacetic acid (IS gj In ethanol (70 cc) The reaction mixture Is then heated for 2 hours at a temperature in the vicinity of 55’C and then conS centrated to dryness under reduced pressure (130 Pa) at a temperature in the vicinity of 60 *C. The residue obtained is crushed in dichloromethane (300 cc) and then washed with distilled water (200 cc). The organic phase is decanted, dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30*C. The residue obtained is distilled under reduced pressure (17 Pa). (S)-N,N-Diethyl-2~acetylthiopropionamide (22 g) is thereby obtained in the form of a slightly yellow oil Eb.p.175?« = 105-107’C; (g]S° = -169* (c = 10; CHC13) ] The (H)-K?S-diethyl“2-chloropropionaa.Ide may be prepared as follows: Diethylaaine (133 g) Is added to a solution, maintained at 20’C, of (H)-2-chloropropionyl chloride (87.7 g) in chloroform (600 cc), in the course of 1 hour.

The reaction mixture Is washed with distilled water (500 cc), with an aqueous IS hydrochloric acid solution (3 x SOO cc) and then with distilled water (500 cc). The organic phase Is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30 *C. The residue obtained is distilled under reduced pressure (17 Pa). (R)-K,S-Diethyl-2-chloroproplonamIde (43 g) Is thereby obtained In the form of a colourless oil (b.p.- 75-80’C? j>3o° * -43.3* (e - 10; caci3)].

BXAMPLB 5 (S)-l-Diethylamino-2-propanethiol (17.6 g) is added, at -38C, to a suspension of pristinemycin IIA (63 g) in methanol (630 cc), in the course of 30 minutes, under a nitrogen atmosphere. After stirring fox 20 hours, distilled water (150 cc) Is added followed by the addition of an aqueous solution (410 cc) of Oxone* (33.6 g) in the course ©f 30 minutes, at a temperature of »38*C. The suspension obtained Is stirred for 1 hour at »38 C, Ο treated with sodium thiosulphate (1,.2 g), filtered at 20C through sintered glass and then washed with distilled water (3 x 200 cc). NORIT SZ ULTRA charcoal (20 g) is added to the aqueous phase and the suspension is stirred for 30 minutes and then filtered through Celite, washing the filtrate with distilled water (3 x 200 cc). The solution is adjusted to pH 7 with solid sodium bicarbonate (15 g) and then washed with diehloromethane (3 x 500 cc). The organic phases are combined, dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. A beige-coloured cake (55 g) is obtained, which is stirred in ethyl ether (500 cc). After filtration, washing with ethyl ether (3 χ 50 cc) and then drying under partial vacuum (270 Pa) at 20*0, a white solid (46-6 g) is obtained, which is dissolved in a diehloromethane s methanol (98:2 by volume) mixture (150 cc) and acetic acid (4 cc) is, then added to it. This solution is purified by flash chromatography [eluent: diehloromethane: methanol (98:2 by volume)], collecting 100-cc fractions. After concentration under reduced pressure (2.7 kPa) at 30 *C, a solid (36 g) is obtained, which is dissolved in distilled water (400 cc) to which potassium hydrogen sulphate (6.5 g) has been added. The solution is washed with ethyl acetate (4 χ 500 ec), adjusted to pH 7 by adding solid sodium bicarbonate (5 g) and then extracted with dichlorosethane (200 cs followed by 2 x 150 cc). The organic phases are combined, dried over saagnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30*C to give a beigecoloured cake (33.8 g), which is stirred in ethyl ether (300 cc). After filtering, 26-(((S)-l-diethylamino2-pfopyl]sulphinyl}pristinamycin IIS (isomer Aa) (29.3 g) in the form of a pale yellow powder, m.p. approximately 140 C, is isolated ., SMS, spectrum (isomer ^) 1.05 1.,27 a* I Hs (d, cs / J ) X “lc2“s (s, -CH3 at 33) (sa, la in ^0¾ at 25) to 2.70 (sa, IH in ^CH, at 25, IH in ^C§,»N (CH2CH3), f (CH,CH3) 2) (sa, H at 4) (a, IB in (CH,CH3),) ' and 3.15 (2dd, ^CH, at 13) (a, -S-CK-) o ch3 (a, E at 26) (s, ^CB, at 17) (broad s, H at 27) (d, H at 13) (d, S at 11) (sa, >NH at 8) (dd, H at 5) (s, B at 20) 1.74 2.10 2.45 2.80 2.88 2.90 3.OS 3.41 3-83 4.77 .50 S.20 .55 6.63 8.11 SaffiRI Oxcrne* (30.7 g) dissolved in distilled water (140 cc) is added, at 0“C, f© 2S-E(2-dlethyiasainoethyl)thia3prisfiBamytis.il® (50 g) dissolved is dichioromethane (200 cc) and distilled water (250 cc), in the course of 20 minutes. After stirring for 10 minutes, the organic phase is decanted, the aqueous phase is washed with dichioromethane (100 cc) and then adjusted to pH 7 hy adding a saturated sodium bicarbonate solution (120 cc). The aqueous phase is washed with dichioromethane (5 x 100 cc), while adjusting the pH to 7 at each washing by adding sodium bicarbonate. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 k£a) at 40 “C. 26-f (S-diethylamlsoethylJsuIphisyljjpristinaarycia IIB (iscaer 85%, isomer Ax; 10%) (31 g) is thereby obtained in the farm of a light beige-coloured powder, the characteristics of which are identical to 2 those of the product obtained in Example I.

EXAMPLE 7 Concentrated sulphuric acid (0.08 cc) and then Oxone* (0.9 g) dissolved in distilled water (10 cc) axe added slowly, at 0C, to 26-<[(S)-l-diethylamino2-propyl]thio)pristin«aaycin IIB (isomer A) (2 g) dissolved . in ethanol (30 cc) and water (20 cc). The solution obtained is stirred for 4 hours at 20C. Solid sodium bicarbonate is then added to adjust the pH to 4 and fhe mixture is left stirring for 2 days at 20 *C. Distilled water (25 cc) and NORIT SS ULTRA charcoal (2 g) are then added. The mixture is filtered through Celite, rinsed with dichloromethane (20 cc) and then adjusted to pH 7 with solid sodium bicarbonate.

The aqueous phase is decanted and then washed with dichloromethane (2 κ 25 cc). The organic phases ar® dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at40*C.

A beige-coloured solid (1.6 g) containing 26—{ [ (S)-l-diethylaMno~2~propyl]sulphinyX}pristinamycia 1I3 (isomer Aj.) (80%), the isomer Αχ (10%) and the starting sulphide (10%), and th® characteristics of which are identical to those described in Bxasaple 4, is thereby obtained.

EXAMPLE, 3 Concentrated sulphuric acid (0.24 ce) is added to 26--(( (S)-l-diethyleaia0-2-propyl3thi©}pristinamycia IIa (isomer A, (6 g) dissolved in distilled water (20 cc) and methanol (90 cc) placed at -30’C, and Oxone* (2.7 g) dissolved in distilled water (10 cc) is then added slowly. The cloudy solution obtained is stirred at -30 *C for X hour. NORIT SX ULTRA charcoal (0.6 g) is then added and the mixture is then filtered through Celite. The filtrate is adjusted to pa 7 by adding solid sodium bicarbonate and then washed with diehloreaaethaae (3 x SO cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ”C.

The resulting solid is stirred in a mixture of 3 ethyl acetate (20 cc) and ethyl ether (70 cc), filtered off and then washed with ethyl ether (50 cc). A light beige-coloured solid (4.6 g) is thereby obtained, which is purified by flash chromatography (eluent: ethyl acetate:methanol (90:10 by volume)], collecting 15-cc fractions. After concentration of fractions 47 to 54 to dryness under reduced pressure (2.7 kPa) at 30 *C, 26-(((8) -l-diethylamino-2-propyl 3 sulphinyl}pristinamycin II„ (isomer A2) (1.7 g), containing the starting sulphide (10%) and having characteristics identical to the product described in Example 4, is obtained.

EXftMPLE 9 Distilled water (200 cc) is added, at -30’C, to 26-{[ (2S)-2-diethylaminopropyl)thio}pristineuaycin IXB (25.5 g) dissolved in ethanol (350 cc), and Oxone* (15.1 g) dissolved in distilled water (70 cc) is then added slowly. After stirring for 1 hour 30 minutes at -30*0, sodium thiosulphate (3.7 g) dissolved in water (20 cc) is added. The reaction mixture is then poured into distilled water (400 cc) and diehloromethane (200 cc) and adjusted to pH 7 with sodium bicarbonate. The organic phase is decanted and the aqueous phase is washed with diehloromethane (3 x 200 cc) - The organic phases are combined, 'dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30’C. A light yellcw solid (24 g) is thereby obtained, which is purified by flash chromatography (eluent: chlorofoxsssaethanol (90:10 by volume)). After concentration of fractions 23 to 2S (volume 50 cc) to dryness under reduced pressure (2.7 kPa) at 30C, a yellow cake is obtained, which is stirred in ethyl ether (100 cc) filtered off and then dried under reduced pressure (90 Pa) at 20‘C. 26-{[(2S)-2-Diethylaaiaopropyl3sulphinyljpristisajgycin XIB (isomer Ag) (11.3 g) is thereby obtained in the form ef a light yellow powder, a.p. approximately 128C. •3 4 NHR spectrum 1.1 ( [a, - -0¾¾ and c-3 ' ) 1.77 (s? ”CH3 at 33 2 (m, , 1H in “CHj- at 25) 2,30 to 2.7 (a, 1H in -C&j- at 25, -n( CHa-CHa 1H in -SO-CMj-) 2.97 (m, 1H in -SO-CSa-) 2.78 (Bi, es\- at 4) 2.92 and 3.10 (2dd, -CB> at 15) 3.13 (a, \cH~ at 26) 3.50 (m, \n~ch~) 3.81 (s. -CHj- at 17) 4.77 (d, ^CH- at 27) 5.52 (d. «CH- at 13) S.18 (d, =CH~ at 11) 6.48 (m, -NH- at 8) 6.57 (dd, , =CH- at 5) 8.12 (s, «Ca- at 20) The 26-(((2S)-2-diethylaminopropyl]thio) pristinamycin IIB (isomer A) may be obtained as followss (S)-2-Diethylaminopropanethiol (10 g) dissolved In chloroform (50 cc) is added, at -40*0, to a solution, placed under a nitrogen atmosphere, of pristlnajaycin 1IA (31.5 g) in methanol (230 cc) and chloroform (70 ecj. After stirring for 4 days at -40C, the mixture Is concentrated to dryness under reduced pressure (2.7 kPa) at 35 *C, and the resulting solid Is then stirred in ethyl ether (500 cc), filtered off and then stirred again in diethyl ether (300 cc). After filtration, the solid is dried (90 Pa) at 20C and then purified by flash chromatography [eluent: chloroforms methanol (90s 10 by volume)), collecting 100-cc fractions. After concentration of fractions 13 to 30 to dryness under reduced pressure (2.7 kPa) at 30*C, 2S-<[i2S)-2-dlethylaslsopropyl]thio}pristinamycin IIS (isomer A) (26.6 g) Is obtained in the fora of a light yellow solid, m.p. approximately 110*0.

NMR spectrum; H N(CH2CH3)2 1.05 (fflf CH3-CH2- and ~S~CH,~C^ ) CH, 1.72 (s, -CH3 at 33) 1.95 to 2.10 (m, -CH2 at 25) 2.50 (m, -K CK -Cn, ,X -2 3 ch2-ck3 2.SO, 2.87 and 3.04 (m, -S-CH,-CK^) 2.77 (a, >CH~ at 4) 2.9 and 3.10 (2dd, -CH2- at 15) 3.35 (m, ^CH- at 2S) 3.82 (s, -CHg- at 17) 4.7 (d, >CH- at 27) .47 (d. =CH- at 13) 6.15 (d, -CH- at 11) 6.46 (c, -NH- at 3) 6.54 (dd , =CH~ at 5) The (S)- 2-diethylaminopropanethiol aay he pre- pared as follows; A 5N aqueous sodium hydroxide solution (59.4 cc) is added to (S)-2-diethylaminopropylisothiouronium dihydrochloride (39 g) in ethyl ether (140 cc). After stirring for 30 minutes under a nitrogen atmosphere, the aqueous phase is decanted and then washed with ethyl ether (3 x 150 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30*C. The liquid obtained Is distilled at 78’c under 2.7 kPa to give (S)-2-diethylaainopropanethiol (10.S g) in the form of a colourless liquid (containing 1-diethylaminoprop&nethiol (6 %)}. (s3)s§° « +32 ± 0.6 (s « 0.943? ethanol).

The (S) -S-diethylaailnopropyllsothlouronlum dihydrochloride may be prepared as follows: A solution of (S)-2-diethylamino-l-chloropropane 6 hydrochloride (45 g) In Ν,Ν-dimethylformamide (150 cc) is added, at 130C, to thiourea (18.2 g) dissolved in Ν,Ν-dimethylf ormamide (80 cc). After 5 minutes at 13O*C, the solution is cooled. The crystals obtained are fil5 tered off, washed with ethyl ether and then dried under reduced pressure (90 Pa) at ' 20’C. (S)-2-Diethvlaminopropylisothiouronium dihydrochloride (39 g) Is thereby obtained in the form of white crystals, m.p. 209*C. [&]|0 - -2.6 (c = 1; ethanol).

The (S)-2~diethylamino-l~chloropropane hydrochloride may be prepared as follows: (S)~2~Diethylaminopr©panol hydrochloride (50 g) is added In small fractions, at 2*C, to thionyl chloride (110 cc). The solution obtained Is then heated for 4 hours to SO*C. The excess thionyl chloride is removed by distillation under reduced pressure (90 kPa) and ethyl ether (250 cc) is then added to the residue obtained. The resulting solid Is filtered off, rinsed with ethyl ether (300 cc) and then recrystallised in methyl isobutyl ketone (ISO cc). After filtration and washing with ethyl ether, (S) -2-diethylamino-2-chloropropane hydrochloride (45.6 g) Is obtained in the for® of white crystals, m.p. 103*C.

C«sTJo ® 0 (c * 0.7? ethanol).

The (S)“2-diethylasiaopropanol hydrochloride say be prepared as followss (S|-2-(K-Asetyl-Si-ethyIasiaes)pxmaaol (48.SS g) dissolved is tetrahydrofuran (300 co) is added to a suspension of lithius alusdnitsi hydride (18.23 g) in tetrahydrofuran (2000 cc) in the course of 20 minutes. The reaction tixtcre is then maintained under reflux for 4 hours and then cooled to 0*C. There is then added slowly distilled water (22 ec), followed by 5N aqueous sodium hydroxide (IS cc), followed by distilled water (72 cc). After stirring for 1 hour at 20C, the mixture is filtered through Celite. The filtrate is concentrated to dryness wader reduced pressure (2.7 kPa) at 30*C, is taken up with dichloromethane (3C0 cc), is dried over magnesium sulphate,. and is filtered and then concentrated to dryness under reduced pressure (2,.7 kPa) at ’Cr to give a light yellow liquid (42.45 g) which is distilled under reduced pressure. (S)-2-Diethylaminopropanol (26.56 g) is thereby obtained is the form of a colourless liquid. (3.p., » 55.5*C).

(S)-2-Diethylaminopropanol hydrochloride (31.41 g) is obtained in the form of a white solid, m.p. 98’C, after filtering off th© crystals obtained, by adding a 4.94M solution (40.5 cc) of hydrochloric acid in ethyl ether to the above product dissolved in acetone (136 cc). [e)|° - +20.7 (c = 1; ethanol).

The (S)«2-(M-acetyl-M-ethylamino)propanol may be obtained as followss Triethylamine (13.7 cc) is added, at 0’C, to (S)-2-(H-ethylamino)propanol (9.15 g) dissolved in dichlorornethane (100 cc), and acetyl chloride (7.1 cc) is then added in the course of 45 minutes. When the addition is complete, the temperature is allowed to rise to 20 *C. The reaction mixture is diluted with water (100 ce), adjusted to pH 9 by adding sodium carbonate and then washed with dichlorornethane (2 x 200 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2..7 kPa) at 30 *C to give a yellow liquid (9.54 g) which is distilled at IOS s 2*C under reduced pressure (26.3 Pa). A colourless liquid (6 g), containing (s) -2” (B-acetyl-N-ethylamino)propanol (approximately 80%) and the corresponding diacetyl derivative (20%), is thereby obtained (the liquid being used in the next step of the synthesis without farther purification).

The (S)-2-(S-ethylamino) propanol may be prepared as follows: Ethyl (5)-2-(acetylamino)propionate (227 g) in tetrahydrofuran (800 cc) is added, at 0*C, to a suspension of lithium aluminium hydride (81 g) ia tetrahydrofuran (4000 cc) in the course of 45 minutes. When the addition is couplets, the temperature is raised to 20*C and the mixture then heated to reflux for 5 hours. . 2S After cooling to O’G, there is then added slowly distilled water (97 cc), followed by 5N aqueous sodium hydroxide solution (72 cc), lastly followed by distilled water (320 cc). The mixture is filtered at 20 *C through Celite. The filtrate is concentrated fo dryness under reduced pressure (2.7 kPa) at 30’C, is taken up with dichioromethane (500 cc), is dried over magnesium sulphate, and is filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30’C to give a yellow liquid (143 g). After distillation under reduced pressure (460 Pa) at 57eC, (S)-2-(N-ethylaxaino)propanol (90.8 g) is obtained in the form of a colourless liquid. [ejg0 ~ *45.4 (c = 1.48; ethanol).

The ethyl 2-(acetylamino) propionate may be prepared as described by J.P. WQLPF III et al., Biochemistry 2, 493 (1963).

Claims (5)

1. a process for the preparation of a new pristinamycin II S derivative of general formula; in which the symbol R represents either a 4- to -membered nitrogen-containing heterocyclic radical, optionally containing 1 or more other hetero atoms chosen from amongst nitrogen, oxygen or sulphur in the sulphoxide or the sulphone fora,, and optionally substituted with an alkyl radical, or an alkyl chain containing 2 to 4 carbon atoms, substituted with 1 or 2 radicals chosen frc® amongst phenyl, cycloalkylemiao or Sf-elkyl-N-cycloalkylamino containing 3 to 6 members, alkylassino, dialkylamino or dialkylsarbamoylory (it being possible for the alkyl parts of these last 2 radicals optionally to form, with the nitrogen atom to which they are attached, a 4- to 7 «-membered saturated or umsaturated heterocycle optionally containing another hetero ate® chosen fress amongst nitrogen, oxygen or sulphur in the snlphoxide or the sulphone fora, and optionally substituted with an alkyl radical) radicals or substituted with one or more 4- to 7-meimbered nitrogen-containing heterocycles optionally containing 1 or 2 other hetero atoms chosen from amongst nitrogen,' oxygen or sulphur in the sulphoxide or the sulphone fora and optionally substituted with as alkyl radical, the said heterocycles feeing attached to the chain which carries the® via a carbon atas», it being understood that at least one of the substituents carried by the alkyl chain above is a nitrogen-containing substituent capable of forming salts, or an ((S)-l-snethyl-2~pyrroiidisyl}aethyl 3 Ο radical, and, unless otherwise stated, the alkyl radicals mentioned above are straight-chain or branched and contain 1 to 10 carbon atoms, in. the isomeric forms thereof or the mixtures thereof and the addition salts thereof with acids, wherein a pristin&mycin II B derivative (a salt thereof or a protected derivative) of general formula: in which B is defined as abovebeing understood that Ln the case where R contains a sulphur-containing heteroaia cycle, the sulphur atom may be in the su sulphoxide or sulphone form, is oxidised, using potassium oeroxvmonosulphate, and the product obtained is separated into its isomers if required and, when appropriate, the protective radical is removed and the product obtained is converted info an addition salt with an acid if required.

2. Process according to claim 1 in which the oxidation is carried out in an aqueous medium at -60° to *25°C.

3. Process according to claim 1 or 2 in which R is alkyl of 2 to 4 carbon atoms substituted by dialkylamino in which each alkyl has 1 to 4 carbon «toms.

4. Process according to claim 1 substantially as described in any one of the foregoing Sxamples. 3 1

5. A Dristinamvcin II_ derivative of formula I as defined in claim 1 including the isomeric forms thereof and mixtures thereof and its acid addition salts when oreoared by the orocess claimed in any of claims 1 to