CA1231307A - PHARMACEUTICAL COMPOSITIONS OF .beta.-II- PRISTINAMYCINE DERIVATES WITH SYNERGISTINS - Google Patents

Abstract

The invention relates to pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the compounds of general formula (I): (I) <IMG> in which R = a substituted alkylthio radical, a radical of general formula: Het -S where Het = pyrrolidinyl-3, piperidyl-3 or 4, azetidinyl-3 or azepinyl-3 or 4 (unsubstituted or substituted) or a dialkoylamino, pyrrolidinyl-1, piperidino, azetidinyl-1 radical , azepinyl-1, morpholino, thiomorpholino or piperazinyl-1 (unsubstituted or substituted), in combination with pristinamycin IA, virginiamycin S and / or at least one of the soluble synergistin derivatives of general formula (V):

Description

~ .Z 3 ~ t ~

This is a clivlslon of the patent application canadlen no ~ 58.720 of 12 julllet L9 ~ 4.
The present invention concerns cornposltlons pharmaceuticals containing at least as active ingredient a derivative of prlstinamycin IIB, subject of the application prln-clpale or its pharmaceutically acceptable addition salts, in combination with pristinamycin IA, virglnl-amyclne S or soluble synerglstlnes derivatives.
It is blen known that the synergistins obtained by fermentation are highly sought after products by doctors for the treatment of many ailments due to Gram-positive bacteria (of the genus Staphylococci, Streptococci, pneumococci, enterococci) and Gram-negative (of the genus Haemophilus, gonococci, meningococci). However these products have the disadvantage of being insoluble in aqueous medium and therefore cannot be administered yue by oral, generally in the form of capsules, dragees or tablets. Given this insolubility, it is impossible to use synergistins known so far when the patient is not able to swallow; this is particularly the case in pediatrics and resuscitation, while the spectrum of activity of these products would make it an indication valuable in many circumstances, for example example in cases of comatose septicemia.
The invention therefore relates to pharmaceutical compositions.
maceuticals, characterized in that they contain as active ingredient, at least one of the compounds of general mule (I):

'' ~

- 2 ~ ~ ~ O (I) in which ~ represents:
- or a substituted alcoylth.io radical:
-i) by one or two alkylamino or dial radicals coylamino whose alkyl parts can form together with the nitrogen atom to which they are linked a heterocycle saturated chosen from the group consisting of radicals pyrrolidinyl-1, piperidino, azetidinyl-1, azepinyl-1, morpholino, thiomorpholino and piperazinyl-1 (unsubstituted or substituted by an alkyl radical), or else -ii) by a pyrrolidinyl-2 or 3 radical, piperi-dyle-2, 3 or 4, azétidinyle-2 or 3 or azépinyle-2, 3 or 4, - either a radical of general formula:

Het - S -in which Het represents a pyrrolidinyl-3 radical, piperidyle-3 or ~, azetidinyl-3 or azepinyl-3 or 4 (no substituted or substituted on the nitrogen atom by a radical alkyl), either a dialkoylamino radical whose alkyl parts can form together with the nitrogen atom to which they are linked a saturated heterocycle chosen from the group consisting of killed by pyrrolidinyl-1, piperidino, azetidinyl- radicals 1, azepinyl-1, morpholino, thiomorpholino and piperazinyl-1 1 '~ .3: ~ 3 ~? ~

(unsubstituted or substituted by an alkyl radical), being understood that the rad: Lcaux and alkyl portions cited above contain 1 to 5 carbon atoms in a straight chain or branched, where appropriate in their isomeric forms and their mixtures, as well as their addition salts with acids pharmaceutically acceptable; in association with de] .a pristinamycin IA, virginiamycin S and / or at least one derivatives of soluble synergistins of general formula (V):

~ CI ~ y H2CH3 O ~ ~
H ~ ~ H3 RI ~ Rl (v --`x ~ H
~

in which Y represents a hydrogen atom or a radical dimethylamino and 1) or - represents a single bond, Z and R1 represent a hydrogen atom and X represents a radical of general formula:

-N ~ VI) \ R3 . , ~ ...

ol. ~ r.- ~ r.) r ~ sl3 ~ (3 l.ln ~ rl-3 ~ I 'tl ~ ldr ~ f' ~, r ~ r ~ 3 r (3r, Jr (': ~ .; cn ~: c3 url ra (l: kfll hydr ~ xy or alkyl not sllbstit-l ~ or suh3t: itu ~ by carboxy radical url, a: Lc: oyloxycarbolly: Le, hydroxy, alcoylarlli.no r) or di ~ lcoyl.am: Jno whose Radi.caux alkyl can form av ~ -3c: I'A atolne, ote to which they are attached url h ~ térocycle with 7 links chosen from the const group: i.tued by grc) uE) elnellts az ~ l :: idirlyJe, pyrrol.id:illyle, pipéridiny1.e, pip ~ r: a-xinylt ~, N- ~ llcoylp1p6raæirlyl and azeplnyl, or else R3 represented sent: e a cycloalcoyl radicaL containing 3 to 7 carbon carbons or a h ~ t ~ saturated rocycle with 4 to 7 chalnons choi. $ i in the group consti.tu ~ by the cycles az ~ tidine, pyrroli-d: ine, piperidine ct azepine, these heter ~ rocycles can be subst: i. ~ u ~ s Sllt-: The nitrogen atom by an alkyl radical, - either R2 represents a formyl or alkylcarbonyl radical and ~ 3 represents ~ an alkyl radical substituted by a radical carboxy, a: l.coylami.no or dialcoylamino whose radicals a: Lcoyle can form with the nitrogen atom to which they are attach ~ s a h ~ térocycle with 4 to 7 chalnons chosen in the group consisting of azetidinyl, pyrrolidi-nyle, pip ~ ridinyle, pipérazinyle, N - alcoylpipéraæinyle and azép.inyle, or R3 represents a hetero ~ rocycle at 4 to 7 links chosen from the group made up of cycles azetidine, pyrro: Lidine, piperidine and azepine, these hetero rings which can be substituted on the nitrogen atom by a radi.cal al.coyle, - either R2 and R3, i.denti.que $ or different, represent a radical a: alkyl unsubstituted or substituted by a radical carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dial-coylamino whose alkyl radicals can form with the nitrogen atom to which they are attached ~ s a heterocycle to 4 to 7 chalnons chosen from the group formed by the groups-merlts azetidinyle, pyrrolidinyle, pipér.idinyle, plp ~ razinyle, N-al.coylpip ~ raxinyle and aæépinyle, ~, ~, 53 ', ~ 3 ~

- either R2 and R3 form together with the nitrogen atom to which They are rat-stained a heterocycle with 4 to 7 selected links the group constituted by the aetetidine, pyrrolidine cycles, piperidine, morpholine and unsubstituted or substituted piperazine killed by an alkyl radical, 2) or --- represents a double bond, X
represents an oxygen atom and Z represents a radical of General formula:

-CH (VII) . R5 defined as follows:
a) either Rl and R5 each represent a hydrogen atom and R4 represents a pyrrolidinyl-3 thio or piperidyl-3 radical or 4 thio (these radicals being unsubstituted or substituted by a radical. alkyl) or else R4 represents a radical alkylthio substituted by one or two hydroxysulfonyl radicals, alkyllamino, dialcoylamino (unsubstituted or substituted by a mercapto or dialcoylamino radical) or by one or two cycles cholsis in the group made up of piperazino groups (not substituted or substituted by an alkyl or mercapto radical alkyl), morpholino, thiomorpholino, pipéridino, pyrrolidi-nyle-1, piperidyle-2, 3 and 4 and pyrrolidinyl-2 and 3 (these last two cycles being unsubstituted or substituted on the nitrogen atom by an alkyl radical), b) either R1 and R5 together form a valence bond and R4 represents a pyrrolidinyl-3 amino, piperidyl-3 radical or 4 amino, pyrrolidinyl-3 oxy, piperidyl-3 or 4 oxy, pyrrolidinyl-3 thio, piperidyl-3 or 4 thio (these radicals being unsubstituted or substituted on the nitrogen atom of cycle by an alkyl radical (e), or else R4 represents a substituted alkyl, alkyloxy or substituted alkylthio radical by one or two hydroxysulfonyl radicals, alkyllamino, dialcoylamino (unsubstituted or substituted by a radical dialcoylamino), trial.coylammonio or imidazolyle-4 or 5 or by one or two cycles chosen from the group consisting of piperazino groups (unsubstituted or substituted by an alkyl or mercaptoalkyl radical), morpholino, thiomor-pholino, piperidino, pyrrolidinyl-1, piperidyl-2, 3 and 4 and pyrrolidinyl-2 and 3 (these last two cycles being non substituted or substituted on the nitrogen atom by a radical alkyl), it being understood that the alkyl radicals and portions alkyl referring to the symbols of the general formula (V) contain 1 to 5 carbon atoms and are in a straight chain or branched; in a non-toxic pharmaceutical excipient acceptable.
In particular, the invention relates to pharmaceutical compositions, characterized in that they contain as active ingredient pristinamycin AI in combination with products of general formula (I) in which R represents an alkylthio radical substituted by one or two dialkoylamino radicals whose alkyl parts can possibly form with the nitrogen atom to which they are attached, a saturated heterocycle chosen from pyrroli-dinyl-1 and piperazinyl-1 optionally substituted by a alkyl radical, or R represents either a radical of general formula (II) in laquell.e Het represents an optional piperidyl-4 radical-ment substituted on the nitrogen atom by an alkyl radical, either a dialkoylamino radical whose alkyl parts can form with the nitrogen atom to which. they are linked, a cycle piperazinyl-1 optionally substituted by an alkyl radical, it being understood that the radicals and alkyl portions mentioned above '3. ~ 31 ~ - 7 above are straight or branched: E: i.e. and contain: 1 ~ 3 ~ Itornes of carbon.
Preferably, parml these products of Eormule (I) The products of General Formula (I) are interesting in which R is a branched alkylthio radical containing 1 to

3 carbon atoms substituted by a dialkoylamino radical or represents a 4-alkyl-piperazinyl-1 ring, it being understood that special mention radi.c ~ ux alkyl contains 1 or 2 carbon atoms;
and in particular the following products:
- (1-diethylamino-2-propyl) thio-26 pristinamycin IIB
- (4-methyl-1-piperazinyl) -26 pristinamycin IIB.
For therapeutic use, it can be done use of compositions containing new products from formula (I ~ subject of the invention of the main application as is, i.e. in the basic state, in association with synergistins already known. However, as the principal pal advantage of the products subject of the invention of the main demand is their possible solubilization in water, it is particularly advantageous to use them in the form of pharmaceutically acceptable salts, in combination ti.on with known synergistins or synergistins of general formula (V) themselves dissolved either in the state pharmaceutically acceptable salts or, where appropriate, in the basic state, when the solubility is sufficient to 2 ~ ~ ue the solution obtained contains a ~ uantity of product at less equal to the therapeutically active dose.
The products of general formula (I) can in particular be prepared according to the main demand process, by the action of a product of general formula:
HR (III) in which R is defined as above on the product of formula:

,! 'j `,`
. ~ f `, '$, ,, ~ NH ~ ~ OH
CH, ~ ~ ¦ O (1 \ 1) vs i.e. pristinamycin IIA.
The reaction is generally carried out without solvent or in an organic solvent such as an alcohol such as metha-~ nol or ethanol or a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform, or in a mixture of these solvents (for example methylene chloride-methanol) at a temperature between 0 and 50C.
It can sometimes be advantageous to operate in proximity a tertiary amine, for example triethylamine, or a ethanolamine (dimethylethanolamine for example) ~
It is understood by those skilled in the art that when R represents a radical which contains a secondary amine function may interfere with the reaction, this last function must be protected beforehand before ~ area react the product of general formula (III) on the product of formula (IV). Any means can be used for this purpose.
usual to block a secondary amine function in the form of a labile radical which can be eliminated after reaction of the product of general formula (III) to the product of formula (I ~). It is particularly advantageous to use serve as a radical blocking the trifluoroacetyl radical. The one-it can then be removed using an aqueous solution alkaline bicarbonate such as sodium bicarbonate or potassium.
The new products of genex formula (I) can be purified by the usual known methods, for example crystallization, chromatography or extractions successive in acidic and basic medium. For the man of trade knowing the se, nsibility of synergistins in the environment alkaline, "basic medium" means a medium which is just sufficient sufficiently alkaline to release the mother substance from its salt addition with an acid, that is to say a medium whose pH
does not exceed 7.5 to 8.
Some of the synergistic derivatives of formula general (V) may have isomeric forms. It is understood that these isomeric forms as well as their mixtures can be advantageously combined with formula products general (I).
The products of general formula (V) defined as previously in 1) with the exception of those for which R2 represents a formyl or alkylcarbonyl radical, can be prepared by the action of an amine of general formula:

(VIII) ~ 5 in which R2 and R3 are defined as above, on a synergistin of general formula:

3, ~ 3, t ~
~ 10 -~ Q ~ ~ Y (IX) ~ C ~ CH3 GN

G ~ ¢ ~ O

~, ~

in which Y represents a hydrogen atom0 (virginiamy-cine S) or the dimethylamino radical (pristinamycin IA), in presence of an alkaline cyanoborohydride.
We generally operate with an excess of General formula (VIII) in the presence of a cyanoborohydride alkaline like sodium cyanoborohydride, in a solvent organic such as an alcohol in which acid has been dissolved hydrochloric gas ~ (hydrochloric methanol or ethanol hydrochloric), at a temperature between 0C and reflux temperature of the reaction mixture, preferably at a temperature close to 20C.
The reaction can advantageously be carried out in presence of a drying agent such as molecular sieves laires.
2S The products of general formula (V) defined as previously in 1) in which R2 represents a radical formyl or alkylcarbonyl and R3 represents an alkyl radical substituted by a carboxy, alkylamino or dialkoylamino radical whose alkyl radicals possibly form with the atom nitrogen to which they are attached, a heterocycle at 4 to 7 chains; selected from azetidinyl, pyrrolidinyl, piperidi-nyle, piperazinyl, alkylpiperazinyl or azepinyl, or represents a 4 to 7-membered saturated heterocycle chosen from the cycles a ~ etidine, pyrrolidine, piperidine and aær7pine, these heterocycles can be substituted on the atom nitrogen by an alkyl radical, and Y is defined as previously, can be prepared by the action of a product of general formula:

R6 ~ CO - Q (X) in which R ~ represents a hydrogen atom or a alkyl radical and Q represents a halogen atom or a alkylcarbonyloxy radical, on a product of general formula rale:

~ CH3 o ~ q / N - n ~ N ~ Y
~ ~ 2C H 3 0 ~ N ~ H, 3 (XI) 0 ~ NH ~ O

2 0 N ~

in which Y is defined as above and R3 has the definition of corresponding R3 given above.
The reaction usually takes place in a soil-organic solvent such as pyridine, in a chlorinated solvent (methylene chloride) or an ether (tetrahydrofuran) in presence of an acid acceptor such as an organic base such as triethylamine or a mineral base such as carbonate or an alkaline bicarbonate such as bicarbonate sodium, operating at a temperature between 0C
and 80C.

3 ~

It is understood for the man of the metler that ~, when R'3 represents a radical containing a secondary amine function daire, said function must be protected before doing react the product of General Formula (X) on the product of General formula (XI). For this purpose, any means of bl.ocage usual used to protect an amino function and can be eliminated later, without affecting the rest of the molecule. It is particularly advantageous to use as a radical blocking the trifluoroacetyl radical; this one can then be removed using an aqueous solution of alkaline bicarbonate such as sodium bicarbonate or potassium.
It is also understood for the skilled person that, when in the general formula (VIII) R2 and / or R3 represent a radical containing a secondary amine function daire, the latter must be previously protected before to react the product of general formula (VIII) on the product of general formula (IX). Blocking and unblocking are carried out as described above.
The products of general formula (V) defined as previously in 2) in which Y is defined as above demment and the other symbols of which defined as above ment in 2) a) can be prepared by the action of a product of general formula:

R 4 (XII) in which R'4 has the definition of R4 given previously in ~) a) on a product of general formula:

o ~, CI ~ \ y ~ IN ~ CcHl ~ C 3 N-- ~ c ~ 2 (XIII) O ~~ o ~ ~
~ H ¢ ~

in which Y is defined as above.
We generally operate 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 ture between 0C and the reflux temperature of the reaction mixture, preferably at a temperature close to 20C.
The products of general formula (XIII) can be prepared by the action of an alkaline borohydride such as sodium cyanoborohydride on a p: product of general formula:

~ C H3 f = = - ~
oq ~ NJ ~ ¦ ~ N ~. . ~ Y
, ~ C ~ H3 o ~ N ~ N ~ CH33 (XI ~ ') o ~ - ~ o ~
25 0; ~ N tl, ~ O
N ~ OJ

in which Y is defined as above.
We generally operate in an organic solvent such as an ether such as tetrahydrofuran or an alcohol by 3 ~ Q: ~ Jt ~, 1 ~ -example lsopropanol in the presence of an acid such as ue acid tr: ifluoroacetic, at a temperature between 0C and the reflux temperature of the reaction mixture, preferably at a temperature close to 20C.
The products of general formula (XIV) can be obtained by action of a product of formula:

N - CH (XV) in which either X1 represents an alkyloxy radical and X2 represents an alkyloxy or dimethylamino radical, or else X1 and X2 both represent a dimethylamino radical, on a product of general formula (IX).
In practice, it is advantageous to react tert-butoxy bis (dimethylamino) methane on the product of general formula (IX), operating in an organic solvent such as a chlorinated solvent such as 1,2-dichloroethane or a amide (dimethylformamide for example) at a temperature taken between 0C and 80C, preferably at a temperature close to 20C.
The products of general formula (XV) can be prepared according to the methods described by H. BREDERECK et al., 25 Chem. Ber., 101, ~ 1 and 3058 (1968) and Chem. Ber., 106, 3725 (1973) -The products of general formula (V) in which Y is defined as above and the other symbols are defined as above in 2) b) except for R4 to represent a pyrroli.dinyl-3 oxy, piperidyl-3 radical or

4 oxy or alkyloxy optionally substituted as defined in 2) b), can be prepared by the action of a formative product general mule:

- l5 -R 4 (XV: t) in which R "4 has the definition of R ~ given above, on a product of general formula (XIV) in which Y
is defined as above.
The reaction is carried out in an organic medium, in presence of an acid (e.g. acetic acid or a mixture acetic acid and catalytic amounts of trifluoric acid acetic acid), in the presence or absence of a solvent, at a temperature between 0 and 50C; preferably at a temperature close to 20C.
If necessary, the solvent can be chosen from organic solvents such as ethers (tetrahydrofuran), alcohols (ethanol) and chlorinated solvents (chloride of methylene or chloroform for example).
The products of general formula (V) in which Y is defined as above and the other symbols are defined as above in 2) b) can be prepared by action of a prodult of general formula:

R ~ 4 - H (XVII) in which R "'4 is defined as R4 in 2) b), on a product of general formula:

~ C ~ 3 O ~ "N '~ N ~ y (~ III) II.N - C i: .5C H ~, N
0 ~ 0 C ~, NH ~ O
3 0 N / ~

in which Y is deEini as before and Zl represents has a tosyloxy, acetyloxy, trimethylsi.lyloxy radical or dialkoyloxyphosphoryloxy the alkyl parts of which contain 1 to 4 carbon atoms in a straight or branched chain, or Zl represents a chlorine atom.
We generally operate in an organic solvent such as an ether such as tetrahydrofuran, an alcohol such ethanol or a chlorine solvan-t (methylene chloride or chloroEorme for example) at a temperature close to 20C.
The reaction is carried out in basic medium, for example in presence of an alkaline hydride or an alkaline alcoholate such as sodium ethylate or potassium tert-butoxide.
When R "'4 is other than substituted alkyloxy or heterocyclyloxy, it is also possible to operate either by neutral medium at a temperature between 0 and 50C, in one of the solvents mentioned above, either in an acid medium under conditions identical to those described above for the action of a product of general formula (XVI) on a product of general formula (XIV), The products of general formula (XVIII) can be prepared by acid hydrolysis of a product of formula general (XIV) to obtain a product of general formula:

O ~ J ~ XIX) C ff2CH3 o N ~ OH
3 hrs ~

~ 0 su: ivie:
~) or the action of a product of general formula:

Z 1 (XX) in which X represents a halogen atom and Z'l has the definition given above for Zl with the exception of re-present a chlorine atom ~) or the action of a product of formula:

(C6Hs) 3P-cl2 (XXI) to obtain a product of general formula (XVIII) in which Zl represents a chlorine atom.
Hydrolysis of the product of general formula (XIV) in general formula (XVIII) of an aqueous solution of a mineral acid such as a solution 0.1N hydrochloric acid by operating at a temperature ture close to 20C.
The reaction of the product of general form (XX) on the pro-duit of general formula (XIX) is generally carried out in a solvent organic such as methylene chloride in the presence of an accept acid such as an organic base com ~ e triethylamine or a base mineral like a carbonate or an alkaline bicarbonate, for example the sodium or potassium bicarbonate. We generally operate at a temperature between -20 and +20 C.
The reaction of the product of general formula (XXI) on the product of general formula (XIX) is generally carried out Lement in a chlorinated solvent such as methylene chloride at a temperature between -20 and + 20C.
The products of general formulas (III), (VIII), (XII), (XVI) and (XVII) can be prepared according to or by analogy with the methods described below in the examples ~
and in particular according to:

- GG Urquart et al., Org. Synth., 21, 36 (19 ~ 1) - AI Vogel, J. Chem. Soc., 1822 (1948) - JH Chapman and LN Owen, J. Chem. Soc., 57g (1950) - HR Snyder et al., J. Am. Chem. Soc., 69, 2672 (1947) - DD Reynolds et al., J. Org. Chem., 26, 5125 (1961) - JW Haeffele et al., Proc. Sci. Toilet Goods Assoc., 32, 52 (1959) - H. Barrer et al., J. Org. Chem., 27, 641 (1962) - JH Biel et al., J. Amer. Chem. Soc., 77, 2250 (1955) in the case of a product of general formula (III), (XII), (XVI) or (XVII) for which R, R'4, R "4 or R"'4 represents a substituted or heterocyclylthio alkyl radical, or according to:
AJW Headlee et al., J. Amer. Chem. Soc., 55, 1066 (1933) - BK Campbell and KN Campbell, J. Amer. Chem. Soc., 60, 1372 (1938) - RC Elderfield et al., J. Amer. Chem. Soc., 68, 1579 15 (1946) in the case of a product of general formula (XVI) or (XVII) for which R'`4 or R "'4 represents an alkyloxy radical substituted or heterocyclyloxy, or according to:
- J. Amer. Chem. Soc., 54, 1499 (1932) and 20 - J. ~ wed. Chem. Soc., 54, 3441 (1932), in the case of a product of general formula (VIII) or of general formula (III), (XVI) or (XVII) for which R, R "4 or R "'4 are substituted alkylamino radicals, or according to:
- EF Elslager et al., J. Med. Chem., I7, 99 (1974) 25 - LM Werbel et al., J. Het. Chem., 10, 363 (1973), when it is a product of general formula (III), (XVI) or (XVII) for which R, R "4 or R"'4 are hetero radicals cyclylamino.
It is understood that in the above methods, when R2, R3, R'4, R "4 or R"'4 contain an alkyl-amlno may interfere with the reaction, the latter is previously protected by any known method which does not alter t ~
, 9 not the rest of the molecule.
Similarly: When the radicals R '~, R "~ and R"' ~ in products of general formulas (XII), (XVI) and (XVII) contain a secondary Amine Ection which may interfere with the reaction, it must be protected before doing react the corresponding products respectively with the products of general formulas (XIII), ~ XIV) and (XVIII). The protective radical is removed after reaction. We operate at this effect under the conditions described above for the radical R of the reagent of general formula (III).
Where appropriate, the isomers of the products of formula general (I) and / or products of general formula (V) can-wind be separated by chromatography ~ aphia or by chromatography high performance liquid.
The products of general formula (V) can be purified as previously mentioned for the products of general formula (I).
In the laboratory, the products of general formula (I) synergize the anti-microbial action of the products of general formula (V) at doses between 5 and 200mg / kg in mice subcutaneously, especially in septi-cemia caused by Staphylococcus aureus Smith when they are mixed with the products of general formula (V) in proportions varying between lO-90 ~ and 90-10 ~.
Acute toxicity of general formula products (I), expressed by the LD50, is generally between 300 and 900 mg / kg subcutaneously in mice.
As pharmaceutically acceptable salts, too both for products of general formula (I) and for products of general formula (V), there may be mentioned the salts addition with mineral acids such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or organic such as acetates, propionates, succinates, maleates, fuma-spleens, methanesulfonates, p.toluenesulfonates, is ~ thionates ~ ~ 3 ~ t ~

or keys derived from subsitute: of these compounds. Com ~ e se: Ls pharmaceutically acceptable, mention may also be made of the salts with alkali metals such as sodium salts, potassium sium, lithium, with alkaline earth metals such as magnesium salt, ammonium salt and addition salts with organic nitrogen bases: ethanolamine, diethanol-amine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimé-thyléthanolamine, benzylamine, dibenzylamine, dicyclohexylbenz.ylamine, N-benzyl- ~ -phenethyl-amine, NN'-dibenzylethylenediamine, benzhydrylamine, arginine, leucine, lysine or N-methylglucamine.
As pharmaceutically acceptable salts for products of general formula (V) in which Z represents a radical of general formula (VII) in which R ~ represents smells a trialkylammonio radical, there may be mentioned the quaternary ammonium salts corresponding to the anions listed above.
The following examples, given without limitation, show how the invention can be put into practice. The NMR spectra of the products illustrated in these examples and in 1.es examples of reference which are following, presented try general characteristics which are common to all the products of general formula (I) or of general formula (V) and special features that are unique to each of the products according to the substituents. In ~ 5 Example 1, as well as in the reference examples 1 and 16, it is given the attribution of all the protons of the mol-ass; in the following examples or reference examples only are mentioned that the special characteristics due to variable radicals. For products of general formula rale (I) all the protons are designated according to the numbering indicated in the following formula:

- 2l -o 6, ~ 7 ~ NH ~ 1 CH3 JI5 o Io CH33 l ~ o CH3, - ~ o ~ N ~ N8 ~ 17 30 ~ r 29 2 1 \ l 126 \ 2 ~ L_ 0 19.
3ClH ~ ~ o For synergistins of general formula (~) all protons are designated according to the numbering indicated in the general formula (XXIII); this numbering is that recommended by JO ANTEUNIS et al., [Eur. J. Biochem., 58, 259 (1975)].
~ 4CH
3 ~ CHI ~
o, ~ N ~ N ~ y 2NHHN l ~ cCHH2CHo o N ~ <(XXIII) O ~) J ~ NH ~ X
O ~ NH lNH

N ~
1 'H 6 ~ 1 ~ H4 1 l H5 All spectra were made at 250 MHz in the deutero-chlorofor ~ e; chemical shifts are expressed in ppm by signal to tetramethylsilane signal. Abbreviations used below are the following:

L r ~
- 2 ~ ~

s = sin ~ ulet d ~ doublet t = triplet mt = multiplet m ~ mas6if dd = doublet of doublet dt r triplet doublet ddd = doublet of doublet of doublet dddd = doublet of doublet of doublet of doublet In the following examples, we call chromatography "flash" a purification technique characterized in that use a short chromatography column and operate under an average pressure (50 kPa) using a silica of ~ ranulo-m-trie 40-53 um, according to WC STILL, M. KAH ~ l and A.MITR ~.
15 ~ J Org. Chem., 43, 2923 (1978) ~.

To a suspension of 13.1 g of pristinamycin IIA in 150 cm3 of methanol, a solution of 3.7 g of diethyl-arino ethanethiol in 15 cm3 of methylene chloride. The solution obtained is stirred for 18 hours at a temperature around ~
20C, then poured into 1500 cm3 of distilled water; the mixture obtained is e ~ trait 3 times per 1000 cm3 in total of methylene chloride.
The organic phases are combined, dried over sulphate of m ~ gnesium, filtered and then concentrated to dryness under reduced pressure (., 7 kPa) at 30C. The residue obtained is purified by chromatography "flash" eluting: chloroform-methanol (90-10 by volume V; apr ~ s dry concentration of fractions 5 to 23 under reduced pressure (2.7 kPa) at 30C, 12.4 g of (2-ethyl diethylamino) are obtained thio-26 pristinamycin IIB under for ~ e of a fondant yellow powder around 105C.

~, ~ 3. ~
~ 23 -_ _ __ _ _ ~ (ppm) For ~ e Attribution ~ _ _ __ ~
8.10 s H 20 6.60 s wide N'H 8 6.55 dd H 5 6.15 d H 11

5.80 dd H 6 5.65 ddd H 10 5.50 d H 13 4.95 ddd H 14 4.77 dd H 3 4.75 d H 27 ~, 27ddd H 24 4.05ddd H 9 3.87ddd H 9 3, ~ 0 s ~ 17 3.55 ddd H 24 3.40 ddd H 26 3.10 dd) H 15 system 2.9 dd3 H 15 20 2.75 s -2 -2 2.74 m H 4 2.60 S -N- (CH2CH3) 2 2.15 to 1.85 m H 25, H 29 1.70 s H 33 25 1.05 m - ~ (CH2CH3) 2+ H 3 0.95 dd H 30+ H 31 An aqueous solution is obtained 3 2 ~ of ~ dieth ~ larinc-2 ethyl) thio-26 pristinamycin IIB (product B. ~.), as hydrochloride, with:
product BA ..................... 0.1 g hydrochloric acid 0.05 ~ ..... 3 c ~ 3 distilled water ................. qs 5 cm3 ~. ~ '; 3 ~

- 2 ~ -~ XEMPI, E 2 By operating in a ~ analogous manner ~ that described in ~ xemplc 1, but from 2.7 g of pristinamycin IIA and 0.58 g of 2-dimethylamino ethanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (90-by volume)] and dry concentration of fractions ll at 17 50US reduced pressure (2.7 kPa) at 30 C, we obtain 1.1 g (2-dimethylaminoamino) -thio-26 pristinamycin IIB in the form of a yellow powder melting around 100C.
NMR spectrum:
2.35 (s, 6H: -N (CH3) 2) 2.80 (m, 4H: -S-CH2CH2-N <) 3.40 (ddd, 1H: H 26) 4.75 (d, 1H: H 27) 8.10 (s, 1H: H 20) A 2% aqueous solution of (dimethy-lamino 2 ethyl) thio-26 pristinamycin IIB (product BB), in the hydrochloride state, with:
BB product ......... ~ ..................... .... 0.1 g hydrochloric acid 0.1N ........... .... 1.6 cm3 distilled water ...................... qs 5 cm3 By operating in a manner analogous to that described in Example 1, but from 5.25 g of pristinamycin IIA and 1.3 g of 3-dimethylamino propanethiol and after purification cation by "Elash" chromatography [eluent: chloroEorme-methanol (90-10 by volume) ~ and dry concentration of fractions 6 to 29 under reduced pressure (2.7 kPa) at 30 C, 3.3 g of (3-dimethylamino propyl) thio-26 pristina are obtained mycine IIB in the form of a yellow powder melting towards 100C.
NMR spectrum:
I, 50 (s, 3H x 0.5: H 33 the first isomer) 1.70 (s, 3H x 0.5: H 33 2 nd lsomer) . .

't ^ `

1.80 (rn, 2 ~ 1 -SCI-12-C ~ 12 ~ Cll2N ~) 2.20 (s, 611 x (), 5: -N (C113) 2 lel. Isorllèr ~) 2.25 (9, 61-1 x 0.5: --N (C113) 2 2nd: isom ~ re) 2, '10 (m, 21-1: -SCH2-C112-C112N ~) 2.70 (m, 2H: -SCH2-CH2-CH2N ~) 3.35 3, '15 (2m, 1H: H 26 of each iomer) 4.60 ~
3 (2d, 1H: H 27 of each lsomer) 7 80` ~
8 1 J (2s, 1H: H 20 of each isomer) A 3.3% aqueous solution of (dimethyl-lamino-3 propyl) thio-26 pristinamycin IIB (product BC), with:
BC product ........................ ... 0.1 g hydrochloric acid 0, lN .......... ... 1.55 cm3 distilled water ...... ~ ................... qs 3 cm3 -By operating in a manner analogous to that described in Example 1, but from 5.25 g of pristinamycin IIA and 1.7 g of (pyrrolidinyl-1) -2 ethanethiol and after purification by "flash" chromatography [eluent: chloroform ~ -methanol (95-5 by volume)] and dry concentration of frac-19 to 60 at reduced pressure (2.7 kPa) at 30 C, we obtains 3.9 g of [(pyrrolidinyl-1) -2 ethyl] thio-26 pristina-mycin IIB in the form of a yellow powder Flowing worms 115C.
NMR spectrum:
CH
1.90 (mt, 4H: -N ~ 1--2 ~ _ CH2 H ~, C
2.50 to 2.80 (m, 6H: -SCH2CH2N ~

3,4i ~ (d, 1H: H 26) 4.75 (d, 1H: H 27) 8.10 (s, 1H: H 20) A 5% aqueous solution of [(pyrroJi-dinyl-1) -2 ethyl] thlo-26 prlstlnarnycine [1 (produltBD), in the hydrochloride state, with:
BD product .......................... ~. 0.1g hydrochloric acid 0, lN ........... .... 1.5 cm3 distilled water ...................... qs 2 cm3 (1-pyrrolidinyl) -2 ethane-thiol can be pre-adorned according to the method described by JW HAEFFELE and RW BROGE, Proc. Sci. Toilet Goods Assoc. 32 52 (1959) hemChem. Abstr. 54 17234e (1960) ¦.

By operating in a manner analogous to that described in Example 1, but from 3.15 g of pristinamycin IIA and 1.1 g of (mercapto - 2 ethyl) -1 methyl-4 piperazine and after puriEication by "flash" chromatography ~ eluent:
chloroform-methanol (95-5 by volume) ~ and concentration dry fractions 14 to 20 under reduced pressure (2.7 kPa) at 30 C, 1.4 g of ~ methyl-4 piperazinyl-1) -2 are obtained 20 ethyl ~ thio-26 pristinamycin IIB in powder form yellow melting around 115C.
NMR spectrum:
2.30 (s, 3H: ~ N-CH3) 2.40 to 2.80 (m, 12H -S-CH2-CH2N ~ -2 -2 \ C 2-CH2 3.35 (d, 1H: H 26) 4.75 (d, 1H: H 27) 8.10 (s, 1H: H 20) A 2% aqueous solution of [(methyl-4 piperazinyl-1) -2 ethyl] thio-26 pristinamycin IIB (product BE), as hydrochloride, with:
BE product ....... ...... ..... ........ 0.1 g hydrochloric acid 0, lN ........... .... 1.46 cm3 distilled water ...................... qs 5 cm3 (Mercapto-2 ethyl) -l methyl-4 piperazine can 3. ~ 3 ~ J ~ i ~

~ be prepared: Lon lcl method described by DD REYNOL.DS
et al., J. Org. Chem., 26, 5125 (1961).
_XAMPLE 6 By operating in a manner analogous to that described in Example 1, but from 3.15 g of pristinamycin IIA and 1.8 g of diethylamino-1 propanethiol-2 and after purification cation by "flash" chromatography [eluent: chloride methylene-methanol (90--10 by volume)] and concentration dry fractions 3 to 5 under reduced pressure (2.7 kPa) at 30C, 1.4 g of (1-diethylamino-2-propyl) thio- are obtained 26 pristinamycin IIB as a melting yellow powder around 160C.
NMR spectrum:
1 (m, 9H H 32 ~ -N (CH2CH3) 2) 2.50 (m, 6H: -CH2N (CH2CH3) 2) 3.30 (m, 1H: H 26) 4.70 (d, 1H: H 27 ~
8.12 (s, 1H: H 20) A 5% aqueous solution of (diethyla-mino-1 propyl-2) thio-26 pristinamycin IIB (product BF), as hydrochloride, with:
BF product ......................... .... 20 mg hydrochloric acid 0, lN ........... .... 0.3 cm3 distilled water ...................... qs 0.4 cm3 Diethylamino-l propanethiol-2 can be prepared by the method declte by RT WRAGG, J. Chem. Soc. (VS), 16, 2087 (1969).

By operating in a manner analogous to that described in Example 1, but from 3.15 g of pristinamycin II and 1.6 g of methyl-1 piperidinethiol-4 and addition of 0.6 g of triethylamine in the reaction mixture and after purification cation by "flash" chromatography [eluent: methyl chlorine-2 / cl -lene-methano: l. (92-8 by volume)] and concentrate: i.on to dry fractions ~ to 20 under reduced presslon: i.e. (2.7] c ~ a) at 30 C, 0.9 g of (rné-thyl-l pipéridinyl- ~ thio-26 pristina- is obtained) mycine IIB in the form of a yellow powder melting towards 1 ~ 0C.
NMR spectrum: CH
2.10 (m, 4H: -S ~ 2 N-) ~., - 2 ~ ~

2.25 (s, 3H: -S ~ N-CH3) rCH2 ~
2.80 (m ~ 4H: -S ~ N ~ -) C ~ 2 3.55 (m, 1H: H 26) 4.62 (m, 1H: H 27) 7.70 (m, 1H: H 8) 8.10 (s, 1H: H 20 ~
An aqueous solution containing 5% methyl-1 pipé is obtained.
ridinyl-4) thio-26 pristinamycin IIB (productBG), 3 the state of hydrochloride, with:
BG product ........................ ..... 10 mg hydrochloric acid ............... ..... 0.14 cm3 distilled water ..................... qs 2 cm3 Methyl-1 piperidinethiol-4 can be prepared by the method described by H. BARRER and RE ~ YLE, J. Org. Chem., 27, 641 (1962).
EXE ~ LE 8 By operating in a manner analogous to that described in exe ~ ple 1, but from 5.25 g of pristinamycin IIA and 10 cm3 of a 5 ~ ethanolic solution of gaseous dimethylamine and after purification by "flash" chromatography [eluent:
chlorofor ~ e-methanol (90-10 by volume) 7 and dry conceneration fractions 14 to 24 under pressure reduced (2.7 kPa) ~ 30C, we obtains 0.8 g of dimethylamino-26 pristinamycin IIB under for ~ e of a yellow powder melting around 230C.
Spectrum R ~ 1 (CDC13 + 10 ~ CD ~ D) 2.35 (s, 6H: - ~ 1 (CH3) 2) 3.25 (d, 1H: H 2f6) 5.05 (d, 1H: H 27) 8.20 (s, 1H: H 20) A 2 × aqueous sclution of dimethylamino-26 is obtained.
pristinamycin IIB (product ~), as hydrochloride, with:

X ~ J ~ 7 proclui.t Bll ..................... .... (), L y hydrochloric acid: 0.1N .......... ....: l., 75 cm3 distilled water ..................... qs 5 cm3 By operating in a manner analogous to that described in Example 1, but from 5.25 g of pristinamycin IlA and 5 g of 4-methyl-piperazine and after purification by "flash" chromatography [eluent: chloroform-methanol (90-10 by volume) ~ and dry concentration of the fractions 20 to 44 under reduced pressure (2.7 kPa) at 30C, we obtain 0.7 g (4-methyl-1 piperazinyl) -26 pristinamycin IIB
in the form of a yellow powder melting around 140C.
NMR spectrum:
2.30 (s, 3H: ~ N-CH3) 2.40 to 2.65 (m 3H: N ~ CH2 ~ CH2 ~
CH -CH
3.40 to 3.70 (m, container H 26) 5.75 (d, 1H: H 27) 8.10 (s, 1H- H 20) An aqueous solution containing 3.3% of (methyl-4 piperazinyl-1) -26 pristinamycin IIB (product BI), eta-t hydrochloride, with:
does BI ....................... .... 0.1 g hydrochloric acid 0, lN .......... .... 1.6 cm3 distilled water ................ ~ .... qs 3 cm3 A solution of 5.2 g of pristinamycin IIA in 20 cm3 of methyl-1 piperazine is stirred for 1 hour 30 minutes at a temperature close to 20 C, then is poured into 600 cm3 of distilled water. The emulsion obtained is extracted 3 times per 600 cm3 in total of methylene chloride; the organic phases are combined, dried over sulphate magnesium,: E ~ rees pUi5 dry concentrated SOlIS press: i.on reduced (2.7 kPa) to 30 CIe residue obtained is pure: LEié
by "fl.ash" chromatography [eluent: chloroform-methano: L
(90-10 by volume)]; after dry concentration of fractions 13 to 30 under reduced pressure (2.7 kPa) at 30C, we obtain 2.6 g (4-methyl-1-piperazinyl) -26 pristinamycin IIB
in the form of a beige powder melting around 140C.
Is the NMR spectrum of this product identical to that of the product described in Example 9.
EXEMP ~ E ll -By operating in a manner analogous to that described in Example 1, but from 12.6 g of pristinamycin IIA and 5.2 g of 2,3-bis-dimethylamino propanethiol and after purification by "flash" chromatography ~ eluent:
methylene chloride-methanol (90-10 by volume)] and concentrated dry tration of fractions 29 to 42 under reduced pressure ~ 2.7 kPa) at 30C, 0.3 g of (bis dimethylamino-2,3 propyl) thio-26 pristinamycin IIB in the form of a yellow powder melting around 110C.
NMR spectrum:
~ CH
2.30 (m, 12H: -N 3) 2.50 (m, 2H: -CH2-N ~) 2.90 (m, 1H: -CH-N ~) 3.56 (m, 1H: H 26) 4.64 (d, 11-l: H 27) 4.66 (d, 1H: H 27) 7.81 (s, 1H: H 20) A 2% a ~ uous solution of (bis dim-thylamino-2,3 propyl) thio-26 pristinamycin IIB (product BJ), in the hydrochloride state, with:
does BJ ....................... .... 10 mg hydrochloric acid 0, lN .......... .... 0.14 cm3 distilled water .................. ~ .. qs 0.5 cm3 Bis 2,3-dimethylamino propanethiol can be prepared according to the method described by H. NISHIMURA and H.
TAKAMATSU, Yakugaku Zasshi, 84, 944 (1964) (Chem. Abstr.
62, 2750 b (1965)).

To a solution of 0.41 cm3 of dimethylamino-3 propylamine in 15 cm3 of methanol containing 2.4 cm3 of a 2N methanolic hydrochloric acid solution maintained at S5 C, 0.5 g of pristinamycin IA and 20 mg of sodium cyanoborohydride. We then let the solution obtained at a temperature close to 20C for about 2 hours, then concentrated to dryness under pressure reduced (2.7 kPa) to 30 ~ -C. The residue obtained is triturated with a mixture of 50 cm3 of methylene chloride and cm3 of a saturated aqueous solution of bicarbonate sodium; the organic phase is decanted and the aqueous phase is extracted twice with a total of 20 cm3 of metal chloride thylene. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness.
under reduced pressure (2.7 kPa) at 30C. The residue obtained is purified by "flash" chromatography [eluent chloroform-methanol (80-20 by volume)]. Fractions 15 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30C; the residue obtained is triturated with 5 cm3 of ether ethyl, filtered and dried under reduced pressure (0.027 kPa) at 20C. 60 mg of deoxy-5y (dimethyla-mino-3 propyl) amino-5 ~ pristinamycin IA as a cream powder melting around 160C.
The full NMR spectrum shows the characteristics following ticks:

~ 3 ____ __ _ _ _ ~ _ ___ _ _ ~
~ (ppm) Form of the sign: l Att: r: ibution __ __ _ ~ ___ __ __ .___ 8.40 d 6 NH
8.25 d 1 NH
7.55 dd llll6 7.05 m 6Y ~ 6 ~ - ~ 6 7 dd 1'H4

6.90 dd 1 ~ 15 6 70 d} 4 ~ + 4 ~
6.50 d 2 NH
5.75 ddd 1 ~
5.45 d 6a 55.25 s (wide) 5 a 4.75 dd 4.60 m 2a 4.45 d (wide) 5 ~ 1 4.40dd .3a 3.4dd (wide) 3 ~ 1 3.20dd (wide) 3 ~ 2 3 s 4 CH3 3 m 5Y + 4 ~ 1 e ~ 2 2.80 s 4 N (C ~ 13) 2 2.65 t -NCH2- (chalne) 2.35 m 5 ~ 2 + 5 ~ 1 2.25 t -NCH2- (chain) 2.20 s -N (C113) 2 (chain) 1.60 m -CH2- (chalne) 23 + 3y 1.25 d ly 0.90 t 2y 0.50 dddd 5 ~ 2 , ~ t ~, ....

We obtain a so: l.ut: Lorl aqueous with lO '., - deoxy-5 (3-dimethylamino propyl) amino-5 ~ pristinamyci.ne: [(produ: it A), as a hydrochloride, with:
product A ......................... .... O, lg hydrochloric acid 2N ............ .... 0.52 cm3 distilled water ..................... qs 1 cm3 By operating in a manner analogous to that described in the example reference 1, the synergistins of general formula are prepared following (V) which can be combined according to the invention to products of formula (I):
[The symbols ----, Z and R1 are defined as in 1) for the general formula (V)].

-_ ~ ___ - 33a -__. __ __ __ ____ _ _.__ __I ~
Example: The of l) Melting point reEerence YX 2) Solubility ____ ____ __ __ ___ 2 -N (CH) -NH (CH) N (CH) 2 1) Yellow powder 3 2 2 2 3 F. approx. 180C
2) Aqueous solution at 10% in the state hydrochloride 3 -N (CH3) 2 ~ 1) White powder -N N-CH3 F. approx. 195C
2) Aqueous solution at 10 ~ at the state hydrochloride _ -I
4 -N (CH) ~ 1) Beige powder 3 2 ~ ~ 3 F. approx. 195C
2) Aqueous solution at 3.7% at the state hydrochloride -N (CH3) 2-NHOH F. approx. 170C

2) Aqueous solution at 10 ~ at the state hydrochloride 6 -N (CH3) 2-NH (CH2) 30H 1) Powder 160C

2) Aqueous solution at 2 ~ at the state hydrochloride _ _

7 -It -NH (CH2) N (CH3 ~ 2 1) Beige powder 3 F. approx. 140C
2) Aqueous solution at 10 ~ at the state hydrochloride _ . ~

- 3 ~ L

E ~ EMPLE DE RÉI ~ ÉRENCE ~ 3 To a solution of 2 g of pristinamycin IA in 25 cm3 of methanol, 2.8 cm3 of an ethanolic solution are added 5N of dimethylamine then 2 cm3 of a methanolic solution 5N hydrochloric acid ga ~ them. To the solution thus obtained, 76 mg of sodium cyanoborohydride are added and then stirred for 43 hours at a temperature close to 20 C. The reaction mixture is then concentrated to dryness under pressure reduced (2.7 kPa) to 30 C. The residue is crushed with a mixture of 25 cm3 of methylene chloride and 25 cm3 of a saturated aqueous sodium bicarbonate solution; the sentence organic is decanted and the aqueous phase is extracted 2 times per 50 cm3 in total of methylene chloride. The phases organics are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30C. ~ e residue is purified by chromatography "~ lash"
[eluent: chloroform-methanol (92-8 by volume) ~. The frac-5 to 12 are combined and concentrated to dryness under pressure 20 reduced (2.7 kPa) to 30nC. 0.7 g of deoxy-5y dimethylamino-5 ~ pristinamycin IA in powder form beige melting around 170C.
NMR spectrum:
0.70 (dt, 1H: 5 ~ 2) 25 2.10 to 2.60 (m, ~ H: 5 ~ 1 + 5 ~ 2 + 5 ~ 1 + 5 ~) 2.15 (s, 3H x 0.8: -N (CH3) 2nd isomer) 2.20 (s, 3H x 0.2: -N (CH3) 2 2nd isomer) We obtain a 2% aqueous solution of deoxy-5Y dimethylamino-5Y pristinamycin IA (product B), as is 30 hydrochloride with:
product B ............................. .... 0.05 g hydrochloric acid 0, lN .............. .... 0.56 cm3 distilled water ........ ............ qs 2,5 cm3 ~ 1.23. ~ 7 -By operating in a manner analogous to that described in reference example 8, 0.35 g of deoxy- is obtained 5y methylamino-5 ~ pristinamycin IA in powder form yellow melting around 185C.
A 1% aqueous solution of deoxy-5y methylamino-5y pristinamycin IA, in the form of hydrochloride.

By operating in a manner analogous to that described reference example 8, we obtain 1.2 g of deso ~ y-S ~ LN- (2-dimethylamino ethyl) N-methylamino] -5y pristinamy-cine IA in the form of a white powder melting towards 120C.
We obtain an aqueous solution at 10 ~ deoxy-5y [N- (2-dimethylamino ethyl) N-methylamino] -5y pristinamycin IA (product D), in the form of hydrochloride.

5 g of 3 A molecular sieve are added to a solution of 3 g of pristinamycin I, 3.3 g of diethylamino-4 m ~ thyl-l butylamine, 0.11 g of sodium cyanoborohydride and 9 cm3 of a 5N methanolic solution of hydrochloric acid gas in 75 cm3 of methanol. The suspension obtained is stirred for 4 days at a temperature in the region of 20 C, then is filtered; the filtrate is concentrated to dryness under pressure reduced (2.7 kPa) to 30 ~. The residue is crushed with a mixture of 50 cm3 of methylene chloride and 50 cm3 a saturated aqueous solution of sodium bicarbonate;
the organic phase is decanted and the aqueous phase is extracted 2 times per 50 cm3 in total of methylene chloride ~ Les organic phases are combined, dried over sulphate magnesium, filtered and then concentrated to dryness under pressure reduced (2.7 kPa) to 30C. The residue is purified by chroma-"flash" tography ~ eluent: chloroform-methanol (90-10 in volumes)]. 0.7 g of deoxy-5 ~ (diethylamino-4 methyl-l butyl) amino-5y pristinamycin t ~ in the form of a Eondant Belgian powder around 160C.
NMR spectrum:
1.10 (mt, 9H: -N (CH2CH3) 2 ~ -C ~ CH3 around 1.7 (m, 4H: -CH2-CH2-CH2-N (C2H5) 2) 2.90 (m, 6H: -CH2N (CH2CH3) 2 7.70 (mt, 1H x 0.45: the H6 isomer) 7.77 (mt, 1H x 0.55: H6 2nd isomer) A 10% aqueous solution of deoxy-5y (4-diethylamino-1-methyl butyl) amino 5y pristinamycin IA (product F), in the hydrochloride state, with:
product F .. ~ ......................... .... 0.1 g hydrochloric acid 0, lN ............. qs 1 cm3 To a solution of 12.5 g of deoxy-5y hydroxyimino-5y pristinamycin IA in 300 cm3 of methanol containing 10 cm3 of a 2N methanolic solution of hydrochloric acid 0.7 g of sodium cyanoborohydride is added. Ia solution obtained is stirred for 2 days at a similar temperature of 20C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30C. The residue is triturated in a mixture of 200 cm3 of methylene chloride and 100 cm3 of a solution saturated aqueous sodium bicarbonate the organic phase is decanted and the aqueous phase is extracted with 100 cm3 methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated dry under reduced pressure (2.7 kPa ~ at 30 C. We obtain after purification by "flash" chromatography ~ eluent:
chloroform-methanol (95-5 by volume)] 6.8 g of deoxy-5y hy-droxyamino-5y pristinamycin IA as a white powder melting around 170C.
NMR spectrum:
0.4 (m, 1H: 5 ~ 2); 2.45 (d, 1H: 5 ~ 2); 3.1 (d: 5y in a complex massif); 7.80 (mt, W x 0.75: H6 ler isomer); 7.95 (mt, 1H x 0.25: H6 2nd isomer).

I, a deoxy-5 ~ hydro ~ y.Lmlno- ~ S ~ prist: inamycl.lle: LA
can be obtained by stirring for 5 hours at a temperatu ~ e close to 20C, 15 g of pristinamyc: Lne IA and 7.5 g of chl.orhy-drate of hydroxylamine in solution in 150 cm3 of methanol containing 8 cm3 of a 2N methanolic solution of chlorhy-gas gas. The reaction mixture is then concentrated dry under reduced pressure (2.7 kPa) at 30 C. The residue is crushed with a mixture of 100 cm3 of chloroform and 100 cm3 of a saturated aqueous bicarbonate solution sodium; the organic phase is decanted and the aqueous phase is extracted twice per 200 cm3 in total of chloroform.
The organic phases are combined, dried over sulfate magnesium, filtered and concentrated to dryness under pressure reduced (2.7 kPa) to 30C. This gives 14 g of deoxy-5y hydroxyimino-5 ~ pristinamycin IA in powder form beige melting at 210C.
NMR spectrum:
0.35 (dd, 1H: 5 ~ 2) 3.25 (m, 2H: 4 ~ 2 ~ 5 ~ 1) ~ 5.05 (d, 1H: 5 ~ 3 5.5 (m, 2H including 5 ~ 1) 7.80 (dd, 1H x 0.40 ~ the H6 isomer) 7.90 (dd, 1H x 0.60: H6 2nd isomer) By operating in a manner analogous to that described in reference example 11, 0.8 g of [N- (carboxy-methyl) methylamino3-5y deoxy-5y pristinamycin IA under form of a cream powder melting around 140C.
A 2% aqueous solution of [N- (carboxy-methyl) methylamino] -5y deoxy-5 ~ pristinamycin IA (product K) with:
product K ........................ .... 0.2 g distilled water .... ~ ................ qs 10 cm3 - 3 ~ -EXAMPLE OF, _IÉ ~ ÉRENCE 14 To a solution of 3.2 g of deoxy-5y (dimethyl ~ l-mino-2 ethyl) amino-5y pr: istinamycin IA in 50 cm3 of chloro-form containing 0.6 crn3 of triethylamine, 0.3 cm3 is added acetyl chloride. The reaction mixture is stirred for 30 minutes at a temperature close to 20 C, then dry concentrated under reduced pressure (2.7 kPa) at 30 C.
The residue is purified by "f1ash" chromatography [eluent:
chloroform-methanol (90-10 by volume) ~; by concentration 10 dry fractions 10 to 21 under reduced pressure (2.7 kPa) at 30 ° C., 1.8 g of deoxy-5y [N- (2-dimethylamino) are obtained ethyl) acetamido] -5y pristinamycin IA as a white powder melting around 170C.
NMR spectrum:
0.9 (m, 4H: 2 + 5 ~ 2) 2.05 to 2.15 (m, 3H: 5 ~ 1 + 5 ~ 2 + 5Y) 2.15 (s, 3H- -COCH3) 2.45 (s, 6H: -N (CH3) 2) 2.35 to 2.60 (m, 5 H: ~, N-CH2 - CH2-N ~ t 5 ~ 1) 7.8 (mt, 1H x 0.75: the H6 isomer)

8.25 (mt, 1H x 0.25: H6 2nd isomer) We obtain an aqueous solution at 10 ~ deoxy-5 [N- (2-dimethylamino ethyl) acetamido ~ -5y pristinamycin IA (product L), in the hydrochloride state, with:
25 product L .... ~ ........................ .... 0.1 g 0.2N hydrochloric acid .... ~ ............. .... 0.51 cm3 distilled water ..................... ........ qs 1 cm3 Deoxy-5y (2-dimethylamino-ethyl) amino-5y pristinamycin IA pe ~ t be prepared as described in the example 5.

By operating in a manner analogous to that described in reference example 14, 1.6 g of deoxy-5y ~ N- are obtained : ~ /

x ~
- 38a -(dimethyl-amino-3 propyl) acetamido ~ -5 ~ pr: istLnamyc: ine IA
BE Eorm of an ocher powder melting at 210C.
An aqueous solution is obtained containing: L0% deoxy-5 ~ ~ N- (3-dimethylamino propyl) ace-tamido ~ ~ 5 ~ pristinamycin IA (product M), in the form of hydrochloride.
_ EMPI.E ~ E REFERENCE 16 To a solution of 3.6 g of methylene-5 ~ taken-ti--namycin I ~ in a mixture of 25 cm3 of methanol and 5 cm3 of chloroform, 1.95 g of 3-dimethylamino propa are added nethiol, then the solution obtained is stirred for 20 hours at a temperature in the region of 20 C. The reaction mixture is then poured into 250 cm3 of distilled water; emulsion obtained is extracted 3 times with 250 cm3 in total of chloride methylene. The organic phases are combined, dried .

't7 - 39 ~

on sulfa ~ e of rnagnésiurn, filtered and then concentrated under prescioo reduced (2.7 kPa) to 3ûC. The residue obtained is purl ~ lé by "flash" chromatography [eluent: chloroform-rnethanol (95-5 in ~ olumes) ~; fractions 10 to 38 are cor, dry centered sc ~ s reduced pressure (2.7 kPa) at 3ûDC. The residue obtained is triturated in 30 cm3 of ethyl ether; the crystals obtained are separated by filtration, then dried under reduced pressure (27 Pa) at 2 ~ C.
ûn thus obtains 2,4 9 of (dimethylamino-3 propyl) thiométh ~ l-5 ~
pris'inamycin IA in the form of white crystals melting at 23'C.
lû Specter ~ `~:
! ~ ~ PP ~ Form ¦A; tribute ~ o ~ I
__ 11.65 S (large) OX
8.70 d 6 ~ H
8.40 d 1 ~ Y, 7.80 dd 1 ~ H6 7.27 m 4 5 7.17 m ~ 6 ~ ~ 6 ~ + 6E
7Jo5 1 AB 4 ~ + 4E system 2û 6.60 dJ
6.47 d 2 NH
5.8 7 ddd lB
5.83 d 6c 5.74 ~ 5c ~ 4c 5.03 ddd 5 1 4.85 dd lo 4.80 ~ 2 4.53 dd 3O
3.53 ~ 30 3.35 dd ~
3.15dd ~ system A ~ X -C ~, -CC ~ .2-3.25 s 3 _ - '1 0 -~ (ppm) E ~ lormeA t tr lbu t: iorl __ _ _ _ _ _ _ ~ ____ ____._ 3, 2S m 3 ~ 2 2.90 s 4 N (CH3) 2 2.90 m 4 ~
2, 5 5 .t CH - N - CH 3 2.50 dd 5 ~ 2 2, 4 0 t - CH 2 SCH 2 ~
2.40 to 2.20 m 5 ~ ~ 5 ~ 1 2.25 s-CH2N (CH3) 2 2 m 3 ~ 1 1.7 5 m-SCH2CH2CH2-1.8 to 1.45 m 2 ~ 232 ~ 3 ~ 1 1.30 d ly 1.25 to 1.05 m 3Y2 + 3 ~ B2 0.9 t 2y 0.60 dd L

A 10% aqueous solution of (dimethyl-3-amino-propyl) 5-thiomethyl ~ pristinamycin IA (product AA), with:
product AA .. ~ ..................... ... 30 mg 25 hydrochloric acid 0, lN ...... qs 0, 3 cm3 5-methylene ~ pristinamycin IA can be prepared as follows:
To a solution of 12 g of d ~ methylaminc ~ nethylene-5 ~ pristinamy-cine IA in 230 cm3 of tetrahydrofuran ~ containing 1.2 cm3 of trifluo- acid roacétiqu ~ e., 0.43 g of sodium cyanoborohydride is added. The solution obtained is stirred for 4 hours at a temperature of around 20 ° C., then. is concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. The residue obtained is purified with a flash flash ~ eluan-t: chlorofo.Lme-methanol (95-5 by volume)]; fractions 4 to 15 are concentrated to dryness ~ lj ~ .23.1 ~ 3 (17 under reduced pressure (2.7 kPa) at 30C. 5.5 g of methylene are thus obtained.
5 ~ pristinamycin IA in for ~ ie crystals b ~ ncs melting at 245C.
NMR spectrum:
0.55 (dd, 1H: 5 ~ 2) 2.40 (d, 1H: 5 ~ 1) 3.55 (dd, 1H: 5 ~ 2) 5.25 (m, 2H: 5 ~ + 5 ~ 1) H
5.30 and 6.10 (2s, 2H: = C -H) 7.85 (dd, 1H: H6) Dimethylaminomethylene-5 ~ pristinamycin IA
can be prepared as follows:
To a solution of 46 g of pristinamycin IA in 460 cm3 of 1,2-dichloroethane, 230 cm3 of tert-butoxy bis (dimethylamino) methane the solution obtained is lS stirred for 18 hours at a temperature close to 20C. The m ~ reaction mixture is diluted with 1 liter of chloride methylene then washed 3 times with 3 liters in total of a solution aqueous with 0.4% ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated dry under reduced pressure (2.7 kPa) at 30 C. The residue obtained is triturated with 600 cm3 of distilled water; The mixture is filtered and the solid product is dried under reduced pressure (2.7 kPa) at 20C. 41 g of dimethylaminomethylene are obtained.
5 ~ crude pristinamycin IA in the form of a beige powder.
This product is of sufficient quality to be used as in the later phases. However, it may be purified as follows:
23.5 g of dimethylaminomethylene-5 ~ pristinamycin Crude AI are purified by "flash" chromatography [eluent:
chloroform-methanol (98-2 by volume)]. Fractions 16 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30C ~ 12 g of dimethylaminomethy- are thus obtained lene-S ~ pristinamycin IA in the form of a melting beige powder around 195C.

3 ~ 7 - ~ 2 -Spectrum. NMR:
0.9 (t, 31-l: 2 ~) 1.0 (dd, 1} l: 5 ~ 2) 2.50 (d, 1H: 5 ~ 1) 3.10 (s, 6H: -N (CH3) 2) 3.70 (d, 1H: 5 ~ 2) 5.50 (d, 1H: 5 ~ 1) 7.40 (s, 1H: = CHN (CH3) 2) 7.75 (dd, 1H: I '} l6) By operating in a manner analogous to that described in the example of reference 16, but from 0.9 g of methyl ene-5 ~ virginiamycin S and 0.52 g of dimethylamino-3 propane-thiol and after purification by "flash" chromatography ~ eluent: chloroform-methanol (90-10 by volume ~ and concentrated dry tration of fractions 13 to 25 under reduced pressure (2.7 kPa) at 30C, 0.3 g of (3-dimethylamino propyl) is obtained thiomethyl-5 ~ virginiamycin S in the form of a white powder ~ undulating around 142C.
NMR spectrum:
0.45 (dd, 1H: 5 ~ 2) 1.90 (m, 2H: -SCH2CH2CH2N
2.40 (s, 6H: -CH2-N ~ -3) 2.60 (m, 4H: -s-cH2-cH2-cH2-N ~) 3.45 (d, 1H: 52) 4.85 (m, 3H including 5 ~ 1) 5.25 (dd, 1H: 5a) 7.78 (dd, lH: 1 '} - l6) A 10% aqueous solution of (dimethyl-thylamino-3 propyl) thiomethyl-5 ~ virginiamycin S (product AB), as hydrochloride, with:
product AB ............................ 0.1 g hydrochloric acid ~ Sp 1 cm3 ~ 1 ~ 3 ~ 1.3 ~) t ~
- ~ 3 -L, a methylene-5 ~ vlrgin: iamyc: ine S can be prepared in an analogous way to that described: ite to the exernp: le de r ~ 3fererlce 16 for methylene - 5 ~ pristinamyc: ine I, but apart: ir 2 g of dimethylarninomé-thylène ~ 5 ~ virginiamycin S and 74 mg of sodium cyanoborohydride. After purification by "flash" chromatography [eluent: chloroform-methanol (98-2 by volume)] and dry concentration of fractions 2 to 5 under reduced pressure (2.7 kPa) at 30 C, 1 g of 5-methylene ~ virginiamycin S in the form of a beige powder 0 melting around 190C.
NMR spectrum:
0.35 (dd, 1H: 532) 2.45 (dd, 1H: 5 ~ 1) 3.55 (dd, 1H: 5 ~ 2) 5.25 (dd, 1H: 5 ~ 1) 5.25 (dd, 1H: 5a) 5.30 and 6.15 (2s, 2H: zC ~ H) 7.75 (dd, 1H: H6) Dimethylaminomethylene-5 ~ virginiamycin S
can be obtained by operating in a similar way to that described in reference example 16 for dimethylaminome-thylène-5 ~ pristinamycin IA, but from 2 g of virginia-mycine S and 10 cm3 of bis-dimethylamino tert-butoxymethane and after purification by "flash" chromatography [eluent:
chloroform-methanol (98-2 by volume)] and concentration dry fractions 9 to 12 under reduced pressure (2.7 kPa) at 30C, 0.8 g of dimethylaminomethylene-5 ~ virginia- is obtained mycine S in the form of a yellow powder melting around 175C.
NMR spectrum: -0.9 (m, 4H: 2y + 5 ~ 2) 3.05 (s, 6H: _CH-N (CH3) 2) 3.65 (d, 1H: 5 ~ 2) 4.85 (d, 1H: 5 ~ 1) 5.15 (dd, 1H: 5 ~) 7, 10 to 7.40 (ITI: aromatic 1- = CI-IN ~) 7.70 (dd, 1ll: il6) _XAMPLE OF _ EFERENCE 18 By operating in a manner analogous to that described in reference example 16, but from 6 g of methYlene 5 ~ pristinamycin IA and 4 cm3 of (methyl-4 piperazinyl-1) -2 ethanethiol and after purification by "flash" chromatography [eluent: chloroform-methanol (97-3 by volume)] and concentrated dry tration of fractions 8 to 20 under reduced pressure (2.7 kPa) at 30C, 2.6 g of ~ (4-methylpiperazinyl-1) -2 ethyl] thiomethyl-5 ~ pristinamycin IA in the form of white crystals melting at 216C.
NMR spectrum:
0.60 (dd, 1H: 5 ~ 2) 2.27 (s, 3H: ~ N-CH3) ,, CH2-CH
2.40 to 2.80 (m, 11H: -CH2-N ~ CH '~' N 1) 5.05 (dd, 1H: 5 ~ 2 5.27 (m, 2H: 5a + 4a) 7.85 (mt, 1H x 0.8: the H6 isomer) 7.95 (mt, W x 0.2: H6 2nd isomer) A 5% aqueous solution of r (methyl-4 piperazinyl-1) -2 ethyl] thiomethyl-5 ~ pristinamycin IA
(product AC), as hydrochloride, with:
product AC ......................... .... 0.1 g hydrochloric acid O, lN ........... .... 0.96 cm3 distilled water ...................... qs 2 cm3 _REFERENCE EXAMPLE 19 By operating in a manner analogous to that described in reference example 16, but from 2 g of methyl lene-5 ~ pristinamycin IA and 3 cm3 of (methyl-4 piperazinyl-1) -3 propanethiol. and after purification by chromatography "Elash" ~ éluan-t: chloroform-methanol (90-10 by volume)]
and dry concentration of fractions 10 to 25 under pressure reduced (2.7 kPa) at 30C, 1.9 g of [(methyl-4 ~.

- ~ 5 -pipera ~ i.ny ~ 3 p: ropyl] t ~ iom ~ thyL-5 ~ p: ri.stinarnycir) el ~
under: Eorme of a pou ~ re b: Lanche ~ undulating towards: 156C.
NMR spec-tre:
0.65 (dd, 1H: 5 ~ 2) 2.30 (s, 3H: ~ N-CH3) ~ CH2CH2 -5.27 (m, 211: 5a ~ 4 ~) 7.85 (dd, 1H x 0.8: the H6 isomer) 7.95 (dd, 1H x 0.2: H6 2nd isomer) A 10% aqueous solution of [(methyl-4 piperazinyl-1) -3 propyl ~ thiomethyl-5 ~ pristinamycin IA
(AD product), as hydrochloride, with:
lS product AD ........................ .... 0, lg hydrochloric acid 0.5N .......... .... 0.38 cm3 distilled water ..................... qs l cm3 By operating in a similar way to that described in reference example 16, but from 4 g of methylene-5 ~ pristinamycin IA and 4 cm3 of bis dimethylamino-1,3 propa-nethiol-2 and after purification by "flash" chromatography ~ eluent: chloroform-methanol (95-5 by volume)] and concentrated dry tration of fractions 20 to 60 under reduced pressure 25 (2.7 kPa) at 30C, 0.59 9 of [bis (dimethylamino) -l, 3 propyl-2] thiomethyl-5 ~ pristinamycin IA under torme of a white powder melting around 170C.
NMR spectrum:
0.63 (dd, 1H: 5 ~ 2) 2.40 (s, 6H: -N (CH3) 2) 2.50 (m, 10H: -CH 2 `+ -N (CH)) CH 2 N `
4.97 (s, l11: 5 ~ 1) 5.30 (m, 2H: 5a -I 4a) 7.85 (mt, 1H x 0.85: the H6 isomer) 7.95 (mt, 1H x 0.15: H6 2nd isomer) - ~ 6 One obt.i.ent Ulle aqueous soluti.on with 7.5 ~ of b: is [(dimethylamino) -: l, 3 propyl - 2] thi.omethyl-5 ~ pri.st:Lnanlycine I (product AE), in the hydrochloride state, with:
AE product ........................... .... 0.03 g hydrochloric acid 0, lN ............. .... 0.3 cm3 distlllated water ........................ qs 0.4 cm3 __ By operating in a manner analogous to that described in reference example 16, but from 3 g of methylene-5 ~ pristinamycin IA and 0.97 g of methyl-1 mercapto-4 piperidine and after purification by "flash" chromatography [eluent:
chloroform-methanol (95-5 by volume) ~ and concentration dry fractions 10 to 16 under reduced pressure (2.7 kPa) at 30C, 1.1 g of (methyl-1 piperidyl-4) thiomethyl- are obtained 5 ~ pristinamycin IA in the form of a white fondant powder at 260C.
NMR spectrum-0.6 (dd, 1H: 5 ~ 2) 2 (m, 4H: -S- <_2 ___ \ N_ 2.20 (s, 3H: -S- ~ N-CH
2.35 (m, 1H: 5 ~ 1) CH
2.90 (m, 4H: -S- C / N-~ CH2 5.30 (m, 2H: 5 ~ + 4 ~) 7.85 (dd, 1H: H6) A 5% aqueous solution of (methyl-1 piperidyl-4) thiomethyl-5 ~ pristinamycin IA (product AE '), as hydrochloride, with:
AF product ........................... .... 0.03 g hydrochloric acid 0, lN ............. .... 0.3 cm3 distilled water ........................ qs 0.6 cm3 - ~ 7 -E ~ E ~ 1PLE OF R ~ ER ~ CE 22 By operating as in the reference example 16 mals 3 leave of 2 9 of meth ~ lene-5 ~ pristinamycir-e lA and of 0.66 9 of di ~ thyl-arnino-2 ethanethiol, obtained after purificati ~ n by chromatograph "flash" [eluent: chloroform-methanol (95-5 by volume) ~ and dry concentration of fractions 9 c ~ 19 under reduced pressure ~ ite (2.7 kPa) at 3ûC, 0, ~ 9 of (2-ethyl diethylamino) thiomethyl-S ~
pristinamycin IA in the form of a beige powder fondant b 230C.
NMR spectrum:
0.65 (dd, 1H: 5B2) 2.38 (d, 1H: 5Bl) c ~ 2-2.3 to 2, B (m, BH: -S CH2CH2 ~ CH -3.15 (dd, 1H: -CH25-) 3.35 (dd, 1H: -CH25-) S, Ol (dd, lH: 5 ~ 1) 7.81 (dd, 111 x 0.9; H6 is the isomer) 7.90 (dd, 1H x O, 1: 1'H6 2nd isomer) We obtain an aqueous solution at 5 ~ 0 of (di ~ thylamino 2 ethyl) thiomethyl-50 pristinamycin IA (product AFl) ~ the state of 20 hydrochloride, with:
product AFl ...................... .... 30 mg hydrochloric acid û, lN ......... .... û, 29 cm3 ea ~ distilled ................ ~ ... qs 0.6 cm3 E ~ E ~ Lr REFERENCE ~ CE 23 Has a solution of 5.5 g of dim ~ h ~ laminomethylene-5 ~
pristinamycin lA in 60 cr ~ 3 acetic acid we add ~ outte 5.3 g of 2-dimethylarino ethylar., ine of m2n c. do not to exceed 25C. The solution obtained is a ~ itée for 2 ~ hours at a temperature close to 20 ^ ~, then is poured slowly into a solutior. a ~ ueuse saturated with sodium bic2rbonate; The mixture where it is extracted twice with 750 cm3 of total chloride of ~ -thvlene. The or ~ ani ~ ues phases are combined, dried over sulfate magnesium, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30CC. The residue is purified by chror., Atogr2phie "flash"

- ~ 3 -[eluant: cl ~ loroform-methanol (90-10 by volume) J; l.e5 Erac-lO to: 1.2 are concentrated to dryness UNDER p: ressl.on r6dui.te (2.7 IcPa) at 30C. 3 g of (dimethylamino--2 ethyl) aminomethylene-5 ~ pristinamycin IA in the form of a beige powder melting around 180C.
NMR spectrum:
0.90 (mt, 4H: 2 ~ f + 5 ~ 2) 2.25 (mt, 6H: -N (CH3) 2) 2.50 (mt, 311: -CH2N ~ ~ 5 ~ 1) 3.25 (mt, 2H: -N-CH2-) 3.50 (mt, 2H: 5 ~ 2 + 3 ~ 1) 4.90 (mt, 1H: 51) / NH-between 7.15 and 7.4 (m, 1H: = C
H

9.90 (mt, lH (exchangeable D20): -NH-) A 1% aqueous solution of tdimethyl- is obtained.
amino-2 ethyl) aminomethylene-5 ~ pristinamycin IA (product AG), a ~ ec:
product AG ......................... .... 0.1 g distilled water ...................... qs 10 cm3 By operating in a manner analogous to that described in reference example 23, but from 13.8 g of dim thylaminomethylene-5 ~ pristinamycin XA and 3.4 g of amino-4 methyl-1 piperidine and after purification by chromatography "flash" [eluent: chloroform-methanol (92.5 - 7.5 in vo-lumes)] and dry concentration of fractions 15 to 20 sous reduced pressure (2.7 kPa) at 30C, 4.0 g of (methyl-1 piperidyl-4) aminomethylene-5 ~ pristinamycin IA in the form of a yellow powder melting at 208C.
NMR spectrum:
0.40 (m, 4H: 2'f + 2 ~ 2) 2.0 (m, 4H: ~ 2-- ~ N_ C ~ '2 ..
`~;,` ~

2.35 (s, 311:> N-CI-13) 2, ~ 5 (~ il: 5 ~ l) ~ --C112 ~
2.90 (- ~ / N-) --C ~ l 3.20 (under a bed, 1H: -CH N--) 3.50 (d, 1H: 52) 4.85 (under a bed, 1H: 5 ~ 1) 6.65 (d, 1H: = CHNH-) 9.70 (cId, 1H x 0.25: = CH-NH- isomer)

10.03 (dd, 1H x 0.85: = CH-NH- 2nd isomer) A 10% aqueous solution of (methyl-1 piperidyl-4) aminomethylene - 5 ~ pristinamycin IA (product AT), as hydrochloride, with:
AT product ................. ~ ....... .... 0.03 g hydrochloric acid 0.1N ~ 0.3 cm3 distilled water .............. ~ ....... qs 0.3 cm3 Amino-4 methyl-1 piperidine can be prepared by the method described after EF ELSLAGER, LM WERBEL, A.
20 CURRY, N. HEADEN, J. JOHNSON, J. Med. Chem. I7, 99 (1974).
By operating as in reference example 23, the following synergistins of general formula (V) are prepared, which can be combined according to the invention with the products of formula (I). [The symbols ---- ~ -, X and Z are defined as in 2b) for the general formula (V) and, unless stated special, Y represents a dimethylamino radical].

_. _ ___._ _. _. ~
Fxem ~ le de K 1) Fuslon point reference 4 2) Solubility __ ___ ~ _________ ~
-NH- (C ~ l2) 2N (c2 ~ J5! 2 1) Yellow po dre 2) Aqueous solution at 5 ~ O to hydrochloride state _. ._ __ 26 -NH (CH2) 2NH CH3 1) Yellow powder 2) Aqueous solution at 1.0 to hydrochloride state _ _ ~ ___ 2, -NH (CH2) 3N (cH3) 2 1) Yellow powder 2) Aqueous solution at 6.6 ~ OD at hydrochloride state _ _ 2E -NH-CH-CH2N (CH) 2 1) Yellow powder I 3 F approx. 16ûDC
CH3 2) 1 O ~ G aqueous solution at the state of hydrochloric acid _ _ -NHCH CH-N (CH) 1) Oranqe powder 2I 3 2 F approx. 175C
2û CH32) Aqueous solution at 10 ~ O to hydrochloride state __ _ 3 ~ -NH-CH- (CH2) 3N (c2H5) 2 1) Powder beiqe CH32) Aqueous solution at 1 ~ O to hydrochloride state .
31 1) Yellow powder -NH- (cH2) 2-N ~ F = 183C
2) Aqueous solution at 1, ~ to hydrochloride state _ 32, 1) Yellow powder ~ NH (cH2) 3-N ~ F - 17ûC
2) 1 ~ aqueous solution _ _ _ 33, 1) Yellow powder -NH (CH2) 2-N ~ F approx. 162DC
2) Aqueous solution at i ~ O at hydrochloride state _ '~ 2 ~

_._ __. ~ _ __. . . ._. .,. ~
Example of l) Poi.nt de ~ us: ion reference R ~ 2) Solubility ~ _ _ _ ___ ~ __ 34 -NH (CH2) 2-N ~ ____ ~ F approx. 172C) C
2) Aqueous solution at 1% in the state of hydrochloride _. _.
CH2CH3 1) Beige powder NF approx. 1.60C
NH-CH ~ ~ 2) Aqueous solution 2 1 to 1% in the state of I _ hydrochloride 36 1) Beige powder -NH ~ F = 177C
l 2) Aqueous solution J at 1% in the state of N 'hydrochloride __ _ - 51a -_ __ _ ___ ____ ____.___ ,. I
Example of R 1) Key point: Eusion reference Y 4 2) Solubility I ______ 37 H-NH- ~ N-CH 1) Beige powder 3 F approx. 195C
2) Aqueous solution at 5% to the state hydrochloride _. _ I
38 -N (CH ~~ - ~~~ 1) Yellow powder 3 2 NH (C ~ 12) 2-N ~ ____ ~ N-CH3 F = 150C
2) Aqueous solution at 10% in the state hydrochloride _ _ 39 -N (CH3) 2 N 1) Yellow powder -NH- (CH2) 2- ~ ~ F = 138C
2) Aqueous solution NH at 10% in the state hydrochloride _ 3a ~. ~ 7 EX EM PL, E DE RE EE ~ E NC E_ '' l O
To a solution of 1.8 ~ g dimethy key: Lam: ir ~ om6thylène-5 ~ pristlnamycin IA in 40 cm3 of acetic acid, we add 2, 1 g of 2-dimethylamino ethanethiol. The solution obtained is stirred for 20 hours at a temperature close to 20 C, then slowly poured into an aqueous solution saturated with sodium bicarbonate; the mixture obtained is extracted 3 ~ ais per 400 cm3 in total of methylene chloride. The organic phases are combined, dried over sulphate magnesium, filtered and concentrated to dryness under reduced pressure (2.7 kPa3 at 30C. The residue obtained is purified by chromatography "flash" script (eluent: chloroform-methanol (96-4 by volume));
fractions 5 and 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. This gives 0.8 g of (dimethylamino-2 ethyl) thiomethylene-5 ~ pristinamycin IA in the form of a yellow powder melting around 150C.
NMR spectrum:
0.68 (dd, 1H: 5 ~ 2) 2.32 (s, 6H x 0.85: -CH2N (CH3) 2nd isomer) 2.35 (s, 6H x 0.15: -CH2N (CH3) 2 2nd isomer) 2.45 (d, 1H: 5 ~ 1) 2.65 (mt, 2H: -SCH2-) 3.05 (t, 2H: -CH2N ~) 3.43 (dd, 1H: 52) 5.15 t in a bed: 5 1) 7.60 (wide s, 1H: = CHS-) 7.83 (mt, 1H: H6 two isomers) An aqueous solution is obtained at 1 ~ of (dimethyl-amino-2 ethyl) thiomethylene-5 ~ pristinamycin IA (product AX), as a hydrochloride, with:
AX product ..................... ~ ... .... 0.1 g hydrochloric acid 0, lN ........... .... 1 cm3 distilled water ...................... qs 10 cm3 By operating like, at: The example of reEé: rerlce ~ 10 on prepare the synergistins of general formula (V) su: i, vante6, which can be associated according to the invention with products, ts of formula (I). ~ The symbols ~, X and Z are defined as in 2b) for the general formula (V) and, unless stated special, Y represents a dimethylamino radical ~.

3qJ ~

- 53a -_ _ ___ _ __ _.__ __ _ E: xemp: The of R: L) Point of ~ us: ion reEerence Y 42) So: Lubilite , ~ __ ____ _ ; ~ _ _ __ ____ _ 41-N (CH3) 2 _ $ - (CH2) 2N (C2Hs) 2 1) Beige powder 2) Aqueous solution at 1% in the state hydrochloride 1 0 _ 42-N (CH3) 2 -S- (CH2) 3N (cH3) 2 1) Beige powder 2) Aqueous solution at 1% in the state . hydrochloride __ 43 -H -S (CH2) 3N (CH3) 2 F approx. 140C

2) Aqueous solution at 10% to the state hydrochloride _ 44 -N (CH3) 2 -s - cH2-clH-cH2N ~ cH3) 2 F - 234C
C 3 2) Aqueous solution at 1% in the state hydrochloride -N (CH3) 2-S-cH2-cN (cH3) 2 1) Powder 200C

CH CH 2) Aqueous solution 3 3 to 1% as is of ~ hydrochloride 46 -N (CH3) 2 (2) 2 ~ 1) Powder 1 ~ 30C
2) Aqueous solution at 1% in the state _ ~ hydrochloride _, - 5 ~ -___ _, __ ___ __ _, _______ ___ ____.
E ~ key example _ 1) Melting point xéEérence R ~ 2) Solubility ~
__. ~ _ ~ _ _ _.______ 47 Cl-13 1) Beige powder NF approx. Z15C
-S- (Cll) - ~ \ 2) Aqueous solution 2 2 1 1 to 0.6 ~ in the state L ~ hydrochloride _ __ _ 48 1) Yellow powder -S- ~ N-CH3 F approx. 170C
2) Aqueous solution at 1% in the state hydrochloride __ 49 ~ 1) Beige powder -S - F approx. 175C
2) Aqueous solution N to 1 ~ in the state l hydrochloride C ~ 2CH3 _ _ _ _ _ 50-S- ~ CH2) 2N- (C ~ l2) 2N (cH3) 2 1) Powder ~ alder 3 2) Aqueous solution at 1%
_ _ 51-s-cH ~ cH2N (cH3) 2] 2 1) POWDER 190gC
2) Aqueous solution at 1 ~ at the state hydrochloride 52 ~ ~ 1) Beige powder S (2) 2 ~ ____ "N-CH3 F approx. 170C
2) Aqueous solution at 1% in the state hydrochloride.
_ 53 ~ 1) Beige powder (2) 3 ~ -CH3 F approx. 190C
2) Aqueous solution at 10 ~ at the state hydrochloride _ ,., ",,, 3 ~ it7 _____ ______ __ ~
Example of R 1) Melting point reEerence 4 2) Solubility ___ _ 54 -S-CH -CH-CH -N (CH) 1) Ocher powder 2 1 2 3 3 F approx. 150C
CH3 2) Aqueous solution at 1% at state hydrochloride _ -S (CH2) 2SO3H 1) Yellow powder ~ _ 2) Aqueous solution To a solution of 0.87 g of (2-mercapto propyl) -l 4-methyl piperazine in 50 cm3 of ethanol supplemented with 0.34 g of sodium ethylate, a solution of 5.2 is added g (4-methylphenyl) sulfonyloxymethylene-5 ~ pristinamycin I ~ in 50 cm3 of methylene chloride. The mixture reacts the mixture is stirred for 16 hours at a temperature close to 20 ° C. and then diluted with 500 cm 3 of methylene chloride and 100 cm3 of distilled water! e. After stirring, the aqueous phase is extracted twice with 50 cm3 of methylene chloride at total. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. The residue is purified by "flash" chromatography [eluent: chloroform-methanol (97.5 - 2.5 by volume) ~. Fractions 33 to 80 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30C. We thus obtains 1.25 g of [(4-methyl-piperazinyl-1) -3 propyl-2] thiomethylene-5 ~ pristinamycin IA in powder form beige melting around 195C.
NMR spectrum:
0.70 (dd, 1H: 5 ~ 2) 1.25 (d, 311: -C111-Cll3) 2.30 (s, 31 ~ N-C1-13) ~ C112cll2 ~
2.50 (, - 2 \ CH C11 '3 3.40 (dd, 1H: 5 ~ 2) 7.85 (dd large, 1H: H6) We obtain a 10% aqueous solution of [(methy: L-4 piperazinyl-1) -3 propyl - 2] thiomethylene-5 ~ pristinamycin IA (AAN product) in hydrochloride form, with:
AAN product ~ 0.03 y hydrochloric acid 0, lN ............... 0.3 cm3 (Mercapto-2 propyl) -l methyl-4 piperazine is prepared by heating at 100 C for 16 hours a mixture 15 of 19 cm3 of propylene sulfide and 29 cm3 of ~ -methylpi-perazine. 32 g of a colorless, dispersed oil are thus obtained.
t-illant a-105C at 1.3 kPa.
(4-methylphenyl) sulfonyloxymethylene-5 ~ pristi-namycin IA can be obtained as follows:
To a solution of 2.7 g of hydroxymethylene-5 ~
pristinamycin IA in 30 cm3 of methylene chloride, we adds, at a temperature in the region of -30C, 0.42 cm3 of triethyl-: laminate then 0.57 g of p-toluenesulfonic acid chloride.
The reaction mixture is then stirred for 2 hours at a temperature close to 20C, then concentrated to dryness under reduced pressure (2.7 kPa) at 30C; the residue obtained is purified by "flash" chromatography [eluent: methylene chloride-methanol (96-4 by volume)]. After dry concentration of fractions 4 to 6 under reduced pressure (2.7 kPa) at 30C, we obtains 2.2 g of (methyl- phenyl ~ sulfonyloxymethylene-5 pristinamycin IA as a white, melting powder around 265C.
NMR spectrum:
0.50 (dd, 1H: 5 ~ 2) , fB ~
- ~ 57 2.35 (s, 3ll: -SO2- ~ \> --Cll3) 3.30 (dd, 1H: 5 ~ 2) 5.25 (d, 1ll: 5 ~) 5.30 (dd, lil: 5 ~ 1) 7.35 to 7.90 (AB + m system, 8H: 4 ~ - ~ 4 ~ +
HH

2 ~ ~ -CH3) 7.85 (dd, 1H: H6) 5-hydroxymethylene ~ pristinamycin IA can be prepared as follows:
420 cm3 of an 0.1N aqueous acid solution hydrochloric, 10.6 g of dimethylamino- are added with stirring 5-methylene ~ pristinamycin IA The solution obtained is then stirred for 3 hours at a similar temperature of 20C. 30 cm3 of a solution are then added dropwise saturated aqueous sodium bicarbonate so as to obtain a pH close to 4. The product which precipitates is separated by filtration then washed 3 times with 30 cm3 in total of distilled water.
After drying under reduced pressure (2.7 kPa) at a temperature close to 20C, we obtain 9.5 g of hydroxymethylene-5 ~ pristi-namycin IA in the form of a beige powder. This product is of sufficient quality to be used as is in the subsequent phases. It can however be purified from as follows:
9.5 g of 5-hydroxymethylene ~ pristinamycin IA
crude are dissolved in 50 cm3 of ethyl acetate; the solution obtained is poured onto 100 g of silica gel contained in a 2.8 cm diameter column. We first elect with 400 cm3 of ethyl acetate and eliminates the corresponding eluate;
then eluted with 1600 Gm3 of ethyl acetate and concentrated J ~
- 5 ~ -the eluate corresponding to dryness under p.reC; si.on redl.l: ite (2.7 kl'a) at 30C. This gives 6.3 q of hydroxyrnethy: Lèrle-5 ~ pr: i.Stirla-mycine IA in the form of c: rista.ux white melting at 220C.
NMR spectrum:
0.69 (dd, 1H: 5 ~ 2) 2.43 (d,] .H: 5 ~ 1) 3.40 (~, 1ll: 5 ~ 2) 4.0 to 4.2 (m, 3H: 4a ~ 5 ~ 1 -t 5a) 8.15 (s,] .H: = CH-OH)

11.63 (broad s, 1H: = CH-OH) By operating in a manner analogous to that described in reference example 56, lg of (dimethylamino-3 propyl-2) thiomethylene-5 ~ pristinamycin IA in the form of a yellow powder melting at 172C.
A 5% aqueous solution of (dimethyl-3-amino-2-propyl) 5-thiomethylene ~ pristinamycin IA (product AAO), in the hydrochloride state.

By operating in a manner analogous to that described in reference example 56, 1.32 g of (diethylamino-pentyl-2) thiomethylene-5 ~ pristinamycin IA in the form of a beige powder melting around 185C.
A 10% aqueous solution of (diethyl-5-amino-2-pentyl) 5-thiomethylene ~ pristinamycin IA (product AAP), as hydrochloride.

A solution of 7.6 g of [(4-methylphenyl) sulfony-loxymethylene] -5 ~ pristinamycin IA in 60 cm3 of tetrahydro-furan is cooled to a temperature close to -10 C.
It is added slowly while maintaining this temperature a ~ ' ~ - 5 ~ -n / a: Issue of 0.65 g of dimethy.Larnino-2 ethanol. in 60 cln3 of tetrahydrofurarlne acldltioned 0.35 g of a di ~ spers: i.on at 50% sodium hydride in: Hui.le m: Lnérale. At the end of the addition, let it rise slowly: The temperature: re in the vicinity of 20C. The reaction mixture is stirred for 24 hours at this temperature then diluted with 500 cm3 of methylene chloride and washed twice with 50 cm3 of a solution saturated with ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The residue obtained is purified by "flash" chromatography [eluent: chloroform-methanol (95-5 by volume) ~. Fractions 12 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 25C. 1.5 g of (2-dimethylamino ethoxymethyl-thylene) -5 ~ pristinamycin IA in the form of a beige powder melting around 160C.
NMR spectrum 0.65 (dd, 1H: 5 ~ 2) 2.3 (s, 6H -N (CH3) 2) 2.65 (m, 2H: -CH2N ~) 3.42 (dd, 1H: 52) 4.15 (t, 2H: -OCH2-) 5.15 (d, 1H: 51) 7.45 (under aromatics, 1H:, C = CHO-) 7.80 (dd, 1H; H6) A 1% aqueous solution of (dimé.hyl-2-amino ethoxymethylene) -5 ~ pristinamycin IA (product AAQ), as hydrochloride, with:
product AAQ ....... ~ ..................... ... 0.03 g hydrochloric acid 0.1 l ~ 0.3 cm3 distilled water .......................... qs 3 cm3 The compositions according to the invention can in addition to containing any other compatible pharmaceutical product, inert or physiologically active. The compositions according to 3 ~

- ~ 9a -the: invention can be used parenterally, ora: The, rec-tale or topical.
Sterile compositions for administration pa: rentérale may preferably be aqueous solutions or nonaqueous, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents.
These compositions can also contain adjuvants, in particular wetting agents, isotonizing agents, emulsifiers, fiants, dispersants and stabilizers. Sterilization can be done in several ways, for example by filtration sanitizer, by incorporating into the composition of sterile agents edging, by irradiation or by heating. ~ they can also be prepared under -~ ~ t ~ q, ~, t ;; ~

Eorm of solid steri compositions: Yui can be dis-bunkers at the time of use in a sterile injectable medium.
As solid compositions for oral administration can be used tablets, pills, powders or granules. In these compositions according to the invention, the active products (possibly associated with another product pharmaceutically compatible) are mixed with one or more diluan-ts or indirect adjuvants, such as sucrose, lactose or starch. These compositions can also include substances other than thinners, for example a lubricant such as magnesium stearate.
As liquid compositions for oral administration, pharmaceutically acceptable emulsions can be used, solutions, suspensions, syrups and essences holding inert diluents such as water or paraffin oil. These compositions may also include sub-stanzas other than thinners, for example products wetting, sweetening or flavoring.
The compositions for rectal administration are suppositories or rectal capsules, which contain in addition to the active ingredient in excipients such as butter cocoa, semi-synthetic glycerides or polyethylene-glycols.
Compositions for topical administration may be for example creams, ointments, lotions, eye drops, col-wrestling, nose drops or aerosols.
In human therapy, the products of formula (I) according to the invention of the main application, associated with known synergistins or preferably synergistins of general formula (V), are particularly useful in the treatment of microbial infections. The doses depend on the desired effect and the duration of treatment;
for an adult, they are generally between 500 and 2000 mg per day parenterally particularly by Ui ~ 7 intravenous route. in pe.rf ~ slow lsion, the dose of syncrg: ist: ine of General formula (V) e-tan-t ell ~ -same included enl: re 500 and 2000 mg per day.
Generally speaking, the doctor will determine the dosage he considers most appropriate based on age, polds and all other factors specific to subject to be dealt with.
The following examples, given without limitation, illustrate compositions according to the invention.
Example A
We prepare, according to the usual technique, a solution injectable for infusion containing 5 9/1 active mixture having the following composition:
- (2-ethyl diethylamino) thio-26 pristinamycin IIB .. ... 3 9 - (3-dimethylamino propyl) thiomethyl-5 ~
pristinamycin IA 2 9 - aqueous sclution of hydrochloric acid O, lN ........ ... 65 cm3 - distilled water ...................................... qs lOOû cm3 Example B
ûn prepares a solution for injection for per ~ usion containing 1 9 / l of active mixture having the following composition:
- (methyl 4 piperazinyl-1) -26 pristinamycin IIB 0.6 9 _ ~ (methyl-4 piFerazinyl-l) -2 ethyl] thiomethyl-5 ~ pristinamycin IA ............. ... 0.4 9 - aqueous solution of hydrochloric acid D, lN ........ ... 15? 4 cm3 - distilled water ...................................... qs 1000 cm3

Claims (3)

The embodiments of the invention, concerning the-which an exclusive property or privilege is claimed, are defined as follows: 1. Pharmaceutical compositions, characterized in that they contain as active ingredient in minus one of the compounds of general formula (I):

(I) in which R represents;
- or a substituted alkylthio radical:
i) by one or two alkylamino radicals or dialcoylamino of which the alkyl parts can form together with the nitrogen atom to which they are linked a saturated heterocycle chosen from the group consisting of pyrrolidinyl-1, piperidino, azetidinyl-1, azepi- radicals nyle-1, morpholino, thiomorpholino and pipérazinyle-1 (no substituted or substituted by an alkyl radical), or else ii) by a pyrrolidinyl-2 or 3 radical, piperi-dyle-2, 3 or 4, azétidinyle-2 or 3 or azépinyle-2, 3 or 4, - either a radical of general formula:
Het - S -in which Het represents a pyrrolidinyl-3 radical, piperidyl-3 or 4, azetidinyl-3 or azepinyl 3 or 4 (not substituted or substituted on the nitrogen atom by a radical alkyl), - either a dialkoylamino radical whose alkyl parts can form together with the nitrogen atom to which they are linked a saturated heterocycle chosen from the group consisting of killed by the pyrrolidinyl-1, piperidino, azetidinyl- radicals 1, azepinyl-1, morpholino, thiomorpholino and piperazinyl-1 (unsubstituted or substituted by an alkyl radical), being understood that the radicals and alkyl portions mentioned above contain 1 to 5 carbon atoms in a straight chain or branched, where appropriate in their isomeric forms and their mixtures, as well as their addition salts with acids pharmaceutically acceptable; in association with pristinamycin IA, virginiamycin S and / or at least one derivatives of soluble synergistins of general formula (V):

(V) in which Y represents a hydrogen atom or a radical dimethylamino and 1) or else? represents a single bond, Z
and R1 represent a hydrogen atom and X represents a radical of general formula:

(VI) in which:
- either R2 represents a hydrogen atom and R3 represents a hydroxy or alkyl radical unsubstituted or substituted by a carboxy, alkyloxycarbonyl, hydroxy, alkylamino radical or dialkoylamino of which the alkyl radicals can form with the nitrogen atom to which they are attached a heterocycle with 4 to 7 links chosen from the group consisting of groups azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl and azepinyl, or else R3 represents a cycloalkyl radical containing 3 to 7 carbon atoms or a 4 to 7 membered saturated heterocycle chosen from the group consisting of the azetidine, pyrrolidine, piperidine rings and azepine, these heterocycles can be substituted on the nitrogen atom by an alkyl radical, - either R2 represents a formyl or alkylcarbonyl radical and R3 represents an alkyl radical substituted by a radical carboxy, alkyllamino or dialcoylamino whose radicals alkyl can form with the nitrogen atom to which they are attached a 4- to 7-membered heterocycle chosen from the group consisting of azetidinyl, pyrrolidi-nyle, piperidinyl, piperazinyl, N-alkylpiperazinyl and azepinyl, or R3 represents a 4- to 7-chain heterocycle we have chosen from the group consisting of azetidine rings, pyrrolidine, piperidine and azepine, these heterocycles can be substituted on the nitrogen atom by an alkyl radical, - either R2 and R3, identical or different, represent a alkyl radical unsubstituted or substituted by a radical carboxy, alkyloxycarbonyl, hydroxy, alkylamino or dial-coylamino whose alkyl radicals can form with the nitrogen atom to which they are attached a heterocycle to 4 to 7 links chosen from the group consisting of groups azetidinyl, pyrrolidinyl, piperidinyl, piperazi-nyle, N-alkylpiperazinyl and azepinyl, - either R2 and R3 form together with the nitrogen atom to which they are attached a chosen 4- to 7-membered heterocycle in the group consisting of the azetidine, pyrrolidine, piperi-dine, morpholine and piperazine unsubstituted or substituted by a alkyl radical, 2) or represents a double bond, X
represents an oxygen atom and Z represents a radical of general formula:

(VII) defined as follows:
a) either R1 and R5 each represent a hydrogen atom and R4 represents a pyrrolidinyl-3 thio or piperidyl- radical 3 or 4 thio (these radicals being unsubstituted or substituted by an alkyl radical) or else R4 represents a radical alkylthio substituted by one or two hydroxysulfonyl radicals, alcoylamino, dialcoylamino (unsubstituted or substituted by a mercapto or dialkoylamino radical) or by one or two rings chosen from the group made up of piperazino groups (unsubstituted or substituted by an alkyl radical or mercap-toalcoyl), morpholino, thiomorpholino, pipéridino, pyrrolidi-nyle-1, piperidyle-2, 3 and 4 and pyrrolidinyl-2 and 3 (these last two cycles being unsubstituted or substituted on the nitrogen atom by an alkyl radical), b) either R1 and R5 together form a valence bond and R4 represents a pyrrolidinyl-3 amino, piperidyl-3 radical or 4 amino, pyrrolidinyl-3 oxy, piperidyl-3 or 4 oxy, pyrroli-dinyl-3 thio, piperidyl-3 or 4 thio (these radicals not being substituted or substituted on the nitrogen atom of the ring by a alkyl radical), or else R4 represents an alkyl radical, alkyloxy or alkylthio substituted by one or two radicals hydroxysulfonyl, alkyllamino, dialkoylamino (unsubstituted or substituted by a dialkoylamino radical), trialcoylammonio or imidazolyle-4 or 5 or by one or two cycles chosen from the group consisting of piperazino groups (unsubstituted or substituted by an alkyl or mercaptoalkyl radical), morpholino, thiomorpholino, piperidino, pyrrolidinyl-1, piperidyle-2, 3 and 4 and pyrrolidinyl-2 and 3 (the latter two rings being unsubstituted or substituted on the nitrogen atom by an alkyl radical), it being understood that the radicals alkyl and alkyl portions relating to the symbols of the general formula (V) contain 1 to 5 carbon atoms and are in a straight or branched chain; in a non-excipient toxic pharmaceutically acceptable.