IL29801A - 7-halo-2-acyl lincomycin derivatives and a process for their preparation - Google Patents

Description

-HALO-2-ACYL LINCOMYCIN DERIVATIVES AND A PROCESS FOR THEIR PREPARATION -HALO-2-ACYL LINCOMYCIN DERIVATIVES AND A PROCESS FOR THEIR PREPARATION ¾¾£SJiLA J- Hf- XHE- XU SCI OSIIRE- Anti bacterial compounds of the formula: and the salts thereof ,. and the 3> -0-aryl i dene derivatives.

The novel compounds of the invention are represented by Formula 1, wherein R2— 2- is a carboxyl ic acid acyl radical, advantageously a hydrocarbon carboxyl i c acid acyl of not more than 18 carbon . atoms; or a halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or lowera 1 koxy- substituted hydrocarbon carboxyl i c aci d acyl radical advantageously of not more than l8 carbon atoms, X is chlorine, or bromine; R, and HRj, are the same or different alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms, advantageously not more than 8 carbon atoms; and R3 is hydrogen, alkyl of not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl . of not more than 12 carbon atoms, advantageous 1 y not more than.8 carbon atoms Exam les of alk l of not more than 20 carbon atoms R heptyl, octyl, nonyl, decyl , undecyl, dodecyl , tridecyl, tetra-decyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl and the isomeric fqrms thereof. Examples of cyclo-alkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl , cyclooctyl , 2-methyrcyclopentyl , 2,3-dimethyl cyclobutyl, -methylcyclobutyl , and 3-cyclopentyl propyl . Examples of aralkyl are benzyl, phenethyl, cs-phenyl propyl , and a-naphthyl-methyl. Examples of carboxyl ic acid acyl radicals are the acyl radicals of the fol lowing. acids: (a) saturated or unsaturated, straight or branched chain al iphatic carboxylic acids, for example acetic,, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproi c, capryl i c, decanoic, dodecanoic, lauric, tridecoic, myristic, pentadecanoi c, palmitic, margaric, stearic, acrylic, crotonic, undecyl enic, oleic, hexynoic, hep-tynoic, octynoic acids, and the like; (b) saturated or unsaturated, al i cycli c carboxyl i c aci ds, for example, cyclobutane-carboxylic acid, cycl opentanecarboxyl i c acid, cyclopentenecar-boxylic acid, methyl cyclopentenecarboxyl i c acid, cyclohexane-carboxylic aci d, d imethyl cyclohexenecarboxyl i c acid, di propyl -eye lohexane carboxyl ic acid, and the like; (c) saturated or unsaturated, a .11 cyclic al i phatic carboxyl i c acids, for example, cyclopentaneacetic acid, cyclopentanepropioni c acid, cyclo-pentaneaceti c acid, cyclohexanebutyr i c acid, methyl cyclohexane-acetic acid, and the like; (d) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethyl-benzoic acid, i sobutyl benzoi c acid, methyl butyl benzl c acid, and the like; and (e) aromatic-a iphatic carboxylic acids, for example, phenylacetic acid, phenyl propi oni c acid, phenyl val eri c acid, cinnamic acid, phenyl propiol ic acid and naphthylacetic acid, and the like. Suitable halo-, nitro-, hydroxy-, amino-, include hydrocarbon carboxylic acids as given above which are substituted by one or more of halogen, nitro, hydroxy, amino, cyano, or thiocyano, or loweralkoxy, advantageously lower-alkoxy of not more than l8 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, amyloxy., hexyloxy, and isomeric forms thereof. Exanples of such substituted hydrocarbon carboxyl i c acids are mono-, di-, and trichloracetic acid; a- and β-chloro-propionic acid; a- and y-bromobutyr i c acid; a- and iodovaleric acid; mevalonic acid; 2- and 4-chlorocyclohexanecarboxyl i c acid; shikimic acid; 2-ni tro-l-methyl -cycl obutanecarboxyl ic acid; l,2,3, ,5i6-hexachIorocyclqhexanecarboxyl ic acid; 3-bromo-2-methyl cycl ohexanecarboxyl i c aci d; 4- and 5-bromo-2-methyl -cycl ohexanecarboxyl i c acid; 5- and 6-bromo-2-methyl cycl ohexane-carboxyl ic acid; 2,3-dibromo-2-methyl -cyclohexanecarboxyl i c acid; 2, 5-di bromo-2-methyl cyclohexanecarboxyl ic acid; 4,5-di-bromo-2-methyl cyclohexanecarboxyl ic acid; 5i6-dibromo-2-methyl -cycl ohexanecarboxyl i c acid; 3-bromo-3-methy 1 cycl ohexaneca rbox- . yl ic acid; 6-bromo-3-methyl cycl ohexanecarboxyl i c acid; 1,6-di-bromo-3-methy 1 cycl ohexanecarboxyl i c acid; 2-bromo-4-methy 1 -cycl ohexanecarboxyl i c acid ; 1, -d i bromo-4-methyl cyclohexanecarboxyl ic acid; 3-bromo-2,2,3-trimethyl cyclopentanecarboxyl i c acid; l-bromo-3i 5-dimethyl cycl ohexanecarboxyl i c aci d; homo-gentisic acid, o-,, m-, and p-chl orobenzoi c acid; anisic acid; sal icyclic acid; p-hydroxybenzoi c acid; β-resorcyl ic acid; gallic acid; veratric acid; trimethoxybenzoic acid; trimethoxy-cinnamic acid; 4,4' -dichlorobenzi 1 ic acid; o-, m-, and p-nitro-benzoic acid; cyanoacetic acid; 3*4- and 3* -di ni trobenzoi c acid) 2,4,6- tri ni trobenzoi c aci d; thiocyanoaceti c acid; cyano-propionic acid; lactic acid; ethoxyformi c acid (ethyl hydrogen carbonate); butyloxyformic acid; pentyloxyformic acid hexy.l -ox formic acid; dodec l ox formi c acid hexadec lox formic acid The compounds of the invention have essentially the same antibacterial spectrum in vivo as the antibiotic 1 i neomycin and can be used for the same purposes as I i neomycin.

The compounds of the invention are more active and can advantageously be used for oral administration to animals, including mamma Is.

The n ondensing a wherein Q with an aromati eoxy-1 ί ncomyci wherein Ar aryl i dene ; and removing the protective groups to form a.1 i ncomyci n-2-acylate of Formula I.

When R3 is hydrogen: it is replaced by a protective group before acylation. Advantageously this group is a protective group removable by hydrogenol ysi s. Suitable such groups are carbobenzoxy and 1 I ke hydrocarbonoxycarbonyl groups, benzyl, and ni trobenzyl .

In carrying out the process of the subject invention, a 7-halo-7-debxy^l i ncomyci n of Formula I I, advantageously as the hydrochloride salt, is first condensed with an aromatic aldehyde, with the aid of mild heat, to form a 3, -0-aryl I dene 7-halo-7-deoxy-l i ncomyci n of Formula III. Acid catalysis of the reaction is unnecessary if the hydrochloride salt of the 7-halo-7-deoxy- 1 i ncomyci n i s used as this provides sufficient catalysis of the reaction. When the hydrogen group at position 1' is substituted by a protective group which renders the molecule non-basic, e.g., by a carbobenzoxy group, i t i s advantageous to supplement reaction mixture with catalytic amounts of mineral acids or, preferabl y, of acidic salts such as ammonium chloride, to facilitate the condensation reaction. The wqter by an organic solvent, for example, benzene, toluene, .. chloroform, ethylene chloride, and the l ike. The azeot rope-forming solvent can be el iminated if water is removed by some other means, such as by evacuation, vaporization with an inert gas, or merely by co-d i st M 1 at ion wi th a sol vent which has a higher boi l ing point than water. The azeot rope- form i ng solvent is used In admixture wi th a highly polar solvent, such as N, N-d i methyl formami de, N, N-d i methyl acetamide,. dimethyl sul fo i de N-methyr pyrrol i done, and. the l ike, in order to sol ubi 1 i ze 7-halo-7-deoxy-l i neomycin hydrochloride and thus produce a homogeneous solution.

The condensation reaction can be conducted between temperatures of about 70° to l80° C. ; the preferred temperature being about 90° - 110° C. The optimum temperature depends on the ratio of polar to non-polar solvent, and on the specific properties of the non-polar solvent, 'such' as. the boil ing temperature of the azeot rope formed with water as wel l as the. boi l ing point of the ηόη-polar solvent itself. The non-polar solvent containing moisture can be continuously removed by disti l lation and replaced peri odi cal 1 y wi th fresh, dry solvent. The water also can be removed by condensation and separation with a water trap or a dessicant can be used, thus permitting the dried solvent to return to the react ion vessel .

The time for complete condensation of the 7-ha1o-7-deoxy-l incomycin hydrochl ori de wi th an aromatic aldehyde, as disclosed above, varies .wi th ' the solvent composition, and the efficiency of removal of the water. When azeot rope- form i ng solvents are used, as described above, the course of the reaction can be fol 1 owed by. measur i ng the amount of water 1 I berated. Alternatively, the reaction vessel can be sampled peri θ- 2 36 benzene and dimethyl formamide, reaction times of about l-l6 hours can be used, with 2-3 hours being optimum. If anhydrous 7-halo-7-deoxy-1 i ncomyci n hydrochloride is used, the reaction time required is reduced by approximately a factor of 1/2 since only one-half of the amount of water i s 1 iberated, compared wi th 7-hal o-7-deoxy- 1 i ncomyci n hydrochl or ide monohydrate. A variety of aromatic aldehydes can be used In the process of the invention, for example, furfural, 5-methyl furfural , benz-ald^hyde, sal icyialdehyde, m-tolualdehyde, o-tol ual dehyde, p-tolual dehyde, o-chl orobenzal dehyde, m-chl orobenzal dehyde, m-bromobenzal dehyde, p-bromobenzal dehyde, p-methoxybenza 1 dehyde, m-methoxybenzal dehyde, o-methoxybenzal dehyde, 3>4-dimethoxy-benzaldehyde (veratric aldehyde), sal icyialdehyde p-hydroxy-benzal dehyde, 3* , 5-trimethoxybenzal dehyde, pi peronal , o-nitro-benzal dehyde, p-chl orobenzal dehyde, phthal dehyde, m-ni trobenz-al dehyde, p-ni trobenzal dehyde, β-naphthal dehyde, p-bromobenz-aldehyde, o-bromobenzal dehyde, 2, -di chl orobenzal dehyde, vanl 1 -1 I n, methaldehyde, terephthal dehyde, protocatechual dehyde, and ci nnamal dehyde.

Also useful are al dehydes I n whi ch the carbonyl group ;. Is separated from the a romati c mol ety by one or more double bonds giving a conjugated structure of: wherein n can be an integer of from 1-4, and Z can be one of the fol 1 owi ng , subst I tuents on the aromatic moiety: CH3 P03H® GHaCHa As03H® CH(CHa)2 OCH3 2*136 3, CH2)4 0(CH2 )2CH3 CF3 0(CH2)3CH3 CN 0(CH2)4CH3 COCHa OC6Hs GO2C2H5 OCOCH3 C02H OH C02 SGH3 CH2Si (CH3)3 SC2Hs Si(CH3)3 SCH(GH3)s Ge(CH3)3 SCOCH3 Ge(C2H5)3 SCN SN(CH3)3 SOCH3 F Sn(C2H5)3 S02GH3 CI N2 SO2NH2 Br NHCOGH3 S(CH3)2 I N(CH3)3 S03 IO2 N02 SeCH3 CH=CHN02 The acetals formed by the above-disclosed process are initially isolated as crystal 1 ine. hydrochloride, sal ts With stable acetals, for example, 3, -benzyl i dene-7-halo-7-deoxy-1 i neomycin, and 3,^-£-chl orobenzyl idene-7-halo-7-deoxy-l i neomycin, recrystal 1 ization of the hydrochlorides can be brought about with hot Methyl Cellosolve, dimethyl formamide, chloroform, and the like. The less stable acetals, for example, 3, -£-ani syl i dene-7-hal o-7-deoxy-l i ncomyci n, 3*^-cl nnamyl idene, and 3,4- tol uyl idene-7-halo-7-deoxy-1 i neomycin, must be converted to the free base form before isolation of the acetal.

The 3,^-0-aryl idene-7-hal o-7-deoxy- 1 i ncomyci n hydrochl oride <5- 2 36 acylation as such or they can be converted to the free base by mixing the salts with a basic material, for example, aqueous sodium hydroxide, a quaternary ammonium hydroxide, ammonium hydroxide, or a strong amine base. Basic ion exchange resin can be used. The i nsol ubl e aryl i dene-7- hal o-7-deoxy- 1 i ncomyci η base can be removed by. f i 11 ration, . or it can be ext racted w i th water- immi sci bl e solvents, for example, chloroform, methylene chloride, ethylene dichloride, ether and the l ike. Alternatively, the 3, -0-aryl i dene-7- hal o-7-deoxy- 1 i ncomyci n hydro- ' chloride salts can be converted to the free base by first neutralizing the salt with a base after placing the salt in solu- tion. ih a solvent such as chloroform, d imethyl formami de, di- , methylacetamide, propylene glycol, and the like. The base can be an a koxi de, an amine, ammonia, or a sol id i norgani c base, for example, sodium hydroxide, potassium. hydroxide, and the like. The resulting solutions, of the 3* -0-aryl i dene-7-hal o- 7-deoxy- 1 i ncomyci n base can be recovered from water-mi sci bl e solvents by di 1 ut ion wi th water to the cloud point resulting in slow crystal 1 ization of the acetals. The solutions, of .3, -0-a ryl i dene-7- a lo-7-deoxy- 1 i ncomyc In base i n wate r- immi s- cible solvents can be recovered by dilution of the solution with a nonpolar solvent, for example, hexane, isomeric hexanes, and the like,. or by simply evaporating the solvent. The. latter procedure for forming the free base from the 3> -0-aryl i dene- 7-ha1o-7-deoxy-1 i ncomyci n hydrochloride salts is suitable for isolating the very labile acetals of 7-halo-7-deoxy-ll ncomyci n, since a nonaqueous procedure can be employed.

Most of the 3* -0-aryl i dene-7-ha 1 o-7-deoxy- 1 i ncomyci n bases can be purified by solution of the compound in acetone, diluting the sol ut ion wi th ether, and then addi ng hexane to the cloud oint to induce s ontaneous cr stallization. 2 5 The 5, -0-aryl i dene-7-ha 1 o-7-deoxy^l ί ncomyci n can be acylated by processes already well known : i n the art, for ex-ampl e, by/ react i ng it with an acylating agent in the presence of an acid-bi ndi ng'agent, for example,. a tertiary amine, to produce a 3^-0-aryl i dene-7-hal o-7-deoxy- 1 i ncomyci n-2-ac.y late. Suitable acylating agents i ncl ude aci d hal i des and acid anhydrides. Suitable tertiary ami nes i ncl ude heterocycl i c amines such as py r idi ne, qui no 1 i ne, and i soqu i nol i ne; trial kyl ami nes such as tr imethyl ami ne, tr i ethyl ami ne, tri i sopropylami ne, and . the 1 i ke; : N, N-di al kyl ani 1 i nes such as d imethyani 1 i ne, di ethyl -ani 1 i ne, and the 1 i ke; and N-al kyl pi per i di nes such as N-ethyl -. piperidine, N-methylpiperidine, and the like. The preferred base i s pyr i di ne.

The acylation.is advantageously conducted by treating a sol ut ion of a J>, -0-aryl i dene-7-hal o-7-deoxy- 1 i ncomyci n or a suspension of the hydrochlori de i n a mixture of an inert solvent and a tertiary amine, for example, pyr ί di ne, wi th an acyl at i ng . agent, for exampl e, acyl . chlori de, and cool i ng the reaction mixture to prevent side reactions. Advantageously, the react ion. is conducted in pyridine at low temperature, ■ preferably -20° to 80° C, however higher or lower temperatures can be used. Suitable inert solvents include chloroform, dimethyl formami de, dime thy lacetami de, ■ ace ton i tri 1 e, methyl ene chloride, acetone, and dioxane.

■ '■ The' 3, -0-aryl idene protective group can be removed by hydrolysis, preferably, a mi 1 d aci d hydrol ys i s. For ex-amp 1 e, 3» ^-0-ani syl i dene^-7-chl oro-7-deoxy- 1 i ncomyci n-2-acyl ate on being heated ,wi th 80# aceti c aci d at 100° C. for 10 to mi n. yields 7-chl oro-7-deoxy-l i ncomyci n-2-acyl ate. Acids such as formi c, . propioni c, dilute hydrochloric and dilute 2 36 The protective group Q can be removed by. hydrogenol y's i s over a palladium catalyst. For example, a syl i dene-7-ch1 oro-7-deoxy-N-carbobenzoxy-l i ncomyci n-2-acyl ate, ei ther before or after the hydrolytic removal of, the ~5> -0-ani syl i dene group, i s hydrogenated us i ng. pal 1 ad i urn : as . catal yst. The hydro-genolysis also removes the 2, -0-ani syl Idene group. The palladium i s usual 1 y deposi ted on a carrier, for. example, carbon. The .hydrogenol ysi s, advantageously, is effected in a solvent at a temperature between about 10° C. and 50° C, and at a pressure not above about 60 1 bs. per, square: i nch guage. Suitable sol vents i ncl ude methanol , acet i c aci d, ethyl acetate, chloroform, and dioxane.

The des i red 2-acyl ate can be i sol ated from , the react ion mixture by various techniques wel 1 known i n the art. The 2-acyl ates so prepared are eas i 1 y i sol ated as the hydrochl or i de salt by preci pi tation wi th a non-sol vent such as acetone or ether. The compounds are usual 1 y i sol ated ί n a pure state by this method although if necessary, recr.ystal 1 i zati on may be achieved from water or acetone plus a : smal 1 < amount of water. 2 56 S- CHA (5, -0-A.r.y.l ldene-7(S)- chloro-7-deoxy-l I neomycin) 7(S)-Ch1oro-7-deoxy- I ncomycl n-2-acy late) The novel compounds of the i nvention are nitrogenous bases and can. exist in a protonated or a non^protonated form according to the pH of the environment. When the protonated form is intended the compound is qual ified as the aci d addi t ion sal t; when the non-protona ted form : i s intended, it is qualified as the free base. The free: bases can: be converted to- stabl e acid-addition salts by neutralizing the free base with the appropriate acid to below about pH.6.0 and advantageously to about pH 2 to pH 6. Suitable acids for this purpose incl ude hydrochloric, sulfuric, phosphoric, thiocyanic, fluosllicic, hexa-f 1 uoroarserii c, hexaf 1 uorophosphor i c, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, chol ic, palmitic, mucic, camphoric, glutaric, gl ycol i c, phthal i c, tartari c, 1 aur i c, steari c, sal i cyl i c, 3-phenyl sal i cyl i c, 5-phenyl sal i cyl i c, 3-methylgl utaric, orthosul fobenzoic, . cyclopentanepropioni c* 1,2-cycl ohexanedi carboxyl i c, -cycl ohexanecarboxyl i c, octa-decenyl succ i n i c, octenyl succi ni c, methanesul foni c, benzene-sul foni c, hel i ant hi c, Rei necke1 s, dimethyl di t hi oca rbami c, cycl dhexyl sufami c, hexadecyl su.l fam? c, octadecyl su.l fami c, sor ic, monochloroaceti c, undecyl eni c, · -hydroxyazobehzene- -sul foni c, octyldecyl sul furic, picric, benzoic, cinnamic, and like acids.

The aci d-addi tion sal ts can be used for the same purposes as the free base or they can be employed to upgrade the same. For example, the free base can be converted to an i nsol ubl e salt, such as the picrate, which can ■ be subjected .to puri fi -cation procedures, for example, solvent extractions and washi ngs chromatography, fractional 1 iquid-l iquid extractions, and crystal 1 i zati on and then used to regenerate the free base form by treatment .wi th -al kali . or to make a di f ferent sal t by metathesis. Or the free base can be converted to a water-sol ubl e 2 36 ' . solution of the salt extracted wi th var ious water- Imrni sci bl e solvents before regenerating the free base form by treatment of the thus-extracted acid solution. or converted to another salt by metathesis. The free bases can be used as a buffer \ or as ,an antacid. They also react wi th i socyanates to form urethanes and.can.be used to modify polyurethane . resi ns. The long chain compounds, i.e., where H a is alkyl of from 8 carbon atoms up, have surface active properties arid can be used as wetting and emulsifying agents. The thiocyani c acid addi ti on salt When condensed wi th formal dehyde forms resinous materials useful as inhibitors according to U.S. Patents 2,425*320 and 2,6o6,155 in the aci d pi ckl i ng of steel. The free bases also make good vehicles. for toxic acids. For example, the fluosi-1 i c I G acid addi ti on sal ts are : useful as mothproof i ng agents according to U. S. Patents 1,915, 33 and 2, 075,359, and the hexaf 1 uoroarseni c acid and hexaf 1 uorophosphori c acid addition salts are useful as parasi ti cides accordi ng to U.S. Patents 3/122, 6 and- 3, 122, 5 2.

The free, bases also form salts wi.th penicillins. These . salts retain the antibacterial activity of the penicillins but . have di f ferent sol ubi 1 i ty characte.ri sti cs whi ch make them useful in situations indicated by the . special sol ubi 1 i ty characteristics and in the isolation and puri f ication of the penicillins, parti cularl y benzyl penicillin. Said salts can be formed either by neutral izat ion. of the free base form. of a compound with the free acid form of a penicillin, or by a meta-thetical exchange of the anion of an acid addi tion sal t of the compound, for example, the chloride ion of a. hydrochloride, wi th the anionic form of a penici 11 in.

The starti ng T-halo-7-deoxy-l i ncomyci ns of Formula II can 2^56 thionyl chloride (Belgian Patent 676,154) or wi th a Rydon reagent (Belgian Patent 676,154).

The following examples are illustrative of the process and products of the present invention, but are not to be con-strued as limiting. Parts and percentages are by weight unless otherwise specified.

Example 1 7 (S ) - Chi oro-7-Deoxy 1 i ncomyc i n-2-Pa 1 m ? ta te A-l 3,4-0-Ani syl idene- 7 (S)-chloro-7-deoxy-l ? ncomyci n hydrochl oride hydrochlor A solution of JO g, of 7(S)-chloro-7-deoxy-l i ncomyci n i n 60 ml. anisaldehyde and 0 ml. of dimethyl formamide was warmed to 50 C. and then dil uted wi th 200 ml . of benzene. The reaction mixture was set up for di sti 1 lation and after col lection of each 100 ml. solvent an add i tional 100 ml . port ion of fresh benzene was added. Crystal 1 izat ion slowl y occurred during. distillation. After col lecti ng 1000 ml . of di sti late by thi s process, 150 ml. of benzene was added and the reaction mixture was allowed to cool to room temperature. The product was i so-lated by fi 1 tration and washed wi th acetone. The yield was g. of white crystal 1 ine 5,4-0-anisyii dene- 7 (S)-chloro-7-deoxy-1 i ncomyci n : hydrochloride.

B-l 3,4-0-Anl syl idene- (S)-chloro-7-deoxy-l i ncomyci n- 2-palmitate hydrochloride A partial sol ution of 25.18 g, of 3,4-0-ani syl idene- 7 (S)-chl pro-7-deoxy^ 1 i ncomyci n hydrochloride in 200 ml. of pyridine and.40' ml. of chl oroform was treated dropwi se wi th a sol ution of 12.19 g» palmitoyl chloride in 50 ml . chloroform over a mi n. per iod. After 1 hr. at room ; temperature the clear orange reaction solution was concentrated to a viscous residue under high vacuum at 60° "C. The residue was di ssol ved ί n 100 ml . 2 ?β a residue of 3*4-0-ani syl idene-7 ( S ) -chl oro-7-deoxy- 1 i ncomyci n-2-palmi tate hydrochloride.

C-l 7 (S ) - Chl oro-7-deoxyrli ncomyci n-2-pa Imi tate hydrochl or i de The residue of part B-l was d i ssol ved i n 200 ml . of acetic acid and di 1 uted wi th 40 ml . of water. After heating on a steam bath at 90° C. for.5 min., the sol vents were removed under high vacuum at 60° C. The orange residue was dissolved in 100 ml. of isopropyl alcohol and the solvent was removed as before. The residue was di ssol ved ί n 150 ml .' of acetone and the resul t i ng sol ut ion was poured i to 1500 ml „of aceto-rii trij e to. precipi tate 7(S)-chloro-7-deoxy-l i ncomyci n-2-pal -mitate hydrochloride. The compound was isolated by filtration under nitrogen and then dried by slowly passing. nitrogen through the fi Iter, for -10 mi n. Final . drying.. was achieved by drawing air through : the f il ter cake! for 1 hr. The yield was 23, g. (84^) of 7>(S)-chloro-7-deoxy-l i ncomyci n-2-palmi tate. hydrochloride, m.p. 126° (dec).

Anal. Galc'd for G34He 20eSei2: ! C, -58.35;. H, 9.22; N, .00; S, 4.58; CI , ;i0.13 Found: C, 58.66;. H, 9.30; N, 3·6θ; S, .4.23; CI , 10.82; H20, Ο.76 (Analyses corrected for HaO content) Exampl e 2 3,4-O-Ani syl i dene-7(S)-chloro-7-deoxy-l i ncomyci n- 2-laurate Hydrochloride and 7(S)-Chloro-7-deoxy- 1 ? ncomyci n-2-1 aurate hydrochloride By substituting the palmi toyl chloride of part B-l by lauroyl chloride (10.5 g. ), there was obtained 3*4-0-ani syl i -dene-7(S)-chloro-7-deoxy-l i ncomyci n-2-1 aurate hydrochloride which on . hydrol ys i s by the procedure of part C-l yielded 7(S)-chloro-7-deoxy-l i ncomyci n, m.p. l45-l6o° C.

Anal . Calc'd for C30H5eN2OeSC12: C, 55.97; H, 8.77; N, 4.35; S, 4.98; CI, 11.02 .Found: . C, 56.11; H, 8.66; N, 4.36;· S, 4.91; CI, 9.96; H20, 0.88 (Analyses corrected for H2O content) Example 3 J 4-0-ani sy 11 dene -7 (S ) - chl oro-7-deoxy- 1 i ncomyc i n- ,2- hexanoate hyd roc hi or ί de and 7 (S ) - chl oro-7-deoxy- 1 i ncomyci n-2-hexanoate hydrochl ori de By substituting the palmitoyl chloride of part B-l by hexanoic acid anhydride, there was obta i ned 3,4-0-ani syl i dene- 7 (S ) -chl oro-7-deoxy- 1 i ncomyci n-2-hexanoate whi ch on hydrol ys i s by the procedure of part C-l; and recrystal li zation . from hot water yi elded 7 (S) -chl oro-7-deoxy-l i ncomyci n-2-hexanoate hydrochloride, m.p. 171-175° C.

Anal. Calc'd for C24H4 N20eSCl 2: C, 51.51; H, 7.93; N, 5.01; S, 5.73; CI, 12.67 Found: C, 50.92; H, 8.14; N, 4.68; S, 5.77; CI, 12.45; H20,2.4l (Anal yses . cor rected for H20 content) ■ ■ Example 4 3 4-0- (p-Acetami dobenzyl idene)-7(S)-chloro-7-deoxy- 1 i ncomyc i n hyd rochl or i de A solution of 10 g. 7-(S ) -chl oro-7-deoxy- 1 i ncomyc i n : hydrochloride in 20 ml . dimethyl formamide was m ixed wi th a : sol ut i on of 15 g. p-acetamidobenzal dehyde in 150 ml . of benzene. The reaction mixture was set up for di sti 11 ation and after collection of 50 ml. of disti 1 late an additional 50 ml. of fresh benzene was added. A total of 500 ml . of benzene was collected by di sti 1 lation.

The reaction vessel was cooled and a small amount of 7.(S)- chloro-7-deoxy-l i ncomyci n hydrochloride was removed by f i 1 tra- tion. The filtrate was di 1 uted wi th ether to precipitate 7.4 g. of 3,4-0-p-acetamidobenzyl idene-7(S)-chloro-7-deoxy- The compound was shaken with a mixture of 50 ml. wateY and 10 ml. concentrated ammonium hydroxide. The resul ti ng 3, -0-p^ acetamidobenzyl idene-7(S)-chloro-7-deoxy-4 incomycin base was isolated by fi ltration to give 5.2 g. of white compound.

This compound and other 3, -0-aryl i di ne compounds as indi-cated above can be substituted for the 3, -0-ani syl idene-7(S)-chloro-7-deoxy-l i ncomyci n in the foregoing examples.

Example 5 By substituting the 7(S)-chloro-7-deoxy-l i ncomyci n of Examples 1, 2, and 3 by 7'(S)-chl oro-7-deoxy-N-carbobenzoxy-1 incomycin there are obtai ned 3> -0-ani syl i dene-7(S)-chloro-7-deoxy-N-carbobenzoxy-l i ncomyci n, ..3> -0-ani syl idene-7(S)-chloro-7-deoxy-N-carbobenzoxy-l i ncomyci n-2-palmi tate, 2-laurate, and 2-hexanoate, 7(S)-chloro-7-deoxy-N-carbobenzoxy-l incomycin-2-palmitate, 2-laurate, and 2-hexanoate. On removal of the carbobenzoxy group by hydrogenol ys i s over pal 1 ad i um or charcoal, there . are obtai ned 7 (S)-chl oro-7-deoxy-N-rdemethy 1-1 i ncomyci n-2-palmitate, 2-laurate, and 2-hexanoate. If desired, the hydrogenol ys is can be effected to remove both the carbobenzoxy apd the ani syl i dene groups.

Example 6 By substituting the .7 (S ) -chl oro-7-deoxy- 1 i ncomyc ί n of Examples 1, 2, and 3 by 7-chloro-6,7>8rtr?deoxy-6- (trans-l-car-bobenzoxy- -penty 1 -L-2-pyrrol i d i neca r boxam f do ) -1 - h i o- L - 1 reo-a-D-gal acto-octopyranos i de of the formula: 2^36 wherein Q is ca rbobenzoxy, there are obtained 3,4-0-ani syl i dene 7-chloro-6,7j8-tr ideoxy-6- (t rans-l-ca rbobenzoxy-4-penty 1 -L-2- pyrrol ? d i ne-ca rboxam i do) -1-th i o-L- threo-a-D-ga 1 acto-octopy ran- oside and the 2-palmi tate, : 2-1 aurate, and 2-hexanoate esters thereof which on hydrol ys i s -yi el d 7-chloro-6,7,8-t r i deoxy-6- (t rans-l-ca rbobenzoxy- L -2 -pyrrol idi ne-carboxamido)-l-theo-L- threo-a-D-qal acto-octopy ranos ? de-2-palmi tate, 2-laurate, and 2-hexanoate. On removal of the carbobenzoxy group by hydro- genolysis over, palladium on charcoal, there are obtained ,7-chloro-6,7j8-trideoxy-6- (t rans- -penty 1 -L-2-pyrrol idi ne- ca rboxam ii do) -1- 1 hi o-L- threo- -D-gal acto-octopy ranos i de-2- palmitate, 2-laurate, and 2-hexanoate. If des i red, the' hydro- genol ysis can , be effected before the hydrol ysi s . i n whi ch case, the Ji^-O-aryl idene group is also removed.

By substituting the 7(S)-ch1oro-7-deoxy-1 i ncomyci n : hydrochloride i n Examples 1, .2, and 3 by 7'(S ) -bromo-7-deoxy- 1 i neomycin there are obtained. the hyd rochl or i de of 2, 4-0-a ryl i dene-•7.(S)-bromo-7-deoxy-l i ncomyci n and the 2-palmi tate, .2-hexanoate thereof whi ch esters on hydrolysis yield the hydrochloride of 7 (S) -bromo-7-deoxy- 1 i ncomyc i n-2-pa lmi tate, 2- 1 aurate, and 2-hexanoate.

By subst i tut i ng the 7.(S)-chl oro-7-deoxy- 1 i ncomyc i n * hyd rochl or ide in: Examples 1, 2, and 3 by.7 (S) -bromo-7-deoxy-N-ca rbobenzoxyl i ncomyc i n, there are obtained 3, 4-0-ani sy 1 i dene-7 (S ) - bromo-7-deoxy-N-carbobenzoxyl i ncomyci n and the 2-palmitate, the 2-laurate, and the 2-hexanoate thereof which esters on hydrolysis yi el d 7 (S)-bromo-7-deoxy-N-ca rbobenzoxyl i ncomyci n-2-pal - mi tate, 2-laurate, and 2-hexahoate, On removal of the carbobenzoxy group . by hydrogenol ys i s over pa 1 lad i urn on charcoa 1 , there are obtai ned 7,(S)-bromo-7-deoxy-N-demethyl 1 i ncomyci n- hydrogenol ys ί s can be effected w i thout the hyd rol ys i s in which case 7 (S)-bromo-7-deoxy-N-demethyl -1 i ncomyci n-2-pal mi tate, 2-laurate, and 2-hexanoate is obta i ned d i recti y.

By subst i tut i ng the 7.(S)-chl oro- and bromo-7-deoxy- 1 i neomycin hydrochlorides or the 7(S)-chloro- and bromo-7-deoxy-N-carbobenzoxyl i ncomyc ί n by the 7-epimers thereof, there are obtained the corresponding 7(R)- compounds. -epimers have the L-theo configuration in the side. chain and the 7(R)-epimers have the D-erythro configuration in the side chain By substituting for ani sa I dehyde, the other aromatic aldehydes 1 i sted above, there are obtained the correspondi g 3, -0-a ryl i dene compounds.

By substituting the acid chl or i des ■ and anhydrides,, by the acid chlorides or. anhydride of the other aci ds .1 i sted above, there are obtai ned the corresponding 2-acylates.

Example 7 Syrup An aqueous oral preparation contai ni ng 00 mg. of 7(S)-chl oro-7-deoxy- 1 i ncomyci n-2-palmi tate hydrochloride i n each five mi 11 i 1 i ters is prepared from the fol lowi ng i ngredients: 7,(S)-chloro-7-deoxy-l i ncomcyi -2-palmi tate hydrochloride .800 gm.

Propylparaben, U.S. P. 2.5 gm.

Sorbic acid 10 gm.

Sacchari n sodi urn ,12.5 gm, Cyclamate sodium 2.5 gm.

Glyceri n 3000 ml .

Tragacanth powder 100 gm.

Orange oil flavor 10 gm.

F.D. & C. orange dye 7.5 gm.

Deionized water q.s. 10,000 ml. f i nal preparation shoul d be adj us ted to pH A* 0-4.5.

Claims (10)

1. -, - n or aralkyl of not more than 12 carbon atoms; and R3 is hydrogen alkyl of not more than 20 carbon atoms, cycloalkyl of from 3 to not more than 8 carbon atoms, and aralkyl of not more than 12 carbon atoms. -2- A compound according to claim 1 having the formula: 2436 and the salt s thereof, and R3 given in claim 1. -3- A compound according to claim 2 having the formul and the salts n in claim 1.

2. A compound according to claim 1 wherein is palmitoyl, lauroyl, or hexano.yl . . -5- o

3. II

4. A compound according to claim 2 wherein Ra — C- is palmitoyl, lauroyl, or hexanoyl .

5. P.A. 29801/11

6. A compound according to Claim 5 wherein is hydrogen, HR-^ is propyl, and R is methyl.

7. A compound according to Claim 5 ■ wherein is hydrogen, HR^ is pentyl , and R is methyl. 0

8. A compound according to Claim 3 wherein R„—C- is palmitoyl, lauroyl, or hexanoyl.

9. 7 (s )-Chloro-7-Deoxy-lincomycin-i?-carboxylic acid acylates, substantially as hereinbefore described and with reference to the examples.

10. A pediatric formulation comprising water and a compounc ' or the salts thereof wherein X, R, HRi, and are as given in claim 1, and 2"~*^' is alkanoyl *of from.12 to not more than 18 carbon atoms. -11- A pediatric formulation according to claim 15 in which the compound i s a compound of the formula: 2 36 0 II or a salt thereof wherein R2 — C- is as given in claim 15. II A pediatric formulation according to claim 14 in which R2— C- i s palmi toyl . A process for control of bacteria in animals which com-prises orally administering a compound of the formula: or the salts , and R3 are as g i ven . i n claim 1. A process for control of bacteria i n animal s according to claim.1'6 In which the compound is a compound of the formula: or a sa It t