IL39658A

IL39658A - 7 deoxy-7(s)-alkylthio-lincosaminide and lincomycin derivatives process for their preparation and pharmaceutical compositions containing 7-deoxy-7(s)-alkylthio-lincomycines

Info

Publication number: IL39658A
Application number: IL39658A
Authority: IL
Original assignee: Upjohn Co
Priority date: 1971-06-23
Filing date: 1972-06-09
Publication date: 1977-04-29
Also published as: YU36743B; AR192797A1; NL7208333A; FR2143295A1; NO138949C; NL176678C; IL39658A0; CA971956A; SE384686B; DE2229950C2; JPS5724359B1; FI56688B; PH13663A; CH587286A5; NO138949B; FR2143295B1; SE384685B; DE2229950A1; FI56688C; NL176678B

Abstract

Title cpds of formula (I) and when AC is H, their acid addn salts: (where n is 1-4; Alk is not >4C alkyl or -CH2CH2OAC1; Ac and Ac1 are both H or both carboxylic acyl; R1 is not >18C satd or is not >10C unsatd aliphatic hydrocarbon, >11C aromatic hydrocarbyl or is not >8C oxa or thiacarbocyclic aromatic hydrocarbyl; and XR3 is H or residue in which X is O or S and R3 is H, carboxylic acyl, lower alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl or alkylthioalkyl, or Ph, Bz, furyl, furfuryl, thienyl or thenyl; when X is O and R3 is alkyl, R1 and R3 can be joined together so as to form a is not >5C oxacycloalkyl residue with 3-6 ring atoms) may be N-acylated with an L-2-pyrrolidinecarboxylic acid to give antibacterially active lincomycin analogues. The free bases of (I; Ac=Ac1-H) can be used as buffers or antacids; they may be used for modifying polyurethane resins, and their thiocyanates form corlrosion-inhibiting condensation prods with HCHO. The fluolsilicate salts are useful as mothproofing agents, and the fluoroarsenates and hexafluorophosphates are useful as pesticides. [FR2143295A1]

Description

39658/2 7-lJ^Y-7ia)*Aa i^HIO-LXNCOaAIlIiiI13]i; AND LIKCOMYCIN jJ IV TiVi,a, ΡϋΟΟϋίϋϋ iOK Τϊϋϋΐϋ PREPARATION AND PIiARi'-ACj-iUT JO L COMPOSITIONS CONTAINING 7-DOXY-7(S) AiAYjCThlO LI COMYCINES ABSTRACT OF THE DISCLOSURE Alkyl 7 -deoxy -7 -RSp "Ot-thi ol i ncosami ni des useful as intermediates for preparing antibacteria 1 ly active 7~deoxy 7 -RSn -1 i neomycins are prepared by heating alkyl N-acyl-6,7 ~az i ri di no-6 -deami no -7 -deoxy -a-th i ol i ncosami n ί des wi th an aliphatic, cycloa 1 i phati c, or aromatic acyclic sulfide (mone, di , tri or tetrasulf ide) in the presence of glacial ace tic acid or other anhydrous lower alkanoic acid, or-anhydrous benzoic acid or other arenoic acid of not more than 12 carbon atoms. 39658/2 BRIEF DESCRIPTION OF THE INVENTION The Invention relates to alkyl 7-deo y-7-RSn- a-thlo-Hncosam1n1des of Formula 1 and acylates thereof and to a process for making the same OH wherein n 1s 1 to 4, Alk 1s alkyl of not more than 4 carbon atoms, to wit, methyl , ethyl , propyl , Isopropyl , butyl , sec-butyl , Isobutyl , and tert. butyl , R 1s a radical - -|- 3 wherein R. 1s a saturated aliphatic hydrocarbon radical of not more than 18 carbon atoms, an unsaturated aliphatic hydrocarbon radical of not more than 10 carbon at«ms, an aromatic hydrocarbon radical of not more than 11 carbon atoms or benzyl , XR3 1s hydrogen or 1 or 2 substltuents wherein X 1s oxygen or sulfur and R3 1s hydrogen, loweralkyl , lower alkenyl , lowercycloalkyl , phenyl , benzyl.

The compounds of Formula I can be obtained by heating * - ♦ 39658/2 in the presence of glacial acetic acid or other anhydrous loveralkenoic acid; or anhydrous bensoic acid or other arenoic acid of not more than 12 carbon atone» an alkyl N-*c l-6»7-a«iridin>-6-d*araino-7~ deexy«^<»tbioUncoeaminide of the formulat wherein Ac and Ac^ are carboxacyl and Alk is as given above* with sulfide of the formula (R^X^-^-^-Rj ( ^)r wherein p^x 3; n is 1.2, 3, or 4| ¾ and ¾ are the same or different and are saturated aliphatic hydrocarbon radicals of not more than than 16 carbon atoms· unsaturated aliphatic hydrocarbon radicals of not more than 10 carbon atomst cycloaliphatic hydrocarbon radicals of not more than 10 carbon atoms» aromatic hydrocarbon radicals of not more than 11 carbon atoms; or are hydrogen or together not more than three eubstituents wherein X and Y are the same or different and are oxygen or sulfur and Rj and the eeme or different end are hydrogen, carboxacyl (Ac^)» loweralk 1, lowerelkenylt lowercycloalky1, phenyl* bensyl* and wherein ^ end Rl# when X is oxygen and Rj ia alkyI, can be linked together to form an oxacycloalky1 of not more than 5 carbon atoms and having from three to 6 members. When it is desired that n be greater than 1 in the final product (Formula I), -R2-YR4 should be a radical that readily forms a carbonium ion, for example, tertiary butyl or allyl.

Opening of the aziridine ring is thus effected yielding an cylated al kyl 7-deoxy-7-RSn-a-thiol i ncosaminide of the following formula: wherein n, c, Aci , X, Ri, R3, and Alk are as given above.

The acyl groups are then removed by hydraz i nol ys i s in a manner already well known in the art (See U. S. 3,179*565) to yield alkyl 7-deoxy-7-RSn-°t- thi ol i ncosami ni de of Formula I .

The compounds of the invention (Formula I) are useful for the same purposes as methyl a-thioli ncosaminide (methyl 6rami no-6,8-d ideoxy-1- thio-D-erythro-a-D-galacto-octopyran-oside, a-MTL) as disclosed in U. S. Patent 3,380,992 and as methyl 6-amino-7-chloro-6,7,8-trideoxy-l-thio-L-threo- and D-rerythro-a-D-galacto-octopyranos ides (U. S. Patents 3* 96,163 and 3,502,648) and moreover can be acylated with trans-l-methyl -4-propyl -L-2-pyrrol idine carboxyl ic acid to form carboxyl ic acids as disclosed in these patents or to form compounds of the formula: where R, n, and Alk are as given and Ac is L-2-pyrrol idine- carboxacyl or an N-methyl, N-ethyl , or N- (2-hydroxyethyl ) - L-2-pyrrol i d i necarboxyacyl any or all of which can be substituted in the -position with loweralkyl or loweral kyl idene.

P IOR ART ' It is known that 7-SH analogs can be prepared by heating an aziridino compound of Formula I I where Ac and Aci are hydrogen with hydrogen sulfide (U. S. Patent 3,5^*551). It has not been possible, heretofore, to replace the S-hydrogen, either directly or indirectly. Moreover, the compounds of the invention are substantially more active than the corresponding 7-SH compounds. For example, 7-deoxy-7(S)- (methyl thio)-l i ncomyci n hydrochloride is several times more active in vitro against Gram positive bacteria than 1 i ncomyci n whereas 7-deoxy-7 (S )-mercaptol i ncomyci n hydrochloride is less active than lincomycin.

It is also known that 7-OR analogs can be prepared by reacting a compound of Formula I I with an alcohol in the presence of an acid. Efforts to produce the sulfur analogs by substituting the alcohol by a mercaptan have been DETAILED DESCRIPTION It has now been found that compounds of Formula I I undergo sulfidolysis when heated with a sulfide (mono, di, tri, or tetra) in glacial acetic acid or other anhydrous lower-al kanoic acid or anhydrous benzoic acid or other arenoic acid of not more than 12 carbon atoms. The reaction appears to take the following course: + ROAc With a mixed sulfide the reaction may be considered as proceeding along these lines S-isoPr MeOAc With a mixed polysulfide an additional compound, namely, a disulfide, may be obtained, for example t hi ophyl i c 0 attack by AcO The formation of the polysulfide takes place when R and/or R1 is a radical which readily forms a carbonium ion, for example, tert. utyl or allyl. In case of tert. butyl, the carbonium ion could lose a proton to form isobutylene.

With any of the sulfides described above, the desired result is obtained simply by heating an alkyl N-acetyl-6, 7-azi ri di no-6-deami no-7-deoxy-a- thiol incpsaminide with the 276 -3 lower alkanoic acid or anhydrous benzoic acid or other arenoic acid of not more than 12 carbon at ms, for example, propionic or butyric acids.

Advantageousl , a solyent boil ing at about 70 to 110° is used. Ordinarily an excess of sulfide is used for this purpose. Such solvents as dioxane, carbon tetrachloride, benzene, or toluene can be used if desired and advantageously with sulfides boiling above about 11.0°.

The proportions are not critical to the reaction, but are critical to the yields. Thus optimum yields are obtained with about 5 to 7 equivalents of acid coupled with a substantial excess, at least twofold, of the sulfide.

That is another advantage of using the sulfide as a solvent. When a sulfide, such as methyl sulfide, which is so low boiling as to give a reaction mixture that refluxes below 70°, is used, super atmospheric pressure can be used; if it is such that the reaction mixture boils above about 110° controlled heating pan be used. Otherwise it is suitable to heat at the reflux temperature.

The reaction mixture can be worked up by procedures already well known in the art such as counter-current distribution, chromatography, gnd solvent extraction or crystal 1 ization.

The starting compounds of Formula II exist in two epimeric forms as follows: 276 -3 6(R),7(R)- form 6(R),7(S)- form the reaction an inversion takes place. For example, whe methyl sulfide is reacted with methyl N-acetyl -2,3, -tr i - 0-acety 1 -6 (R ) , 7 (R ) -az i r i d i no-6-deami no-7-deoxy-c th i ol i ncos -aminide, methyl N-acetyl -2, 3» -tr? -0-acetyl -7-deoxy-7(S)-(methyl thio)-ot-thiol i ncosami nide is obtained.

The starting compounds of Formula II are obtained by acylating a compound of the formula with a carboxacyl acylating agent, such as, acetic anhydride or other lower alkanoic acid anhydride or benzoyl chloride or like carboxacyl halide, in a manner already known in the art. Since the amino and hydroxy groups acylate at different rates the N-acyl, Ac, and the 0-acyls, ACi, can be the same or d i f ferent.

Inasmuch as these acyl groups (Ac and Aci ) do not appear 276 -3 is immaterial what they are as long as they are carboxyacyl.

Suitable such carboxacyls are hydrocarboncarboxacyl containing not more than l8 carbon atoms or halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or al koxysubsti tuted hydrocarbon carboxacyls of not more than l8 carbon atoms. Advantageousl , they are inert carboxacyls, that is to say, carboxacyls that are not affected by the reaction. Most commonly they will be acetyl or other lower alkanoyl, or benzoyl or other aroyl of not more than 12 carbon atoms. Nonetheless, they may be any carboxacyl.

The starting compounds of Formula VI can be prepared by the dehydrohal ogenat ion of compounds of the formula: The atent 3*544,551 by heating a compound of Formula VII in an inert solvent in the presence of an acid acceptor. A suitable process is to heat a reaction mixture of starting compound, anhydrous sodium carbonate, and dimethyl formamide at reflux for a short time, remove the solvent, and crystallize from a suitable solvent, for example, methanol. See. Belgian Patent 732,352, October 30, 199. 276 -3 known compounds. R in Formula I is the radical ReX-Rx- as def i ned above.

Suitable such starting sulfides (mono and poly) include for example, saturated aliphatic hydrocarbon sulfides, alkyl sulfides, which may be symmetrical or unsymmetri cal , where alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl , octyl , nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl and the isomeric forms thereof, for example, methyl sulfide, ethyl -methyl sulfide, ethyl sulfide, butyl sulfide, 2-butyl sulfide, tert. butyl sulfide, methyl propyl sulfide, isopropyl methyl sulfide, ethyl propyl sulfide, ethyl isopropyl sulfide, butyl methy 1. sul fide, 2-butyl methy 1 sulfide, i sobutylmethyl sulfide, tert. butyl methyl sul fide; methyl pentyl sulfide, isopropyl propyl sulfide, 1-ethyl propyl methyl sulfide, ethyl isobutyl sulfide, tert. butyl ethyl sulfide, sec. butyl ethyl sulfide, butyl ethyl sulfide, propyl sulfide, isopropyl sulfide, hexyl methyl sulfide, ethyl pentyl sulfide, isobutyl propyl sulfide, sec. butyl propyl sulfide, butyl propyl sulfide, isobutyl isopropyl sulfide, sec. butyl isopropyl sulfide, tert. butyl isopropyl sulfide, butyl isopropyl sulfide, pentyl propyl sulfide, heptyl methyl sulfide, ethyl 1 -methyl pentyl sulfide, ethyl hexyl sulfide, ethyl 1-ethyl -butyl sulfide, ethyl 1,3-dimethyl butyl sulfide, butyl iso-butyl sulfide, butyl sec. butyl sulfide, isobutyl sulfide, tert.butyl sulfide, sec. butyl sulfide, butyl sulfide, methyl octyl sulfide, hexyl propyl sulfide, butyl pentyl sulfide, butyl isopentyl sulfide, isopentyl. sul fide, pentyl sulfide, isopropyl octyl sulfide, isopropyl 1 -methyl heptyl sulfide, 276 -3 pentyl sulfide, butyl octyl sulfide, butyl l->methyl heptyl sulfide, bis (l,3-dimethylbutyl )sul fide, i sohexyl sulfide, hexyl sulfide, dodecyl methyl sulfide, propyl undecyl sulfide, nonyl pentyl sulfide, hexyl octyl sulfide, hexyl l-^methyl heptyl sulfide, dodecyl ethyl sulfide, butyl decyl -sulfide, bi s (5-methyl hexyl )sul fide, bi s (l, -dimethyl pentyl )-sulfide, heptyl sulfide, methyl tetradecyl sulfide, 2-ethyl-hexyl 1-methyl heptyl sulfide, bi s (i sopropyl. pentyl )sul fide, bi s (2-ethyl hexyl )sul fide, octyl sulfide, hexadecyl methyl sulfide, nonyl sulfide, tert. butyl 1-ethyl -1-methyl butyl sulfide, butyl heptyl sulfide, decyl methyl sulfide, ethyl nonyl sulfide, octyl propyl sulfide, hexyl pentyl sulfide, decyl sulfide, decyl disulfide, butyl hexadecyl sulfide, dodecyl octyl sulfide, ethyl octadecyl sulfide, heptadecyl propyl sulfide, dodecyl sulfide, tert. dodecyl sulfide, tert. dodecyl disulfide, tert. dodecyl trisulfide, tetradecyl disulfide, tetradecyl tetrasul ide, dodecyl octadecyl sulfide, hexadecyl sulfide, hexadecyl disulfide, hexadecyl trisulfide, hexadecyl tetrasul fide, tert. hexadecyl tetrasul fi de, bi s (lil-d i pentyl hexyl )d i sul fi de, octadecyl disulfide, octadecyl trisulfide, and octadecyl tetrasul fi de; unsaturated aliphatic hydrocarbon sulfides, for example, vinyl sulfide, vinyl disulfide, methyl vinyl sulfide, ethyl vinyl sulfide, propyl vinyl sulfide, isopropyl vinyl sulfide, butyl vinyl sulfide, allyl sulfide, al yl disulfide, a lyl methyl sulfide, allyl methyl disulfide, allyl ethyl sulfide, allyl ethyl disulfide, allyl propyl sulfide, allyl propyl disulfide, propenyl sulfide, allyl 2-methyl al 1 yl sulfide, methyl propenyl sulfide, bis (2-methylal 1 yl )sul f ide, ethyl propenyl 2764-3 propenyl propyl disulfide, methyl 1-methyl al 1 yl sulfide, ethyl methallyl sulfide, 2-butenyl methyl sulfide, 1-butenyl ethyl sulfide, 2-butenyl ethyl sulfide, methyl 1-methyl -2-butenyl sulfide, methyl 2-methyl -2-butenyl sulfide, methyl 3-methyl -3-butenyl sulfide, methyl 2-pentenyl -1-butenyl sulfide, methyl 3-pentenyl -1-butenyl sulfide, methyl 1-methyl eneal 1 yl sul f ide, ethyl 1-methyl eneal 1 yl sulfide, 1,3-butadienyl methyl sulfide, 1,2-butadienyl ethyl sulfide, 2,3-butadi enyl ethyl sulfide, ethynyl methyl sulfide, ethyl ethynyl sulfide, ethynyl isopropyl sulfide, butyl ethynyl sulfide, tert. butyl ethynyl sulfide, ethyl 1-propynyl sulfide, ethyl 2-propynyl sulfide, 1-propynyl vinyl sulfide, isopropyl propynyl sulfide, methyl 1-propynyl sulfide, 1-butynyl methyl sulfide, 3-butynyl methyl sulfide, 1-butynyl ethyl sulfide, 3-butynyl ethyl sulfide, l-buten-3-ynyl methyl sulfide, l-buten-3-ynyl butyl sulfide, 3-buten-l-ynyl methyl sulfide; 3-buten-l-ynyl ethyl sulfide, 1-propynyl sulfide, 1-butynyl sulfide, 1-hexynyl vinyl sulfide, and ethyl 1-heptynyl sulfide; cycl oal i phat i c hydrocarbon sul-fides, for example cyclopentyl methyl sulfide, cyclopentyl ethyl sulfide, cyclopentyl propyl sulfide, cyclopentyl isopropyl sulfide, cyclopentyl butyl sulfide, cyclopentyl isobutyl sulfide, cyclopentyl sec. butyl sulfide, cyclopentyl tert. butyl sulfide, cyclopentyl pentyl sulfide, cyclopentyl sulfide, cyclopentyl disulfide, cyclohexyl methyl sulfide, cyclohexyl ethyl sulfide, cyclohexyl vinyl sulfide, cyclohexyl butyl sulfide, cyclohexyl sec. butyl sulfide, cyclohexyl pentyl sulfide, cyclohexyl cyclopentyl sulfide, cyclohexyl sulfide, cyclohexyl disulfide, bi s (cyclohexyl - 2764-3 2- norbornene, bi s (4-methyl cyciohexyl )sul fide, 3-methyl-1- (4-methyl cycl ohexyl thio)butane, 1-cyclohexen-l-yl octyl sulfide, 3-cyclohexen-l-yl 3-vi nyl cyciohexyl sulfide, 3- cycl ohexen-l-yl 4-vi nyl cyciohexyl sulfide, 1-cycl ohexen-1-yl vinyl sulfide, and 2,4,6-cycloheptatri en-l-yl sulfide; aromatic sulfides, for example, methyl phenyl sulfide, ethyl phenyl sulfide, propyl phenyl sulfide, isopropyl phenyl sulfide, butyl phenyl sulfide, sec. butyl phenyl sulfide, isobutyl phenyl sulfide, tert. butyl phenyl sulfide, pentyl phenyl sulfide, isopentyl phenyl sulfide, hexyl phenyl sulfide, isohexyl phenyl sulfide, i so. sec. hexyl phenyl sulfide, 1-ethyl -1-methyl propyl phenyl sulfide, 1, 1-d imethyl butyl phenyl sulfide, 1, 5-hexad ienyl phenyl sulfide, 1-ethyl -1-butenyl phenyl sulfide, 1-tert. butyl vinyl phenyl sulfide, phenyl 1-vi nyl -3-butenyl sulfide, cyciohexyl phenyl sulfide, cyciohexyl phenyl disulfide, 1-cycl ohexen- phenyl sulfide, 2-cycl ohexen-l-yl phenyl sulfide, 3-cyclohexen-l-yl phenyl sulfide, 1-methyl cycl ohexyl phenyl sulfide, octyl phenyl sulfide, 1-ethyl -1-methyl pentyl phenyl sulfide, 1-methyl heptyl phenyl sulfide, phenyl 1,1,4- trimethyl -3-pentenyl sulfide, 3,4-dimethyl -3-cycl o-hexen-l-yl phenyl sulfide, 3- (cycloocten-l-yl )phenyl sulfide, 2- (cycloocten-l-yl Jphenyl sulfide, 4- (cycloocten-l-yl )-phenyl sulfide, 2- (3-cyclohexen-l-yl )ethyl phenyl sulfide, pentyl p-tolyl sulfide, hexyl o-tolyl sulfide, 1-ethyl - 1-butenyl p-tolyl sulfide, m-tolyl sulfide, o-tolyl sulfide, p-tolyl sulfide, m-tolyl disulfide, o-tolyl disulfide, p-tolyl disulfide, o-tolyl p-tolyl sulfide, butyl 3>4-xylyl sulfide, phenyl 3,4-xylyl sulfide, propyl o-propyl phenyl isopropyl sulfide, isopropyl thymyl sulfide, tert. butyl p-tert. butyl phenyl sulfide, sec. butyl o-sec. butyl phenyl sulfide, tert. butyl o- (2-methylal 1 yl )phenyl sul f ide,.4-tert. -butyl -o-tol yl methyl sulfide, 2-cyclopenten-l-yl p-tolyl sulfide, 2,4,6-cycl oheptatr ien-l-yl p-tolyl sulfide, 2-cycl opropyl phenyl sulfide, p- (2,4, 6-cycloheptatr ien-l-yl )-phenyl methyl sulfide, butyl 1-naphthyl sulfide, butyl 2-naphthyl sulfide, 1 -methyl -2^ (methyl thio)acenaphthalene, 2- (methyl thiofl uorine, benzyl pentyl sulfide, benzyl hexyl Sulfide, benzyl 1-ethyl -2-methyl propyl sulfide, benzyl 1,1-dimethylbutyl sulfide, benzyl 1,3-dimethyl -2-butenyl sulfide, benzyl 2,4,6-cycloheptatrien-l-yl sulfide, benzyl cyclohejtyl sulfide, methyl 5-phenyl pentyl sulfide, benzyl 1,1-dimethyl -2-propynyl sulfide, p-methyl benzyl phenyl sulfide, o-methyl benzyl phenyl sulfide, phenethyl phenyl sulfide, benzyl p-tolyl tetrasul f ide, benzyl p-tolyl disulfide, benzyl m-tolyl sulfide, benzyl p-tolyl sulfide, benzyl disulfide, tert. butyl styryl sulfide, butyl styryl sulfide, butyl 1-phenyl inyl sulfide, phenyl styryl sulfide, phenyl 1-phenyl vi nyl sulfide, ethyl 1- i sopropyl -3-phenyl propadi enyl sulfide, ethyl 1 -methyl -3-phenyl propad ienyl sulfide, tert.-butyl phenyl ethynyl sulfide, isobutyl phenyl ethynyl sulfide, 2- (methyl thio)-furan, 3- (methyl thio)-furan, 2- (ethyl thio)-furan, 2<-[ (methyl thio)methyl ]-furan, 2-[ (ethyl thio)methyl ]-furan, 2-ethyl thio-5-methyl -furan, 2-ethyl -4- (ethyl thi o)-furan, 2-ethyl -5- (ethyl thio)-furan, 2- (butyl thio)-5-methyl -furan, 2-[ (isopropy thio)methyl ]-furan, l-[ (propy hio)-methyl ]- furan, 2- [ (butyl thi o)methyl ]- furan, 2-[ (tert. butyl -thio)methyl ] -furan, 2-[ (isobutyl thio)methyl ]-furan, 2- (butyl - 2764-3 ^ 2-[ (ί sopentyl thio)methyl ]-furan, 2-[ (pentyl thio)methyl ]-furan, 2-[ (hexyl thio)methyl ]-furan, 2-[ (octyl thio)methyl ]-furan, 2-[ (al 1 yl thiojmethyl ]-furan, 2- (methyl thio)thiophene, 3- (methyl thio)-thiophene, 2-ethy] thiophene, 3-ethyl thiophene, 2- (propyl thio)-thiJophene, 2- (i sopropyl thio)-thiophene, 2- (butyl thio)-thiophene, 2- (sec. butyl thio)-thiophene, 2- (tert. butyl thio)!-thi ophene, 3- (butyl thio)-thiophene, 3- (butyldi thio)-thiophene, 2- (pentyl thi o)-thi ophene, 2-(iso-pentyl thi o)-thiophene, 2- (nonyl thio)-thiophene, 2-(decyl-thi o)-thiophene, 3- (decyl thi o)-thi ophene, 2- (undecyl thio)-thiophene, 2- (dode'cyl thio)-thiophene, 2- (tetradecyl thi o)-thiophene, 2- (vi nyl thiomethyl )-thi ophene, 2- (cycl opentyl thio)-thiophene, 2- (phenyl di thio)-thi ophene, 2-methyl -5- (methyl -thio)-thiophene, 3-methyl -2- (methyl thio)-thiophene, 2-(ethyl-thip)-5-methyl -thiophene, 3- (ethyl thio)-2,5-dimethyl -thiophene, 2- (butyl thi o)-5-methyl -thiophene, 2- (tert. butyl thio)-5-methyl - thi ophene,: 2- (benzyl thio)-5-methyl - thi ophene, 2- (benzyl thi o)-5-ethy -thi ophene, 2-[ (ethy thi o)methyi ] -thiophene, 2-[ (butyl thi o)methyl ] -thi ophene, 2-[ (i sobutyl thio)-methyl ]-thiophene, 2-[ (butyl thiojmethyl ]-5-methyl -thiophene, 2- [ (isobutyl thio)methyl ] -5-methyl -thiophene, 2-[ (3-hexyl )-thio]-propyl -thiophene, 2-[o-methyl -a- (p-tol yl thio)benzyl ]-furan, 2- [p-methyl -a- (p- tol yl thio)benzyl ]- uran, 2- [ [2- (butyl -thio)ethoxy]methyl ]-furan, 2, 5-bi s (pheny thio)-3, -bis (p-tol yl thio)-thiophene, and l ike compounds were one or both 1 and R2 groups are substituted as above, for example, 3- (methyl thio)-l-propanol , 1- (methyl thi o)-2-propanol , 2- (ethyl thio)-ethanol , 3- (ethyl thio)-l-propanol , 1- (ethyl -thio)-2-propanol , 2- (isopropyl thio)-ethanol , 4- (methyl thio)- 2764-3 ethanol, 2- (buty 1 thio)-ethanol , 2- (tert. butyl thi o)-ethanol , 3- (methyl thio)-l-hexanol , 3- (tert. butyl thio)-l-propahol , 2- (hexyl thio)-ethanol , 8- (methyl thio)-l-octanol , 9- (methyl -thio)-l-nonanol , 2* (octyl th io)-ethanol , 2- (ethyl hexyl thio)-ethanol, 1- (octyl thio)-2-butanol , 2-methyl -1- (octyl thio)- 2-propanol, 3-methyl -1- (octyl thio)-2-butanol , 3- (methyl thio)-1,2-propanediol , 2,2· -dithiodiethanol , l-[ (2-hydroxyethyl )-thio]-2-propanol , 2- [ (2-methoxyethyl )thio] -ethanol , 2-[2- (ethyl hexyl oxy)ethyl thio]ethanol , 2-[ (l-methyl heptyl )-thio]-2-propanol , 1- (octyl thio)-2-propanol , 2- (decyl thio)-ethanol, 5- (heptyl thio)-l-pentanol , 2- (methyl thi o)-ethane-thiol, 2-(ethylthio)-ethanethiol, 2- (2-mercaptoethyl thio)-ethanol, 2- (ethyl thio)-ethanethiol , 1- (2-mercaptoethyl th i o) -2-propanethiol , 1- (ethyl thio)-2-propanethiol , 2- ( i sopropyl -thi o)-ethanethi ol , 3- (octyl thio)-l-propanethiol , (methyl thio) acetaldehyde, dimethyl mercaptal, methyl 2- (methyl thi o)-ethyl ether, ethyl 2- (methyl thio)-ethyl ether, l-(methoxy-methoxy)-2- (methy thi o) -ethane, bis (2-methoxyethyl )sul ide, bis (2-methoxypropyl )sul f ide, bis ( i sopropoxymethyl )sul f ide, butyl 2-ethoxyethyl sulfide, 2-butoxyethyl ethyl sulfide, 2-butoxyethyl butyl sulfide, b i s[2- (docenyl oxy)ethyl ] sul f i de, 1,2-bis (methyl thi o)-ethane, 1, 2-bi s (methyl thio)-propane, 1- (ethyl thi o)-2- (methyl thio) -ethane, 1,2-bi s (methyl thio)-propane, 1,3-bis (methyl thio)-propane, 1,2-bi s (ethyl thio)-propane, 1,2-bis (butyl thio)-propane, 1,3-bis (butyl thio)-propane, 1,3-bis (tert. butyl thio)-propane, 1,10-bi s (methyl -thio)-decane, 1, -bi s (butyl thio)-butane, 1,6-bi s (butyl thio)-hexane, 1,2-bis (butyl thio)-3i3-dimethylbutane, 1,2-bi s (hexyl -thio) -ethane, 1,3-bis (butyl thio)-2,2-bis[ (butyl thio)methyl ]- 276 -3 butane, 1,2-bi s (decyl thio)-ethane, 1, 5-b i s (dodecyl thio)-pentane, 1,4-bis (dodecyl thio)-butane, 1,3-bi s (dodecyl thio)-propane, 1,2-bis (dodecyl thio)-ethane, 1, 5-bi s (tetradecyl thi o)-pentane, l,4-bis(tetradecylthio)-butane, 1,3-bi s (tetradecyl -thio)-propane, 1,2-bj s (tetradecyl thi o)-ethane, bis(hexa-decyl thio) -methane, 1,2-bi s (hexadecyl thio)-ethane, 1,3-bis-(hexadecyl thio)-propane, 1,4-bis (hexadecyl thio)-butane, 1.5- bi s (hexadecyl thio)-pentane, 1,2-bis (octadecyl thi o) -ethane, 1- (hexadecyl thio)-4-» (octadecyl thio)-butane, 1- (hexadecyl thi o) 4- (octadecyl thi o)-pentane, 1- (octadecyl thio)-6- (pentadecyl -thio)-hexane, 2,3-bis(methyl thio)-propyl methyl ether, 2,3-bis(ethylthio)-l-propanol, 3,4-bi s (ethyl thi o)-2-methyl - 2- butanol, 2- (2-ethoxyethyldi thio)-ethanethiol , 1- (al 1 yl thi o) 2-propanethio , 3- (al 1 yl thi o)-l-propanethi ol , 2- (l-propynyl -thio)-ethanol , 2- (2-propynyl thio)-ethanol , 4-(methyl thio)-2-buten-l-ol , 4- (methyl thio)-2-buten-2-ol , 4- (ethyl thi o)-4-buten-l-ol , 1- (ethyl thio)-3-buten-l-ol , 2-methyl -1- (methyl -thio)-3-buten-l-ol , 1- (vi nyl thio)-2-propanol , 1,2-b.i s (methyl -thio)-ethylene, 1,2-bi s (ethyl hio)-ethylene, bi s (ethyl thi o)-acetylene, 2- (cyclohexyl thio)-ethanol , 3- (cyclohexyl thio)- 1-propanol, β- (ethyl thio) -Δχ '^-cyclopentaneethanol , β- (ethyl -thio)-Ai *P-cyclohexane-ethano , β- (ethyl thio)-2-cyclohexyl -ethanol, β- (ethyl thio)-3-cyclohexyl -1-propanol , 3-[(4-tert.-butyl cyclohexyl ) thio] -1-propanol , 2- (methyl thio)-cyclopen-tanol, 2- (ethyl thi o)-cyclopentanol , l-[2-(ethyl thio)vinyl ]-cyclohexanol, 2- (butyl thio)-cyclohexano1 , 2- (ethyl th i o)-ethynyl cyclohexanol , 2-[ (4-tert. butyl cyclohexyl )thio]-ethyl ethyl ether, cyclohexyl 4- (ethyl thio)-l,3-butadienyl ether, 1.6- bi s (cyclopentyl thi o)-hexane, 1,2-bi s (ethyl thio)-cyc o- 2764-3 thio)-3-methyl nonyn-3-ol , 2- (hexyl thio)-ethynyl vinyl sulfide, 1- butenyl 2- (butyl th io) -ethyl sulfide, butyl 4- (ethyl thio)-1,5-butadienyl sulfide, bis[4- (methyl thiojbutyl ]ether, bis[2- (butyl thio)ethyl ]ether, 2- (butyl thio)-ethyl vinyl ether, 2- (butyl thio)-vinyl ethyl ether, 2- (tert. butyl thio)-vi nyl ethyl ether, butyl 2- (vi nyl th?o)-ethyl ether, sec. butyl 2- (vinyl thio)-ethyl ether, 2- (al 1 yl thi o)-ethyl vinyl ether, 2- (methyl thi o)-tetrahydropyran, 3- (methyl thio)-3-oxetane-methanol, 2- (ethyl thi o)-ethanol acetate, 4- (methyl thio)-1-butanol benzoate, 3- (methyl thio)-2-propen-l-ol acetate, 2- (vi nyl thio)-2-propano1 acetate, and 1,2,4-tris- (ethylsul -f ide)-benzene, l,3*5-tri s (ethyl sul f ide)-benzene, 2- (butyl -thi )-l- (p-tol yl t hi o) -propane, 1,2-bis (butyl thio) -benzene, 1- (methyl thi o)-2- (phenyl thio)-propane, 2- (methyl thio)-1- (phenyl thi o) -propane, 1,2-bis (phenyl thio)-ethylene, 1,2-bis (phenyl thi o) -ethane, 1- (benzyl thio) -2- (methyl thio)-benzene, p- (methyl thio)-a- (phenyl thi o) -tol uene, 2-[[p-(l -methyl entyl Jphenyl ]thio]-ethanol , 2-[ (p-sec.butylphenyl )-thioj-ethanol , 2-[ (p- tert. butyl phenyl )thio]-ethanol , 3-[ (p-tert.butylphenyl )thio]-l-propanol , 2-[ (3-tert. butyl β 5-methylsal icyl )thio]-ethanol , 5- (benzyl thio)-l-pentanol , o- (benzyl thio)-benzyl alcohol, p- (benzyl thi o)-benzyl alcohol, 5- (p-tol yl thio)-l-pentanol , 1- (phenyl thio)-2-hexanol , 2,3-di-methyl -1- (phenyl thio)-3-buten-2-o , 2-methyl -5- (phenyl thio)-2-pentenol, 2-methyl -7- (phenyl thio)-3i 5-heptadiyn-2-ol , 2- [ (l,2,3*4-tetrahydro-2-naphthyl )thio]-ethanol , 3- (phenyl -thio)-2-norbornene methanol, 2-methylene-5- (phenyl thio)-2-norbornane, 2-methyl ene-6- (phenyl thio)-2-norbornane, β- (phenyl thio)-phenethyl alcohol, m- (hexyl thi o)-phenol , 276 -5 phenol, o- (octyl thio)-pheno1 , p- (octyl thio) -phenol , 6- (ethyl - thio) thymol , 2,6-di I sopropyl -4- (methyl thio)-phenol , 2,3>5>6-tetramethyl -4-[ (methyl thio)methyl ]-phenol , 3-methoxy 4- (phenyl thio)-o-cresol , 3- (ethyl thio)-4- (hexyl thi o)-phenol , 1- (butyl thlo)-2-naphthol , p-[ (phenyl thio)methyl ]-ani sole, p- (o-tol l thio)-anisole, p- (p-tol yl thi o)-ani sol e, p-(p-tolyl- di thio) -an i sole, p-( (2,2-dimethyl propyl ) thio] -an i sol e, 3- (butyl thio)-phenetole, l,2-dimethoxy-4- (pheny thio)-benzene 2.4- dimethoxy-l- (phenyl thio)-benzene, benzyl oxy- (phenyl thio)- methane, 2-[ (2-methoxyethyl )thio]-l,2,3,4-tetrahydronaphthyl - ene, benzyl p- (methyl thio)phenyl ether, β- (ethyl thio)-2- iso- propyl -4-methyl -phenetole, 3-methyl -4- (propyl thio)-benzyl propyl ether, phenyl 2- (phenyl thio)-vi nyl ether, 2- (benzyl - thio)-tetrahydro-pyran, 3-[ (m-tol yl thio)methyl ]-3-oxetane- methanol, 3-[ (o-tol yl thio)methyl ]-3-oxetanemethanol , 3- [ (p-tol l thio)methyl ] -3-oxetanemethanol , 1- (epoxyethyl )- 4- (phenyl thlo)-benzene, 2,5-bis (ethyl thio)-furan, 2- [l-[2- (butyl thio) -ethoxy]propyl ]-furan, 2-[l-[2- (butyl thio) '"' ethoxy]butyl ]-furan, 2-[l-[2- (butyl thio)-ethoxy]butyl ]-furan, 2-[l-[2- (butyl thio)ethoxy]pentyl ]-f uran, 2,3-bis[ (ethyl thio)- methyl ] -thiophene, 3*4-bis[ (ethyl thio)methyl ]-thiophene, 2.5- bis[ (propyl thi o)methyl ]-furan, 2-[ [2- (butyl thio)ethoxy]- methyl ]-furan, 2,5-bis (butyl thio)-thiophene, 2,5-bis (tert. - butyl thio)-thiophene, 2- (tert. butyl thio)-5- (hexyl thio)- thiophene, 2- (tert. butyl thio)-5- (isopentyl thio)-thiophene, 3,4-bis (cyclohexyl thi o)-thiophene, 2,5-bis (phenyl thio)- thiophene, 2,5-bis (l-naphthyl thi o)-thiophene, 2- (me thy 1 thi o) - 3- thiophenethiol , 5- (methyl thio) -2- thiophene thiol , 3-:(methyl- thi o)-4-thiophenethi ol , 3- (methyl thio)-5-thi ophenethiol , 2764-3 thiophene, 2- (tert. butyl thio)-5- (hexyl thio)-thi ophene, 2- (d iethoxymethyl )-5-ethyl -3- (ethyl thio)-thiophene, 3-(di-ethoxymethyl )-5-ethyl -2- (ethyl thi o) -thi ophene, 2- (benzyl thio) 3- (d iethoxymethyl )-5-ethyl -thiophene, 2, -b i s (2- thi enyl thi o)-thiophene, 2,5-bis (3-thienyl thio)-thiophene, 3, -bi s (2-thi -enyl thio)-thiophene, 3, -bis (3-thienyl thio)-thiophene, 3,4-bi s(cyclohexyl thi o)-2, 5-b is (ethyl thi o)- thi ophene.

Any of the above sulfides that contain one or more hydroxy or sulfhydryl groups can be esteri f ied. Usually these esters will be the acetate or the benzoate but for reasons given above in respect to the Ac and Aci groups, they can be any carboxacyl . In other words any of the hydrogens of these hydroxy or sulfhydryl groups can be replaced by an Aci group which may be the same or different from the Aci groups in the 2-, 3-* 4-0-posi tions.

By acylating the compounds of the invention (Formula I) with an L-2-pyrrol idinecarboxyl ic acid, compounds of Formula IV in which Ac is the acyl of the L-2-pyrrol id i necarboxyl i c acid are obtained. When Al k and R are methyl and the L-2-pyrrol idi necarboxyl ic acid is trans-l-methyl -4-propyl -L-2-pyrrol idi necarboxyl i c acid and the configuration is (S), the compound i s 7-deoxy-7(S )- (methyl thi o)-l i ncomyci n which has antibacterial activity several times that of lincomycin. It and its analogs can be util ized for the same purposes and in the same way as l incomycin.

The compounds of the invention (Formula l) as ell as the acylates thereof with an L-2-pyrrol idi necarboxyl i c acid can exist in either the free base form or in the form of an acid addition salt. Unless otherwise specified or otherwise 2764-3 free base form are intended. These acid addition salts can be made by neutralizing the free base with the appropriate acid to below about pH 7.0, and advantageously to about pH 2 to pH 6, Suitable acids for this purpose include hydro-chloric, sulfuric, phosphoric, thibcyanic, fluosil icic, hexaf 1 uoroarseni c, hexaf uorophosphori c, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycol ic, phthal ic, tartaric, lauric, stearic, salicylic, 3-phenyl sal i cyl ic, 5-phenyl sal i -cyl ic, 2-methylgl utaric, orthosul fobenzoi c, cyclohexanesul -famic, cyclopentanepropionic, 1,2-cyclohexanedi carboxyl ic, -cyclohexenecarboxyl ic, octadecenyl succi ni c, octenyl succi ni c, methanesul foni c, benzenesul fonic, hel ianthic, Reinecke's, dimethyldi thiocarbamic, hexadecyl sul fami c, octadecyl sul ami c, sorbic, monochloroacetic, undecylenic, -hydroxyazobenzene-4-sulfonic, octyl decyl sul fur i c, picric, benzoic, cinnamic, and 1 i ke acf ds.

The acid addi t ion 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 insoluble salt, such as the picrate, which can be subjected to purification procedures, for example, solvent extractions and washings, chromatography, fractional liquid-liquid extractions, and crystallization and then used to regenerate the free base form by treatment with alkal i or to make a different salt by metathesis. Or the free base can. e converted to a water-soluble salt, such as the, hydrochloride or sulfate and the aqueous solution of the salt extracted with various water- immi scible solvents, before 2764-3 extracted acid solution or converted to another salt by metathesi s.

The free bases can be used as buffers or as antacids. They react with isocyanates to form urethanes and can be used to modify polyurethane resins. The thiocyanic acid addition salt when condensed with formaldehyde forms resinous materials useful as pickling inhibitors according to U. S. Patents 2,425*320 and 2,6o6,155. The free bases also make good vehicles for toxic acids. For example, the fluosilicic acid addition salts are useful as mothproofing agents according to U. S. Patents 1,915.334 and 2,075,359 and the hexa-f 1 uoroarseni c acid and hexafl uorophosphoric acid addition salts are useful as parasiticides according to U. S. Patents 3,122,536 and 3,122,552.

The invention may now be more full understood by reference to the following examples in which the parts are by weight except where solvent ratios are given or except as otherwise specified and the c.g.s. system is used unless otherwise specified.

EXAMPLE 1 7-Deoxy-7(S)- (methyl thio)-l i ncomyci n Hydrochloride Part A-l: Methyl N-acetyl -2,3,4-tri -0-acetyl -7-deoxy-7(S )- (methyl thio)-a-thiol incosaminide 2764-3 A mixture of .5.0 gms. (l mol . equiv.) methyl N-acetyl-2,3,4-ti i-0-acetyl -6 (R),7(R)-azi ridi no-6-deami no-7-deoxy-cx-thiol i ncosami nide, 50 ccs. methyl sulfide, and 5.25 gms. (7 mol. equivs.) glacial acetic acid is heated in a Pyrex sealed tube for 20 hours in a steam-bath. Volatile materials are removed from the slightly pink reaction solution by dis-tillation at 100° C, the residue is dissolved in methylene chloride and stirred with an excess of saturated aqueous sodium bicarbonate. Washing of the organic layer with water, drying over anhydrous sodium sulfate, and removal of the solvent on a rotating evaporator at 40°/7 mm. gives a slightl pink solid (5.92 gms.), showing no starting material by TLC (S1O2 gel, 1 acetone: 1 Skellysolve B) and a major new zone of si ightl y . lower Rf. TLC refers to thin layer chromatography and Skellysolve B is technical hexane.

Countercurrent distribution of this sol id in the system 1 ethanol :1 water:l ethyl acetate:2 cyclohexane gives methyl N-acetyl -2,3,4-tri -0-acetyl -7-deoxy-7 (S )- (methyl thio)-a-thiol i ncosami nide at a K value of 1.21, as colorless rods from ethyl acetate-Skel 1 ysol ve B having the following cha racteristics: [α]0 +225° (c, 0.9876, CHCI3) Analysis: Calcd. for CieH2908NS2: C, 47.88; H, 6. 7; N, 3.10; S, 14.20; M. Wt. 451.55.

Found: C, 47.87; H, 6.49; N, 3.19; S, 14.31; M. Wt. (Mass spec, M+) 451.

Part B-l: Methyl 7-deoxy-7($ )-methyl thi ο-α-thiol i ncosami nide A mixture of 8.05 gms. methyl N-acetyl -2,3,4-tri -0-acetyl -7-deoxy-7(S)-methyl thio -α-thiol i ncosami nide (Part A-l) and 100 ccs. hydrazine hydrate is stirred magneticall and heated under gentle reflux in an oil bath at l60° C. for 22 hrs. Removal of the volatile material from the colorless solution by distillation from the oil bath at 110° C. T mm. gives methyl 7-deoxy-7(S)-methyl thio- x-thio 1 incosaminide (B-l) as a colorless solid which crystallizes from methanol in colorless needles having the following characteristics: m.p. 174-175° C [ ]Q +260° (c, Ο.679Ο, H20) An l ys is: Calcd. for C10H21O4NS2: M. Wt. 283.41.

Found: C, 42.39; H, 7.52; N, 4.65; S, 22.78; M. Wt. (Mass spec, M+) 283.

C-l: 7-Deoxy-7(S)- (methyl thio)-l incomycin hydrochloride [Methyl 6,7,8-trideoxy-7- (methyl thio)-6-trans- (l -methyl -4-propyl -L-2-pyrrol i d i neca rboxam i do ) - 1-thio-L-threo-a-O-galacto-octopyranosi de hydrochloride] To a suspension of 4.15 gms. (2 mol. equivalents) trans-propylhygric acid in 150 ccs. anhydrous acetonitrile is added 4.44 gms. (4.4 mol. equivs.) triethylami ne. After the solid dissolves, the solution is cooled to -5° C. in an ice-methanol bath, causing the separation of tri ethyl ammonium chloride. To this solution is added 2.73 gms. (2 mol.. equivs.) of isobutyl chloroformate so that the temperature did not exceed -3° C, and the reaction mixture stirred at -3 to -5° C. for 20 minutes. Then 2.83 gms. (l mol. equiv.) of methyl 7-deoxy-7(S)-methyl thio-ct-thiol incosaminide (B-l), in 20 ccs. methanol and 20 ccs. water is added to the mixed 4 dissolving at once. After 2 hrs. TLC (S102 gel, 1 MeOH:10 CHCI3) shows the disappearance of aminosugar, and the generation of a new zone of higher Rf. Volatile solvent is removed on a rotating evaporator at 40°/7 mm., and the syrupy residue dissolved in water by the addition of dilute aqueous hydrochloric acid (iN) till the resultant solution is at ca. pH 2. This acid solution is extracted twice with methylene chloride, and the organic extracts discarded. The aqueous solution is adjusted to pH 11 by the addition of aqueous sodium hydroxide (50$), the resulting milky reaction mixture extracted three times with methylene chloride, and the combined extracts dried over anhydrous sodium sulfate, the residual alkaline aqueous layer being discarded.

Removal of solvent from the methylene chloride extract on a rotating evaporator at 40° C. T mm. gives a slightly yellow syrup which is chromatographed on silica (1200 gms., column dimensions 5.8 x 90 cms., hold-up volume 2000 ccs.) in the system 1 methanol :15 chloroform. After a forerun of 18OO ccs., 50 cc. fractions are collected, and the elution of material followed by TLC on silica in the same system.

Fractions nos. 21-54, inclusive, are combined to yield, on removal of solvent, a colorless syrup which is converted to the hydrochloride by dissolving in water to which dilute aqueous hydrochloric acid (JN) is added till the solution is at ca. pH 3. This solution is then shell-frozen and lyophilized yielding 7-deoxy-7(S )- (methyl thio)-l incomyci n hydrochloride (C-3) as a colorless solid having the following characteristics: [a]D +125° (c, 0.8840, H20) 276 -3 Calcd. for CigH3e05N2S2. HC1 : C, 48.23; H, 7.88; N, 5-92; S, 13.56; CI, 7.50; M. t. 473.10 (M. Wt. free base, 436.63).

Found: C, 48.84; H, 7.71; N, 5.90) S, 12.96; CI, 7.25; M. Wt, (Mass spec, M+ of free base) 436.

Biological Activity: In vitro; about 8 times lincomycin, with improved Gram negative activity.

EXAMPLE 2 7-Deoxy-7(S )- (ethyl th ϊ o) - 1 ϊ neomycin Hydrochloride Part A-2: Methyl N-acetyl -2,3j4-tri -0-acetyl -7-deoxy-7(S)- (ethyl thi o)-a- thi ol i ncosami ni de Following the procedure of Part A-1, but substituting the methyl sulfide by ethyl sulfide and heating under reflux for 7 hours, there is obtained methyl N-acetyl -2,3, 4-tri -0-acetyl -7-deoxy-7(S )- (ethyl thio)- -thi ol incosami nide (A-2) having the following characteristics: K = I.85 (same solvent system) m.p. 236-237° C [a]D +215° (c, 0.95, CHC13) Andl ys i s : Calcd, for CiSH3i0eNS2: C, 49.01; H, 6.71; N, 3.01; S, 13-77.

Found: C, 49.18; H, 6.47; N, 3.4l; S, 13.17.

This compound is also obtained at a K value of 6.15 in the countercur rent distribution of Example 12.

Part Β-Ϊ2: Methyl 7-deoxy-7(S)- (ethyl thio)-a-thiol i ncosami nide Following the procedure of Part B-1 the above compound 2764-3 thiol i ncosami nide (B-2). It crystall izes from methanol as colorless prisms having the following characteristics: m.p. 192-4° C. [a]D +253° (c, 0.73, H20) Analysis: Ca led. for CnH2304NS2: C, 44.42; H, 7.79; N, 4.71; S, 21.56.

Found: C, 44. l6; H, 7-78; N, 4.72; S, 21.78.

Part C-2: 7-Deoxy-7(S )- (ethyl thio)-l i ncomyci n hydrochloride Following the procedure of Part C-l, the above compound (B-2) is converted to 7-deoxy-7(S)- (ethyl thio)-l i ncomyci n hydrochloride (C-2). It is obtained as a lyophilized colorless sol id having the following properties: [a]D +111° (c, Ο.83, H20) Analysis: Calcd. for C2OH3805N2S2» HC1 : C, 49.31; H, 8.07; N, 5.75; CI, 7.28; S, 13.17; M. Wt. 450.65 for free base.

Found (Corrected for 9·23# H20): C, 49.52; H, 7.99; N, 5.6l; CI, 7.55; S, 13.46; M. Wt. (Mass spec, M+ of free base) 450.

Biological activity: about 8 times l incomycin.

EXAMPLE 3 Alternative Process to Example 2 Following the procedure of Part A-l, substituting the ethyl sulfide by ethyl disulfide and heating in an oil bath at 110° for 20 hours, the same 7 (S )- (ethyl thi o) compound is obtained but in higher yields.

EXAMPLE 4 276 -3 Part A-4: Methyl N-acetyl -2,3,4-tri -O-acetyl -7-deoxy-7(S)- (propyl thio)-a-thiol incosaminide Following the procedure of Part A-l, substituting the methyl sulfide by methyl propyl sulfide, methyl N-acetyl -2,3,4-tri -O-acetyl -7-deoxy-7(S )- (propyl thi o)-a- thi ol incos-aminide (A-4) is obtained from ethyl acetate.Skel 1 ysol e B as colorless needles having the following characteristics: m.p. 259-61° C. [a]D +203° (c, 0.96, CHCI3) Anal ys i s : Calcd. for C2OH3308NS2: C, 50.08; H, 6.93; N, 2.92; S, 13.37.

Found: C, 49.89; H, 6.96; N, 3.02; S, 13.4l.

K = 3.10 (Same solvent system) There is also obtained the corresponding 7(S)-methyl-thio)- compound (A-l ) at a K value of 1.32, in the ratio of one part to three parts of the 7 (S )- (propyl thi o)- compound (A-4).

Part B-4: Methyl 7-deoxy-7(S )- (propyl thi o)-a-thi ol i ncos- ami nide Following the procedure of Part B-l, the above compound (A-4) is converted to methyl 7-deoxy-7 (S )- (propyl thio)-a-thi ol i ncosami ni de (B-4). It crystallizes from methanol as colorless platelets having the following characteristics: m.p. 189-I900 C. [a]D +257° (c, 0.71, pyridine) Anal ys i s : Calcd. for Cl2H2504NS2: C, 46.27; H, 8.09; N, 4.50; S, 20.59. 2764-3 Part C-4: 7-Deoxy-7 (S )- (propyl thi o)-l i ncomyc ί n hydrochloride Following the procedure of Part C-l, the above compound (B-4) is converted to 7-deoxy-7(S )- (propyl thio)-l i ncomyc i n hydrochloride (C-4) as a lyophilized colorless amorphous solid having the following characteristics: [a]D +112° (c, 0.83, HaO) Analysis: Calcd. for C2iH4o0sN2S2*HCl : C, 50.33; H, 8.25; N, 5.59; CI, 7.08; S, 12.80; M. Wt. free base 464.68.

Found (Corrected for 5.33 H20): C, 50.12; H, 8.03; N, 5-74; CI, 6.94; S, 12.57; M. Wt. (Mass spec, M+ of free base) 464.

Biological Activity: about 8 times 1 incomycin.

EXAMPLE 5 Alternative for Example 4 • Following the procedure of Part A-2, substituting the ethyl sulfide by propyl sulfide, there is obtained methyl N-acety -2,3,4-tri -0-acetyl -7-deoxy-7(S)- (propyl thio)-a-thiol incosaminide (A-4).

EXAMPLE 6 7-Deoxy-7(S ) - (i sop ropy 1 thi o) - 1 i ncomyc i n Hydrochlor ide Part A-6: Methyl N-acetyl -2, 3»4-tri -0-acetyl -7-deoxy-7(S)- (isopropyl thi o) -x- thiol incosaminide Following the procedure of Parg A-2 substituting the ethyl sulfide by methyl isopropyl sulfide, there is obtained methyl N-acetyl -2,3, 4-tri -0-acetyl -7-deoxy-7(S)- (i sopropyl - 2764-3 crystallizes as colorless needles having the following character i sti cs: K β 2.9 in the system 1 ethanol.l wateril ethyl acetate: 2 cyclohexane m.p. 274.5-275.5° C. [a]D +200° (c, 0.87, CHCla) Analysis: Calcd. for C2oH3308NS2: C, 50.08; H, 6.93; N, 2.92; S, 13.37.

Found: C, 49.79; H, 6.95; N, 2.78; S, 13.60.

Also formed is the 7 (S ) -methyl thio compound (K = 1.32) in the ratio of 1.5 methylthio to 1 i sopropyl thi o.

Substituting the methyl isopropyl sulfide by ί sopropyl disulfide there is obtained exclusively methyl N-acetyl-2,3,4-tri -0-acetyl -7-deoxy-7(S )- (i sopropyl thio) -a- thi ol in-cosaminide.

Part B-6: Methyl 7-deoxy-7(S)- (i sopropyl thio)- -thiol i ncos- aminide Following the procedure of Part B-l, the above iso-propylthio compound (A-6) is converted to methyl 7-deoxy-7 (S)- (i sopropyl thi o)-a- thiol i ncosami nide as colorless platelets from methanol having the following characteristics: m.p. 220-221° C. [a]D +269° (c, Ο.85, pyridine) Anal ys i s: Calcd. for C12H2504NS2: C, 46.27; H, 8.09; N, 4.50; S, 20.59.

Found: C, 46.02; H, 8.10; N, 4.45; S, 20.73.

Part C-6: 7-Deoxy-7(S)- (i sopropyl thio) -1 i ncomyci n hydro 27 -3 Following the procedure of Example 1, Part C-l, there is obtained 7-deoxy-7(S)- (isopropyl thio)-l i neomycin hydrochloride having the following characteristics: +109° (c, 0.97, H20) Anal ysi s: Calcd. for C2iH4o05N2S2. HC1 : C, 50.33; H, 8.25; N, 5.59; CI, 7.08; S, 12.80; M. Wt. free base 464.68.

Found (Corrected for 5.00$ H20): C, 50.74; H, 8.50; N, 5.36; CI, 6.74; S, 12.67; M. Wt. (Mass spec, M+ of free base) 464.

EXAMPLE 7 7(S)- (cycl oHexyl thi o)-7-deoxyl i ncomyci n Hydrochloride Part A-7: Methyl N-acetyl -2,3,4-tr i -0-acetyl -7-deoxy-7 (S )- (cyclohexyl thio)-a- thiol incosaminide Following the procedure of Example 1, Part A-l, substituting the methyl sulfide by cyclohexyl methyl sulfide but heating in an oil bath at 115° for 24 hours, there is ob-tained methyl N-acetyl -2,3, 4-tr i -0-acetyl -7-deoxy-7(S ) -(cyclohexyl thio) -a-thi ol incosaminide ( = 5.95 using the system 1 ethanol :1 water:l ethyl acetate:5 cyclohexane) as colorless prisms from ethyl acetate having the following characteristics: m.p. 248-250° C. [a]D +184° (c, 0.86, CHC13) Ana 1 ys i s : Calcd. for C23H370eNS2: C, 53.15; H, 7.l8; N, 2.70; S, 12.34. 276 -3 There is also obtained corresponding 7(S)-(methyl thio)-compound (K = 0.57) and otherwise characterized as the compound of Part A-l in a ratio of about 1 part to each 5 parts of the 7(S)-cyclohexyl thio compound.

Part B-7: Methyl 7-deoxy-7(S)- (cyclohexyl thio)-a-thiol i n- cosaminide Following the procedure of Example 1, Part B-l, there is obtai ned methyl 7-deoxy-7 (S )- (cycl ohexyl thio)-a-thi ol i n-cosaminide as colorless needles from methanol having the following characteristics: m.p. 222-225° C. [a]Q +255° (c, 0.62, pyridine) Analysis: Calcd. for Ci5H2a04NS2: C, 51.25; H, 8.52; N, 5-99; S, 18.24.

Found: C, 50.9 ; H, 8.46; N, .6 ; S, 18.47.

Part C-7: 7(S)- (cycloHexyl thio)-7-deoxyl i ncomyci n hydrochloride Following the procedure of Example 1, Part C-l, there is obtained 7(S)- (cyclohexyl thio)-7-deoxyl incomycin hydrochloride having the following characteristics: [ Found (Corrected for 4.42# H20): C, 55.50; H, 8.45; N, 5.l6; S, ll.96; CI, 6.55; M. Wt. (Mass spec, M+ of free base) 504. 2764-3 Part A-8: Methyl N-acetyl -2,3,4-tri -O-acetyl -7-deoxy- 7(S)- (cyclopentyl thio)-a-thiol i ncosami nide Following the procedure of Example 1, Part A-l, substituting the methyl sulfide by methyl cyclopentyl sulfide but heating, in an oil bath at 100° C. for l6 hrs., there is obtained methyl N-acetyl -2,3, -tri -0-acetyl -7-deoxy-7(S)- (cyclopentyl thio)-a-thiol incosami nide (A-8) at a K Vcllue of 4.0 using 1 ethanol :1 water.l ethyl acetate:3 cyclo-hexane. It is obtained as colorless needles from ethyl acetate having the following characteristics: m.p. 265-265.5° [a]D +I870 (c, 0.99. chloroform) Anal ys i s : Calcd. for C22H350e S2: C, 52.25; H, 6.98; N, 2.77; S, 12.68.

Mol. Wt. 505.64.

Found: C, 52.07; H, 6.88; N, 2.68; S, 12.62.

Mol. Wt. (Mass spec, M+) 505.

When methyl cyclopentyl sulfide is substituted by cyclopentyl disulfide, the same compound is obtained.

EXAMPLE 9 7(S)- (Butyl thio)-7-deoxyl i neomycin hydrochloride Part A-9: Methyl N-acetyl -2,3, 4-tri -0-acetyl -7 (S )- (butyl - thio)-7-deoxy-a-thiol incosami nide Following the procedure of Example 3* substituting the ethyl disulfide by butyl disulfide, there is obtained methyl N-acetyl -2,3,4-tri -0-acetyl -7 (S)- (butyl thio)-7-deoxy-a-thio-1 i ncosami ni de (K = 3-35* 1 ethanol :1 water:l ethyl acetate:3 2764-5 the following characteristics: m.p. 254-5° C. [a]Q +197° (c, 0.51, CHCls) Analysis: Calcd. for CaiH350e S2: C, 51.09; H, 7.15; N, 2.84; S, 12.99.

Found: C, 51.05; H, 7.21; N, 2.65; S, 12.76.

Part B-9: Methyl 7(S )- (butyl thio)-7-deoxy-a- thi ol i ncos- aminide Following the procedure of Example 1, Part B-l, there is obtained methyl 7(S)- (butyl thio)-7-deoxy-a-thiol i ncos-aminide as colorless plates from methanol having the .following properties: m.p. 188-190° C. [a]D +250° (c, 1.00, pyridine) Analysis: Calcd. for Ci3H2704NS2: C, 47.97; H, 8.56; N, 4.50; S, 19.70.

Found: C, 47.88; H, 8.55; N, 4.57; S, 19.69.

Part C-9: 7-Deoxy-7(S )- (butyl thio)-l i ncomyc i n hydrochloride Following the procedure of Example 1, Part C-l, there is obtained 7-deoxy-7 (S )- (butyl thio)-l i neomycin hydrochloride having the following characteristics: [ ]D +106° (c, Ο.65, H20) Analysis: Calcd. for C22H4405N2S2« HC1 : C, 51.29; H, 8.4l; N, 5.44;. S, 12.45; CI, 6.88; M. Wt. of free bases 78.70.

Found (Corrected for 5.82¾ water): 2764-5 M. Wt. (Mass spec, M+ of free base) 78.

EXAMPLE 10 7-Deoxy-7(S)- (2-hydroxyethyl thio)- li neomycin hydrochloride Part A-l Qa: Methyl N-acetyl -2,3, 4-tri -0-acetyl -7-deoxy- 7 (S)- (2-hydroxyethyl thio)-a-thiol i ncosami nide Following the procedure of Example 1, Part A-l, substituting the methyl sulfide by 2-hydroxyethyl methyl sulfide but heating* on a steam bath at 100° for 5 hours, there is obtained methyl N-acetyl -2, 3, 4-tri -0-acetyl -7-deoxy- ; 7 ($)- (2-hydroxyethyl thio)-a-thiol incosaminide (K = 0.97, 1 ethanol.l water:l ethyl acetate: 0.5 cyclohexane) as colorless needles from ethyl acetate-Skel 1 ysol e B having the following properties: m.p. 226-228° C.

[ ]D +185° (c, 1.00, CHCls) Anal ys i s : Calcd. for Ci9H3i09NS2: C, 47.38; H, 6.49; N, 2.91; S, 13.32.

Found: C, 47.18; H, 6.79; N, 2.86; S, 12.73.

Part A-lOb: Methyl N-acetyl -2, 3,4-tri -0-acetyl -7-deoxy- 7(S )- (2-acetoxyethyl thi o) -a- thiol i ncosami nide Following the procedure of Example 1, Part A-l, substituting the methyl sulfide by 2-acetoxyethyl methyl sulfide but heating on a steam bath at 100° for 5 hours, there is obtained methyl N-acetyl -2, 3*4-tri -0-acetyl -7-deoxy-7(S)- (2-acetoxyethyl thio)-a-thiol incosami nide (K = 0.53, 1 ethanol:l water:l ethyl acetate:3 cyclohexane) as colorless needles from ethyl acetate-Skel 1 ysol e B having the 276 -3 m.p. 206-7° C. [a]D +180° (c, 0.79, CHCI3) Anal ys i s: Calcd. for C21H33O1 oNS2 : C, 48.17; H, 6.35; N, 2.68} S, 12.25.

Found: C, 48.12; H, 6.37; N, 2.58; S, 11.95.

Part B-10: Methyl 7 (S)- (2-hydroxyethyl thi o)-7-deoxy-a- thi o- i ncosami nide Following the procedure of Example 1, Part B-l, there is obtained from compound A-lOa or A-lOb, 7-deoxy- 7(5)- (2-hydroxyethyl thio)-a-thiol incosami nide as colorless platelets from acetoni tri le-ethanol having the following properties: m.p. 175-6° C. [a]D +234° (c, 0.52, H20) Anal ys i s: Calcd. for CiiH2305NS2: C, 42.15; H, 7.40; N, 4.47; S, 20.46.

Found: C, 42.05; H, 7.55; N, 4.43; S, 20.36.

Part C-10: 7-Deoxy-7(S)- (2-hydroxyethyl thio)-l i ncomyci n hydrochlori de Following the procedure of Example 1, Part C-l, there is obtained 7-deoxy-7(S )- (2-hyd rbxyethyl thio)-l i ncomyci n hydrochloride as a colorless amorphous material by lyophil-ization from aqueous solution having the following character-i sti cs: [a]D +114° (c, 0.91, H20) Analysis: Calcd. for C2oH380e 2S2*HCl : 276 -3 M. Wt. of free base 466.65.

Found (Corrected for 6.75 This compound is about 8 times as active as l incomycin and has greater Gram negative activity in vivo, and is less toxic, than 7-deoxy-7(S)-chlorol i eomycin hydrochloride.

EXAMPLE 11 7(S)- (tert. Butyl thi o)-7-deoxyl i ncomyci n hydrochloride Pa,rt A-ll: Methyl N-acetyl -2,3, 4-tri -0-acetyl -7 (S)- (tert. - butyl thio)-7-deoxy-a-thiol i ncosaminide Following the procedure of Example 1, Part A-l, substituting the methyl sulfide by tert. butyl 2-mercaptoethyl sulfide but heating in an oil bath at 100° C. for 16 hrs., there is obtained crude methyl N-acetyl -2,3,4- t ri -0-acetyl -7(S)- (tert. butyl thio)-7-deoxy-a- thiol incosami nide.

Countercur rent distribution in the system 1 ethanolrl water:l ethyl acetate:3 cyclohexane yields methyl N-acetyl -2, 3i -tri -0-acetyl -7 (S)- (tert. butyl thio)-7-deoxy-a-thiol incosami nide at a K value of 2.38. It is obtained as small colorless needles from ethyl acetate having the following characteristics: m.p. 272-3° C. [a]D +I87 (c, 0.64, chloroform) Analysis: Calcd. for C2iH3508 S2: C, 51.09; H, 7.15; N, 2.84; S, 12.99- : Mol. Wt. 493.63. 2764-3 Mol. Wt. (Mass spec, M+) 493.

The same compound is obtained but in lower yields when the methyl sulfide of Part A-l is substituted by tert. butyl sulfide.

Methyl Part B-ll: / 7(S)- (tert. Butyl thio)-7-deoxy-a-thiol i ncos- ami nide Following the procedure of Part B-l, there is obtained methyl 7(S)- (tert. butyl t hi o)-7-deoxy-a- thiol i ncosami nide.

Part C-ll: 7(S)- (tert. Butyl thio)-7-deoxyl i neomycin hydrochloride Following the procedure of Part C-l, there is obtained 7(S)-(tert.butylthio)-7-deoxyl incpmycin. hydrochloride as an amorphous solid obtained by lyophilizing an aqueous solution. Part D-.11: Methyl N-acety -2, 3,4-tri -0-acetyl - 7(S)-[2- (tert. butyl thio)ethyl thi o] -7-deoxy-a- thi ol i ncosami ni de The above countercurrent distribution (Part'A-ll) yields also methyl N-acetyl -2,3*4-tri -O-acety -7(S)-[2- (tert. butyl thio)ethyl thi o] -7-deoxy-a^ thi ol incos-aminide at a value of 7·95. It is obtained as colorless, irregular platelets from ethyl acetate-Skel 1 ysol ve B having the following characteristics: fx o m.p. 164-5 C. [a]D +164° (c, 0.58, chloroform) Anal si s: Calcd. for C23H39O8NS3: C, 49.88; H, 7.10; N, 2.53; S, 17.37.

Mol. Wt. 553.75.

Found: C, 49.76; H, 7.03; N, 2.63; %, 17.39.

The tert. butyl 2-mercaptoethyl sulfide is obtained from the reaction between sodium tert. butyl mercaptide and ethylene sulfide in ethanol solution.

Following the procedures of Parts B-l and C-l there are obtained methyl 7(S)-[2- (tert. butyl thiojethyl thio]-7-deoxy-a-thiol incosami nide and 7(S)-[2- (tert. butyl thio)-ethyl thio] -7-deoxyl i ncomyci n hydrochloride.

EXAMPLE 12 Part A-12: Methyl N-acetyl -2,3,4-tri -O-acetyl -7-deoxy- 7(S)- (ethyl dithio)-a-thiol i cosami nide Following the procedure of Example 1 substituting the methyl sulfide by tert. butyl ethyl disulfide but heating in an oil bath at 100° C, for l6 hrs. there is obtained a crude product contain! ng methyl N-acetyl -2,3, -tri -0-acetyl -7-deoxy-7(S)-(ethyldithio)-a-thiol incosami nide. Counter-current distribution of this crude material in the system 1 ethanol :1 water.l ethyl acetate:3 cyclohexane yields methyl 4-acetyl -2,3,4-tr i -0-acetyl -7-deoxy-7(S)- (ethyl di -thio)-a*thiol i ncosami nide (A-12) admixed with methyl -acetyl -2,3* -tri -0-acetyl -7(S)- (tert. butyl thio)-7-deoxy-a-thiol incosami nide (A-ll) in the proportions of 30 to 70, respectively. The value of this mixture is 2.57· The two products are separable by vapor-phase chromatography and are differentiated by the fact that the former (A-12) shows a UV absorption at 2 5 nm, e, 546 whereas the latter (A-ll) shows no UV absorption. The former compound (A-12) shows a molecular ion at m/e 497 by mass spec, as against a calculated value of 497.65. The latter compound (A-ll) is identical with that obtained in Part A-ll. £ solution of 600 mg. of the mixture ( -11 and £-12) of Part £-12 in 60 ml. of benzene and 2.72 g. of tris-d iethyl ami nophosphi ne is heated under gentle reflux for 10 hrs. The solvent is removed by distillation under reduced pressure and the resulting syrup chromatographed on sil ica using 1 ethyl acetate.l Skellysolve B as the solvent system in order to separate excess reagent and copro-duce tris-diethylaminophosphine sulfide from the product which appears at an Rf of 0.51-0.54. Countercurrent distri-bution of this product in 1 ethanol:l water.l ethyl acetate: 3 cyclohexane yields methyl N-acetyl -2,3, -tr i -0-acetyl -7-deoxy-7(S)- (ethyl thio)-a-thi o i ncosami nide (£-2) at a K value of 1. 3 and tert. butyl analog (£-11) at a K value 2.57. Following the procedures of Parts B-l and C-l, there are obtained from the above 30-70 mixture, l) a corresponding mixture of methyl 7-deoxy-7 (S )- (ethyl d i thi o) -a- thi ol i n-cosaminide and methyl 7(S)- (tert. butyl thi o)-7-deoxy-a-thio-1 i ncosami nde, and 2) a corresponding mixture of 7-deoxy-7 (S )- (ethyl d i thio)-l i ncomyci n hydrochloride and 7(S)-(tert.-butyl thio)-l i ncomyci n hydrochloride.

EXAMPLE 13 7(S )- (tert. Butyl di thio)-7-deoxyl i ncomyci n hydrochloride Part £-13: Methyl N-acetyl -2,3,4-tri -0-acetyl -7(S)- (tert. - butyl di thio)-7-deoxy-a- thiol i ncosami nide Following the procedure of Example , substituting the ethyl disulfide by tert. butyl disulfide, there is obtained methyl N-acetyl -2,3,4-tr i -0-acetyl -7(S)- (te rt. butyl di thi o)-7-deoxy-ot- hiol i ncosami nide as small colorless rods from cha racteri sties: m.p. 2 1,2° C. [a]D +220° (c, 0.56, CHCls) ( = 7.35* 1 water.l ethanol:l ethyl acetate:? cyclo-hexane) Anal ysi s: Calcd. for C21H3508NS3: C, 47.98; H, 6.71; N, 2.67; S, 18.30.

Found: C, 48.03; H, 6.65; N, 2.65; S, 18.65; M. Wt. (Calcd.) : 525.70.

Found (Mass spec, M+) : 525 This compound is also obtained at a value of 1. in the countercurrent distribution in Example 12.

EXAMPLE 14 Alternate for Example 1 Following the procedure of Example 3, substituting the ethyl disulfide by methyl tertiary butyl sulfide, there is obtained methyl N-acetyl -2,3* 4-tri -0-acetyl -7-deoxy-7(S)« (methyl thio)-a-thiol i ncosami nide whi ch is the same compound as obtained in Example 1, Part A-l. The advantage of this alternative process is that higher yields of the desired product are obtained.

EXAMPLE 15 Alternative for Example 1 Following the procedure of Example * substituting the ethyl disulfide by 1,2-bis (methyl thio)-ethane, there is obtained methyl N-acetyl -2,3*4- tri -0-acetyl -7-deoxy-7(S)- (methyl thio)-a- thiol incosaminide which is identical to the product obtained in Example 1, Part A-l. This process, produce any of the 7(S)-[2- (methyl thio)ethyl thio]- compound.

EXAMPLE 16 7-Deoxy-7(S)-[ (2-methyl thio)ethyl thio]- 1 i ncomyci n hydrochloride and Alternative to Example 1 Part A-16: Following the procedure of Example 5* substituting the ethyl disulfide by 2- (methyl thio)ethanethiol , there is obtained methyl N-acety -2,3,4-tr i -O-acetyl -7-deoxy-7 (S )- (methyl thi o)-a-thi ol i ncosami ni de, which is the same compound as obtained in Example 1, together with methyl N-acetyl -2,3,4-tri -0-acetyl -7-deoxy-7(S)-[ (2-methyl thio)-ethyl thi o]- -thi 61 incosaminide in the proportions of 80 parts of the former and 20 parts of the latter. Counter-current distribution in the system 1 ethanol.l water.l ethyl acetate:3 cyclohexane yields the latter compound at a value of 1.8 . It is obtained as colorless needles from ethyl acetate-Skel 1 ysol ve B having the following characteristics: - o m.p. 256-7 C [a]D +185° (c, 0.95, chloroform) Anal ys is: Calcd. for C2oH330e S2: C, 46.94, H, 6.50; N, 2.74; S, I8.8O; Hoi. Wt. 511.67.

Found: C, 46.96; H, 6.92; N, 2.49; S, 18.38; Mol. Wt. (Mass spec., M+) 511.

Part B-16: Methyl 7-deoxy-7(S )-[ (2-methyl thio)ethyl thio]- a-thiol incosami nide 2764-3 compound (A-l6) as the starting compound, there is obtained methyl 7-deoxy-7(S )-[ (2-methyl thio)ethyl thio] -ct-thi ol i ncos-aminide.

Part C-16: 7-Deoxy-7(S)-[ (2-methyl thio)ethyl thi o] 1 i ncomyci n hydrochloride Following the procedure of Part C-l using the above compound (B-l6) as starting compound, there is obtained 7-deoxy-7(S )-[ (2-methyl thio)ethy thio] 1 i ncomyci n hydrochloride.

EXAMPLE 17 Alternative to Example 1 Following the procedure of Example 3, substituting the ethyl disulfide by 4- (methyl thi o)butanethi ol , there is obtained methyl N-acetyl -2,3, -t ri -O-acetyl -7-deoxy-7(S)-methyl thio-a-thiol incosaminide which is identical with the compound of Part A-l.

The 4- (methyl thi o)butanethiol is obtained by the mono-S-methylation of the 1,4-butanedi thi ol using one equivalent of sodium hydroxide and methyl iodide in ethyl alcohol.

EXAMPLE 18 Alternative to Example 3 Following the procedure of Example 3* substituting the ethyl disulfide by ethyl trisulfide but heating in an oil bath at 100° for l6 hrs., the same 7 (S) -ethy thio compound is obtained in good yields.

EXAMPLE 19 7-Deoxy-7(S)-[ (3-methyl thio)propyl - thi o] 1 i ncomyci n hydrochloride Part A-19: Methyl N-acetyl -2,3^-tri -0-acetyl -7-deoxy- 276 -5 aminide 18, Following the procedure of Example Ί$, substituting the ethyl trisulfide by 1,5-bi s (methyl thi o)-propane, there is obtained methyl N-acetyl -2, * 4-tri -0-acetyl -7-deoxy-7(S)-[ (5-methyl thi o)p ropy 1 thio]-a-thi ol i ncosami nide.

By countercurrerit distribution using the same solvent system as in Example 16, the above compound is obtained at a K value of 2.24. It crystallizes from ethyl acetate as colorless needles having the following characteristics: m.p. 211-12° C. [a]D +I8l° (c, 1.1, chloroform) Analysis: Calcd. for C21H35O8NS3: C, 47.98; H, 6.71; N, 2.67; S, 18.5O; Mol. Wt. 525.70.

Found: C, 47-97; H, 6.78; N, 2.62; S, 17-75; Mol. Wt. (Mass spec, M+) 525.

Following the procedures of Parts B-l and C-l, using the above compound (A-19) as the starting compound, there are obtained methyl 7-deoxy<-7(S )-[ (5-methyl thio)propyl thio] -a-thiol incosaminide and 7-deoxy-7(S)<-[ (5-methyl thio)propyl ]-lincomycin hydrocyloride. This process does not produce the methyl thio derivative. The product is exclusively the 5- (methyl thi o) ropyl thio compound.

EXAMPLE 00 Paitt A-20: 276 -3 aminide; cou^tercurrent distribution usjng the same solvent l i neomycin hydrochloride.

EXAMPLE Part A-21: Following the procedure of Example 1, Part A-l, substi tuting the methyl sulfide by 2-methoxyethyl methyl sulfide and heating in an oil bath at 100° for l6 hours, there is obtained methyl N-acetyl -2,3,4- tr i -0-acetyl -7-deoxy-7(S)- (2-methoxyethyl thio)-a-thiol incosaminide. Countercur- rent distribution using 1 ethanol:l water:l ethyl acetate:2 cyciohexane as the "solvent system gave this compound at a value of 0.88. It is obtained as colorless rods from ethyl acetate having the following characteristics: m.p. 225-7° C. 276 -5 Ana 1 ys i s : Calcd. for C20H33O9NS2: C, 48.47; H, 6.71; N, 2.83; S, 12.94; Mol. Wt. 495.60.

Found: C, 48.72; H, 6.82; N, 2.79; S, 12.77; Mol. Wt. (Mass spec, M+) 495-Part B-21: Methyl 7-deoxy-7 (S )- (2-methoxyethyl thi o) -α-thi o- 1 i ncosami nide Following the procedure of Part B-l, there is obtained methyl 7-deoxy-7(S )- (2-methoxyethyl thi o)-a- thiol i ncosami ni de as colorless needles from acetonitrile having the following characteristics: m.p. 169-170° C. [a]D +223° (c, 0.93, water) Anal ys I s : Calcd. for C12H25O5NS2: C, 44.01; H, 7.70; N, 4.28; S, 19-58; Mol. WtT 327.46.

Found: C, 44.31; H, 7.53; N, 4.20; S, 19.42; Mol. Wt. (Mass spec, M+) 327.

Part C-21: 7-Deoxy-7 (S )- (2-methoxyethyl thi o) 1 i ncomyc i n hydrochloride Following the procedure of Part C-l, there is obtained 7-deoxy-7(S)- (2-methoxyethyl thio)l i ncomyci n hydrochloride as a lyophil ized colorless amorphous solid having the following character! st i cs : [ ]D +106° (c, O.70, water) Analysis: Calcd. for C2iH4o06N2S2«HCl ; 276 -5 Mol. Wt. (of free base) 480.68.

Found (Corrected for 4.94$ water): C, 48.90; H, 7.95; N, 5.51; CI, 6.60; S, 12.23; Mol. Wt. (Mass spec, M+ of free base) 480.

EXAMPLE 22- 21 Part A-22: Methyl N-acetyl -2,3,4-tr i -0-acetyl -7-deoxy- 7(S)-(vinylthio)-a-thiol i ncosami ni de Following the procedure of Part A-l, substituting the methyl sulfide by methyl vinyl sulfide and then heating at 100° for l6 hours, there is obtained methyl N-acetyl - 2, 3, 4-tri -0-acetyl -7-deoxy-7 (S )- (vi nyl thi o)-a- thiol incos-aminide. Countercur rent distribution in the solvent system 1 ethanol :1 water.l ethyl acetate:3 cyclohexane yields this compound at a K value of 1.57· It is obtained as colorless needles from ethyl acetate-Skel 1 ysol ve B having the following characteristics: m.p. 215.5-216° C. [a]D +168° (c, 0.79, chloroform) Analysis: Calcd. for Cl9rl290eNS2: C, 49.23; H, 6.31; N, 3.02; S, 13.83; Mol. Wt. 463.56.

Found: C, 49.06; H, 6.39; N, 3.13; S, 13.33; Mol. Wt. (Mass spec, M+) 463.

Following the procedures of Parts B-l and C-l, using the above compound (A-22) as the starting compound, there are obtained methyl 7-deoxy-7 (S )- (v inyl thi o) -a-thi ol i ncos-aminide and 7-deoxy-7 (S )- (vi nyl thi o) 1 i ncomyc i n hydrochloride.

EXAMPLE -2-3 22 2764-3 7(S )- (al 1 yl thi o)-a-thi ol i ncosam i n i de and Methyl N-acetyl -2,3, -tri -O-acetyl -7-deoxy-7 (S )- (pro- penyl thio)-a-thiol incosami nide Following the procedure of Part A-l, substituting the methyl sulfide by allyl sulfide and heating at 100° for l6 hours, there is obta i ned methyl N-acetyl -2,3,4-tr i -0-acetyl -7(S)- (al 1 yl thio)-7-deoxy-a-thiol i ncosami nide. There is also obtained methyl N-acetyl -2,3, 4-tri -0-acetyl -7-deoxy-7(S )- (propenyl thi o)-a-thi ol i ncosami nide. Countercurrent distribution using the solvent system 1 ethanol :1 water.l ethyl acetate:2 cyclohexane yields the allyl compound at a K value of 1.76 and the propenyl compound at a value of 3.30. The allyl compound crystall ized from ethyl acetate-Skellysolve B as colorless needles having the following characteristics: m.p. 235-7° C. [α]β +194° (c, 0.63, chloroform) Analysis: Calcd. for C2oH3i08NS2: C, 50.29; H, 6.54; N, 2.93 S, 13.43; Mol. Wt. 477.59.

Found: C, 50.10; H, 6.67; N, 2.79; S, 13.00; Mol. Wt. (Mass spec, M+) 477.

The propenyl compound is obtained as colorless needles from ethyl acetate-Skel 1 ysol ve B having the following characteristics: m.p. 273-5° C [a]D +157° (c, 1.05, chloroform) Anal ysi s: Found: C, 50. 3; H, 6.45; N, 2.96; S, 13.37; Mol. Wt. (Mass spec, M+) 477.

Following the procedure of Parts B-l and C-l, using the above compounds (A-23 all l and A-23 propenyl) as the starting compounds, there are obtained methyl 7(S)- (allyl -thi o) -7-deoxy-a- thi ol i ncosaminide, methyl 7-deoxy-7(S )- (propenyl thi o) -a- thiol incosami nide, (S ) - (a 11 yl thi o) -7-deoxy-lincomycin hydrochlori de,' and 7-deoxy-7(S )- (propenyl thi o)-li neomycin hydrochloride.

EXAMPLE l?M 23 Part A-24: Methyl fl-acetyl -2,3,4-tri -0-acetyl -7(S)- (al 1 yl - di thio)-7-deoxy-ot-thiol incosami nide The procedure of Part A-l, substituting the methyl sulfide by allyl disulfide and heating at 100° C. for l6 hours is followed and the product chroma tog raphed over silica gel using 1. ethyl acetaterl Skellysolve B as the solvent system to remove excess reagent (of low polarity) followed by straight ethyl acetate to remove the more polar desired products. Countercur rent distribution .of the latter using 1 ethanolil eaterrl ethyl acetate:3 cyclohexane as the solvent system yields methyl N-acetyl -2,3,4-tri -0-acetyl -7(S)-(allyldithio)-a-thiol incosaminide (A-24) at a K value of 5.66. It crystal 1 izes from ethyl acetate as stout, colorless prisms having the following characteristics: m.p. 211-3° C. [a]Q +251° (c, 1.00, chloroform) Anal ysi s: Calcd. for C2oH3i0eNS3: C, 47.13; H, 6.13; N, 2.75; S, 18.88; 276 -3 Found: C, 47.03; H, 6.l6; N, 2.56; S, 18.68; Mol. Wt. (Mass spec, M+) 509.

The al 1 yl thio analog (A-21 al 1 yl ) is al so obtai ned at a K value of 2.03.

Following the procedures of parts B-1 and C-1 there are obtained methyl 7(S )- (al 1 yl di thi o)-7-deoxy-o thi ol i ncosami n id and 7(S)- (al 1 yldi thio)-7-deoxyl i ncomyci n hydrochloride.

EXAMPLE 5 24 Part A-25: Methyl N-ac*tyl -2,3,4-t ri -0-acetyl -7-deoxy- 7(S)- (2,3-di hydroxypropyl thio) -a- thiol i ncosami nide Following the procedure of Part A-l, substituting the methyl sulfide by 2,3-di hydroxypropyl methyl sulfide, there is obtained methyl N-acetyl -2, 3,4-tri -0-acetyl -7-deoxy-7(S )- (2,3-di hydroxypropyl thio) -a- thiol i ncosami nide. Counter-current distribution using 1 ethanol:l water:1.5 ethyl acetate:0.5 cyclohexane yielded this compound at a K value of 0.91. It is obtained as colorless platelets from ethyl acetate having the followi g characteristics: m.p. 255-7° C. [a]D +l64° (c, .67, chloroform) Analysis: Calcd. for C2OH330! 0NS2: C, 46.95; H, 6.50; N, 2.7 ; S, 12.54; Mol. Wt. 511.60.

Found: C, 46.64; H, 6.67; N, 2.73; S, 12.59; Mol. Wt. (Mass spec, M+) 511.

Following the procedure of Parts B-1 and C-1, using the above compound (A-25) as the starting compound, there are 2764-3 thiol incosaminide and 7-deoxy-7 (S )- (2,5-di hydroxypropyl thi o) -l incomycin hydrochloride.

The starting 2, 5- i hydroxypropyl methyl sulfide is obtained by reacting l-chloro-2,3-di hydroxypropane with methanol ic sodium methyl mercaptide.

EXAMPLE #5 25 7-Deoxy-7 (S )- (phenyl thio)l i neomycin hydrochloride Part A-26a: Methyl N-acetyl -2,5* 4-tri -0-acetyl -7-deoxy- 7(S)- (phenylthio)-a-thiol incosaminide Following the procedure of Part A-l, substituting the methyl sulfide by methyl phenyl sulfide, methyl N-acetyl -2,5, - tri -0-acetyl -7-deoxy-7 (S )- (phenyl thio)-a-thi ol i ncos-aminide is obtained as "fine colorless needles from ethyl acetate having the following characteristics: m.p. 275-276° ( = .17, 1 ethanolil water.l ethyl acetate:5 cyclohexane) [a]D +164° (c, 0.55, CHC13) Anal ys i s : Calcd. for C23H3i08NS2: C, 55.78; H, 6.08; N, 2.75; S, 12.49.

Found: C, 55-87; H, 6.07; N, 2.48; S, 12.51.

Part A-26b: Alternate process Following the procedure of Example 13, substituting the methyl phenyl sulfide by benzyl phenyl sulfide the same compounds are obtained. This process has the advantage of giving higher yields of the product.

Part B-26: Methyl 7-deoxy-7(S)- (phenyl thi o)-a-thi ol incosaminide 276 -3 methyl 7-deoxy-7(S )- (phenyl thio)-a-thi ol incosami nide as colorless flat needles from methanol having the following character i st i cs: m.p. 193-4° C. [a]D +201° (c, 0.88, pyridine) Analysis: Calcd. for C15H2304NS2: C, 52.15; H, 6.71; N, 4.06; S, 18.56.

Found: C, 52.50; H, 6.78; N, 4.24; S, 18.33.

Part C-26: 7-Deoxy-7(S)- (phenyl thio)-l incomycin hydrochloride Following the procedure of Part C-1, there is obtained 7-deoxy-7 (S )- (phenyl thi o)-l i ncomyc i n hydrochloride as a colorless amorphous sol id having the following character-istics: [a] 481 (c, Ο.63, H20) D Anal ys is: Calcd. for C2 H3e05N2S2' HC1 : C, 53.86; H, 7.35; N, 5.24; S, 11.98; CI, 6.63; M. Wt. of free base 498.69.

Found (Corrected for .4.64$ H20): C, 54.08; H, 7.71; N, 5.55; S, 11.86; CI, 6. 9; M. Wt. (Mass spec, M+ of free base) 498.

EXAMPLE m 26 7(S)- (Benzyl thio)-7-deoxyl incomycin hyd rochloride Part A-27: Methyl N-acetyl -2,3,4- tri -0-acetyl -7 (S )- (benzyl - thio)-7-deoxy-a-thiol incosami nide Following the procedure of Example lo, substituting 2764-3 obtained methyl N-acetyl -2,3,4-tri -O-acetyl -7(S)- (benzyl thio) 7-deoxy-a- thiol incosaminide.

Countercurrent distribution using as the solvent system 1 ethanol :1 water:0.5 ethyl acetate:3 cyclohexane yields this compound at a value of 1.38. It is obtained as flattened prisms from ethyl acetate-Skel 1 ysol ve B having the following characteristics: m.p. 216-18° C. [a]D +l6l° (c, I.07, chloroform) Analysis: Calcd. for C24H330eNS2: C, 54.63; H, 6,30; N, 2.66; S, 12.15.

Found: C, 55.02; H, 6.44; N, 2.94; S, 12.19.

Mol. Wt. Calcd. : 527.64.

Mol. Wt. Found (Mass spec, M+) : 527 Part B-27: Following the procedure of Part B-l, using the above compound (A-27) as the starting compound there is obtained methyl 7(S)- (benzyl thi o)-7-deoxy-ct- thiol i ncosami nide as colorless plates from methanol having the following characteristics: m.p. 215-6° C. [a]D +219° (c, 0.97, pyridine) Analysis: Calcd. for CieH2S04NS2: C, 53.45; H, 7.01; N, 3.90; S, 17.84; Mol. Wt. 359.50.

Found: C, 53-37; H, 7.07; N, 4.12; S, 18.07; Mol. Wt. (Mdss spec, M+) 359. 2764-3 Following the procedure of Part C-1, using the above compound (B-27) as the starting compound there is obtained 7(S)- (benzyl thio)-7-deoxyl i neomycin hydrochloride as a colorless amorphous solid having the following characteristics: [α]β +96.5° (c, 0.80, water) Analysis: Calcd. for C25H4o05N2S2*HCl : C, 5^.6 ; H, 7.55; N, 5.10; C , 6.46; S, 11.68; Mol. Wt. (free base): 512.72.

Found (Corrected for 2.7*1 water): C, 5^.89 H, 7.72; N, 4.83; CI, 6.28; S, 11.86; Mol. Wt. (Mass spec, M+) 512.

EXAMPLE 2a. 27 1' -Oemethyl -l1 - (2-hydroxyethyl )-4' -depropyl - 4'-cis- trans-pentyl -7-deoxy-7(S)- (methyl - thio)l i ncomyci n hydrochloride (Methyl 6,7,8-trideoxy)-7- (methyl thio)-6-cis- trans-1- (2-hydroxyethyl )-4-pentyl -L-2-pyr- rol idi necarboxamido)-l-thio-L-threo-a-D-galacto- octopyranos ide hydrochloride) Part A-28: l1 -Demethyl -l1 -carbobenzoxy-41 -depropyl -4· -cis- trans-pentyl -7-deoxy-7(S)- (methyl thio) 1 i ncomyci n hydrochloride Following the procedure of Part C-1 substituting the trans-propyl hygric acid by cis- trans-l-carbobenzoxy-4-pentyl -L-2-pyrrol idinecarboxyl ic acid using 2.2 mol. equiv of triethylamine, there is obtained 11 -demethyl -1-carboben-zoxy-41 -depropyl -4· -ci s- trans-pentyl -7-deoxy-7(S)- (methyl - 276 -3 It separates from ethyl acetate as fine needles melting o at 158-9 C. which are further characterized as follows: [a]Q +118° (c, 0.84, chloroform) Ana 1 ys i s: Calcd. for C28H4407N2S2 : C, 57.51; H, 7.58; N, 4.79; S, 10.97; Mol. Wt. 584.78.

Found: C, 57.^7; H, 7.51; N, 4.73; S, 11.19; Mol. Wt. (Mass spec, M+) 584.

Part B-28: 11 -Demethyl -4· -depropyl -4· -ci s- trans-pentyl - 7-deoxy-7(S) - (methyl thio)-l incomyci n hydrochloride A solution of the above carbobenzoxy compound (A-28) in ethanol is hydrogenated in the presence of 104 pal lad i um-on-carbon catal yst at a pressure of 50 lbs. per square inch hydrogen. The spent catalyst is removed by filtration and the solvent evaporated to dryness. Residue is taken up in acetone and a stoichiometric amount of aqueous 6N-hydro-chloric acid is added. On the addition of ether, l'-demethyl 4' -depropyl -4· -ci s- trans-pentyl -7-deoxy-7 (S )- (methyl thio)-l incomycin hydrochloride (B-28) crystallizes as minute colorless needles melting at 183-4° C. (dec.) having the following characteristics: [a]D +139° (c, 0.36, pyridine) Anal sis: Calcd. for CsoHaeOsNaSa'HCl : C, 49.31; H, 8.07; N, 5.75; CI, 7.28; S, 13.17; Mol. Wt. (free base) 450.65.

Found (Corrected for 4.31$ water): 2764-3 Mol. Wt. 450.

Part C-28: l1 -Demethyl -1' - (2-hydroxyethyl )-4f -depropyl - 4' -cis- trans-pentyl -7-deoxy-7(S)- (methyl thio)- li neomycin hydrochloride The N-demethyl hydrochloride named above (B-28) is dissolved in ethyl alcohol, the solution cooled to 0° C, an excess of ethylene oxide added, the container sealed and heated for 2 hours at 100° C. Removal of the volatile material gives a pale yellow syrupy residue which is dissolved in a mixture of chloroform and water and the pH adjusted to 10 with 50$ aqueous sodium hydroxide. The organic layer is removed and dried over anhydrous sodium sulfate. The chloroform is removed and the residue chroma tog rap he d on silica gel using 1 methanol: 10 chloroform as the solvent system. Fractions corresponding to Rf 0.31 are pooled, and evaporated to dryness. The residue is slurried with water and normal hydrochloric acid added to pH 4 at which time all the solid is dissolved. The desired product is recovered as an amorphous sol id by 1 yophi 1 ization. It has the follow-ing characteristics: [a]D 880 (c, Ο.82, water) Analysis: Calcd. for C22H420eN2S2» HC1 : C, 49.74; H, 8.16; N, 5.28; CI, 6.68; S, 12.07; Mol. Wt. (free base) 494.70.

Found (Corrected for 4.23$ water): C, 49.76; H, 7.99; N, 4.95; CI, 6.76; S, 12.31; Mol. Wt. (Mass spec, M+ of free base) 494.

EXAMPLE 29- 28 276 -5 7 (S )- (2-hydroxyphenyl thi o) -a- thi ol i ncosami ni de Following the procedure of Part A-l8, substituting the ethyl trisulfide by allyl 2-hydroxyphenyl sulfide, there is obtained methyl N-acetyl -2,5*4-tr i -0-acetyl -7-deoxy-7 (S )- (2-hydroxyphe nyl thio)-ot-thi ol i ncosami nide. Counter-current distribution in the system 1 ethanol :1 water.l ethyl acetate:2 cyclohexane yields this compound at a K value of 1.54. It is isolated as colorless rods from ethyl acetate having the following characteristics: m.p. 240-1° C. [a]D +15 0 (c, 0.85, chloroform) Anal ysi s: Calcd. for C23H31O9NS2: C, 52.I6; H, 5.90; N, 2.65; S, 12.11; Mol. Wt. 529.62.

Found: C, 52.25; H, 5.92; N, 2.72; S, 11.99; Mol. Wt. (Mass spec, M+) 529.

Following the procedures of Parts B-l and C-l, there are obta i ned methyl 7-deoxy-7 (S ) - (2-hydroxyphenyl thio)-a-thiol i ncosaminide and 7-deoxy-7(S )- (2-hydroxyphenyl thi o) -l i neomycin hydrochloride.

EXAMPLE tfo 29 Methyl N-acetyl -2,5j4-tri -0-acetyl -7-deoxy- 7(S)- (2-hydroxy-2-methylethyl thio)-ct-thi o- 1 i ncosami nide Following the procedure of Part A-l, substituting the methyl sulfide by 2-hydroxy-2-methyl ethyl methyl sulfide but heating. in an oil bath at 100° C. for 24 hrs. there is obtained methyl N-acetyl -2,5*4- tr i -0-acetyl -7-deoxy- 276 -3 1.0 in 1 ethanol;! water:l ethyl acetate:0.75 cyclohexane) as colorless prisms from ethyl acetate having the following prope rt ies : m.p. 246-251° C. [<*]„ +171° (c, 0.88, CHC13) Anal ys i s : Calcd. for C20H33O9 S2: C, 48.47; H, 6.71; N, 2.83; S, 12.94; Mol . Wt. 495. 0, Found: C, 48.51; H, 6.71; N, 2.77; S, 12.72; Mol. Wt. (Mass spec, M+) 495.

The starting 2- hydroxy-2-methyl ethyl methyl sulfide is prepared by heating 2-hydroxy-2-methyIethyl bromide or 2-hydroxy-l-methylethyl bromide or a mixture of the two with sodium methyl mercaptide in ethanol.

By starting with 2-acetoxy-2-methyl ethyl methyl sulfide in place o the 2-hydroxy-2-methyl ethyl methyl sulfide, methyl 7(S)- (2-acetoxy-2-methy1 ethy thio) -N-acetyl -2,3,4-tr i -0-acetyl -7-deoxy-a-thiol incosaminide, m.p. 199-200° C, is obtained.

Following the procedures of Parts B-l and C-l methyl N-acetyl -2,3,4-tri -0-acetyl -7-deoxy-7(S )- (2-hydroxy-2-methyl -ethyl thi o)-a- thiol incosaminide and methyl 7(S )- (2-acetoxy-2-methylethyl thi o)-N-acetyl -2,3,4-tr i -0-acetyl -7-deoxy-a-thi ol i ncosami nide are converted to methyl 7-debxy- 7(S)- (2-hydroxy-2-methyl ethyl thio)-a-thiol incosaminide and 7-deoxy-7(S)- (2-hydroxy-2-methyl ethyl thio)-l i ncomyci n.

EXAMPLE #L 30 7-Deoxy-7(S)- (3-hydroxyp ropy 1 thio) - 2764-3 Part A-31: Methyl N-acetyl -2, 3,4-tri-O-acetyl - (S)- (3-ace- toxypropyl thio)-7-deoxy-a-thiol ί ncosami nide Following the procedure of Part A-l, substituting the methyl sulfide by 3-acetoxypropyl methyl sulfide, there is obtained methyl N-acetyl -2,3* - tr i -0-acetyl -7(S )- (3-acetoxypropyl thio)-7-deoxy-a- thi ol incosaminide ( = 1.0, 1 ethanol : 1 waterrl ethyl acetate:2 cy.cl ohexane ) as colorless needles from ethyl acetate: Skel 1 ysol e B having the following character i sti cs : -m.p. 172.5-174° [ ]ο +178° (c, 0.94, CHC13) Anal ys i s : Calcd. for C22H350NS2: C, 49.15; H, 6.56; N, 2.6l S, 11.93- Found: C, 4£.31; H, 6.58; N, 2.68; S, 11.83.

Part B-31: Methyl 7-deoxy-7(S)- (3-hydroxypropyl thio)-a-thio- 1 incosaminide Following the procedure of Part B-l, substituting the methyl N-acetyl -2,3,4-tri -0-acetyl -7(S)- (methyl thio)-a-thio-1 i ncosami nide by methyl N-acetyl -2,3*4- tri -0-acetyl -7(S)- (3-acetoxypropyl thio)-7i-deoxy-a-thiol i ncosami nide, there is obtai ned methyl 7-deoxy-7 (S )- (3-hydroxypropyl thio)-a-thiol incosaminide as colorless needles from water having the following characteristics: m.p. 194-19 ° [a]D +234° (c, 0.79* pyridine) Analysis: Calcd. for C12H2505NS2: C, 44.01; H, 7.70; N, 4.28; S, 19.58.

Part C-31: 7-Deoxy-7 (S )- (3-hydroxypropyl thi o)l i ncomyci n hydrochloride Following the procedure of Part C-l, substituting the methyl 7-deoxy-7(S )- (methyl thiq)-a- thi ol incosami ni de by methyl 7-deoxy-7 (S )- (3-hydroxypropyl thi o)-a- thi ol i ncosami ni de, there is obtained 7-deoxy-7(S)- (3-hydroxypropyl thio)l inco-mycin hydrochloride as an amorphous solid having the following characteristics: [a]D +110° (c, 0.82, H20) nalysis: Calcd. for C2iH4o0eN2S2«HCl C, 48.77; H, 7.99; N, 5.42; CI, 6.86; S, l2.4o; Mol. Wt. of free base 480.68.

Found (Corrected for 2.86$ water): C, 49.11; H, 8.10; N, 5.88; S, 12.15; CI, 6.82; Mol. Wt. (Mass spec, M+) 480.

EXAMPLE -323 \ 7(S )- (4-Acetoxybutyl thio)-7-deoxyl i ncomyci n hydrochl oride N-acetyl -2,3,4- tri-O-acetyl-Part A-32: Methyl /7 (S )- (4-acetoxybutyl thi o) -7-deoxy-a-thi o- 1 i ncosami nide Following the procedure of Part A-l, substituting the methyl sulfide by 4-acetoxybutyl methyl sulfide but heating at 110° C. for 20 hours, there is obtained methyl N-acetyl -2, 3, 4-tri-O-acetyl -7 (S)- (4-acetoxybutyl thi o) -7-deoxy-a-thi o-1 i ncosami nide (K = 1.32, 1 ethanol:l water:l ethyl acetate:2 cyclohexane) as fine rosettes of needles from ethyl acetate-Skellysolve B having the following characteristics: m.p. 149-150° C.

Anal ys i s : Calcd. for C23H37O1 oNS2 : C, 50.07; H, 6.76; N, 2. ^; S, 11.62.

Found: C, 49.97; H, 6.86; N, 2.50; S, 11.35.

Part B-32: Methyl 7-deoxy-7(S)- (4-hydroxybutyl )-a- thiol f n- cosaminide Following the procedure of Part B-l, there is obtained methyl 7-deoxy-7 (S )- (4-hydroxybutyl thio)-a-thiol incosaminide as mi crocrystal 1 i ne needles from methanol having the following characteristics: m.p. 164-5° [a] +218° (c, 0.41, H20) Analysis: Calcd. for C13H27O5NS2: C, 45.72; H, 7-97; N, 4.10; S, 18.78.

Found: C, 45-73; H, 8.13; N, 4.22; S, 18.33.

Part C-32: 7-Qeoxy-7(S )- (4-hydroxybutyl thio)-l i ncomyci n hydrochloride Following the procedure of Part C-l, there is obtained 7-deoxy-7 (S )- (4-hydroxybutyl thi o)-l i ncomyc i n hydrochl ori de as an amorphous sol id having the fol lowi ng character! sties: [a]0 +105° (c, Ο.96, H20) Anal ysi s: Calcd. for CgahUaOeNaSa- HCl : C, 49.7^; H, 8.16; N, 5.28; CI, 6.68; S, 12.07; M. Wt. of free base 494.70.

Found (Corrected for 3.70$ H20): C, 49.58; H, 8.19; N, 5.23; CI, 6.48; S, 12.10; M. Wt. (Mass spec., M+ of free base) 494.

Methyl N-acetyl -2, 3> - tri -O-acetyl - 7(S)- (5-acetoxypentyl thio)-7-deoxy- a- thiol incosami nide Fol lowing the procedure of Part A-l, substituting the methyl sulfide by 5-acetoxypentyl methyl sulfide and heating at 100° C. for l6 hrs,, there is obtained methyl N-acetyl - 2,3,4-tri -0-acetyl -7 (S)- (5-acetoxypentyl thi o)-7-deoxy-a- thi o- 1 i ncosami ni de having a value of 1.94 in 1 ethanol rl Ι½0:1 ethyl acetate:2 cyclohexane and the fol lowing characteristics as recrys tal 1 ized from ethyl acetate-Skel 1 ysol e B. m.p. 158-9° C. (needles) [*]„ +16 0 (c, 0.60, CHCI3) Ana lysis: Calcd. for CZAWSBOI ONS2 : C, 50.95; H, 6.95; N, 2.48; S, 11.34.

Found: C, 50.88; H, 6.98; N, 2.4l; S, 11.22.

Following the procedures of Parts B-l and C-2, there are obtained methyl 7-deoxy-7(S )- (5-hydroxypentyl thio)-a-thiol i ncosami nide and 7-deoxy-7 (S )- (5-hydroxypentyl thi o)-l i neomycin hydrochloride.

EXAMPLE 33 Methyl N-acetyl -2, 3,4-t;ri -0-acetyl - 7(S)- (2-acetoxycyclohexyl thio)- 7-deoxy-a-thiol i ncosami nide Following the procedure of Part A-l, substituting the methyl sulfide, by 2-acetoxy cyclohexyl methyl sulfide and o heating at 100 C. for lo hours, there is obtained methyl N-acetyl -2,3,4- tri -0-acetyl -7 (S)- (2-acetoxycyclohexyl thio)-7-deoxy-a-thiol incosaminide. Countercur rent distribution in 2764-5 cyclohexane yielded this compound at a K value of 0.80. It is obtained as colorless needles from ethyl acetate having the following characteristics: m.p. 205-6° C. [o]D +155° (c, 0.64, CHCI3) Anal ys i s : Calcd. for oNS2 : C, 51.97; H, 6.8Ο; N, 2.43; S, 11.10; Mol. Wt. 577.70.

Found: C, 51.82; H, 6.87; N, 2.29; S, 11.12; Mol. Wt. (Mass spec, M+) 577.

Following the procedure of Parts B-l and C-l, there are obtained methyl 7-deoxy-7 (S )-[ (2-hydroxycyclohexyl )thio]-a- thi ol i ncosami ni de and 7-deoxy-7(S )-[ (2-hydroxycyclo-hexyl ) thi o] 1 i ncomyc i n hydrochloride. [a]- j + 69 (c, 0.976 In water) Analysis Calculated: C24H38N2°6S2 HC1 C, 52.30; H, 7.21; CI ,6.54; N, 5.08; S, 11.64 Found: C, 52.05; H, 7.21; CI.6.54; N, 5.21; S, 11.80 (corrected for 3.38% H90)

Claims

1. IS A process for making compounds of the A whic h comprises heating a compound of the formula 18 wherein Ac and are and is alkyl of not 19 than carbon atoms or with sulfide of the 20 formula r wherein n is or 21 and are the or differei t and are saturated iphatic 22 hydiocarbon radicals of not more than l8 carbon turated al iphatic hydrocarbon radicals of more than 24 10 arbon cycl oal i phat i hydrocarbon radicals of not 25 than 10 carbon a t i hyd roca rbon radicals not mo than 11 carbon benzyl or aromatic heterocyclic or alkyl aromatic heterocyclic radicals of not than 8 carbon atoms wherein the heterc or atoms are oxygen or and are hydrogen or together more than three wherein X end Y ere the or different and are oxygen or sulfur and and are lower lower lower lower henayl or where Ac the acid addition aalta wherein designates acetyl for and and wherein for Ac designates acetyl or the acyl of an acid or where la 2 The process of claim 1 in which n is 1 or 3 The process of claim 1 which when than 4 carbon is alfcyl or with X 4 The process of claim 1 which or 5 The proceas of claim 1 wherein is and la of 1 to carbon of 2 to 6 carbon cycloalkyl of 5 or 6 carbon atoms or 6 The process of claim 1 in which is 7 The process of claim 1 in which a starting compound has tha The process of 7 which n 1s process of claim 7 1n which n The process of 7 1n whic Is butyl or The process of claim 9 In which s or compound of the wherein Alk of not mora than 4 carbon or Ac are either hydrogen or carboxacyl Is a saturated aliphatic hydrocarbon radical of not more than 18 carbon a an aliphatic hydrocarbon radical o not more than 10 carbon atoms of up to 10 carbon atoms an aromatic hydrocarbon radical of not more than 11 carbon benzyl XR3 s or a group wherein X 1s oxygen or sulfur and 1s lower lower alky lower lower phenyls and where Ac the acid addition 1 wherein designates acetyl for and wherein carboxacyl for Ac designates acetyl or the of an carboxylic acid or where is A compound according to olaim 12 in which Ac and are A compound according to claim 13 in which Alk is Methyl a compound of claim wherein is Methyl Methyl hiol Methyl Methyl Methyl Methyl o thlo Methyl thlo Methyl thlo Methyl 3 Methyl Methyl 3 Methyl Methyl 2 Methyl Methyl Methyl Methyl Methyl Methyl Methyl propylthio e butylthio a compound of claim wherein Methyl pentylthio Methyl hexylthio 4 Α compound or an addition thereof according to claim 12 wherein Ao and are Alk is or A eompound or an acid addition salt thereof to claim 12 wherein Ao and Αοχ are and Alk Methyl Methyl hio Methyl Methyl a compound of claim 42 wherein is eyclohexyl Methyl Methyl Methyl Methyl Methyl d 4 be z l Methyl Hethyl A compound or an addition salt thereof according to oladLm 12 wherein is hydrogen and Ae is the aoyl of an and Alk is or A compound or an aoid addition salt thereof aeeording to olaim 56 the acid is substituted in the by a lower alkyl or a lower alkylidene A compound or an aoid addition salt thereof according to claim 57 which the substituted by a ethyl or group and the by A compound or an addition salt thereof according to claim 12 wheredLn s hydrogen and Ao is the aoyl of a Alk is topyrano side 7 S thlo hydroohloride thlo hydro ide Me thyl S oxyethylthlo ye thlo Ohio thlo hydroohloride S llnooayoln hydro 1 thlo l th1 11 cl n hydrochl de A pharmaceutical composition containing as acti ve Ingredient and acid addition sal ts where designates lower yl of 1 to 6 carbon atoms or lower Attorneys for App can insufficientOCRQuality