US3544551A - 7-mercapto-7-deoxylincomycins and process for preparing the same - Google Patents

7-mercapto-7-deoxylincomycins and process for preparing the same Download PDF

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US3544551A
US3544551A US3544551DA US3544551A US 3544551 A US3544551 A US 3544551A US 3544551D A US3544551D A US 3544551DA US 3544551 A US3544551 A US 3544551A
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Fred Kagan
Barney J Magerlein
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Upjohn Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02Acyclic radicals, not substituted by cyclic structures
    • C07H15/14Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16Lincomycin; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00Polymeric products of isocyanates or isothiocyanates
    • C08G18/06Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30Low-molecular-weight compounds
    • C08G18/38Low-molecular-weight compounds having heteroatoms other than oxygen
    • C08G18/3855Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur
    • C08G18/3863Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms
    • C08G18/3865Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms containing groups having one sulfur atom between two carbon atoms
    • C08G18/3868Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms containing groups having one sulfur atom between two carbon atoms the sulfur atom belonging to a sulfide group
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S516/00Colloid systems and wetting agents; subcombinations thereof; processes of
    • Y10S516/01Wetting, emulsifying, dispersing, or stabilizing agents
    • Y10S516/07Organic amine, amide, or n-base containing

Description

United States Patent ()flice 3,544,551 Patented Dec. 1, 1970 US. Cl. 260-210 10 Claims ABSTRACT OF THE DISCLOSURE Novel antibacterial compounds of the formula:

are prepared either by heating a compound of the formula IS -Halo OH II with water in dimethylformamide, the 2-, 3-, and 4-hydroxy group may be covered with protective groups, or by heating a novel compound of the formula:

HO O OH III with hydrogen sulfide in an inert solvent to form a novel compound of the formula:

produces predominantly compounds having the opposite configuration, 7 (S)- or L-threo.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel compounds and to processes for preparing them, and is particularly directed to 7-mercapto-7-deoxylincomycins, and analogs thereof, to processes whereby they and like compounds are produced, and to intermediates formed in these processes.

The novel compounds of the invention can be repre sented by the following structural formula:

wherein R is 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, advantageously not more than 8 carbon atoms; and

is the acyl radical of a 4-substituted-L-2-pyrrolidine-carboxylic acid of the formulas:

HIlh l a N IQI 16 I C-OH l C-OH R1 ll H wherein R and R are alkylidene of not more than 20 carbon atoms (including methylene), advantageously not more than 8 carbon atoms, cycloalkylidene of from 3 to not more than 8 carbon atoms, and aralkylidene of not more than 12 carbon atoms, advantageously not more than 8 carbon atoms; and R is hydrogen or HR Any or all of the 2-, 3-, and 4-hydroxy groups as Well as the --SH group can be esterified or etherified.

Examples of alkyl of not more than 20 carbon atoms (R, HR and HR are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl and the isomeric forms thereof. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4- methylcyclobutyl, and 3-cyclopentylpropyl. Examples of aralkyl are benzyl, phenethyl, a-phenylpropyl, and anaphthylmethyl. Examples of alkylidene, cycloalkylidene,

and aralkylidene groups (R; and. R include methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidene, nonylidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentadecylidene, hexadecylidene, heptadecylidene, octadecylidene, nonadecylidene, eicosylidene, and the isomeric forms thereof, cyclopropylidene, cyclobutylidene, cyclopeutylidene, cyclohexylidene, cycloheptylidene, cyclooctylidene, Z-cyclopropylethylidene, 3-cyclopentylpropylidene, benzylidene, 2-phenylethylidene, 3-phenylpropylidene, and a-naphthylmethylene.

The novel compounds of the invention, Formula I, as well as other related compounds, can be prepared by heating a compound of the formula:

3 wherein s ll R4G-- is the S-isolog of with water in dimethylformamide or by heating a novel compound of the formula:

CH3 HN/ with hydrogen sulfide in an inert solvent to form a novel compound of the formula:

which on acylation yields compounds of Formula I. The first process produces predominantly compounds having the 7(R)- or D-erythro configuration whereas the second produces predominantly compounds having the opposite configuration, 7 (S)- or L-threo.

The HR group can be in either the cis or trans position as illustrated in the following formulas:

If desired, the cis and trans isomers can be separated by counter current distribution of chromatography, either before or after replacement of the 7-hydroxy group.

When R in Formula B is hydrogen, it can be replaced by suitable alkylation or like procedure. Advantageously, this replacement is effected by reacting the compound according to Formula LB, or II-B, wherein R is hydrogen with an oxo compound (an aldehyde or a ketone) and hydrogenating the resulting adduct with a catalyst effective to saturate an olefinic double bond. Either platinum or palladium can be used as the catalyst. Suitable oxo compounds having the formula R R CO wherein R R C= STARTING MATERIALS The starting compounds of Formula II are prepared by N-acylating a compound of the formula:

011 VII wherein R is as given above with a 4-substituted-L-2-pyrrolidinecarboxylic acid of Formula A or B, covering the 2-, 3-, and 4-position by a blocking group, and then heating the resulting compound of the formula:

(I) -Hal0 OAc VIII with phosphorus pentasulfide in an inert solvent. Ac represents a blocking group, for example, acetyl. The acylation and like N-acylations referred to herein, can be effected by procedures already well known in the art for acylating amino sugars. The blocking of the 2-, 3-, and 4-positions can also be effected by groups well known in the art of sugar chemistry.

The starting compounds of Formula VII can be prepared by replacing the 7OH group of a compound of the formula:

NHz-

by halogen by procedures given below which are not part of this invention, followed by N-acylation with the appropriate acid. Alternatively the N-acylation can be effected before the halogenation to give a compound of the formula:

which can then be converted to compounds of the formula:

be prepared as described in US. Pat. 3,380,992 from starting compounds of Formula X wherein is a 4-substituted pyrrolidinecarboxylic acid of the formula:

i i i N N N K1 Kn Kn I -OH, i C-OH, i I (/OH 0 H R1 II HR; 1] O O 0 wherein Z is a protective group removable by solvolysis 0r hydrogenolysis, for example, as described in US. Pat. 3,380,992. Any and all of the compounds thus described in US. Pat. 3,380,992 can be converted to the corresponding compound of Formula I by the processes of this invention and all such compounds are to be considered as disclosed herein the same as if they had been specifically named.

The starting compound of Formula VII and its N- acylate can be prepared by heating a compound of Formula IX or X with Rydon reagent. The mechanism by which Rydon reagent eifects the substitution of the 7- hydroxy by halogen is not fully understood. The mechanism is such that a change in configuration results. Thus, a 7(R)-hydroxy compound of the D-erythro configuration yields a 7(S)-halo compound of the L-threo configuration. For example, 7(S)-chloro-7-deoxylincomycin which is derived from lincomycin (lincomycin has D- erythro configuration), has the L-threo configuration.

Rydon reagents are formed by the addition of halogen to triphenylphosphine or triphenylphosphite or addition of an alkyl halide to triphenylphosphite and can be rep resented by the formula:

wherein X is halogen, e.g., chlorine, bromine, and iodine. Rydon et al., J. Chem. Soc., 2224 (1953); Ibid, 2281 (1954); Ibid, 3043 (1956). The Rydon reagent can be formed in situ by addition of halogen or methyl halide to a solution of the triphenylphosphine or triphenylphosphite in an inert solvent such as acetonitrile or dimethylformamide, or it can be isolated as a separate entity. In either case the reaction with the lincomycin or related compound is eifected by contacting the Rydon reagent therewith in an inert solvent, e.g., acetonitrile or dimethylformamide, until the desired substitution of the 7-hydroxy is obtained. The reaction takes place at ordinary temperature, though gentle heating can be effected if desired. Advantageously the temperature is maintained be tween about 20 C. and about 55 C. The product can be recovered from the reaction mixture by well-known techniques such as filtration, solvent extraction, etc. The reaction mixture advantageously is treated with methanol to destroy any excess Rydon reagent, filtered to remove any solid such as triphenylphosphine oxide, formed in the reaction, and then treated to recover the product. The methanol can be added either before or after the filtration. Advantageously the treated and filtered reaction mixture is evaporated to dryness and purified by solvent extraction and/ or chromatography.

To eifect the substitution of the 7-hydroxy with chlo rine by the thionyl chloride process, the starting compound of Formula IX or X, advantageously in the form of an acid-addition salt, e.g., the hydrochloride, is mixed with thionyl chloride, advantageously in the presence of an inert solvent, with mild heating, advantageously at reflux temperature, until the desired substitution of the 7- hydroxy group by chlorine is effected. Advantageously, the reaction is carried out in an inert atmosphere, e.g., under nitrogen. Carbon tetrachloride can be used effectively as the solvent vehicle but other inert solvents such as chloroform, methylene chloride, ethylene chloride, ether, benzene, and the like can be used. A satisfactory procedure is to stir the reaction mixture at room temperature for a considerable period, say from about 1 to 18 hours or as long as necessary to obtain a reasonable clear solution and then to raise the temperature to between about 50 and C., for example, to the reflux temperature (77 C. for carbon tetrachloride). After the reaction is complete, usually after heating at reflux for about 1 to 5 hours, the reaction mixture is allowed to cool, advantageously under nitrogen. Any material that separates on the cooling is collected and dried. The solvent is removed by vacuum distillation at a pot temperature advantageously less than about 35 C. and the material which precipitates is collected and dried and treated with ethanol to convert any residual sulfite intermediates to the desired product. The collected material can then be further purified by solvent extraction and/or recrystallization and can be recovered either as the free base or an acid addition salt.

The proportions of the reagents can be varied widely. Stoichiometrically, however, at least 3 moles of thionyl chloride is required for each mole of starting compound. Any larger amount can be used but ordinarily it is not necessary or desirable to use more than about a 10 mold excess. Advantageously, an excess of about 2 to 3 told is used. The amount of solvent is not critical and can be varied widely in accordance with the practices in the art. Ordinarily from about 15 to about 30 volumes of solvent for each part of solid starting compound will suflice. The proportion of solvent to thionyl chloride, however, is important because of the solubility of the product in thionyl chloride. If the ratio of solvent to thionyl chloride (v./v.) is high, the desired product precipitates on cooling of the reaction mixture and work up of the product is simplified. For example, with carbon tetrachloride a mixture of products precipitates directly on cooling the reaction mixture if the v./v. proportion of carbon tetrachloride to thionyl chloride is kept above about 10 to 1.

Substitution of the 7-hydroxy by iodine is effected by a modification of the Rydon reagent process. In this process, the desired halogen substitution is effected simply by mixing the starting compound of Formula IX or X with triphenylphosphine and carbon tetraiodide in an inert solvent. The reaction takes place at room temperature (25 C.) but gentle heating up to reflux temperature of 50 to 60 C. can be used.

Acetonitrile and nitromethane are illustrative solvents. The triphenylphosphine and carbon tetraiodide are optimally used in equimolar proportions and advantageously in a substantial molar excess of the starting compound. Optimally about 4 moles of triphenylphosphine and 4 moles of carbon tetraiodide are used for each mole of starting compound of Formula IX or X. The process can also be used for efiecting chlorination and bromination by substituting carbon tetrachloride or carbon tetrabromide for the carbon tetraiodide.

Any or all of the 2-, 3-, and 4-hydroxy groups and the 7--SH group can be esterified either before or after the halogenations, for example, with hydrocarbon carboxylic acids, advantageously of not more than 18 carbon atoms, or halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or alkoxy substituted hydrocarbon carboxylic acids, advantageously also of not more than 18 carbon atoms.

Example of carboxylic acid acyl radicals are the acyl radicals of the following acids: (a) saturated or unsaturated, straight or branched chain aliphatic carboxylic acids, for example, acetic, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, lauric, tridecoic, myristic, pentadecanoic, palmitic, margaric, stearic, acrylic, crotonic, undecyclenic, oleic, hexynoic, heptynoic, octnoic acids, and the like; (b) saturated or unsaturated, alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentenecarboxylic acid, methylcyclopentenecarboxylic acid, cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid, dipropylcyclohexanecarboxylic acid, and the like; saturated or unsaturated, alicyclic aliphatic carboxylic acids, for example, cyclopentanepropionic acid, cyclohexanebutyric acid, methylcyclohexaneacetic acid, and the like; ((1) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid, and the like; (e) aromatic-aliphatic carboxylic acids, for example, phenyl acetic acid, phenylpropionic acid, phenylvaleric acid, cinnamic acid, phenylpropiolic acid and naphthylacetic acid, and the like. Suitable halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, and lower alkoxyhydrocarbon carboxylic acids include hydrocarbon carboxylic acids as given above which are substituted by one or more of halo-l gen, nitro, hydroxy, amino, cyano, or thiocyano, containing a total of not more than 18 carbon atoms, or alkoxyhydrocarbon carboxylic acids of not more than 18 carbon atoms. Suitable such alkoxy groups include methoxy, ethoxy, propoxy, butoxy, amyloxy, hexyloxy, dodecyloxy, hexadecyloxy, and isomeric forms thereof. Examples of such substituted hydrocarbon carboxylic acids are mono-, di-, and trichloracetic acid; 41- and ,B-chloropropionic acid; aand 'y-bromobutyric acid; ocand fl-iodovaleric acid; mevalonic acid; 2- and 4-chlorocyclohexanecarboxylic acid; shikimic acid; Z-nitro-l-methylcyclobutanecarboxylic acid; 1,2,3,4,5,6 hexachlorocyclohexanecarboxylic acid; 3 bromo 2 methylcyclohexanecarboxylic acid; 4- and 5 bromo 2 methylcyclohexanecarboxylic acid; 5- and 6 bromo 2 methylcyclohexanecarboxylic acid; 2,3-dibromo 2 methylcyclohexanecarboxylic acid; 2,S-dibromo-2-methylcyclohexanecarboxylic acid; 4,5 dibromo-2-methylcyclohexanecarboxylic acid; 5,6-dibromo- 2 methylcyclohexanecarboxylic acid; 3-bromo-3-methylcyclohexanecarboxylic acid; 6 bromo-3-methylcyclohexanecarboxylic acid; 1,6-dibromo 3 methylcyclohexanecarboxylic acid; 2 bromo-4-methylcyclohexanecarboxylic acid; 1,2-dibromo 4 methylcyclohexanecarboxylic acid;

3-bromo 2,2,3 trimethylcyclopentanecarboxylic acid; 1- bromo 3,5 dimethylcyclohexanecarboxylic acid; homogentisic acid, 0-, m-, and p-chlorobenzoic acid; anisic acid; salicyclic acid; p-hydroxybenzoic acid; fl-resorcylic acid; gallic acid; veratric acid; trimethoxybenzoic acid; trimethoxycinnamic acid; 4,4'-dichlorobenzilic acid; 0-, m-, and p-nitrobenzoic acid; cyanoacetic acid; 3,4- and 3,5-dinitrobenzoic acid; 2,4,6-trinitrobenzoic acid; triocyanoacetic acid; cyanopropionic acid; and lactic acid. Examples of such alkoxyhydrocarbon carboxylic acids are ethoxyformic acid (ethyl hydrogen carbonate); butyloxyformic acid; pentyloxyformic acid; hexyloxyformic acid; dodecyloxyformic acid; hexadecyloxyformic acid; and the like.

Any or all of the 2-, 3-, and 4-hydroxy groups and the 7SH groups can also be etherified, for example, with alkyl, advantageously of not more than 20 carbon atoms; cycloalkyl, advantageously of from 3 to not more than 12 carbon atoms; or ylidene (e.g., 3,4-o-ylidene) group for example alkylidene, advantageously of not more than 20 carbon atoms and aramethylidine and vinylogs thereof, advantageously of not more than 12 carbon atoms. Examples of alkylidene are given above and examples of aralkylidene are furfurylidene, S-methylfurfurylidene, benzylidene, m-tolylidene, o-tolylidene, p-tolylidene, ochlorobenzylidene, m-chlorobenzylidene, m-bromobenzylidene, p-bromobenzylidene, p-methoxybenzylidene, mmethoxybenzylidene, o methoxybenzylidene, 3,4 dimethoxybenzylidene, salicylylidene, p-hydroxybenzylidene, 3,4,S-trimethoxybenzylidene, piperonylidene, o-nitrobenzylidene, p-chlorobenzylidene, m-nitrobenzylidene, pnitrobenzylidene, 18 naphthylidene, o-bromobenzylidene, 2,4-dichlorobenzylidene, 3-methoxy 4 hydroxy-benzylidene, terephthylidene, 3,4-dihydroxybenzylidene, and cinnamylidene.

Starting compounds of Formula III are prepared by dehydrohalogenation of compounds of Formula VII. This suitably is efiected by heating a compound of Formula VII with an acid acceptor in a solvent. Suitable acid acceptors include anhydrous sodium carbonate, potassium carbonate, triethylamine, collidine, and potassium hydroxide. Suitable solvents are dimethylformamide, dimethylsulfoxide, ethyleneglycol, benzene, and alcohol. The temperature can range from about 25 C. to about the boiling point of solvent.

DETAILED DESCRIPTION According to one embodiment of the invention a starting compound of Formula II is heated with water in dimethylformamide. The 2-, 3-, and 4-hydroxy group advantageously, though not necessarily, are covered with protective groups. These protective groups sometimes result from the process for the preparation of compounds of Formula II, in which case it is not necessary to remove them at this stage. The amount of water is not critical as long as a substantial excess is present and as long as an essentially homogeneous solution is produced. Advantageously the ratio of water to dimethylformamide is 1:9 to 1:1. The solution advantageously is heated at reflux. Higher or lower temperatures, however, can be used. Ordinarily, however, it is not necessary or desirable to go below about 25 C. or above about 160 C.

According to another embodiment, a starting compound of Formula III is converted to a compound of Formula IV by heating in an inert solvent under a pressure of hydrogen sulfide. Suitably the compound of Formula III is mixed with 2-propanol, or like solvent, saturated with hydrogen sulfide and heated in a bomb at a temperature of about C. Higher or lower temperatures, say from about 25 C. to about C., can be used. The resulting compound, Formula IV, can then be N-acylated to form compounds of Formula I. This process produces predominantly compounds having the 7(S)- or L-threo configuration; that previously described produces predominantly the opposite configuration.

9 An alternative process starts with a compound of Formula VII, reacts it with an acylating agent to form a compound of the formula:

- -Halo AGNH- A0 XII The acylation can be efiected in a known manner with acetic anhydride or acetyl chloride, or the acid anhydrides and acid halides of any of the carboxylic acids listed above. The compound of Formula XII is then reacted with phosphorous pentasulfide as described above to form a compound of the formula:

where si l is the S-isolog of Ac. The compound of Formula XIII is then heated in contact with water in dimethylformamide as described above to form a compound of the formula:

AcNH- which on hydrazinolysis (heating with hydrazine in an inert solvent) yields a compound of the formula:

no K

l 1 SR 0H XV The compound of Formula XV can then be N-acylated as described above to form a compound of Formula I. This process produces predominantly compounds having the 7 (R) or D-erythro configurations.

The compounds and intermediates of Formulas I-A, I-B, III, and 1V exist either in the protonated or nonprotonated forms according to the pH of the environment. When the protonated form is intended, the compound is qualified as an acid-addition salt and when the non-protonated form is intended it is qualified as the free base. The free bases can be converted to stable acid-addition salts 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 hydrochloric, sulfuric, phosphoric, thiocyanic, fiuosilicic, hexafluoroarsenic, hexafluorophosphoric, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic, phthalic, tartaric,

lauric, stearic, salicylic, 3-phenylsalicylic, 5-phenylsalicylic, S-methylglutaric, orthosulfobenzoic, cyclopentanepropionic, 1,2-cyclohexanedicarboxylic, 4-cyclohexanecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, dimethyldithiocarbamic, cyclohexylsulfamic, hexadecysulfamic, octadecylsulfamic, sorbic, monochloroacetic, undecylenic, 4'-hydroxyazobenzene-4-sulfonic, octyldecylsulfiuric, picric, benzoic, cinnamic, and like acids.

The acid-addition salts 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 alkali or to make a different salt by metathesis. Or the free base can be converted to a water-soluble salt, such as the hydrochloride or sulfate and the aqueous solution of the salt extracted with various water-immiscible 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 of Formulas IA, I-B, III, and IV can be used as a buffer or as an antiacid. The compounds of Formulas I, II, III, and IV react with isocyanates to form urethanes and can be used to modify polyurethane resins. The long chain compounds, i.e., where HR is alkyl of from 8 carbon atoms up, have surface active properties and can be used as wetting and emulsifying agents. The thiocyanic acid addition salt when condensed with formaldehyde forms resinous materials useful as pickling inhibitors according to U.S. Pats. 2,425,320 and 2,606,155. 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. Pats. 1,915,334 and 2,075,359 and the hexafluoroarsenic acid and hexafluorophosphoric acid addition salts are useful as parasiticides according to U.S. Pats. 3,122,536 and 3,122,552. The compounds of Formulas I and IV are scavengers for free radicals and can be used to terminate free radical reactions.

7-mercapto-7-deoxylincomycin, and its close analogues, i.e., where R H is cis or trans alkyl of not more than 8 carbon atoms; R is hydrogen, methyl, or ethyl; R is alkyl of not more than 8 carbon atoms, have antibacterial properties somewhat inferior to lincomycin but can be used for the same purposes as lincomycin. The other analogues and isomers have similar antibacterial properties but to a lesser degree and can be used for the same purposes as lincomycin where larger amounts are not objectionable.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. The parts and percentages are by weight and the solvent ratios are by volume unless otherwise specified.

EXAMPLE 1 7(S)-mercapto 7 deoxylincomycin [methyl 7-mercapto- 6,7,8-trideoxy-6-(trans-l-methyl 4 propyl-L-2-pyrrolidinecarboxamido)-l-thio-L-threo 0c D galactooctopyranoside] 11 Part A-1.-Methyl 6,7-aziridino-7-deoxy-uthiolincosaminide HO 0. I

I OH

XVII XVIII A mixture of 1 g. of methyl 7(S)-chloro'7-deoxy-u-thiolincosaminide and 3 g. of anhydrous sodium carbonate in 40 ml. of dimethylformamide was heated at reflux for 5 min. This solvent was distilled under vacuum. The residue was crystallized from methanol affording 370 mg. (45.2% yield) of methyl 6,7-aziridino-7-deoxy-uthiolincosaminide; M.P. 192-198. A second crop of crystals, M.P. 182-189", 160 mg. (18.5%), was obtained on concentration of the mother liquors. Two recrystallizations from methanol-acetone gave crystals, MP. 203-- 220, [a] -[320 (dimethyl sulfoxide).

Analysis.-Calcd. for C H NO S (percent): C, 45.94; H, 7.28; N, 5.95. Found (percent): C, 45.97; H, 7.44;

SMe

Part B1.Methyl 7(S -mercapto-7-deoxy-uthiolincosaminide CH3 CH3 T SH HN/ HzN- H0 HO O K K N l SMe SMe OH XVIII OH XIX A mixture of 1.5 g. of methyl 6,7-aziridino-7-deoxya-thiolincosaminide in 30 ml. of 2-propanol was saturated with H S while cooling in a bath of ice-methanol. The reaction mixture was heated in a bomb on a steam bath for 5 hours. During this time methyl 6,7-aziridino- 7-deoxy-a-thiolincosaminide gradually dissolved forming a solution from which crystalline methyl 7(S)-mercapto- 7-deoxy-u-thiolincosaminide began to precipitate. Filtration of the cooled mixture gave 1.6 g. of methyl 7 (S)- mercapto-7-deoxy-a-thiolincosaminide, M.P. 190-197 C. A portion was recrystallized from ethanol to form the analytical sample, M.P. 195-198 C.

Analysis.-Calcd. for C I-I NO S (percent) C, 40.13; H, 7.11; N, 5.20; S, 23.80. Found (percent): C, 40.36; H, 7.12; N, 5.03; S, 24.21.

Part C1.-7 (S) -mercapto-7-deoxylincomycin hydrochloride CH3 CH3 XIX ride. After drying the methylene chloride was distilled leaving a residue of 10.2 g. The crude oil was dissolved in 50 ml, of acetone and excess dilute HCl added. An additional 250 ml. of acetone was added causing the precipitation of a gummy solid. This precipitate hardened when triturated with 250 ml. of fresh acetone. It was collected by filtration. A l g. portion was chromatographed over silica gel using methanol-chloroform 1:4 for elution. The fractions showing antibacterial activity were pooled and evaporated to dryness. This material (307 mg.) was dissolved in acetone and acidified. Evaporation of the solvent gave 7(S)-mercapto 7 deoxylincomycin hydrochloride as a glassy solid.

Analysis.-Calcd for C H N O S -HCI (percent): C, 47.09; H, 7.69; N, 6.10. Found (percent): C, 47.25; H, 7.87; N, 5.60.

Antibacterial spectrum: Meg/ml. Staphylococcus aureus 1.6 Streptococcus hemolyticus 0.8 Streptococcus faecalis 1.6 Bacillus subtilis 6.4

Gram negative 200 1 Two-fold dilution end points in brain-heart infusion broth at 20 hours.

EXAMPLE 2 XXII Part A2.Methyl 7 (S)-Chl0l'O-7-dOXy-uthiolincosaminide XVII i SMe 0 SMe XXIII To a suspension of 197.2 g. of triphenylphosphine in 1.5 l. of anhydrous acetonitrile was added 52.5 g. of chlorine. With stirring, 18.75 g. of methyl-a-thiolincosaminide (U.S. Pat. 3,179,565) was added. After 2.5 hrs. at ambient temperature, 50 ml. of methanol was added. The mixture was concentrated to a thick syrup. The concentrate was diluted with methylene chloride and extracted three times with water. The aqueous extracts were washed twice with methylene chloride. The extracts were made alkaline with sodium hydroxide and extracted repeatedly with methylene chloride. The organic extract was dried and evaporated under vacuum. The residue was chromatographed over 1.1 kg. of silica gel using chloroform-methanol (4; 1) for elution. The major fraction selected on the basis of its TLC (thin layer chromatography) profile Weighed 4.4 g. Recrystallization from methanol-water afforded 2.73 g. of methyl 7 (S)-chloro-7-deoxy-a-thiolin cosaminide, M.P. l78181 C.

Analysis.-Calcd. for C H ClNO S (percent): C, 39.77; H, 6.67; N, 5.16; S, 11.80; 0, 13.05. Found (percent): C, 39.91; H, 7.02; N, 5.57; S, 11.99; 0, 13.33.

SMe SMe XVII XXII A solution of 2 g. of methyl 7(S)-chloro-7-deoxy-athiolincosaminide in 5 ml. of acetic anhydride and 5 m1. of pyridine was maintained at 26 for 5 hrs. Dilution with ice-water afforded a crystalline product which was collected by filtration. The yield of crude product, M.P. 174-198 C. dec., was 2.17 g. Chromatography over silica gel using cyclohexanezethyl acetate (1:2) for elution led to the separation of 1.08 g. methyl 7(S)-chloro-7-deoxytx-thlOllIlCOSBITllHldC tetraacetate which after several recrystallizations from acetone-water melted at 249252 C. and had [a] -|-235.

Part C2.-N-thioacetyl-2,3,4-tri-O-acetyl-7 (S -chloro-7- deoxy-u-thiolincosaminide A mixture of 4.63 g. of methyl 7(S)-chloro-7-deoXy-uthiolincosaminide tetraacetate and 2.22 g. of phosphorus pentasulfide in 55 ml. of dioxane was heated at reflux for 1 hr. The solvent was evaporated under vacuum and the residue dissolved in methylene chloride. After washing twice with dilute alkali followed by washing with water and drying over sodium sulfate the solvent was distilled leaving a crystalline residue of 4.7 g. This residue was recrystallized from ethyl acetate-Skellysolve B (technical hexane) to give 1.73 g. of first crop crystals, M.P. 208- 21-6 C. and 0.81 g. of second crop crystals, M.P. 206- 212 C., the total yield was 2.54 g. (53.2%).

A portion was recrystallized successively from ethyl acetate-Skellysolve B, acetone-water, and ethyl acetate- Skellysolve B to furnish an analytical sample. It melted at 208-210 C., with a small amount of solid remaining to 218 C., and rotated at 259 (CHCl Analysis.-Calcd. for C H NO S (percent): C, 47.58; H, 6.10; N, 2.92; S, 13.37. Found (percent): C, 47.60; H, 6.06; N, 3.05; S, 13.05.

Part D-2.Methyl 7(R)-mercapto-7-deoXy-a-thiolincosaminide 2-0, 3-0, 4-0,N-tetraacetate A solution of 870 mg. of thioamide of Part C2 in 20 ml. of dimethylformamide and 10 ml. of water was heated under reflux for 1.5 hrs. The solvent was distilled in vacuo. The residue was purified by chromatography over silica gel using cyclohexaneacetone (2: 1) for elution. The product fraction of 619 mg. was recrystallized from ethyl acetate. The yield of methyl 7(R)-mercapto-7-deoxy-uthiolincosamiuide tetraacetate, M.P. 245247,

[ ha-F (CHCl was 300 mg.

Analysis.-Calcd. for C H NO S (percent): C, 46.66; H, 6.22; N, 3.20; S, 14.66. Found (percent): C, 46.44; H, 6.22; N, 3.18; S, 14.38.

Part E-2.Methyl 7(R)-mercapto-7-deoxy-a-thiolincosaminide XXVII Eight grams of the tetraacetate of Part D2 was heated at reflux in 70 ml. of hydrazine hydrate for 2 hrs. The solution was evaporated to dryness under 1 mm. pressure. To the residue was added 50 ml. of 2-propanol with warming and stirring. Crystals formed rapidly. The solution was cooled and filtered. After drying a bluish-gray solid of 5.2 g. was obtained, M.P. 152-165 C., gradually darkened (sintered) and decomposed at 186 C. TLC on silica gel using systems of chloroform-methanol of 4:1 or 2:1 showed two major products and only a trace of material moving with acetyl hydrazine. The smaller of the two major products on TLC moves with the 7(5) isomer (Part B-l), th larger (the 7(R) isomer) moving slightly slower. The product as well as the mother liquors had a strong odor of H 8. One attempt of chromatography led to decomposition and low recovery. Therefore this product was used in the next step where separation of a pure product proved to be less complicated.

Part F2.7 (R -mercapto-7-deoxylincomycin hydrochloride H L Me XXVIII XXIX *Isobutyl chloroformate (2.72 ml, 20 mM.) was added at 5 to a solution of 4.14 g. (20 mM.) of trans-1- methyl-4-n-propyl'L-proline and 5.6 ml. (40 mM.) of triethylamine in 250 ml. of acetonitrile. After 10 min. stirring a solution of 5.2 g. of the methyl 7(R)-mercapto- 7-deoxy-a-thiolincosaminide of Part 15-2 in 130 ml. of water was added. The resulting mixture was stirred for 2 hrs. The acetonitrile was removed by distillation and the aqueous solution extracted with methylene chloride. A residue of 6.26 g. was obtained by evaporation of the solvent. TLC (CHCl -MeOH 4: 1) showed chiefly two materials active vs. S. lutea. The smaller spot was not separated by TLC from the 7 (S) isomer. The larger spot possessed a slightly less Rf. Chromatography over silica gel using methanol-chloroform 1:4 for elution gave a fraction of 5.96 g. of good quality 7 (R)-mercapto-7- deoxylincomycin. A center cut of this fraction was dried at 50 C. for elemental analysis. It gave [a] (H O).

15 Analysis.Calcd. for C H N O S (percent): C, 51:15; H, 8.11; N, 6.63. Found (percent): C, 51.18; H, 8.16; N, 6.96.

Antibacterial spectrum. Meg/ml. Staphylococcus aureus 3.2-6.4

Streptococcus hemolyticus 6.4 Streptococcus faecalis 6.4 Bacillus subtilis 50 Gram negative 200 Two-fold dilution end point in brain-heart infusion broth at 20 hours.

EXAMPLE 3 7 (R) -mercapto-7-deoxylincomycin hydrochloride Part A3.7(S)-chloro-7-deoxylincomycin hydrochloride A solution of 50 g. of lincomycin hydrochloride, 120 g. of triphenylphosphine, and 500 ml. of acetonitrile in a 3-1. flask equipped with a stirrer was cooled in an ice bath and 500 ml. of carbon tetrachloride was added in one portion. The reaction mixture was then stirred for 18 hr. without addition of ice to the cooling bath. The reaction was evaporated to dryness under vacuum on a 50-60 water bath, yielding a clear, pale yellow viscous oil. An equal volume of water was added and the mixture shaken until all of the oil was dissolved. The resulting suspension of white solid PO) was filtered through a sintered glass mat and discarded. The filtrate was adjusted to pH 11 by addition of 6 N aqueous sodium hydroxide. A solid precipitated. The resulting slurry was extracted with four 300 ml. portions of chloroform. The aqueous phase was discarded. The combined chloroform extract was washed once with 100 ml. of saturated aqueous sodium chloride solution and the sodium chloride phase was discarded. The chloroform phase was evaporated to dryness under vacuum on a 5060 C. water bath and an equal volume of methanol was added to the residue and the resulting solution heated at reflux for 1 hr. The methanol solution was evaporated to dryness under vacuum on a 50-60 C. water bath. The residue was a clear pale yellow viscous oil. An equal volume of water and 10 ml. of 37% aqueous HCl was added and the resultant was shaken until the oil dissolved and a white solid (more PO) remained in suspension. The suspension was filtered through a sintered glass mat at pH 1-2 and the solid discarded. The filtrate was extracted twice with 100 ml. of carbon tetrachloride. The carbon tetrachloride phase was discarded. The aqueous phase was adjusted to pH 11 by addition of 6 N aq. sodium hydroxide and extracted four times with 300 ml. portions of chloroform. The combined chloroform extract was washed three times with 100 ml. of saturated aq. sodium chloride solution and the sodium chloride phase was discarded. The chloroform extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness under vacuum on a 50-60 C. water bath. The residue was a clear, colorless glass weighing 45 g. analyzing about 95% 7(S)chloro-7-deoxylincomycin. To the crude product there was added 100 ml. of ethanol with warming until a clear solution was obtained. Then 150 ml. ethyl acetate was added and the resultant filtered through a glass mat and the filtrate adjusted to pH 1 by the addition of saturated ethanolic-HCl. Crystallization soon occurred. The resultant was allowed to stand at 0 C. for 18 hrs. and then filtered through a sintered glass mat. The solid was dried under vacuum at 60 C. for 18 hr. yielding 35 g. (67% yield) of 7(S)-chloro-7-deoxylincomycin hydrochloride as an ethanol solvate. On recrystallization from aqueous acetone (7 ml. H O to 300 ml. acetone) there was obtained an analytical sample having the following analysis:

16 Analysis.--Calcd. for C H ClN O S-HCl-H O (percent): C, 45.18; H, 7.37; S, 6.70; H O, 3.77. Found (percent): H, 45.()9; H, 7.74; S, 6.45; H O, 4.24. [OL]DH20+145.

Part B3.7(S)-chloro-7-deoxylincomycin triacetate 25 g. of 7 (S)-chloro-7-deoxylincomycin hydrochloride was dissolved with warming in 125 ml. of pyridine and 125 ml. of acetic anhydride. After 17 hrs. at ambient temperature water was added while cooling until no further exothermine effect was noted. The solution was concentrated under vacuum. The residue was dissolved in 250 ml. of water and 20% aqueous sodium hydroxide added with cooling and stirring until the solution gave an alkaline reaction to test paper. The solid was collected by filtration, washed with water and dried at 50 C. under vacuum. The yield was 28 g. of 7 (S)-chloro-7-deoxylincomycin triacetate. On heating in a mp bath it liquified at By substituting lincomycin in Examples 1 and 2 by other alkyl, cycloalkyl, or aralkyl 6,8-dideoxy 6 (trans-lmethyl-4-propyl-L-2-pyrrolidinecarboxamido)-l-thio D- erythro-a-D-galacto-octopyranosides where alkyl, for example, is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, monadecyl, and eicosyl and the isomeric forms thereof; cycloalkyl, for example, is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2, 3-dimethylcyclobutyl, Z-methylcyclobutyl, and 3-cyclopentylpropyl; and aralkyl, for example, is benzyl, phenethyl, 3-phenylpropyl, and l-naphthylmethyl, the corresponding alkyl, cycloalkyl, and aralkyl, 6-acylaminoand 6 thioacylamino 6,8 dideoxy-l-thio-D-erythro-u-D- galacto-octopyranosides are obtained. For example, by substituting the lincomycin by ethyl, propyl, butyl, pentyl, and hexyl 6,8-dideoxy-6-acylaminoand 6-thioacylaminol-thio-D-erythrdot-D-galacto-octopyranosides, the ethyl, propyl, butyl, pentyl, and hexyl 6-acylaminoand 6-thioacylamino 6,8 dideoxy-l-thio-D-erythro-u-D-galactooctopyranosides and the corresponding 6-acylaminoand 6 thioacylamino-7-halo-6,7,8-trideoxy-l-thio-L-threo-u- D-galacto-octopyranosides, are obtained.

The acyl amino and thioacylamino groups can be 4- substituted-L-7-pyrrolidinecarb0xamido and 4-substituted- L-Z-pyrrolidine thiocarboxamido of the formula:

IITRz 1'13 Where R R and R are as given above. Advantageously R and R can be methylene, ethylene, propylene, butylene, pentylene, or hexylene, and R can be hydrogen or HR in any combinations.

By substituting the lincomycins in the foregoing by 7- epilincomycins, the like compounds in the opposite configuration at the 7-position are obtained.

Part C3 .--7 (S) -chloro-7-deoxy-thiamidolincomycin triacetate Four grams of 7(S)-chloro-7-deoxylincomycin triacetate was mixed with ml. of benzene and 25 ml. of

the solvent distilled. The mixture was clarified by filtration, removing a small cloudy precipitate. The benzene was removed by distillation. The residue was dissolved in 100 ml. of dioxane and 4 g. of phosphorus pentasulfide added. The mixture was heated to reflux for 1.5 hrs. An additional 4 g. of phosphorus pentasulfide was added followed by a third addition of 4 g. of phosphorus pentasulfide after 4 hrs. longer reflux. The mixture was finally refluxed for 2 hrs. more and then the solvent distilled in vacuo. The residue was dissolved in methylene dichloride and washed twice with dilute sodium hydroxide solution. The organic phase was dried and the solvent distilled. The residue of 8.6 g. was chromatographed over 500 g. of silica gel using cyclohexaneacetone (2-1) for elution. A fraction of 880 mg. was obtained which contained 7(S)- chloro-7-deoxythiamidolincomycin triacetate as well as other materials. This material was rechromatographed over 100 g. of silica gel using chloroform-methanol (40-1) for elution. A fraction of 320 mg. was obtained which after crystallization from methanol melted at 178- 181. The yield was 120 mg. 7(S)-chloro-7-deoxythiamidolincomycin triacetate.

Analytical data was obtained for a sample prepared as above which melted at 179-180".

Analysis.Calcd. for C24H39C1N207S2 (percent): C, 50.82; H, 6.93; N, 4.94; S, 11.31. Found (percent): C, 50.75; H, 7.08;N, 4.88; S, 11.55.

Part D-3 .7 (R) -mercapto-7-deoxylincomycin Following the procedure of Part C-2 substituting the methyl 7(S)-chloro-7-deoxy-a-thiolincosaminide tetraacetate by 7(S)-chloro-7-deoxythiamidolincomycin triacetate there was obtained 7(R)-mercapto-7-deoxylincomycin 2-0, 3-0, 4-0-triacetate which on saponification with aqueous potassium hydroxide at pH 10.5 yielded 7(R)-mercapto-7-deoxylincomycin identical with that of Part F-2.

In place of trans-1-methyl-4-propyl-L-proline there can be substituted other 4-substituted prolines of Formulas A and B. Also, there can be substituted other oc-thiO- lincosaminides of Formula IX.

We claim:

1. A compound of the formula:

wherein R is alkyl of not more than 20 carbon atoms, cycloalkyl of 3 to not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms; Ac is hydrogen or the acyl radical of a carboxylic acid of not more than 18 carbon atoms, and Ac is hydrogen, Ac, or an acyl radical of a 4-substituted-L-Z-pyrrolidinecarboxylic acid.

2. A compound according to claim 1 in which Ac and Ac are hydrogen and R is lower alkyl.

3. A compound according to claim 1 in which Ac and Ac are acetyl and R is lower alkyl.

4. A compound according to claim 1 in which R is lower alkyl, Ac is hydrogen and Ac is an acyl of the HR: I!

' wherein R and R are alkylidene of not more than 20 carbon atoms, cycloalkylidene of 3 to not more than 8 carbon atoms, or aralkylidine of not more than 12 carbon atoms and R is hydrogen or H12 5. A compound according to claim 4 in which Ac is 1-rnethyl-4-propyl L 2-pyrrolidinecarboxacyl and R is methyl or ethyl.

6. The 7(S) compound according to claim 4 wherein Ac is trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxacyl and R is methyl.

7. The 7 (R) compound according to claim 4 wherein Ac is trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxacyl and R is methyl.

8. A process for making a compound of the formula:

AeO

OAc l l SR which comprises heating a compound of the formula:

where R is the radical of a mercaptan, Ac is the acyl group of a carboxylic acid,

with water in dimethylformamide.

9. The process of claim 10 in. which the Ac and groups in the product are removed by hydrazinolysis to rform a product of the formula:

wherein R is the radical of a mercaptan.

10. The process according to claim 11 in which the is the acyl group of a 4-su bstituted pyrrolidine carboxylic acid and R is the radical of a mercaptan.

References Cited 5 UNITED STATES PATENTS 3,366,624 1/1968 Argoudelis et al 260210 3,380,992 4/1968 Argoudelis et al 260210 0 LEWIS GO'ITS, Primary Examiner J. R. BROWN, Assistant Examiner US. Cl. X.R.

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US5767098A (en) * 1985-12-12 1998-06-16 Dermik Laboratories, Inc. Anti-acne method and composition
US6013637A (en) * 1998-06-12 2000-01-11 Dermik Laboratories Inc. Anti-acne method and composition
US20040116690A1 (en) * 2002-08-15 2004-06-17 Jason Lewis Lincomycin derivatives possessing antibacterial activity
US20040230046A1 (en) * 2002-08-15 2004-11-18 Vicuron Pharmaceuticals Inc. Lincomycin derivatives possessing antibacterial activity
US20050192236A1 (en) * 2001-08-28 2005-09-01 Chao Robert S. Crystaline clindamycin free base
US20060148722A1 (en) * 2004-02-11 2006-07-06 Vicuron Pharmaceuticals Inc. Novel lincomycin derivatives possessing antibacterial activity
US7199106B2 (en) 2003-06-17 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antimicrobial activity
WO2007066805A1 (en) 2005-12-09 2007-06-14 Meiji Seika Kaisha, Ltd. Lincomycin derivative and antibacterial agent containing the same as active ingredient
US7256177B2 (en) 2003-06-17 2007-08-14 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US20080033031A1 (en) * 2004-11-19 2008-02-07 Aventis Pharmaceuticals Inc. Antibiotic compounds, compositions and methods of treatment
WO2008146919A1 (en) 2007-05-31 2008-12-04 Meiji Seika Kaisha, Ltd. Lincosamide derivative, and antibacterial agent comprising the same as active ingredient
EP2151447A1 (en) * 2007-05-31 2010-02-10 Meiji Seika Kaisha Ltd. Lincomycin derivatives and antibacterial agents containing the same as the active ingredient
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
EP2277556A1 (en) 2001-05-01 2011-01-26 A. V. Topchiev Institute of Petrochemical Synthesis Two-phase, water-absorbent bioadhesive composition
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US3689474A (en) * 1970-08-04 1972-09-05 Upjohn Co 7-mercapto-7-deoxylincomycins and process for preparing the same

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US3366624A (en) * 1964-08-05 1968-01-30 Upjohn Co Lincomycin derivatives and process for preparing same
US3380992A (en) * 1965-06-14 1968-04-30 Upjohn Co Lincomycin derivatives and process for preparing same

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US3366624A (en) * 1964-08-05 1968-01-30 Upjohn Co Lincomycin derivatives and process for preparing same
US3380992A (en) * 1965-06-14 1968-04-30 Upjohn Co Lincomycin derivatives and process for preparing same

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US5767098A (en) * 1985-12-12 1998-06-16 Dermik Laboratories, Inc. Anti-acne method and composition
US6013637A (en) * 1998-06-12 2000-01-11 Dermik Laboratories Inc. Anti-acne method and composition
EP2277556A1 (en) 2001-05-01 2011-01-26 A. V. Topchiev Institute of Petrochemical Synthesis Two-phase, water-absorbent bioadhesive composition
US20050192236A1 (en) * 2001-08-28 2005-09-01 Chao Robert S. Crystaline clindamycin free base
US7199105B2 (en) 2002-08-15 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US20040116690A1 (en) * 2002-08-15 2004-06-17 Jason Lewis Lincomycin derivatives possessing antibacterial activity
US20040230046A1 (en) * 2002-08-15 2004-11-18 Vicuron Pharmaceuticals Inc. Lincomycin derivatives possessing antibacterial activity
US7164011B2 (en) 2002-08-15 2007-01-16 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
EP2289512A1 (en) 2003-01-24 2011-03-02 Stiefel Research Australia Pty Ltd Pharmaceutical foam
US7256177B2 (en) 2003-06-17 2007-08-14 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7199106B2 (en) 2003-06-17 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antimicrobial activity
US7361743B2 (en) 2004-02-11 2008-04-22 Pfizer Inc Lincomycin derivatives possessing antibacterial activity
US20060148722A1 (en) * 2004-02-11 2006-07-06 Vicuron Pharmaceuticals Inc. Novel lincomycin derivatives possessing antibacterial activity
US20080033031A1 (en) * 2004-11-19 2008-02-07 Aventis Pharmaceuticals Inc. Antibiotic compounds, compositions and methods of treatment
WO2007066805A1 (en) 2005-12-09 2007-06-14 Meiji Seika Kaisha, Ltd. Lincomycin derivative and antibacterial agent containing the same as active ingredient
EP1970377A1 (en) * 2005-12-09 2008-09-17 Meiji Seika Kaisha Ltd. Lincomycin derivative and antibacterial agent containing the same as active ingredient
EP1970377A4 (en) * 2005-12-09 2013-02-27 Meiji Seika Kaisha Lincomycin derivative and antibacterial agent containing the same as active ingredient
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
EP2166015A1 (en) * 2007-05-31 2010-03-24 Meiji Seika Kaisha Ltd. Lincosamide derivative, and antibacterial agent comprising the same as active ingredient
US20100184746A1 (en) * 2007-05-31 2010-07-22 Meiji Seika Kaisha Ltd Lincosamide derivatives and antimicrobial agents comprising the same as active ingredient
US20100210570A1 (en) * 2007-05-31 2010-08-19 Yoshinari Wakiyama Lincomycin derivatives and antimicrobial agents comprising the same as active ingredient
EP2151447A1 (en) * 2007-05-31 2010-02-10 Meiji Seika Kaisha Ltd. Lincomycin derivatives and antibacterial agents containing the same as the active ingredient
US7879808B2 (en) 2007-05-31 2011-02-01 Meiji Seika Kaisha, Ltd. Lincomycin derivatives and antimicrobial agents comprising the same as active ingredient
WO2008146919A1 (en) 2007-05-31 2008-12-04 Meiji Seika Kaisha, Ltd. Lincosamide derivative, and antibacterial agent comprising the same as active ingredient
EP2166015A4 (en) * 2007-05-31 2012-09-05 Meiji Seika Kaisha Lincosamide derivative, and antibacterial agent comprising the same as active ingredient
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US7867980B2 (en) 2007-05-31 2011-01-11 Meiji Seika Kaisha, Ltd. Lincosamide derivatives and antimicrobial agents comprising the same as active ingredient

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