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 US725531A US3544551DA US3544551A US 3544551 A US3544551 A US 3544551A US 725531 A US725531 A US 725531A 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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Pharmacia and Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
    • C08G18/3855—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur
    • C08G18/3863—Low-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
    • C08G18/3865—Low-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
    • C08G18/3868—Low-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
    • Y—GENERAL 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S516/00—Colloid systems and wetting agents; subcombinations thereof; processes of
    • Y10S516/01—Wetting, emulsifying, dispersing, or stabilizing agents
    • Y10S516/07—Organic amine, amide, or n-base containing

Definitions

  • 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.
  • novel compounds of the invention can be repre sented by the following structural formula:
  • 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;
  • 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.
  • alkyl of not more than 20 carbon atoms 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.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4- methylcyclobutyl, and 3-cyclopentylpropyl.
  • aralkyl examples include benzyl, phenethyl, a-phenylpropyl, and anaphthylmethyl.
  • R aralkylidene groups
  • 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-cyclopropyleth
  • novel compounds of the invention can be prepared by heating a compound of the formula:
  • 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:
  • the cis and trans isomers can be separated by counter current distribution of chromatography, either before or after replacement of the 7-hydroxy group.
  • R in Formula B When R in Formula B is hydrogen, it can be replaced by suitable alkylation or like procedure.
  • 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.
  • a catalyst effective to saturate an olefinic double bond.
  • platinum or palladium can be used as the catalyst.
  • 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:
  • 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.
  • a 7(R)-hydroxy compound of the D-erythro configuration yields a 7(S)-halo compound of the L-threo configuration.
  • 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:
  • X is halogen, e.g., chlorine, bromine, and iodine.
  • 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.
  • 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.
  • an inert solvent e.g., acetonitrile or dimethylformamide
  • the reaction takes place at ordinary temperature, though gentle heating can be effected if desired.
  • 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.
  • the treated and filtered reaction mixture is evaporated to dryness and purified by solvent extraction and/ or chromat
  • the starting compound of Formula IX or X advantageously in the form of an acid-addition salt, e.g., the hydrochloride
  • 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.
  • 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).
  • 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.
  • 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 is important because of the solubility of the product in thionyl chloride.
  • 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.
  • 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.
  • 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, cyclohexan
  • 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.
  • 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 dibrom
  • 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.
  • alkoxyhydrocarbon carboxylic acids examples include 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.
  • alkyl advantageously of not more than 20 carbon atoms
  • cycloalkyl advantageously of from 3 to not more than 12 carbon atoms
  • ylidene e.g., 3,4-o-ylidene
  • alkylidene examples 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • the compound 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,
  • the acid-addition salts can be used for the same purposes as the free base or they can be employed to upgrade the same.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • alkyl for example, is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, monadecyl, and eicosyl
  • acyl amino and thioacylamino groups can be 4- substituted-L-7-pyrrolidinecarb0xamido and 4-substituted- L-Z-pyrrolidine thiocarboxamido of the formula:
  • R and R are as given above.
  • R and R can be methylene, ethylene, propylene, butylene, pentylene, or hexylene, and R can be hydrogen or HR in any combinations.
  • Part D-3 .7 (R) -mercapto-7-deoxylincomycin
  • 7(S)-chloro-7-deoxy-a-thiolincosaminide tetraacetate by 7(S)-chloro-7-deoxythiamidolincomycin triacetate
  • 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.
  • 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.
  • 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.
  • 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.
  • R is the radical of a mercaptan
  • Ac is the acyl group of a carboxylic acid
  • R is the radical of a mercaptan

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2005074894A1 (en) 2004-01-30 2005-08-18 Corium International Rapidly dissolving film for delivery of an active agent
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 (ja) 2005-12-09 2007-06-14 Meiji Seika Kaisha, Ltd. リンコマイシン誘導体およびこれを有効成分とする抗菌剤
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 (ja) 2007-05-31 2008-12-04 Meiji Seika Kaisha, Ltd. リンコサミド誘導体及びこれを有効成分とする抗菌剤
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
US20100210570A1 (en) * 2007-05-31 2010-08-19 Yoshinari Wakiyama Lincomycin derivatives and antimicrobial agents comprising the same as active ingredient
EP2277556A1 (en) 2001-05-01 2011-01-26 A. V. Topchiev Institute of Petrochemical Synthesis Two-phase, water-absorbent bioadhesive composition
EP2289512A1 (en) 2003-01-24 2011-03-02 Stiefel Research Australia Pty Ltd Pharmaceutical foam
US10463768B2 (en) 2014-08-15 2019-11-05 The Johns Hopkins University Composite material for tissue restoration
WO2019217765A1 (en) 2018-05-09 2019-11-14 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery
WO2019217767A1 (en) 2018-05-09 2019-11-14 The Johns Hopkins University Nanofiber-hydrogel composites for enhanced soft tissue replacement and regeneration
US11191853B2 (en) 2014-08-15 2021-12-07 The Johns Hopkins University Post-surgical imaging marker
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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
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
US7199105B2 (en) 2002-08-15 2007-04-03 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
WO2005074894A1 (en) 2004-01-30 2005-08-18 Corium International Rapidly dissolving film for delivery of an active agent
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
EP1970377A4 (en) * 2005-12-09 2013-02-27 Meiji Seika Kaisha LINCOMYCIN DERIVATIVE AND ANTIBACTERIAL AGENT CONTAINING THIS AS AN ACTIVE SUBSTANCE
WO2007066805A1 (ja) 2005-12-09 2007-06-14 Meiji Seika Kaisha, Ltd. リンコマイシン誘導体およびこれを有効成分とする抗菌剤
EP2206494A1 (en) 2006-03-31 2010-07-14 Stiefel Research Australia Pty Ltd Foamable suspension gel
US7867980B2 (en) 2007-05-31 2011-01-11 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
US7879808B2 (en) 2007-05-31 2011-02-01 Meiji Seika Kaisha, Ltd. Lincomycin derivatives and antimicrobial agents 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
EP2151447A4 (en) * 2007-05-31 2012-09-05 Meiji Seika Kaisha LINCOMYCIN DERIVATIVES AND ANTIBACTERIAL AGENTS CONTAINING SAME AS ACTIVE INGREDIENTS
EP2166015A4 (en) * 2007-05-31 2012-09-05 Meiji Seika Kaisha LINCOSAMIDE DERIVATIVE AND ANTIBACTERIAL AGENT CONTAINING ACTIVE SUBSTANCE
WO2008146919A1 (ja) 2007-05-31 2008-12-04 Meiji Seika Kaisha, Ltd. リンコサミド誘導体及びこれを有効成分とする抗菌剤
US11707553B2 (en) 2014-08-15 2023-07-25 The Johns Hopkins University Composite material for tissue restoration
US11191853B2 (en) 2014-08-15 2021-12-07 The Johns Hopkins University Post-surgical imaging marker
US11684700B2 (en) 2014-08-15 2023-06-27 The Johns Hopkins University Composite material for tissue restoration
US10463768B2 (en) 2014-08-15 2019-11-05 The Johns Hopkins University Composite material for tissue restoration
EP4574179A2 (en) 2014-08-15 2025-06-25 The Johns Hopkins University Composite material for tissue restoration
EP4091639A1 (en) 2015-08-17 2022-11-23 The Johns Hopkins University In situ forming composite material for tissue restoration
WO2019217765A1 (en) 2018-05-09 2019-11-14 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery
WO2019217767A1 (en) 2018-05-09 2019-11-14 The Johns Hopkins University Nanofiber-hydrogel composites for enhanced soft tissue replacement and regeneration
US11771807B2 (en) 2018-05-09 2023-10-03 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery
US12036339B2 (en) 2018-05-09 2024-07-16 The Johns Hopkins University Nanofiber-hydrogel composites for enhanced soft tissue replacement and regeneration
US12161781B2 (en) 2018-05-09 2024-12-10 The Johns Hopkins University Nanofiber-hydrogel composites for cell and tissue delivery

Also Published As

Publication number Publication date
NL6905963A (enrdf_load_stackoverflow) 1969-11-03
CH546791A (de) 1974-03-15
CH536855A (de) 1973-06-29
DE1920542A1 (de) 1969-11-13
IL31950A0 (en) 1969-06-25
FR2007569A1 (enrdf_load_stackoverflow) 1970-01-09
IL31950A (en) 1974-05-16
CH528536A (de) 1972-09-30
BE732352A (enrdf_load_stackoverflow) 1969-10-30
GB1258944A (enrdf_load_stackoverflow) 1971-12-30

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