NO784298L - SPECTINOMYCIN DERIVATIVES FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE - Google Patents

SPECTINOMYCIN DERIVATIVES FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE

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Publication number
NO784298L
NO784298L NO784298A NO784298A NO784298L NO 784298 L NO784298 L NO 784298L NO 784298 A NO784298 A NO 784298A NO 784298 A NO784298 A NO 784298A NO 784298 L NO784298 L NO 784298L
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group
carbon atoms
substituted
general formula
methyl
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NO784298A
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Norwegian (no)
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Roland Maier
Eberhard Woitun
Wolfgang Reuter
Bernd Wetzel
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Thomae Gmbh Dr K
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Publication of NO784298L publication Critical patent/NO784298L/en

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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
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/224—Cyclohexane rings substituted by at least two nitrogen atoms with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

• "Spectinomycinderivater for fremstilling• “Spectinomycin derivatives for manufacture

av terapeutisk aktivt 4- spectinomycylamin" of therapeutically active 4-spectinomycylamine"

Denne oppfinnelse angår■nye spectinomycylaminderivater med den generelle formel I This invention relates to new spectinomycylamine derivatives of the general formula I

og syreaddisjonssalter derav med uorganiske eller organiske syrer, hvis forbindelsene med den generelle formel I inneholder basiske rester, og fremgangsmåte for fremstilling derav. and acid addition salts thereof with inorganic or organic acids, if the compounds of the general formula I contain basic residues, and process for their preparation.

Forbindelsene med den generelle formel I er verdifulle mellomprodukter for fremstilling av den sterkt antimikrobielt aktive forbindelse 4-spectinomycylamin. The compounds of the general formula I are valuable intermediates for the preparation of the highly antimicrobially active compound 4-spectinomycylamine.

I den ovenstående generelle formel I betyrIn the above general formula I means

X en organisk gruppe som er kjent fra peptidkjemien og som lett kan avspaltes ved behandling med syrer, baser eller ved reduksjon, f.eks. en benzyloksykarbonylgruppe, en 4-brom- eller 4-nitro-eller 4-klor-benzyloksykarbonylgruppe, en 4-metoksy- eller 3,4-dimetoksy- eller 3,4-metylen-dihydroksy- eller 3,4,5-trimetoksy-eller 4-decyloksy- eller 4-acetoksy- eller 4-etoksykarbonyloksy-benzyloksykarbonylgruppe, en mettet eller umettet alkoksykarbonylgruppe med 1 til 12 karbonatomer som eventuelt kan være substituert med en furyl-(2)-gruppe, en p-tolylsulfonylgruppe, ett eller flere halogenatomer, en alkoksy- eller alkoksyalkoksygruppe med 1 til 3 karbonatomer i alkyIdelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-metoksykarbonyl-, allyloksykarbonyl-, 2- (p-tolylsulfonyl)-etoksykarbonyl-, 2-brom-etoksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, 2-(2-metoksyetoksy)etoksykarbonyl-, 3- metyl-pentyl-(3)-oksykarbonylgruppe, særlig tert.butyloksy-karbonyl, en cykloalkyloksykarbonylgruppe med 5 til 12 karbonatomer, så som en cyklopentyloksykarbonyl- eller cykloheksyloksykarbonylgruppe som begge kan være substituert med en metyl-, X an organic group which is known from peptide chemistry and which can be easily split off by treatment with acids, bases or by reduction, e.g. a benzyloxycarbonyl group, a 4-bromo- or 4-nitro- or 4-chloro-benzyloxycarbonyl group, a 4-methoxy- or 3,4-dimethoxy- or 3,4-methylene-dihydroxy- or 3,4,5-trimethoxy- or 4-decyloxy- or 4-acetoxy- or 4-ethoxycarbonyloxy-benzyloxycarbonyl group, a saturated or unsaturated alkoxycarbonyl group with 1 to 12 carbon atoms which may optionally be substituted with a furyl-(2) group, a p-tolylsulfonyl group, one or more halogen atoms, an alkoxy or alkoxy alkoxy group with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkylene part, e.g. a furyl-(2)-methoxycarbonyl-, allyloxycarbonyl-, 2-(p-tolylsulfonyl)ethoxycarbonyl-, 2-bromoethoxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, 2-(2-methoxyethoxy)ethoxycarbonyl -, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxy-carbonyl, a cycloalkyloxycarbonyl group with 5 to 12 carbon atoms, such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group which may both be substituted with a methyl-,

etyl- eller tert.butylgruppe, en isobornyloksykarbonyl- eller adamantyl-(1)-oksykarbonylgruppe, en fenyl- eller bifenylalkoksy-karbonylgruppe som i fenylresten kan være substituert med 1 til 3 metyl- eller metoksygrupper og hvis alkylengruppe, som kan være lineær eller forgrenet, inneholder 2 til 4 karbonatomer, som f.eks. en a,a-dimetyl-3,5-dimetoksy-benzyloksykarbonyl- eller 2-[bifenylyl-(4)]-propyl-(2)-oksykarbonylgruppe, en difenylmetoksykarbonyl-gruppe, en fenyloksykarbonylgruppe som eventuelt kan være substituert med en nitro-, metoksy- eller metylgruppe, en dialkylaminooksykarbonylgruppe så som en dimetylaminooksykarbonylgruppe eller en piperidinooksykarbonylgruppe, en alkyltiokarbonylgruppe med 1 til 4 karbonatomer i alkylresten, en benzyltiokarbonyl-gruppe, en formylgruppe eller en annen alifatisk acylgruppe med ethyl or tert.butyl group, an isobornyloxycarbonyl or adamantyl-(1)-oxycarbonyl group, a phenyl or biphenyl alkoxycarbonyl group which in the phenyl radical may be substituted with 1 to 3 methyl or methoxy groups and whose alkylene group, which may be linear or branched , contains 2 to 4 carbon atoms, such as e.g. an α,α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl- or 2-[biphenylyl-(4)]-propyl-(2)-oxycarbonyl group, a diphenylmethoxycarbonyl group, a phenyloxycarbonyl group which may optionally be substituted with a nitro- , methoxy or methyl group, a dialkylaminooxycarbonyl group such as a dimethylaminooxycarbonyl group or a piperidinoxycarbonyl group, an alkylthiocarbonyl group with 1 to 4 carbon atoms in the alkyl residue, a benzylthiocarbonyl group, a formyl group or another aliphatic acyl group with

1 til 10 karbonatomer som eventuelt kan være substituert med1 to 10 carbon atoms which may optionally be substituted with

1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, f.eks. en trifluoracetyl-, acetoacetyl-, 2-nitrofenoksyacetyl-, monokloracetyl-, 3-klor-butyroyl-, 3-hydroksy-isbkaproylgruppe, o.g dessuten kan X bety en benzoyl-, 2-nitrobenzoyl-, 4-toluensulfonyl-, benzylsulfonyl- eller p-metoksybenzensulfonylgruppe, eller også en benzyl- eller tritylgruppe. 1 to 3 halogen atoms, hydroxy groups, acyl residues or with a nitro group, e.g. a trifluoroacetyl-, acetoacetyl-, 2-nitrophenoxyacetyl-, monochloroacetyl-, 3-chloro-butyroyl-, 3-hydroxy-isbcaproyl group, etc. X can also mean a benzoyl-, 2-nitrobenzoyl-, 4-toluenesulfonyl-, benzylsulfonyl- or p-methoxybenzenesulfonyl group, or also a benzyl or trityl group.

Forbindelsene med den generelle formel I kan frem-The compounds with the general formula I can produce

stilles som følger:set as follows:

1) Fra forbindelser med den generelle formel1) From compounds with the general formula

hvor X har de ovenfor angitte betydninger, ved omsetning med ammoniumsalter i nærvær av metallborhydrider. where X has the meanings given above, by reaction with ammonium salts in the presence of metal borohydrides.

Omsetningen foretas i vann eller i organiske oppløsnings-midler, fortrinnsvis i alkoholer, eller i blandinger av de angitte oppløsningsmidler, ved temperaturer mellom 0 og 100°C, fortrinnsvis mellom 0 og 50°C. Som ammoniumsalter kan f.eks. anvéndes saltene av ammoniakk med halogenhydrogensyrer, svovelsyre, fosforsyre og salpetersyre, som metallborhydrider fortrinnsvis alkalicyanborhydrider. The reaction is carried out in water or in organic solvents, preferably in alcohols, or in mixtures of the specified solvents, at temperatures between 0 and 100°C, preferably between 0 and 50°C. As ammonium salts, e.g. the salts of ammonia with hydrohalogen acids, sulfuric acid, phosphoric acid and nitric acid are used, as metal borohydrides, preferably alkali cyanoborohydrides.

2) Ved reduksjon av forbindelser med den generelle formel 2) When reducing compounds with the general formula

hvor X<1>har de følgende betydninger: where X<1> has the following meanings:

en mettet eller umettet alkoksykarbonylgruppe med 1 til 12 karbonatomer som eventuelt kan være substituert med en furyl-(2)-gruppe, en p-tolylsulfonylgruppe, ett eller flere halogenatomer, en alkoksy- eller alkoksy-alkoksygruppe med 1 til 3 karbonatomer i alkyldelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-metoksykarbonyl-, allyloksykarbonyl-, 3-(p-tolyl-sulfonyl)-etoksykarbonyl-, 2-brometoksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, 2-(2-metoksyetoksy)-etoksykarbonyl-, 3-metyl-pentyl-(3)-oksykarbonylgruppe, særlig tert.butyloksykarbonyl, a saturated or unsaturated alkoxycarbonyl group with 1 to 12 carbon atoms which may optionally be substituted with a furyl-(2) group, a p-tolylsulfonyl group, one or more halogen atoms, an alkoxy or alkoxy-alkoxy group with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkylene moiety, e.g. a furyl-(2)-methoxycarbonyl-, allyloxycarbonyl-, 3-(p-tolyl-sulfonyl)-ethoxycarbonyl-, 2-bromomethoxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, 2-(2-methoxyethoxy)- ethoxycarbonyl, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxycarbonyl,

en cykloalkyloksykarbonylgruppe med 5 til 12 karbonatomer så som en cyklopentyloksykarbonyl- eller cykloheksyloksykarbonylgruppe,. som begge kan være substituert med en metyl-, etyl-,eller tert.-butylgruppe, en isobornyloksykarbonyl- eller adamantyl-(1)-oksy-karbonylgruppe , en fenyloksykarbonylgruppe som eventuelt kan være substituert med en nitro-, metoksy- eller metylgruppe, en formylgruppe eller en annen alifatisk acylgruppe med 1 til 10 karbonatomer som eventuelt kan være substituert med 1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, så som en trifluoracetyl-, acetoacetyl-, 2-nitro-fenoksy-acetyl-, monokloracetyl-, 3-klor-butyroyl-, 3-hydroksyisopropylgruppe og dessuten kan X' bety en benzoyl-, 2-nitrobenzoyl-, 4-toluensulfohyl-, benzylsulfonyl- eller p-metoksybenzensulfonylgruppe, a cycloalkyloxycarbonyl group of 5 to 12 carbon atoms such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group. both of which can be substituted with a methyl, ethyl or tert.-butyl group, an isobornyloxycarbonyl or adamantyl-(1)-oxycarbonyl group, a phenyloxycarbonyl group which can optionally be substituted with a nitro, methoxy or methyl group, a formyl group or another aliphatic acyl group with 1 to 10 carbon atoms which may optionally be substituted with 1 to 3 halogen atoms, hydroxy groups, acyl residues or with a nitro group, such as a trifluoroacetyl-, acetoacetyl-, 2-nitro-phenoxy-acetyl-, monochloroacetyl -, 3-chloro-butyroyl, 3-hydroxyisopropyl group and furthermore X' can mean a benzoyl, 2-nitrobenzoyl, 4-toluenesulfoyl, benzylsulfonyl or p-methoxybenzenesulfonyl group,

og Y betyr en hydroksygruppe, en alkoksygruppe med 1 til 10 and Y means a hydroxy group, a 1 to 10 alkoxy group

karbonatomer, en fenalkoksygruppe med ialt 7 til 12 karbonatomer, carbon atoms, a phenalkoxy group with a total of 7 to 12 carbon atoms,

eller gruppen med formelen or the group with the formula

hvor og R2betyr hydrogenatomer, alkylgrupper med 1 til 6 karbonatomer, fenalkylgrupper med ialt 7 til 10 karbonatomer eller en fenylgruppe, hvor også kan bety en alifatisk acylgruppe med 1 til 10 karbonatomer eller en benzoylgruppe hvis R2 har en av de andre ovenfor angitte betydninger, eller en gruppe med formelen where and R 2 means hydrogen atoms, alkyl groups with 1 to 6 carbon atoms, phenalkyl groups with a total of 7 to 10 carbon atoms or a phenyl group, where can also mean an aliphatic acyl group with 1 to 10 carbon atoms or a benzoyl group if R 2 has one of the other meanings stated above, or a group with the formula

hvor R3og R^ where R 3 and R 3

betyr hydrogenatomer, alkylgrupper med 1 til 6 karbonatomer, fenalkylgrupper med 7 til 10 karbonatomer eller en fenylgruppe, hvor R^og R^sammen med det mellomliggende karbonatom også kan danne en 5- til 8-leddet karbocyklisk ring. means hydrogen atoms, alkyl groups with 1 to 6 carbon atoms, phenalkyl groups with 7 to 10 carbon atoms or a phenyl group, where R^ and R^ together with the intermediate carbon atom can also form a 5- to 8-membered carbocyclic ring.

For reduksjonen anvendes hensiktsmessig katalytisk hydrogenering i nærvær av metallkatalysatorer så som platina-, palladium- eller platinadioksyd-katalysatorer. Hydrogeneringen foretas i vann, i organiske oppløsningsmidler så som alkoholer, karboksylsyrer, dioksan, tetrahydrofuran eller i blandinger av de angitte oppløsningsmidler ved temperaturer mellom 0 og 100°C, fortrinnsvis mellom 20 og 50°C, og ved trykk mellom 1 og 100 atm. For the reduction, catalytic hydrogenation is suitably used in the presence of metal catalysts such as platinum, palladium or platinum dioxide catalysts. The hydrogenation is carried out in water, in organic solvents such as alcohols, carboxylic acids, dioxane, tetrahydrofuran or in mixtures of the stated solvents at temperatures between 0 and 100°C, preferably between 20 and 50°C, and at pressures between 1 and 100 atm.

Fordelaktig foretas hydrogeneringen i nærvær av en uorganisk eller organisk syre så som hydrogenklorid, hydrogenbromid, trifluoreddiksyre, metansulfonsyre eller triklormetansulfonsyre. Advantageously, the hydrogenation is carried out in the presence of an inorganic or organic acid such as hydrogen chloride, hydrogen bromide, trifluoroacetic acid, methanesulfonic acid or trichloromethanesulfonic acid.

Hvis forbindelsene med den generelle formel I inneholder en basisk rest, kan de overføres til sine syreaddisjonssalter med uorganiske eller organiske syrer ved kjente metoder. Som syrer anvendes hensiktsmessig f.eks. klorhydrogensyre, svovelsyre, fosforsyr-e, maleinsyre, fumarsyre, sitronsyre eller vinsyre. If the compounds of the general formula I contain a basic residue, they can be converted to their acid addition salts with inorganic or organic acids by known methods. Suitable acids are used e.g. hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid or tartaric acid.

Utgangsforbindelsene med den generelle formel II erThe starting compounds of the general formula II are

kjent fra litteraturen (kfr. P.F. Wiley, A.D. Argoudelis og H. Hoeksema, J. Am. Chem. Soc' 85, 2652-2659 [1963]) eller kan fremstilles ved i og for seg kjente metoder. known from the literature (cf. P.F. Wiley, A.D. Argoudelis and H. Hoeksema, J. Am. Chem. Soc' 85, 2652-2659 [1963]) or can be prepared by methods known per se.

Utgangsforbindelsene med den generelle formel III fremstilles ved at man omsetter forbindelser med den generelle formel II med forbindelser med den generelle formel NH^-Y, hvor Y har den ovenfor angitte betydning. Omsetningen foretas i vann eller i et organisk oppløsningsmiddel, så som etanol, metanol, The starting compounds of the general formula III are prepared by reacting compounds of the general formula II with compounds of the general formula NH 2 -Y, where Y has the above meaning. The reaction is carried out in water or in an organic solvent, such as ethanol, methanol,

isopropanol, iseddik, forskjellige estere eller etere så som dioksan, eller i blandinger av slike oppløsningsmidler ved temperaturer mellom 0 og 100°C. isopropanol, glacial acetic acid, various esters or ethers such as dioxane, or in mixtures of such solvents at temperatures between 0 and 100°C.

Spectinomycinderivatene med den generelle formel I er mellomprodukter for syntese av forbindelser med verdifulle biologiske egenskaper. Således kan forbindelsene med den generelle formel I ved avspaltning av resten X f.eks. omdannes til 4-spectinomycylamin med formelen The spectinomycin derivatives of the general formula I are intermediates for the synthesis of compounds with valuable biological properties. Thus, the compounds with the general formula I can, by splitting off the residue X, e.g. is converted to 4-spectinomycylamine with the formula

Denne forbindelse er i besittelse av meget gode This compound is in possession of very good

antimikrobielle egenskaper.antimicrobial properties.

4R-spectinomycylamin med formel IV ble sammenlignet med det kjente spectinomycin med hensyn til virkningen mot Staphylococcus aureus SG 511, Streptococcus Aronson, Escherichia Coli ATCC 96 37, Pseudomonas aeruginosa, Serratia marcescens ATCC 13 880, Klebsiella pneumoniae ATCC 10 031, Proteus mirabilis og Proteus vulgaris og med hensyn til den aktutte toksisitet. 4R-spectinomycylamine of formula IV was compared with the known spectinomycin with regard to its activity against Staphylococcus aureus SG 511, Streptococcus Aronson, Escherichia Coli ATCC 96 37, Pseudomonas aeruginosa, Serratia marcescens ATCC 13 880, Klebsiella pneumoniae ATCC 10 031, Proteus mirabilis and Proteus vulgaris and with regard to the current toxicity.

For undersøkelsene ble metoden med rekkefortynningstestFor the investigations, the method was a serial dilution test

i mikrotitersystem anvendt. Undersøkelse av forbindelsene på bakteristase ble foretatt i flytende medium. Bakteriostase-virkningen ble undersøkt ved følgende konsentrasjoner: 80, 40, in microtiter system used. Investigation of the compounds on bacterial stasis was carried out in liquid medium. The bacteriostasis effect was investigated at the following concentrations: 80, 40,

20, 10, 5, 2,5,1,25, 0,6 og 0,3 yg/ml. Som næringsmedium tjente en buljong av 5 g pepton, 3 g kjøttekstrakt, fortynnet med destillert vann til et volum på 1000 ml, pH-verdi 6,7. Primær-kulturens alder var 24 timer. Innstilling av kimsuspensjonen ble foretatt på fotometer (ifølge "Eppendorf") (reagensglass-tverrsnitt 14 mm, filter 546 nm) ved hjelp av uklarheten i en bariumsulfat-sammenligningssuspensjon oppnådd med en bariumsulfat-oppslemning som ble dannet ved tilsetning av 3,0 ml l%ig bariumklorid-oppløsning i 97 ml l%ig svovelsyre. Efter innstillingen ble Streptococcus Aronson fortynnet videre i forholdet 1:150 og de øvrige pr.øvekim i forholdet 1:1500 med en koksaltoppløsning. 16 mg av den aktuelle forbindelse ble veiet inn i 10 ml målekolber og fortynnet med oppløsningsmiddel til merket. Den videre fortynningsrekke ble fremstilt med destillert vann eller det passende oppløsningsmiddel. 20, 10, 5, 2.5, 1.25, 0.6 and 0.3 ug/ml. A broth of 5 g of peptone, 3 g of meat extract, diluted with distilled water to a volume of 1000 ml, pH value 6.7, served as a nutrient medium. The age of the primary culture was 24 hours. Adjustment of the germ suspension was made on a photometer (according to "Eppendorf") (tube cross-section 14 mm, filter 546 nm) by means of the turbidity of a barium sulfate comparison suspension obtained with a barium sulfate slurry formed by adding 3.0 ml l 1% barium chloride solution in 97 ml 1% sulfuric acid. After the setting, Streptococcus Aronson was further diluted in a ratio of 1:150 and the other practicum germs in a ratio of 1:1500 with a sodium chloride solution. 16 mg of the compound in question was weighed into 10 ml volumetric flasks and diluted with solvent to the mark. The further dilution series was made with distilled water or the appropriate solvent.

Fordypningene i mikrotiterplatene ble fyllt med 0,2 ml næringsmedium,.0,01 ml av den ønskede fortynning av prøve-forbindelsene og 1 dråpe kimsuspensjon, og det hele ble dyrket i 18 til 20 timer ved 37°C. En oppløsningsmiddelkontroll ble alltid tatt med. The wells in the microtiter plates were filled with 0.2 ml of nutrient medium, 0.01 ml of the desired dilution of the test compounds and 1 drop of germ suspension, and the whole was grown for 18 to 20 hours at 37°C. A solvent control was always included.

Avlesningen ble foretatt makroskopisk, idet grense-konsentrasjonen (= laveste, ennu ikke bakteriostatisk aktive konsentrasjon) ble funnet. The reading was carried out macroscopically, as the limit concentration (= lowest, not yet bacteriostatically active concentration) was found.

I den følgende tabell er de fundne konsentrasjoner resp. minimale hemmende konsentrasjoner for begge ovennevnte forbindelser angitt. In the following table, the concentrations found are resp. minimum inhibitory concentrations for both of the above compounds indicated.

Verdiene i parentes betyr de konsentrasjoner hvor man kunne se en vekstreduksjon, men ingen fullstendig vekststillstand. The values in parentheses mean the concentrations where a reduction in growth could be seen, but no complete cessation of growth.

Den akutte toksisitet ble bestemt ved peroral og subkutan administrering av begge forbindelser til hvite laboratoriemus i stigende doser. LD5q er ^en dose som fører til at 50% av dyrene dør i løpet av 8 dager efter administrering. Begge forbindelsene viste en LD^^ over 5 g/kg, idet ved 5 g/kg døde ingen dyr med noen av forbindelsene. Efter subkutan injeksjon har begge forbindelser en LD^0 på over 1000 mg/kg, hvilket betyr at de i praksis er fullstendig ugiftige. The acute toxicity was determined by oral and subcutaneous administration of both compounds to white laboratory mice in increasing doses. LD5q is a dose that causes 50% of the animals to die within 8 days of administration. Both compounds showed an LD^^ above 5 g/kg, since at 5 g/kg no animals died with either compound. After subcutaneous injection, both compounds have an LD^0 of over 1000 mg/kg, which means that they are practically completely non-toxic.

Eksempel på fremstilling av utgangsproduktene: Example of production of the output products:

6 , 8- bis-( 3, 3 , 3- trikloretoksykarbonylspectinomycin- benzyloksim6,8-bis-(3,3,3-trichloroethoxycarbonylspectinomycin-benzyloxime

6 g (0,008 mol) 6 ,8-bis-3 ,3 ,(3-trikloretoksykarbonylspectinomycin og 1,5 g (0,01 mol) O-benzylhydroksylamin-hydroklorid oppløses i 40 ml dioksan og 40 ml vann. Ved tilsetning av 4N natronlut innstilles pH-verdien på 3 til 4. Efter 18 timers omrøring ved romtemperatur røres blandingen inn i 150 ml vann og ekstraheres med etylacetat. Den organiske fase tørres og inndampes. Man får 6 g farveløst produkt (93% av det teoretiske). Dissolve 6 g (0.008 mol) 6,8-bis-3,3,(3-trichloroethoxycarbonylspectinomycin and 1.5 g (0.01 mol) O-benzylhydroxylamine hydrochloride in 40 ml dioxane and 40 ml water. By adding 4N caustic soda, the pH value is set to 3 to 4. After 18 hours of stirring at room temperature, the mixture is stirred into 150 ml of water and extracted with ethyl acetate. The organic phase is dried and evaporated. 6 g of colorless product are obtained (93% of the theoretical).

Rf: 0,30 (silikagel, kloroform/metanol = 9:1)Rf: 0.30 (silica gel, chloroform/methanol = 9:1)

NMR (oppløsningsmiddel:deuterokloroform)NMR (solvent: deuterochloroform)

ppm: 1,35 dublett 2H (2-CHg)ppm: 1.35 doublet 2H (2-CHg)

3,15 dublett 6H (-N-CH3)3.15 doublet 6H (-N-CH3)

4.7 singlett lH(10aH)4.7 singlet lH(10aH)

4.8 diffus singlett (-CH2~CC13)4.8 diffuse singlet (-CH2~CC13)

.5,2 singlett 2H (benzyl-CH2).5,2 singlet 2H (benzyl-CH2)

7,4 singlett 5H (fenyl)7.4 singlet 5H (phenyl)

Utgangsmaterialet 6,8-bis-p,3,Ø-trikloretoksykarbonylspectinomycin kan fremstilles ved'den metode som er angitt i J. Antibiotics XXVIII, s. 140 (1975) for 6,8-bisbenzyloksykarbonyl-4-dihydro-spectinomycin, fra spectinomycin og klormaursyre-3,3,3-triklor-etylester. The starting material 6,8-bis-p,3,O-trichloroethoxycarbonylspectinomycin can be prepared by the method indicated in J. Antibiotics XXVIII, p. 140 (1975) for 6,8-bisbenzyloxycarbonyl-4-dihydro-spectinomycin, from spectinomycin and chloroformic acid 3,3,3-trichloroethyl ester.

Rf: 0,26 (silikagel, kloroform/metanol (11:1).Rf: 0.26 (silica gel, chloroform/methanol (11:1).

På samme måte ble følgende forbindelser fremstilt:In the same way, the following compounds were prepared:

a) 6,8-bis-p-metoksybenzensulfonylspectinomycin-oksim fra 6,8-bis-p-metoksybenzensulfonylspectinomycin og hydroksylamin. a) 6,8-bis-p-methoxybenzenesulfonylspectinomycin oxime from 6,8-bis-p-methoxybenzenesulfonylspectinomycin and hydroxylamine.

Rf: 0,32 (silikagel, kloroform/metanol = 11:1)Rf: 0.32 (silica gel, chloroform/methanol = 11:1)

Utgangsmaterialet 6,8-bis-p-metoksybenzensulfonylspectinomycin ble, som angitt ovenfor, erholdt fra p-metoksybenzensulfoklorid og spectinomycin. The starting material 6,8-bis-p-methoxybenzenesulfonylspectinomycin was, as indicated above, obtained from p-methoxybenzenesulfochloride and spectinomycin.

Rf: 0,40 (silikagel, kloroform/metanol =9:1)Rf: 0.40 (silica gel, chloroform/methanol =9:1)

b) 6,8-bis-3/3,3-trikloretoksykarbonylspectinomycin-metyloksim fra 6,8-bis~3,3?3_trikloretoksykarbonylspectinomycin og 0-metyl-hydroksylamin, b) 6,8-bis-3/3,3-trichloroethoxycarbonylspectinomycin-methyloxime from 6,8-bis~3,3?3_trichloroethoxycarbonylspectinomycin and 0-methyl-hydroxylamine,

Rf: 0,27 (silikagel,. kloroform/metanol = 11:1).Rf: 0.27 (silica gel, chloroform/methanol = 11:1).

c) 6,8-bis-3,3, 3-trikloretoksykarbonylspectinomycin-benzhydrazon fra 6,8-bis-Ø,0,3-trikloretoksykarbonylspectinomycin c) 6,8-bis-3,3,3-trichloroethoxycarbonylspectinomycin benzhydrazone from 6,8-bis-Ø,0,3-trichloroethoxycarbonylspectinomycin

og benzhydrazid.and benzhydrazide.

Rf: 0,26 (silikagel, kloroform/metanol =11:1)Rf: 0.26 (silica gel, chloroform/methanol = 11:1)

d) 6 , 8-bis-(3 , 3 / Ø-trikloretoksykarbonylspectinomycin-acethydrazon fra 6,8-bis-Ø,3,3~trikloretoksykarbonylspectinomycin d) 6, 8-bis-(3, 3 / Ø-trichloroethoxycarbonylspectinomycin-acethydrazone from 6,8-bis-Ø,3,3~trichloroethoxycarbonylspectinomycin

og acethydrazid.and acethydrazide.

Rf: 0,25 (silikagel, kloroform/metanol = 11:1).Rf: 0.25 (silica gel, chloroform/methanol = 11:1).

e) 6,8-bis-isobornyloksykarbonylspectinomycin-benzyloksim fra 6,8-bis-isobornyloksykarbonylspectinomycin og 0-benzyl-hydroksylamin . e) 6,8-bis-isobornyloxycarbonylspectinomycin-benzyl oxime from 6,8-bis-isobornyloxycarbonylspectinomycin and O-benzyl-hydroxylamine.

Rf: 0,55 (silikagel, kloroform/metanol = 10:1),Rf: 0.55 (silica gel, chloroform/methanol = 10:1),

Smeltepunkt: 120°C (spaltning) .Melting point: 120°C (decomposition).

Utgangsmaterialet ble, som angitt ovenfor, fremstilt fra spectinomycin og isobornyloksykarbonylklorid. The starting material was, as indicated above, prepared from spectinomycin and isobornyloxycarbonyl chloride.

Rf: 0,42 (silikagel, kloroform/metanol = 10:1).Rf: 0.42 (silica gel, chloroform/methanol = 10:1).

Eksempler på fremstilling av sluttproduktet:Examples of the production of the final product:

Eksempel 1Example 1

6, 8- bis- benzyloksykarbonylspectinomycylamin6,8-bis-benzyloxycarbonylspectinomycylamine

1,85 g. (0,003 mol) 6,8-bis-benzyloksykarbonylspectinomycin og 2,4 g.ammoniumnitrat oppløses i 15 ml absolutt metanol og omrøres i 15 minutter ved 40°C. Derefter tilsettes prosjonsvis 0,131 g natriumcyanborhydrid i løpet av 3 minutter ved 20°C. 1.85 g (0.003 mol) of 6,8-bis-benzyloxycarbonylspectinomycin and 2.4 g of ammonium nitrate are dissolved in 15 ml of absolute methanol and stirred for 15 minutes at 40°C. 0.131 g of sodium cyanoborohydride is then added portionwise over the course of 3 minutes at 20°C.

Efter 30 minutter ved romtemperatur foretas avsugning, filtratet røres inn i 70 ml av en mettet koksaltoppløsning, ekstraheres med etylacetat, ekstrakten tørres og inndampes. Residuet utgnies med eter og avsuges. Dette residuum (1,2 g) kromatograferes på silikagel (kloroform/metanol = 5:1) . Man får 0,-6 g av et f arveløst pulver med spaltningsområde 110-130°C. After 30 minutes at room temperature, suction is carried out, the filtrate is stirred into 70 ml of a saturated sodium chloride solution, extracted with ethyl acetate, the extract is dried and evaporated. The residue is triturated with ether and filtered off with suction. This residue (1.2 g) is chromatographed on silica gel (chloroform/methanol = 5:1). 0.6 g of a colorless powder with a decomposition range of 110-130°C is obtained.

<C>30<H>39<N>3°10 ra°lekylvekt.601,66 '<C>30<H>39<N>3°10 ra°lekyl weight.601.66 '

Beregnet: C 58,89, H 6,53, N 6,57Calculated: C 58.89, H 6.53, N 6.57

Funnet: 5 9,10 6,9 9 6,76 Found: 5 9.10 6.9 9 6.76

Massespektrum for den silylerte forbindelse:Mass spectrum for the silylated compound:

M<+>: 817 = 601 + 3x72 (3 silylrester)M<+>: 817 = 601 + 3x72 (3 silyl residues)

745 = 601 + 2x72 (2 silylrester)745 = 601 + 2x72 (2 silyl residues)

Rf: 0,47 (silikagel, kloroform/metanol = 5:1)Rf: 0.47 (silica gel, chloroform/methanol = 5:1)

På samme måte ble fremstilt:In the same way was produced:

a) 6,8-bis-p-metoksybenzensulfonylspectinomycylamin fra 6,8-bis-p-metoksybenzensulfonylspectinomycin, ammoniumnitrat og a) 6,8-bis-p-methoxybenzenesulfonylspectinomycin from 6,8-bis-p-methoxybenzenesulfonylspectinomycin, ammonium nitrate and

natriumcyanborhydrid.sodium cyanoborohydride.

Rf: 0,55 (silikagel, kloroform/metanol = 9:1)Rf: 0.55 (silica gel, chloroform/methanol = 9:1)

b) 6 ,8-bis-Ø ,0 , Ø-trikloretoksykarbonylspectinomycylamin fra 6,8-bis-Ø,0,Ø-trikloretoksykarbonylspectinomycin, ammoniumnitrat b) 6,8-bis-Ø,0,Ø-trichloroethoxycarbonylspectinomycylamine from 6,8-bis-Ø,0,Ø-trichloroethoxycarbonylspectinomycin, ammonium nitrate

og natriumcyanborhydrid.and sodium cyanoborohydride.

Rf: 0,41 (silikagel, kloroform/metanol = 9:2)Rf: 0.41 (silica gel, chloroform/methanol = 9:2)

Massespektrum for den silylerte forbindelse:Mass spectrum for the silylated compound:

•M<+>: 969 = 681 + 4x72 (4 silylrester)•M<+>: 969 = 681 + 4x72 (4 silyl residues)

Beregnet molekylvekt: 6 84,18.Calculated molecular weight: 6 84.18.

c) 6,8-bis-isobornyloksykarbonylspectinomycylamin fra 6,8-bis-isobornyloksykarbonylspectinomycin, ammoniumnitrat og c) 6,8-bis-isobornyloxycarbonylspectinomycylamine from 6,8-bis-isobornyloxycarbonylspectinomycin, ammonium nitrate and

natriumcyanborhydrid.sodium cyanoborohydride.

Massespektrum for den silylerte forbindelse:Mass spectrum for the silylated compound:

M<+>: 909 = 693 + 3x72 (3 silylrester)M<+>: 909 = 693 + 3x72 (3 silyl residues)

837 = 693 + 2x72 (2 silylrester)837 = 693 + 2x72 (2 silyl residues)

693 = beregnet molekylvekt693 = calculated molecular weight

Smeltepunkt: 160°C (spaltning)Melting point: 160°C (decomposition)

d) 6,8-bis-4-metoksybenzyloksykarbonylspectinomycylamin fra 6,8-bis-4-metoksybenzyloksykarbonylspectinomycin, ammoniumnitrat d) 6,8-bis-4-methoxybenzyloxycarbonylspectinomycylamine from 6,8-bis-4-methoxybenzyloxycarbonylspectinomycin, ammonium nitrate

og natriumcyanborhydrid.and sodium cyanoborohydride.

Rf: 0,29 (silikagel, kloroform/metanol 5:1)Rf: 0.29 (silica gel, chloroform/methanol 5:1)

Massespektrum for den silylerte forbindelse:Mass spectrum for the silylated compound:

M<+>: 877 = 661 + 3x72 (3 silylrester)M<+>: 877 = 661 + 3x72 (3 silyl residues)

Beregnet molekylvekt: 661,6.Calculated molecular weight: 661.6.

Utgangsmaterialet 6,8-bis-4-metoksybenzyloksykarbonyl-spectinomycin kan fremstilles ved den metode som er beskrevet i J. Antibiotics XXVIII, s. 140 (1975) for 6,8-bisbenzyloksykarbonyl-4-dihydrospectinomycin, fra spectinomycin og klormaursyre-4-metoksybenzylester. The starting material 6,8-bis-4-methoxybenzyloxycarbonylspectinomycin can be prepared by the method described in J. Antibiotics XXVIII, p. 140 (1975) for 6,8-bisbenzyloxycarbonyl-4-dihydrospectinomycin, from spectinomycin and chloroformate-4- methoxybenzyl ester.

Rf: 0,32 (silikagel, kloroform/metanol (11:1). Rf: 0.32 (silica gel, chloroform/methanol (11:1).

Klormaursyre-4-metoksybenzylesteren fremstilles fra 4-metoksy-benzylalkohol og fosgen i tetrahydrofuran ved -15°C og omsettes videre ved denne temperatur i oppløsning på grunn av sin ustabilitet. The chloroformic acid 4-methoxybenzyl ester is prepared from 4-methoxybenzyl alcohol and phosgene in tetrahydrofuran at -15°C and is further reacted at this temperature in solution due to its instability.

Eksempel 2 Example 2

6, 8- bis- isobornyroksykarbonyl- spectinomycylamin6, 8- bis-isobornoxycarbonyl-spectinomycylamine

7,98 g (0,01 mol) 6,8-bis-isobornyloksykarbonyl-spectinomycylbenzyloksim, oppløst i 150 ml 3%ig etanolisk saltsyre, reduseres i nærvær av 8 g platinaoksyd med hydrogen ved 25°C. 7.98 g (0.01 mol) of 6,8-bis-isobornyloxycarbonyl-spectinomycylbenzyloxime, dissolved in 150 ml of 3% ethanolic hydrochloric acid, is reduced in the presence of 8 g of platinum oxide with hydrogen at 25°C.

(hydrogentrykk: 5 atmosfærer; reaksjonstid: 6 2 timer eller 50 atmosfærer ved en reaksjonstid på 30 timer). (hydrogen pressure: 5 atmospheres; reaction time: 6 2 hours or 50 atmospheres for a reaction time of 30 hours).

Efter avsluttet reduksjon frafiltreres katalysatoren, og etanolen avdestilleres i vakuum. Man oppløser det gjenværende, faste residuum i vann, innstiller oppløsningens pH-verdi på 3,5 After completion of the reduction, the catalyst is filtered off, and the ethanol is distilled off in a vacuum. The remaining solid residue is dissolved in water, the solution's pH value is set to 3.5

og fraskiller biproduktene ved ekstraksjon med eter. Derefter and separates the by-products by extraction with ether. After that

■forhøyes oppløsningens pH-verdi til 7, og den ekstraheres påny■the pH value of the solution is increased to 7, and it is extracted again

med eter. Efter tørring med natriumsulfat og avdrivning av eteren får man det ønskede produkt i form av et hvitt pulver. with ether. After drying with sodium sulphate and stripping off the ether, the desired product is obtained in the form of a white powder.

Utbytte: 4,1 g (59% av det teoretiske),Yield: 4.1 g (59% of theoretical),

Sm.p.: 160°C (spaltning)Melting point: 160°C (decomposition)

<C>36<H>59<N>3°10(6",97) <C>36<H>59<N>3°10(6",97)

Beregnet: C 49,41, H 6,12, N 8,23Calculated: C 49.41, H 6.12, N 8.23

Funnet: 49,29 6,25 8,37 Found: 49.29 6.25 8.37

Hydrokloridet kan fremstilles ved at man behandler den etanoliske oppløsning av den frie base med eterisk saltsyre. Smeltepunkt: 182-185°C (spaltning). The hydrochloride can be prepared by treating the ethanolic solution of the free base with ethereal hydrochloric acid. Melting point: 182-185°C (decomposition).

På samme mate ble fremstilt:In the same way, the following was produced:

a) 6,8-bis-3,3,3-trikloretoksykarbonylspectinomycylamin fra 6,8-bis-3,3/3_trikloretoksykarbonylspectinomycin-benzyloksim a) 6,8-bis-3,3,3-trichloroethoxycarbonylspectinomycin 6,8-bis-3,3/3_trichloroethoxycarbonylspectinomycin-benzyl oxime

og platinadioksyd.and platinum dioxide.

Rf: 0,41 (silikagel, kloroform/metanol = 9:2)Rf: 0.41 (silica gel, chloroform/methanol = 9:2)

Massespektrum for den silylerte forbindelse:'Mass spectrum of the silylated compound:'

M<+>969 = 681 + 4x72 (4 silylrester)M<+>969 = 681 + 4x72 (4 silyl residues)

897 = 681 + 3x72 (3 silylrester)897 = 681 + 3x72 (3 silyl residues)

825 = 681 +.2x72 (2 silylrester)825 = 681 +.2x72 (2 silyl residues)

Beregnet molekylvekt: 684,18.Calculated molecular weight: 684.18.

b) 6,8-bis-p-metoksybenzensulfonylspectinomycylamin fra 6,8-bis-p-metoksybenzensulfonylspectinomycin-oksim og platinadioksyd. b) 6,8-bis-p-methoxybenzenesulfonylspectinomycin amine from 6,8-bis-p-methoxybenzenesulfonylspectinomycin oxime and platinum dioxide.

Rf: 0,55 (silikagel, kloroform/metanol = 9:1).Rf: 0.55 (silica gel, chloroform/methanol = 9:1).

c) 6 ,8-bis~3,3,3~trikloretoksykarbonylspectinomycylamin fra 6,8-bis-3,3/3~trikloretoksykarbonylspeetinomycin-metyloksim c) 6,8-bis~3,3,3~trichloroethoxycarbonylspectinomycylamine from 6,8-bis-3,3/3~trichloroethoxycarbonylspeetinomycin-methyloxime

og platinadioksyd.and platinum dioxide.

I henhold til blandingskromatogram er produktet identisk 'med det under a) erholdte produkt. According to the mixture chromatogram, the product is identical to the product obtained under a).

d) 6,8-bis-3/3 13-trikloretoksykarbonylspeGtinomycylamin fra 6,8-bis~3,3,3~trikloretoksykarbonylspectinomycin-benzhydrazon d) 6,8-bis-3/3 13-trichloroethoxycarbonylspectinomycin from 6,8-bis~3,3,3~trichloroethoxycarbonylspectinomycin-benzhydrazone

og platinadioksyd.and platinum dioxide.

I henhold til blandingskromatogram er produktet identisk medAccording to the mixture chromatogram, the product is identical to

det under a) erholdte produkt.the product obtained under a).

e) 6,8-bis-3 , 3/3_trikloretoksykarbonylspectinomycylamin fra 6 ,8-bis-3,3,3~trikloretoksykarbonylspectinomycin-acethydrazon e) 6,8-bis-3,3/3-trichloroethoxycarbonylspectinomycin from 6,8-bis-3,3,3-trichloroethoxycarbonylspectinomycin-acethydrazone

og platinadioksyd.and platinum dioxide.

I henhold til blandingskromatogram er produktet identisk med det under a) erholdte produkt. According to the mixture chromatogram, the product is identical to the product obtained under a).

Eksempel på fremstilling av farmakologisk verdifulle produkter: Example of the production of pharmacologically valuable products:

Eksempel 3Example 3

4- R- spectinomycylamin- trihydroklorid4- R-spectinomycylamine trihydrochloride

500 mg 6,8-bisbenzyloksykarbonylspectinomycylamin (R-form) hydrogeneres i 25 ml 3,4%ig etanolisk saltsyre med 500 mg of 6,8-bisbenzyloxycarbonylspectinomycylamine (R-form) is hydrogenated in 25 ml of 3.4% ethanolic hydrochloric acid with

500 mg 20%ig palladiumkull i 2 timer ved romtemperatur i et ristekar. Katalysatoren frafiltreres, filtratet inndampes til 5 ml, og residuet tilsettes 100 ml eter. Man får 230 mg (65% av det teoretiske) farveløst pulver med smeltepunkt 189-194°C. 500 mg of 20% palladium charcoal for 2 hours at room temperature in a shaking vessel. The catalyst is filtered off, the filtrate is evaporated to 5 ml, and the residue is added to 100 ml of ether. You get 230 mg (65% of the theoretical) colorless powder with a melting point of 189-194°C.

Rf: 0,5 (silikagel,. kloroform/metanol/kons. ammoniakk = 40/40/15) Massespektrum for den silylerte forbindelse: Rf: 0.5 (silica gel, chloroform/methanol/con. ammonia = 40/40/15) Mass spectrum for the silylated compound:

M<+>693 = 333 + 5x72 (5 silylrester)M<+>693 = 333 + 5x72 (5 silyl residues)

621 = 333 + 4x72 (4 silylrester621 = 333 + 4x72 (4 silyl residues

549 = 333 + 3x72 (3 silylrester)549 = 333 + 3x72 (3 silyl residues)

477 = 333 + 2x72 (2 silylrester)477 = 333 + 2x72 (2 silyl residues)

Beregnet molekylvekt for den frie base 333. Calculated molecular weight for the free base 333.

Claims (7)

1. Nye spectinomycylaminderivater for anvendelse ved fremstilling av terapeutisk aktivt 4-spectinomycylamin, karakterisert ved at de har den generelle formel I 1. New spectinomycylamine derivatives for use in the production of therapeutically active 4-spectinomycylamine, characterized in that they have the general formula I hvor X betyr en fra peptidkjemien kjent, ved behandling med syrer, baser eller ved reduksjon lett avspaltbar organisk gruppe, og syreaddisjonssalter derav med uorganiske eller organiske syrer.where X means an organic group known from peptide chemistry, when treated with acids, bases or by reduction, easily cleavable, and acid addition salts thereof with inorganic or organic acids. 2. Nye spectinomycylaminderivater som angitt i krav 1 og syreaddisjonssalter derav med uorganiske eller organiske syrer, karakterisert ved at de har den generelle formel I hvor X. betyr en benzyloksykarbonylgruppe, en 4-brom-^ eller 4-nitro- eller 4-klor-benzyloksykarbonylgruppe, en 4-metoksy--eller 3,4-dimetoksy- eller 3,4-metylen-dihydroksy- eller 3,4,5-trimetoksy- eller 4-decyloksy- eller 4-acetoksy- eller 4-etoksy-karbonyloksy-benzyloksykarbonylgruppe, en mettet eller umettet alkoksykarbonylgruppe med 1 til 12 karbonatomer som eventuelt kan være substituert med en furyl-(2)-gruppe, en p-tolylsulfonylgruppe, ett eller flere halogenatomer, en alkoksy- eller alkoksyalkoksygruppe med 1 til 3 karbonatomer i alkyldelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-metoksykarbonyl-, allyloksykarbonyl-, 2-(p-tolylsulfonyl)-etoksykarbonyl-, 2-brom-etoksykarbonyl-, 2,2,2-triklor-etoksykarbony1-, 2-(2-metoksy-etoksy)etoksykarbonyl-, 3-metyl-pentyl-(3)-oksykarbonylgruppe, særlig tert.butyloksykarbonyl, en cykloalkyloksykarbonylgruppe med 5 til 12 karbonatomer, så som en cyklopentyloksykarbonyl- eller cykloheksyloksykarbonylgruppe som begge kan være substituert med en metyl-, etyl- eller tert.butylgruppe, en isob <p> rnyloksykarbony1-eller adamantyl-(1)-oksykarbonylgruppe, en fenyl- eller bifenyl-alkoksykarbonylgruppe som i fenylresten kan være substituert med 1 til 3 metyl- eller metoksygrupper og hvis alkylengruppe, som kan være lineær eller forgrenet, inneholder 2 til 4 karbonatomer, som f.eks.en a,a-dimetyl-3,5-dimetoksy-benzyloksykarbonyl- eller 2-[bifenylyl-(4)]-propyl-(2)-oksykarbonylgruppe, en difenyl-metoksykarbonylgruppe, en fenyloksykarbonylgruppe som eventuelt kan være substituert med en nitro-, metoksy- eller metylgruppe, en dialkylaminooksykarbonylgruppe så som en dimetylaminooksykarbonylgruppe eller en piperidinooksykarbonylgruppe, en alkyltiokarbonylgruppe med 1 til 4 karbonatomer i alkylresten, en benzyl-tiokarbonylgruppe, en formylgruppe eller en annen alifatisk acylgruppe med 1 til 10 karbonatomer som eventuelt kan være substituert med .1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, f.eks.en trifluoracetyl-, acetoacety1-,2. New spectinomycylamine derivatives as specified in claim 1 and acid addition salts thereof with inorganic or organic acids, characterized in that they have the general formula I where X. means a benzyloxycarbonyl group, a 4-bromo-^ or 4-nitro- or 4-chloro- benzyloxycarbonyl group, a 4-methoxy- or 3,4-dimethoxy- or 3,4-methylene-dihydroxy- or 3,4,5-trimethoxy- or 4-decyloxy- or 4-acetoxy- or 4-ethoxy-carbonyloxy- benzyloxycarbonyl group, a saturated or unsaturated alkoxycarbonyl group with 1 to 12 carbon atoms which may optionally be substituted with a furyl-(2) group, a p-tolylsulfonyl group, one or more halogen atoms, an alkoxy or alkoxy alkoxy group with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkylene moiety, e.g. a furyl-(2)-methoxycarbonyl-, allyloxycarbonyl-, 2-(p-tolylsulfonyl)-ethoxycarbonyl-, 2-bromo-ethoxycarbonyl-, 2,2,2-trichloro-ethoxycarbonyl-, 2-(2-methoxy-ethoxy )ethoxycarbonyl-, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxycarbonyl, a cycloalkyloxycarbonyl group of 5 to 12 carbon atoms, such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group both of which may be substituted with a methyl, ethyl or tert .butyl group, an isob<p>rnyloxycarbonyl- or adamantyl-(1)-oxycarbonyl group, a phenyl- or biphenyl-alkoxycarbonyl group which in the phenyl radical may be substituted by 1 to 3 methyl or methoxy groups and whose alkylene group, which may be linear or branched , contains 2 to 4 carbon atoms, such as, for example, an α,α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl- or 2-[biphenylyl-(4)]-propyl-(2)-oxycarbonyl group, a diphenyl-methoxycarbonyl group, a phenyloxycarbonyl group which may optionally be substituted with a nitro, methoxy or methyl group, a dialkylaminooxycarbonyl group such as a dimethylaminooxycarbonyl group or a piperidineoxycarbonyl group, an alkylthiocarbonyl group with 1 to 4 carbon atoms in the alkyl residue, a benzylthiocarbonyl group, a formyl group or another aliphatic acyl group with 1 to 10 carbon atoms which may optionally be substituted with .1 to 3 halogen atoms, hydroxy groups , acyl residues or with a nitro group, e.g. a trifluoroacetyl-, acetoacety1-, 2- nitrofenoksyacetyl-, monokloracety1-, 3-klor-butyroyl-,2- nitrophenoxyacetyl-, monochloroacety1-, 3-chloro-butyroyl-, 3- hydroksy-isokaproylgruppe, og dessuten kan X bety en benzoyl-, 2-nitrobenzoyl-, 4-toluensulfonyl-, benzylsulfonyl- eller p-metoksybenzensulfonylgruppe, eller også en benzyl- eller tritylgruppe.3-hydroxyisocaproyl group, and furthermore X can mean a benzoyl, 2-nitrobenzoyl, 4-toluenesulfonyl, benzylsulfonyl or p-methoxybenzenesulfonyl group, or also a benzyl or trityl group. 3. Nye spectinomycylaminderivater som angitt i krav 1, og syreaddisjonssalter derav med uorganiske eller organiske syrer, karakterisert ved at de har den generelle formel I, hvor X betyr en benzyloksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, isobornyloksykarbonyl- eller p-metoksybenzensulfonylgruppe.3. New spectinomycylamine derivatives as stated in claim 1, and acid addition salts thereof with inorganic or organic acids, characterized in that they have the general formula I, where X means a benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isobornyloxycarbonyl or p-methoxybenzenesulfonyl group. 4. Fremgangsmåte for fremstilling av nye spectinomycylaminderivater med den generelle formel I i henhold til krav 1, 2 og 3, og salter derav med uorganiske eller organiske syrer, karakterisert ved „ ata) forbindelser med den generelle formel II 4. Process for the production of new spectinomycylamine derivatives with the general formula I according to claims 1, 2 and 3, and salts thereof with inorganic or organic acids, characterized by „ata) compounds with the general formula II hvor X er som ovenfor angitt, omsettes med ammoniumsalter i nærvær av metallborhydrider i vann eller i organiske opplø snings- midler ved temperaturer mellom. 0 og 100°C, ellerb) forbindelser med den generelle formel III where X is as indicated above, is reacted with ammonium salts in the presence of metal borohydrides in water or in organic solvents means at temperatures between. 0 and 100°C, orb) compounds of the general formula III hvor X <1> har de følgende betydninger: en mettet eller umettet alkoksykarbonylgruppe med 1 til 12 karbonatomer som eventuelt kan være substituert med en furyl-(2)- gruppe, en p-tolylsulfonylgruppe, ett eller flere halogenatomer, en alkoksy- eller alkoksy-alkoksygruppe med 1 til 3 karbonatomer i alkyldelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-metoksykarbonyl-, allyloksykarbonyl-, 3-(p-tolyl-sulfonyl)-etoksykarbonyl-, 2-brometoksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, 2-(2-metoksyetoksy)-etoksykarbonyl-, 3-metyl-pentyl-(3)-oksykarbonylgruppe, særlig tert.butyloksykarbonyl, en cykloalkyloksykarbonylgruppe med 5 til 12 karbonatomer så som en cyklopentyloksykarbonyl- eller cykloheksyloksykarbonylgruppe, som begge kan være substituert med en metyl-, etyl- eller tert.-butylgruppe, en isobornyloksykarbonyl- eller adamantyl-(1)-oksy-karbonylgruppe , en fenyloksykarbonylgruppe som eventuelt kan være substituert med en nitro-, metoksy- eller metylgruppe, en formylgruppe eller en annen alifatisk acylgruppé med 1 til 10 karbonatomer som eventuelt kan være substituert med 1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, så som en trifluoracetyl-, acetoacety1-, 2-nitro-fenoksy-acetyl-, monokloracetyl-, 3-klor-butyroyl-, 3-hydroksyisopropylgruppe og dessuten kan X' bety en benzoyl-, 2-nitrobenzoy1-, 4-toluensulfonyl-, benzylsulfonyl- eller p-metoksybenzensulfonylgruppe, og Y betyr en hydroksygruppe, en alkoksygruppe med 1 til 10 karbonatomer, en fenalkoksygruppe med ialt 7 til 12 karbonatomer, eller gruppen med formelen where X <1> has the following meanings: a saturated or unsaturated alkoxycarbonyl group with 1 to 12 carbon atoms which may optionally be substituted with a furyl-(2)- group, a p-tolylsulfonyl group, one or more halogen atoms, an alkoxy or alkoxy-alkoxy group with 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkylene part, e.g. a furyl-(2)-methoxycarbonyl-, allyloxycarbonyl-, 3-(p-tolyl-sulfonyl)-ethoxycarbonyl-, 2-bromomethoxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, 2-(2-methoxyethoxy)- ethoxycarbonyl, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxycarbonyl, a cycloalkyloxycarbonyl group of 5 to 12 carbon atoms such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group, both of which may be substituted with a methyl, ethyl or tert.-butyl group, an isobornyloxycarbonyl or adamantyl-(1)-oxycarbonyl group, a phenyloxycarbonyl group which may optionally be substituted with a nitro, methoxy or methyl group, a formyl group or another aliphatic acyl group with 1 to 10 carbon atoms which may optionally be substituted with 1 to 3 halogen atoms, hydroxy groups, acyl residues or with a nitro group, such as a trifluoroacetyl-, acetoacety1-, 2-nitro-phenoxy-acetyl-, monochloroacetyl- , 3-chloro-butyroyl-, 3-hydroxyisopropyl group and furthermore X' can mean a benzoyl-, 2-nitrobenzoyl-, 4-toluenesulfonyl-, benzylsulfonyl or p-methoxybenzenesulfonyl group, and Y means a hydroxy group, an alkoxy group of 1 to 10 carbon atoms, a phenalkoxy group of a total of 7 to 12 carbon atoms, or the group with the formula hvor og R2 betyr hydrogen atomer, alkylgrupper med 1 til 6 karbonatomer, fenalkylgrupper med ialt 7 til 10 karbonatomer eller en fenylgruppe, hvor R-^ også kan bety en alifatisk acylgruppe med 1 til 10 karbonatomer eller en benzoylgruppe hvis R2 har en av de andre ovenfor angitte betydninger, eller en gruppe med formelen where and R 2 means hydrogen atoms, alkyl groups with 1 to 6 carbon atoms, phenalkyl groups with a total of 7 to 10 carbon atoms or a phenyl group, where R-^ can also mean an aliphatic acyl group with 1 to 10 carbon atoms or a benzoyl group if R 2 has one of the others stated above meanings, or a group with the formula hvor R^ og R^ betyr hydrogenatomer, alkylgrupper med 1 til 6 karbonatomer, fenalkylgrupper med 7 til 10 karbonatomer eller en fenylgruppe, hvor R^ og R^ sammen med det mellomliggende karbonatom også kan danne en 5- til 8-leddet karbocyklisk ring, hydrogeneres katalytisk i vann eller i et organisk oppløsnings-middel eller i blandinger av disse oppløsningsmidler, fordelaktig i nærvær av en organisk eller uorganisk syre, ved temperaturer mellom 0 og 100°C ved et trykk på 1 til 100 atm., og eventuelt overføres de således erholdte forbindelser med den generelle formel I til sine salter ved hjelp av uorganiske eller organiske syrer.where R^ and R^ means hydrogen atoms, alkyl groups with 1 to 6 carbon atoms, phenalkyl groups with 7 to 10 carbon atoms or a phenyl group, where R^ and R^ together with the intermediate carbon atom can also form a 5- to 8-membered carbocyclic ring, is hydrogenated catalytically in water or in an organic solvent or in mixtures of these solvents, advantageously in the presence of an organic or inorganic acid, at temperatures between 0 and 100°C at a pressure of 1 to 100 atm., and optionally the thus obtained compounds of the general formula I are transferred to their salts by means of inorganic or organic acids. 5. Fremgangsmåte som angitt i krav 4a, karakterisert ved at det som ammoniumsalter anvendes salter av ammoniakk med halogenhydrogensyrer, svovelsyre, fosforsyre eller salpetersyre, som metallborhydrider alkalicyanborhydrider ved temperaturer mellom 0 og 50°C.5. Method as specified in claim 4a, characterized in that the ammonium salts used are salts of ammonia with hydrohalogen acids, sulfuric acid, phosphoric acid or nitric acid, such as metal borohydrides alkali cyanoborohydrides at temperatures between 0 and 50°C. 6. Fremgangsmåte som angitt i krav 4b, karakterisert ved at det for katalytisk hydrogenering anvendes platina-,•palladium- eller platinadioksyd-katalysatorer, og som oppløsningsmidler anvendes vann, alkoholer, karboksylsyrer, dioksan, tetrahydrofuran eller blandinger av disse.6. Process as stated in claim 4b, characterized in that platinum, palladium or platinum dioxide catalysts are used for catalytic hydrogenation, and water, alcohols, carboxylic acids, dioxane, tetrahydrofuran or mixtures thereof are used as solvents. 7. Anvendelse av en forbindelse med den generelle- formel I i henhold til krav 1 for fremstilling av antibakterielt virksomme 4-spectinomycylaminer.7. Use of a compound with the general formula I according to claim 1 for the production of antibacterially active 4-spectinomycylamines.
NO784298A 1977-12-21 1978-12-20 SPECTINOMYCIN DERIVATIVES FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE NO784298L (en)

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US4523022A (en) * 1983-07-07 1985-06-11 The Upjohn Company Analogs of the antibiotic spectinomycin
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