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NO784297L - SPECTINOMYCIN DERIVATIVES FOR USE IN THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE - Google Patents

SPECTINOMYCIN DERIVATIVES FOR USE IN THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE

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Publication number
NO784297L
NO784297L NO784297A NO784297A NO784297L NO 784297 L NO784297 L NO 784297L NO 784297 A NO784297 A NO 784297A NO 784297 A NO784297 A NO 784297A NO 784297 L NO784297 L NO 784297L
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Norway
Prior art keywords
group
spectinomycin
general formula
substituted
methyl
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NO784297A
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Norwegian (no)
Inventor
Roland Maier
Eberhard Woitun
Wolfgang Reuter
Bernd Wetzel
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Thomae Gmbh Dr K
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Publication of NO784297L publication Critical patent/NO784297L/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)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

"Spectinomycinderivater for anvendelse ved fremstilling av terapeutisk aktivt 4- spectinomycylamin" "Spectinomycin derivatives for use in the preparation of therapeutically active 4-spectinomycinylamine"

Denne oppfinnelse angår nye spectinomycinderivater med den generelle formel. I This invention relates to new spectinomycin derivatives of the general formula. IN

og deres syreaddisjonssalter med uorganiské eller organiske syrer hvis forbindelsene med den generelle formel I inneholder basiske rester, og fremgangsmåte for fremstilling derav. Forbindelsene med den generelle formel I er verdifulle mellomprodukter for fremstilling av sterkt antimikrobielt aktive spectinomycylaminer. and their acid addition salts with inorganic or organic acids if the compounds of the general formula I contain basic residues, and process for their preparation. The compounds of the general formula I are valuable intermediates for the preparation of highly antimicrobially active spectinomycyl amines.

I den ovenstående generelle formel I betyr:In the above general formula I means:

X et hydrogenatom, en organisk gruppe som er kjent fra peptid-kjemien 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-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 alkoksy- alkoksygruppe med 1 til 3 karbonatomer i alkyldelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-métoksykarbonyl-, allyloksykarbonyl-, 2-(p-tolylsulfonyl)-etoksykarbonyl-, 2-brom-etoksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, 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 isobornyloksykarbonyl- eller adamantyl-(1)-oksykarbonylgruppe, en fenyl- eller bifenylalkoksykarbonylgruppe som i fenylresten kan være substituert med 1 til 3 metyl- eller metoksygrupper og hvis alkylengruppe, X a hydrogen atom, 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-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, a 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-bromo-ethoxycarbonyl-, 2,2,2-trichloro-ethoxycarbonyl-, 2-(2-methoxy-ethoxy )ethoxycarbonyl, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxycarbonyl, a cycloalkyloxycarbonyl group with 5 to 12 carbon atoms, such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group which may both be substituted with a methyl, 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,

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 difehyl-metoksykarbonylgruppe ,. en fenyloksykarbonylgruppe som eventuelt kan være substituert med en nitro-, metoksy- eller metylgruppe, en dialkylaminooksykarbonylgruppe så som en dimetylaminooksykarbonyl-gruppe eller en piperidinooksykarbonylgruppe, en alkyltio-karbonylgruppe med 1 til 4 karbonatomer i alkylresten, en benzyl-tiokarbonylgruppe, en formylgruppe eller en annen alifatisk acyl-gruppe med 1 til 10 karbonatomer som eventuelt kan være substituert med 1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, f.eks., en tri fluoracetyl-, acetoacetyl-, 2-nitro-fenoksyacetyl-, monokloracetyl-, 3-klor-butyroyl-, 3-hydroksy-isokaproylgruppe, og dessuten kan X bety en benzoy1-, 2-nitro-benzoyl-, 4-toluensulfonyl-, benzylsulfonyl- eller p-metoksybenzen-sulfonylgruppe, eller også en benzyl- eller tritylgruppe, which can be. linear or branched, contains 2 to 4 carbon atoms, such as an α,α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl-or 2-[biphenylyl-(4)]-propyl-(2)-oxycarbonyl group, a dipheyl-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 piperidinoxycarbonyl group, an alkylthiocarbonyl group with 1 to 4 carbon atoms in the alkyl residue, a benzylthiocarbonyl group, a formyl group or a other 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-, acetoacetyl-, 2-nitro-phenoxyacetyl-, monochloroacetyl -. or trityl group,

Y en hydroksy-, metoksy- eller benzyloksygruppe, en piperidino-gruppe, en gruppe med formelen. Y a hydroxy, methoxy or benzyloxy group, a piperidino group, a group of the formula.

hvor Z betyr et oksygen- eller svovelatom og en eventuelt med en cyano- eller morfolino-, N-metylanilino- eller N,N-metyl-benzylaminogruppe substituert metylgruppe, en eventuelt med en hydroksy- eller aminogruppe substituert fenylgruppe, en pyridyl-gruppe, en amino- eller anilinogruppe,' samt en alkoksygruppe med 1 til 6 karbonatomer, en aralkoksygruppe med 7 til 10 karbonatomer eller en fenoksygruppe, where Z means an oxygen or sulfur atom and a methyl group optionally substituted with a cyano- or morpholino-, N-methylanilino- or N,N-methyl-benzylamino group, a phenyl group optionally substituted with a hydroxy or amino group, a pyridyl group, an amino or anilino group,' as well as an alkoxy group with 1 to 6 carbon atoms, an aralkyl group with 7 to 10 carbon atoms or a phenoxy group,

og Y betyr dessuten en gruppe med den generelle formel and Y further means a group of the general formula

-NH-S02-R2f nvor ^2 er en ^tyi- eller p-tolylgruppe, eller en gruppe med den generelle formel -NH-SO2-R2f where ^2 is a β- or p-tolyl group, or a group of the general formula

hvor R., og R^betyr en metyl-, fenyl- eller aminogruppe, where R, and R^ means a methyl, phenyl or amino group,

eller en pyridyl-(2)-amino-, pyrimidyl-(2)-amino-, benzoksazol-2-on-3-yl-, 3,4-dihydro-kinolin-2-on-l-yl- eller en eventuelt i den aromatiske del med en metoksygruppe substituert tetrahydro-isokinolin-4 , 4-dimetyl-l, 3-dion-2-yl-gruppe ," en imidazolidin-2-on-l-ylgruppe, en eventuelt i 3-stilling med en fenylrest substituert imidazolidin-2,4-dion-l-yl-gruppe eller en eventuelt or a pyridyl-(2)-amino-, pyrimidyl-(2)-amino-, benzoxazol-2-on-3-yl-, 3,4-dihydro-quinolin-2-on-1-yl- or an optionally in the aromatic part with a methoxy group substituted tetrahydro-isoquinolin-4,4-dimethyl-1,3-dion-2-yl group," an imidazolidin-2-on-1-yl group, an optionally in the 3-position with a phenyl radical substituted imidazolidin-2,4-dion-1-yl group or an optionally

i 5-stilling med en metyl- eller etylgruppe, med en bénzyl-eller p-klorbenzylgruppe eller med en eventuelt med 1 til 3 halogenatomer eller en metoksygruppe substituert fenylgruppe, substituert oksazolidin-2-on-3-yl-gruppe. in the 5-position with a methyl or ethyl group, with a benzyl or p-chlorobenzyl group or with a phenyl group optionally substituted with 1 to 3 halogen atoms or a methoxy group, substituted oxazolidin-2-on-3-yl group.

Forbindelsene med den generelle formel I kan fremstilles The compounds of the general formula I can be prepared

som følger:as follows:

Ved omsetning av spectinomycinderivater med den generelle formel When reacting spectinomycin derivatives with the general formula

hvor X er som ovenfor angitt, med forbindelser méd den generelle formel where X is as stated above, with connections with the general formula

hvor Y likeledes er som ovenfor angitt. where Y is also as stated above.

Omsetningen foretas i vann eller i et organisk opp-løsningsmiddel, f.eks. i alkoholer, så som etanol eller isopropanol, i karboksylsyrer så som iseddik, i estere eller etere, så som dioksan, eller i blandinger av slike oppløsningsmidler ved temperaturer mellom 0 og 100°C, fortrinnsvis mellom 0 og 50°C. The reaction is carried out in water or in an organic solvent, e.g. in alcohols, such as ethanol or isopropanol, in carboxylic acids such as glacial acetic acid, in esters or ethers, such as dioxane, or in mixtures of such solvents at temperatures between 0 and 100°C, preferably between 0 and 50°C.

Fra litteraturen (se P.F. Wiley, A.D. Argoudelis ogFrom the literature (see P.F. Wiley, A.D. Argoudelis and

H. Hoeksema, J. Am. Chem. Soc. 8J5 , 2652 til 2659 [1963]) er det kjent at den ketoniske karbonylgruppe i et spectinomycin (som der er kalt actinospectacin) med formel II bare har en lav reaktivitet og ikke reagerer med de fleste karbonylreagenser; H. Hoeksema, J. Am. Chem. Soc. 8J5 , 2652 to 2659 [1963]) it is known that the ketonic carbonyl group of a spectinomycin (which is there called actinospectacin) of formula II has only a low reactivity and does not react with most carbonyl reagents;

bare med tiosemikarbazid dannes et tiosemikarbazon, men sistnevnte avgir imidlertid ved sin dannelse et molekyl vann, hvorved det oppstår en olefinisk binding i molekylet. Desto mer overraskende er det at en forbindelse med den generelle formel II f.eks. med et hydrazin med den generelle formel III allerede ved temperaturer opptil 50°C fører til hydrazoner med den generelle formel I med meget godt utbytte. only with thiosemicarbazide a thiosemicarbazone is formed, but the latter, however, releases a molecule of water during its formation, whereby an olefinic bond arises in the molecule. It is all the more surprising that a compound with the general formula II e.g. with a hydrazine of the general formula III already at temperatures up to 50°C leads to hydrazones of the general formula I in very good yield.

Forbindelsene med den generelle formel I, hvis de inneholder en basisk rest, kan eventuelt overføres til sine syreaddisjonssalter ved hjelp av uorganiske eller organiske syrer. The compounds of the general formula I, if they contain a basic residue, can optionally be transferred to their acid addition salts by means of inorganic or organic acids.

Som syrer anvendes hensiktsmessig f.eks. klorhydrogensyre, svovelsyre, fosforsyre, fumarsyre eller eplesyre. Suitable acids are used e.g. hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid or malic acid.

Utgangsforbindelsene med den generelle formel II er kjent fra litteraturen (se ovenfor angitte litteratur) eller kan fremstilles i henhold til kjente metoder. The starting compounds of the general formula II are known from the literature (see the above-mentioned literature) or can be prepared according to known methods.

Spectinomycinderivatene med den generelle formel I er utgangsstoffer for fremstilling av farmakologisk aktive 4-spectinomycylaminer med meget gode virkninger mot grampositive og gramnegative bakterier. The spectinomycin derivatives with the general formula I are starting materials for the production of pharmacologically active 4-spectinomycylamines with very good effects against gram-positive and gram-negative bacteria.

Ved reduksjon av forbindelser med den generelle formel I, f.eks. med hydrogen i nærvær av metallkatalysatorer så som platina, palladium eller platinadioksyd, får man spectinomycinderivater med den generelle formel som, såfremt X ikke betyr hydrogen, derefter f.eks. ved hydrogeno-lytisk eller eventuelt acidolytisk eller basisk avspaltning av resten X, overføres til 4-spectinomycylamin med formel IV hvor In the reduction of compounds with the general formula I, e.g. with hydrogen in the presence of metal catalysts such as platinum, palladium or platinum dioxide, one obtains spectinomycin derivatives with the general formula which, if X does not mean hydrogen, then e.g. by hydrogenolytic or optionally acidolytic or basic cleavage of the residue X, is transferred to 4-spectinomycylamine of formula IV where

X betyr hydrogen. 4-spectinomycylamin resp. dekahydro-4a,7,9-trihydroksy-4-amino-2-metyl-6,8-bis(metylamino)-pyrano[2,3-b]-ti,4]benzodioksin, bestående av en 4R-form med aksial aminogruppe og/eller en 4S-form med ekvatorial aminogruppe, og de farmakologisk forlikelige salter derav med uorganiske eller organiske syrer, særlig 4-R-isomeren, er i besittelse av en meget sterk anti-mikrobiell virkning, og er i denne henseende langt bedre enn det tidligere kjente actinospectacin (se J. Am. Chem. Soc. 85,. 2652-2659 X means hydrogen. 4-spectinomycylamine resp. decahydro-4a,7,9-trihydroxy-4-amino-2-methyl-6,8-bis(methylamino)-pyrano[2,3-b]-thi,4]benzodioxin, consisting of a 4R form with axial amino group and/or a 4S form with an equatorial amino group, and the pharmacologically compatible salts thereof with inorganic or organic acids, especially the 4-R isomer, possess a very strong anti-microbial effect, and are in this respect far better than the previously known actinospectacin (see J. Am. Chem. Soc. 85,. 2652-2659

[1963]). Det henvises til ansøkning 78.4299. [1963]). Reference is made to application 78.4299.

De følgende eksempler skal illustrere oppfinnelsen ytterligere: The following examples shall further illustrate the invention:

Spectinomycin- benzyloksimSpectinomycin- benzyl oxime

6 g (0,012 mol) spectinomycin-dihydroklorid-pentahydrat6 g (0.012 mol) spectinomycin dihydrochloride pentahydrate

og 3 g O-bénzylhydroksylamin oppløses i 25 ml vann og 25 ml metanol. Oppløsningen omrøres natten over, inndampes, residuet oppløses and 3 g of O-benzylhydroxylamine are dissolved in 25 ml of water and 25 ml of methanol. The solution is stirred overnight, evaporated, the residue dissolved

i litt absolutt etanol og tilsettes etere inntil uklarhet oppstår. Man får 5,Og (83% av det teoretiske) farveløst pulver med spaltningspunkt 175°C. in a little absolute ethanol and add ethers until cloudiness occurs. You get 5.Og (83% of the theoretical) colorless powder with a decomposition point of 175°C.

Rf: 0,8 (silikagel, kloroform/metanol/kons. ammoniakk = 20:20:3) NMR-spektrum (oppløsningsmiddel CD^OD) Rf: 0.8 (silica gel, chloroform/methanol/conc. ammonia = 20:20:3) NMR spectrum (solvent CD^OD)

ppm: 1,3 (dublett, 3H 2_CH3)ppm: 1.3 (doublet, 3H 2_CH3)

2,8 (dublett 6H -N-CH3)2.8 (doublet 6H -N-CH3)

4,45 (singlett 1H 10aH)4.45 (singlet 1H 10aH)

5,2 (singlett 2H benzyl-CH2)5.2 (singlet 2H benzyl-CH2)

7,4 (singlett 5H C6H5)7.4 (singlet 5H C6H5)

Den frie forbindelse får man ved at man til den vandig-metanoliske oppløsning av dihydrokloridet setter en ionebytter The free compound is obtained by adding an ion exchanger to the aqueous-methanolic solution of the dihydrochloride

(Dowex 2x8 (OH -form) til blivende pH-verdi på 10,4.(Dowex 2x8 (OH form) to a permanent pH value of 10.4.

Farveløse krystaller med smelteområde 86-106°C.Colorless crystals with melting range 86-106°C.

På samme måte fremstilles de følgende forbindelser:In the same way, the following compounds are produced:

a) 6,8-bis-benzyloksykarbonyl-spectinomycin-oksim fra 6,8-bis-benzyloksykarbonylspectinomycin og hydroksylamin. a) 6,8-bis-benzyloxycarbonylspectinomycin oxime from 6,8-bis-benzyloxycarbonylspectinomycin and hydroxylamine.

Rf: 0,38 (silikagel, kloroform/metanol = 9:1)Rf: 0.38 (silica gel, chloroform/methanol = 9:1)

<C>30<H>37<N>3°n molekylvekt 615,6<C>30<H>37<N>3°n molecular weight 615.6

Beregnet: C 58,52, H 6,06, N 6,82Calculated: C 58.52, H 6.06, N 6.82

Funnet: ' 58,00 6,21 6,65. Found: ' 58.00 6.21 6.65.

Utgangsmaterialet 6,8-bis-benzyloksykarbonylspectinomycin erThe starting material is 6,8-bis-benzyloxycarbonylspectinomycin

kjent fra litteraturen (J.A.C.S.. 85, s. 2657 (1963)).known from the literature (J.A.C.S.. 85, p. 2657 (1963)).

b) 6,8-bis-benzyloksykarbony1-spectinomycinbenzyloksim fra 6,8-bis-benzyloksykarbonylspectinomycin og O-benzylhydroksylamin b) 6,8-bis-benzyloxycarbonylspectinomycin benzyloxime from 6,8-bis-benzyloxycarbonylspectinomycin and O-benzylhydroxylamine

Rf: 0,42 (silikagel, kloroform/metanol = 9:1)Rf: 0.42 (silica gel, chloroform/methanol = 9:1)

c) 6,8-bisbenzyloksykarbonyl-spectinomycin-metyloksim fra 6,8-bis-benzyloksykarbonylspectinomycin og O-metylhydroksylamin. c) 6,8-bisbenzyloxycarbonylspectinomycin methyloxime from 6,8-bisbenzyloxycarbonylspectinomycin and O-methylhydroxylamine.

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

d) 6 ,8-bis-p-tosylspectinomycin-oksim fra 6,8-bis-p-tosylspectinomycin og hydroksylamin. d) 6,8-bis-p-tosylspectinomycin oxime from 6,8-bis-p-tosylspectinomycin and hydroxylamine.

Rf: 0,3 (silikagel, kloroform/metanol = 11:1).Rf: 0.3 (silica gel, chloroform/methanol = 11:1).

Utgangsmaterialet 6 , 8-bis-p-tosyl-spectinomycin ble f rems tilt - i ved metoden beskrevet i J. Antibiotics XXVIII, s. 140 (1975) for 6 , 8-bis-benzyloksykarbonyl-4-dihydrospectinomycin fra spectinomycin og p-toluensulfoklorid. The starting material 6,8-bis-p-tosyl-spectinomycin was prepared by the method described in J. Antibiotics XXVIII, p. 140 (1975) for 6,8-bis-benzyloxycarbonyl-4-dihydrospectinomycin from spectinomycin and p- toluene sulfochloride.

Rf: 0,29 (silikagel, kloroform/metanol 9:1). e) 6,8-bis-p-metoksybenzensulfonylspectinomycin-oksim fra 6,8-bis-p-metoksybenzensulfonylspectinomycin og hydroksylamin. Rf: 0.29 (silica gel, chloroform/methanol 9:1). e) 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-metoksybenzen-sulfonylspectinomycin ble, som beskrevet ovenfor, fremstilt fra spectinomycin og p-metoksy-benzensulfoklorid. The starting material 6,8-bis-p-methoxybenzenesulfonylspectinomycin was, as described above, prepared from spectinomycin and p-methoxybenzenesulfochloride.

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

f) 6,8-bis-3,3,3-trikloretoksykarbonyl-spectinomycin-benzyloksim fra 6 , 8-bis-p, 3 ,3-trikloretoksykarbonyl-spectinomycin f) 6,8-bis-3,3,3-trichloroethoxycarbonyl-spectinomycin-benzyl oxime from 6,8-bis-p,3,3-trichloroethoxycarbonyl-spectinomycin

og 0-benzylhydroksylamin.and O-benzylhydroxylamine.

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

Utgangsmaterialet 6,8-bis~3,3,3-trikloretoksykarbonylspectinomycin ble, som beskrevet ovenfor, fremstilt fra spectinomycin og The starting material 6,8-bis~3,3,3-trichloroethoxycarbonylspectinomycin was, as described above, prepared from spectinomycin and

3,0,3-trikloretoksykarbonylklorid.3,0,3-trichloroethoxycarbonyl chloride.

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

g) 6,8-bis-fenoksykarbonylspectinomycin-oksim fra 6,8-bisfenoksykarbonylspectinomycin og hydroksylamin. g) 6,8-bis-phenoxycarbonylspectinomycin oxime from 6,8-bis-phenoxycarbonylspectinomycin and hydroxylamine.

Rf: 0,35 (silikagel, kloroform/metanol = 9:1). Rf: 0.35 (silica gel, chloroform/methanol = 9:1).

Utgangsmaterialet 6,8-bisfenoksykarbonylspectinomycin ble, som beskrevet ovenfor, erholdt fra spectinomycin og fenoksykarbonyl-klorid, The starting material 6,8-bisphenoxycarbonylspectinomycin was, as described above, obtained from spectinomycin and phenoxycarbonyl chloride,

Rf: 0,54 (silikagel, kloroform/metanol =5:1).Rf: 0.54 (silica gel, chloroform/methanol =5:1).

h) 6,8-bis-benzoylspectinomycin-oksim fra 6 ,8-bis-benzoy1-spectinomycin og hydroksylamin. h) 6,8-bis-benzoylspectinomycin oxime from 6,8-bis-benzoylspectinomycin and hydroxylamine.

Rf: 0,24 (silikagel, kloroform/metanol = 9:1). Rf: 0.24 (silica gel, chloroform/methanol = 9:1).

Utgangsmaterialet 6,8-bisbenzoylspectinomycin ble, ,som beskrevet ovenfor, fremstilt fra spectinomycin og benzoylklorid. The starting material 6,8-bisbenzoylspectinomycin was, as described above, prepared from spectinomycin and benzoyl chloride.

Rf: 0,20 (silikagel, kloroform/metanol = 9:1).Rf: 0.20 (silica gel, chloroform/methanol = 9:1).

i) 6,8-bis-isobornyloksykarbonyl-spectinomycin-benzyloksim fra 6,8-bis-isobornyloksykarbony1-spectinomycin og 0-benzylhydroksylamin. i) 6,8-bis-isobornyloxycarbonyl-spectinomycin-benzyl oxime from 6,8-bis-isobornyloxycarbonyl-spectinomycin and O-benzylhydroxylamine.

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

Utgangsproduktet 6,8-bis-isobornyloksykarbonyl-spectinomycin ble, som ovenfor beskrevet, fremstilt fra spectinomycin og isobornyl-oksykarbonylklorid. The starting product 6,8-bis-isobornyloxycarbonyl-spectinomycin was, as described above, prepared from spectinomycin and isobornyloxycarbonyl chloride.

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

j) 6,8-bis-kloracety1-spectinomycin-benzyloksim fra 6,8-bis-kloracety1-spectinomycin og 0-benzylhydroksylamin. j) 6,8-bis-chloroacety1-spectinomycin benzyl oxime from 6,8-bis-chloroacety1-spectinomycin and O-benzylhydroxylamine.

Rf: 0,3 (silikagel, kloroform/metanol = 10:1). Rf: 0.3 (silica gel, chloroform/methanol = 10:1).

Utgangsproduktet 6,8-bis-kloracetyl-spectinomycin ble, som ovenfor beskrevet, fremstilt fra spectinomycin og kloracetyl-klorid. The starting product 6,8-bis-chloroacetyl-spectinomycin was, as described above, prepared from spectinomycin and chloroacetyl chloride.

Rf: 0,17 (silikagel, kloroform/metanol = 10:1).Rf: 0.17 (silica gel, chloroform/methanol = 10:1).

k) 6,8-bis-acety1-spectinomycin-benzyloksim fra 6,8-bis-acetyl-spectinomycin og O-benzylhydroksylamin k) 6,8-bis-acety1-spectinomycin-benzyloxime from 6,8-bis-acetyl-spectinomycin and O-benzylhydroxylamine

Rf: 0,25 (silikagel, kloroform/metanol = 10:1)Rf: 0.25 (silica gel, chloroform/methanol = 10:1)

Utgangsproduktet 6,8-bis-acetyl-spectinomycin ble, som ovenfor beskrevet, fremstilt fra spectinomycin og acetylklorid. The starting product 6,8-bis-acetyl-spectinomycin was, as described above, prepared from spectinomycin and acetyl chloride.

Rf: 0,1 (silikagel, kloroform/metanol = .10:1).Rf: 0.1 (silica gel, chloroform/methanol = .10:1).

1) Spectinomycin-benzhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og benzoylhydrazin. 1) Spectinomycin benzhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and benzoylhydrazine.

Spaltningspunkt 180°C.Decomposition point 180°C.

Rf: 0,35 (cellulose, butanol/metanol/vann = 90:25:20)Rf: 0.35 (cellulose, butanol/methanol/water = 90:25:20)

m) spectinoraycin-p-tosylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og p-tosylhydrazin. Spaltningsområde 130-143°C, m) spectinoraycin p-tosylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and p-tosylhydrazine. Decomposition range 130-143°C,

Rf: 0,32 (cellulose, butanol/metanol/vann = 90:25:20).Rf: 0.32 (cellulose, butanol/methanol/water = 90:25:20).

n) spectinomycin-acetylhydrazondihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og acetylhydrazin. n) spectinomycin acetylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and acetylhydrazine.

Spaltningsområde 160-180°CDecomposition range 160-180°C

Rf: 0,29 (cellulose, butanol/metanol/vann =90:40:20).Rf: 0.29 (cellulose, butanol/methanol/water =90:40:20).

o) spectinomycin-metylsulfonylhydrazon-dihydroklorid fra spectinomycin-dihydrokiorid-petftahydrat og metylsulfonylhydrazin. Rf: 0,22 (cellulose, butanol/metanol/vann = 90:25:20). o) spectinomycin methylsulfonylhydrazone dihydrochloride from spectinomycin dihydrochloride petphtahydrate and methylsulfonylhydrazine. Rf: 0.22 (cellulose, butanol/methanol/water = 90:25:20).

p) spectinomycin-4-pyridoylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og pyridin-4-karboksylsyrehydrazid. p) spectinomycin-4-pyridoylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and pyridine-4-carboxylic acid hydrazide.

Rf: 0,31 (cellulose: butanol/metanol/vann =90:25:20).Rf: 0.31 (cellulose: butanol/methanol/water =90:25:20).

q) spectinomycin-fenyltiosemikarbazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 4-fenyltiosemikarbazid. Smeltepunkt: 180-185°C (etanol/eter). q) spectinomycin phenylthiosemicarbazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 4-phenylthiosemicarbazide. Melting point: 180-185°C (ethanol/ether).

r) spectinomycin-semikarbazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og semikarbazid. r) spectinomycin semicarbazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and semicarbazide.

Smeltepunkt: 205-210°C.Melting point: 205-210°C.

s) spectinomycin-fenoksykarbonylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og hydrazin-karboksylsyre-■ fenylester. s) spectinomycin phenoxycarbonylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and hydrazine carboxylic acid ■ phenyl ester.

Rf: 0,45 (cellulose, butanol/metanol/vann = 90:25:20).Rf: 0.45 (cellulose, butanol/methanol/water = 90:25:20).

t) spectinomycin-etoksykarbonylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og hydrazinkarboksylsyre-etylester. t) spectinomycin ethoxycarbonylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and hydrazine carboxylic acid ethyl ester.

Rf: 0,26 (cellulose, butanol/metanol/vann = 90:25:25).Rf: 0.26 (cellulose, butanol/methanol/water = 90:25:25).

u) spectinomycin-cyanacetylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og cyanacetylhydrazid. u) spectinomycin cyanoacetylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and cyanoacetylhydrazide.

Rf: 0,29 (cellulose, butanol/metanol/vann = 90:25:25).Rf: 0.29 (cellulose, butanol/methanol/water = 90:25:25).

v) spectinomycin-p-metoksybenzyloksykarbonyl-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og hydrazinkarboksylsyre-p-metoksybenzylester. v) spectinomycin p-methoxybenzyloxycarbonyl hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and hydrazine carboxylic acid p-methoxybenzyl ester.

Rf: 0,45 (cellulose, butanol/metanol/vann = 90:25:25).Rf: 0.45 (cellulose, butanol/methanol/water = 90:25:25).

w) spectinomycin-p-aminobenzoylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og p-aminobenzoesyre-hydrazid-dihydroklorid. w) spectinomycin p-aminobenzoylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and p-aminobenzoic acid hydrazide dihydrochloride.

Smeltepunkt: 200-205°C.Melting point: 200-205°C.

x) spectinomycin-morfolinoacetylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og morfolino-acetylhydrazid. x) spectinomycin morpholinoacetylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and morpholino acetylhydrazide.

Smeltepunkt: 16 5-170°C..Melting point: 16 5-170°C..

y) spectinomycin-p-hydroksybenzoylhydrazon-dihydroklorid fra spectinbmycin-dihydroklorid-pentahydrat og p-hydroksy-benzoesyrehydrazid. y) spectinomycin p-hydroxybenzoylhydrazone dihydrochloride from spectinbmycin dihydrochloride pentahydrate and p-hydroxybenzoic acid hydrazide.

Smeltepunkt:-185-190°C.Melting point: -185-190°C.

z) spectinomycin-(N-metylanilino)acetylhydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og (N-metylanilino)-acetylhydrazid. z) spectinomycin-(N-methylanilino)acetylhydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and (N-methylanilino)acetylhydrazide.

Smeltepunkt: 175-180°C. Melting point: 175-180°C.

aa) spectinomycin-(N-metyl-N-benzyl)acety1-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og (N-metyl-N-benzyl)-acetylhydrazid. Smeltepunkt: 175-180°C. aa) spectinomycin-(N-methyl-N-benzyl)acety1-hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and (N-methyl-N-benzyl)-acetylhydrazide. Melting point: 175-180°C.

ab) spectinomycin-pyridy1-2-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2-hydrazinopyridin. Smeltepunkt: 80°C. ab) spectinomycin-pyridy1-2-hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 2-hydrazinopyridine. Melting point: 80°C.

ac) spectinomycin-(2-amino-6-metylpyrimidyl-4)-hydrazon fra spectinomycin-dihydroklorid-pentahydrat og 2-amino-4-hydrazino-6-metyl-pyrimidin. ac) spectinomycin-(2-amino-6-methylpyrimidyl-4)-hydrazone from spectinomycin dihydrochloride pentahydrate and 2-amino-4-hydrazino-6-methyl-pyrimidine.

Smeltepunkt: 150°C.Melting point: 150°C.

ad) spectinomycin-pyrimidyl-(2)-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2-hydrazinopyrimidin. Smeltepunkt: 160-165°C (spaltning). ad) spectinomycin pyrimidyl-(2)-hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 2-hydrazinopyrimidine. Melting point: 160-165°C (decomposition).

ae) spectinomycin-[2,6-dimetyl-pyrimidy1-(4)]-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2,6-dimetyl-4-hydrazino-pyrimidin. ae) spectinomycin-[2,6-dimethyl-pyrimidy1-(4)]-hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 2,6-dimethyl-4-hydrazino-pyrimidine.

Smeltepunkt: 170-175°C.Melting point: 170-175°C.

af) spectinomycin-[6-amino-2-metyl-pyrimidyl-(4)]hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 6-amino-2-metyl-4-hydrazino-pyrimidin. af) spectinomycin-[6-amino-2-methyl-pyrimidyl-(4)]hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 6-amino-2-methyl-4-hydrazino-pyrimidine.

Smeltepunkt: 16 5-170°C.Melting point: 16 5-170°C.

ag) spectinomycin-[2-metyl-6-fenyl-pyrimidyl-(4)]-hydrazon-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2-metyl-6-fenyl-4-hydrazino-pyrimidin. ag) spectinomycin-[2-methyl-6-phenyl-pyrimidyl-(4)]-hydrazone dihydrochloride from spectinomycin dihydrochloride pentahydrate and 2-methyl-6-phenyl-4-hydrazino-pyrimidine.

Smeltepunkt: 170-175°C.Melting point: 170-175°C.

ah) spectinomycin[imidazolidin-on-(2)-yl-1-)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 1-amino-imidazolidinon- (2).. ah) spectinomycin[imidazolidin-one-(2)-yl-1-)]imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 1-amino-imidazolidinone-(2)..

Smeltepunkt: 180°C (spaltning).Melting point: 180°C (decomposition).

ai) spectinomcyin-[imidazolidin-dion(2,4)-yl-(1)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 1-amino-imidazolidin-dion-(2,4). ai) spectinomcyin-[imidazolidine-dione(2,4)-yl-(1)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 1-amino-imidazolidine-dione-(2,4).

Smeltepunkt:' 190-195°C (spaltning) .Melting point: 190-195°C (decomposition).

aj ) spectinomycin - [ ( 3-f enyl-imidazolidin-dion- (2 , 4) -yl- (.1) ] - imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og l-amino-3-fenyl-imidazolidin-dion-(2,4). Smeltepunkt: 185-190°C. aj) spectinomycin-[(3-phenyl-imidazolidine-dione-(2,4)-yl-(.1)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and l-amino-3-phenyl-imidazolidine-dione -(2,4).Melting point: 185-190°C.

ak) spectinomycin-[5-fenyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-5-fenyloksazolidinon-(2). ak) spectinomycin-[5-phenyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-phenyloxazolidinone-(2).

Smeltepunkt: 175-180°C.Melting point: 175-180°C.

al) spectinomycin-[5-metyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklprid-pentahydrat og 3-amino-5-metyl-oksazolidinon-(2). al) spectinomycin-[5-methyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-methyl-oxazolidinone-(2).

Smeltepunkt: 180-185°C.Melting point: 180-185°C.

am) spectinomycin-[(oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-oksazolidinon-(2). am) spectinomycin-[(oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-oxazolidinone-(2).

Smeltepunkt: 180°C (spaltning).Melting point: 180°C (decomposition).

an) spectinomycin-[5-benzyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-5-benzyl~oksazolidinon-(2). an) spectinomycin-[5-benzyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-benzyl~oxazolidinone-(2).

Smeltepunkt: 170-175<Q>C.Melting point: 170-175<Q>C.

ao) spectinomycin-[5-etyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinpmycin-dihydroklorid-pentahydrat og 3-amino-5-etyl-oksazolidinon-(2). ao) spectinomycin-[5-ethyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinpmycin dihydrochloride pentahydrate and 3-amino-5-ethyl-oxazolidinone-(2).

Smeltepunkt: 170-175°C.Melting point: 170-175°C.

ap) spectinomycin-[5-p-klorbenzyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-5-p-klorbenzyl-oksazolidinon-(2). ap) spectinomycin-[5-p-chlorobenzyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-p-chlorobenzyl-oxazolidinone-(2).

Smeltepunkt: 175-180°C. ' .Melting point: 175-180°C. ' .

aq) spectinomycin-[5-(3,4-diklor)fenyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-5-(3,4-diklor)-fenyl-oksazolidinon-(2). Smeltepunkt: 170-175°C. aq) spectinomycin-[5-(3,4-dichloro)phenyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-(3,4- dichloro)-phenyl-oxazolidinone-(2). Melting point: 170-175°C.

ar) spectinomycin-[5-p-klorfenyl-oksazolidin-on-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 3-amino-5-p-klorfenyl-oksazolidin-on-(2). ar) spectinomycin-[5-p-chlorophenyl-oxazolidin-one-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 3-amino-5-p-chlorophenyl-oxazolidin-one- (2).

Smeltepunkt:-185-190°C (spaltning).Melting point: -185-190°C (decomposition).

as) spectinomycin-[5-p-metoksyfenyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 5-p-metoksyfenyl-3-amino-oksazolidinon-(2). as) spectinomycin-[5-p-methoxyphenyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 5-p-methoxyphenyl-3-amino-oxazolidinone-(2).

Smeltepunkt: 175-180°G.Melting point: 175-180°G.

at) spectinomycin-[5-p-bromfenyl-oksazolidinon-(2)-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat at) spectinomycin-[5-p-bromophenyl-oxazolidinone-(2)-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate

og 3-amino-5-p-bromfenyl-oksazolidinon-(2).and 3-amino-5-p-bromophenyl-oxazolidinone-(2).

Smeltepunkt: 185-190°C.Melting point: 185-190°C.

au) spectinomycin-[4,4-dimetyl-7-metoksy-l,2,3,4-tetrahydro-isokinolin- (1, 3)-dion-yl- (2) ] -imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2-amino-4,4-dimety1-7-metoksy-1,2,3,4-tetrahydro-isokinolin-(1,3)-dion. au) spectinomycin-[4,4-dimethyl-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-(1,3)-dion-yl-(2)]-imine dihydrochloride from spectinomycin dihydrochloride- pentahydrate and 2-amino-4,4-dimethyl-7-methoxy-1,2,3,4-tetrahydro-isoquinoline-(1,3)-dione.

Smeltepunkt: 109-111°C (spaltning).Melting point: 109-111°C (decomposition).

av) spectinomycin-[4,4-dimetyl-l,2,3,4-tetrahydro-isokinolin-(1,3)-dion-yl-(2)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 2-amino-4,4-dimety1-1,2,3,4-tetra-hydro-isokinolin- (1,3)-dion. of) spectinomycin-[4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-(1,3)-dion-yl-(2)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 2- amino-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-(1,3)-dione.

Smeltepunkt: 117-119°C (spaltning).Melting point: 117-119°C (decomposition).

aw) spectinomycin-[piperidin-yl-(1)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 1-aminopiperidin. Smeltepunkt: 123-125°C (spaltning). aw) spectinomycin-[piperidin-yl-(1)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 1-aminopiperidine. Melting point: 123-125°C (decomposition).

ax) spectinomycin-[2,3-dihydro-benzoksazol-(2)-on-yl-(3)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat pg 3-amino-2 , 3-dihydro-benzoksazol-(2)-"on . ax) spectinomycin-[2,3-dihydro-benzoxazole-(2)-on-yl-(3)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate pg 3-amino-2 , 3-dihydro-benzoxazole-(2 )-"on .

Smeltepunkt: 220-222°C (spaltning).Melting point: 220-222°C (decomposition).

ay) spectinomycin-[1,2,3,4-tetrahydro-kinolin-(2)-on-yl- (1)]-imin-dihydroklorid fra spectinomycin-dihydroklorid-pentahydrat og 1-amino-l,2,3,4-tetrahydro-kinolin-(2)-on. ay) spectinomycin-[1,2,3,4-tetrahydro-quinolin-(2)-on-yl-(1)]-imine dihydrochloride from spectinomycin dihydrochloride pentahydrate and 1-amino-1,2,3, 4-tetrahydro-quinolin-(2)-one.

Smeltepunkt: 129-131°C (spaltning). Melting point: 129-131°C (decomposition).

Claims (4)

1. Nye spectinomycinderivater for fremstilling av terapeutisk aktivt 4-spectinomycylamin, karakterisert ved at de har den generelle formel 1. New spectinomycin derivatives for the production of therapeutically active 4-spectinomycylamine, characterized in that they have the general formula hvor X betyr et hydrogenatom, en organisk gruppe som er kjent fra peptid-kjemien 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-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 alkoksyalkoksy- gruppe med 1 til 3 karbonatomer i alkyldelen og 1 til 3 karbonatomer i alkylendelen, f.eks. en furyl-(2)-metoksykarbony1-, allyloksykarbonyl-, 2-(p-tolylsulfonyl)-etoksykarbonyl-, 2-brom-etoksykarbonyl-, 2,2,2-triklor-etoksykarbonyl-, 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 isobornyloksykarbonyl- eller adamantyl-(1)-oksykarbonylgruppe, en fenyl- eller bi fenylalkoksykarbonylgruppe 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 dimetylaminooksykarbonyl-gruppe eller en piperidinooksykarbonylgruppe, en alkyltio-karbonylgruppe med 1 til 4 karbonatomer i alkylresten, en benzyl-tiokarbonylgruppe, en formylgruppe eller en annen alifatisk acyl-gruppe med 1 til 10 karbonatomer som eventuelt kan være substituert med 1 til 3 halogenatomer, hydroksygrupper, acylrester eller med en nitrogruppe, f. eks., en tri f luoracety 1-, ace toacetyl-, 2-nitro-fenoksyacetyl-, monokloracetyl-, 3-klor-butyroy1-, 3-hydroksy-isokaproylgruppe, og dessuten kan X bety en benzoyl-, 2-nitro-benzoyl-, 4-toluensulfonyl-, benzylsulfonyl- eller p-metoksybenzen- sulfonylgruppe, eller også en benzyl- eller tritylgruppe, Y betyr en hydroksy-, metoksy- eller benzyloksygruppe, en piperidino-gruppe, en gruppe med formelen where X means a hydrogen atom, 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-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, a 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-bromo-ethoxycarbonyl-, 2,2,2-trichloro-ethoxycarbonyl-, 2-(2-methoxy-ethoxy )ethoxycarbonyl, 3-methyl-pentyl-(3)-oxycarbonyl group, especially tert-butyloxycarbonyl, a cycloalkyloxycarbonyl group with 5 to 12 carbon atoms, such as a cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group which may both be substituted with a methyl, 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, contain 2 to 4 carbon atoms, such as 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 trifluoracety 1-, acetoacetyl-, 2-nitro-phenoxyacetyl-, monochloroacetyl-, 3-chloro-butyroy1- , 3-hydroxy-isocaproyl group, and furthermore X can mean a benzoyl-, 2-nitro-benzoyl-, 4-toluenesulfonyl-, benzylsulfonyl- or p-methoxybenzene- sulfonyl group, or also a benzyl or trityl group, Y means a hydroxy, methoxy or benzyloxy group, a piperidino group, a group of the formula hvor Z betyr et oksygen- eller svovelatom og R^ en eventuelt med en cyano- eller morfolino-, N-metylanilino- eller N,N-metyl— benzylaminogruppe substituert metylgruppe, en eventuelt med en hydroksy- eller aminogruppe substituert fenylgruppe, en pyridyl-gruppe, en amino- eller anilinogruppe, samt en alkoksygruppe med 1 til 6 karbonatomer, en aralkoksygruppe med 7 til 10 karbonatomer eller en fenoksygruppe, og Y betyr dessuten en gruppe med den generelle formel • -NH-SC^-F^/ hvor er en metyl- eller p-tolylgruppe, eller en gruppe med den generelle formel where Z means an oxygen or sulfur atom and R^ a methyl group optionally substituted with a cyano- or morpholino-, N-methylanilino- or N,N-methyl- benzylamino group, a phenyl group optionally substituted with a hydroxy or amino group, a pyridyl- group, an amino or anilino group, as well as an alkoxy group with 1 to 6 carbon atoms, an aralkyl group with 7 to 10 carbon atoms or a phenoxy group, and Y further means a group of the general formula • -NH-SC^-F^/ where is a methyl or p-tolyl group, or a group with the general formula hvor R., og R^ betyr en metyl-, fenyl- eller aminogruppe, eller eri pyridyl-(2)-amino-, pyrimidyl-(2)-amino-, benzoksazol-2-on-3-yl-, 3,4-dihydro-kinolin-2-on-l-yl- eller en eventuelt i den aromatiske del med en metoksygruppe substituert tetrahydro-isokinolin-4,4-dimety1-1,3-dion-2-y1-gruppe, en imidazolidin-2-on-l-ylgruppe, en eventuelt i 3-stilling med en. fenylrest substituert imidazolidin-2,4-dion-l-yl-gruppe eller en eventuelt i 5-stilling-med en metyl- eller etylgruppe, med en benzyl- eller p-klorbenzylgruppe eller med en eventuelt med 1 til 3 halogenatomer eller en metoksygruppe substituert fenylgruppe, substituert oksazolidin-2-on-3-y1-gruppe, og fysiologisk forlikelige syreaddisjonssalter derav med uorganiske eller organiske syrer, hvis forbindelsene med den generelle formel I inneholder basiske rester.where R, and R^ means a methyl, phenyl or amino group, or eri pyridyl-(2)-amino-, pyrimidyl-(2)-amino-, benzoxazol-2-on-3-yl-, 3,4-dihydro-quinolin-2-on-1-yl- or an optionally in the aromatic part with a methoxy group substituted tetrahydro-isoquinolin-4,4-dimethyl-1,3-dione-2-yl group, an imidazolidin-2-on-l-yl group, an optionally in the 3-position with a. phenyl radical substituted imidazolidin-2,4-dion-1-yl group or an optionally in the 5-position-with a methyl or ethyl group, with a benzyl or p-chlorobenzyl group or with an optionally with 1 to 3 halogen atoms or a methoxy group substituted phenyl group, substituted oxazolidin-2-one-3-y1 group, and physiologically compatible acid addition salts thereof with inorganic or organic acids, if the compounds of the general formula I contain basic residues. 2. Spectinomycinderivater som angitt i krav 1, karakterisert ved at.X i den generelle formel I betyr et hydrogenatom, en benzyloksykarbony1-, 2,2,2-triklor-etoksykarbonyl-, isobornyloksykarbony1-, p-metoksybenzensulfonyl-eller benzoylgruppe, og Y har de "i krav 1 angitte betydninger.2. Spectinomycin derivatives as stated in claim 1, characterized in that X in the general formula I means a hydrogen atom, a benzyloxycarbonyl-, 2,2,2-trichloro-ethoxycarbonyl-, isobornyloxycarbonyl-, p-methoxybenzenesulfonyl- or benzoyl group, and Y have the meanings given in claim 1. 3. Fremgangsmåte for fremstilling av nye spectinomycinderivater med den generelle formel I ifølge kravene 1 og 2, og salter derav med uorganiske eller organiske syrer hvis for-bindelsen inneholder en basisk rest, karakterisert ved at et spectinomycinderivat med den generelle formel hvor X er som angitt i krav 1, omsettes med forbindelser med den generelle formel 3. Process for the production of new spectinomycin derivatives with the general formula I according to claims 1 and 2, and salts thereof with inorganic or organic acids if the compound contains a basic residue, characterized in that a spectinomycin derivative of the general formula where X is as stated in claim 1, is reacted with compounds of the general formula hvor Y er som ovenfor angitt, i vann eller i et organisk opp-løsningsmiddel ved temperaturer mellom 0 og 100°C, fortrinnsvis mellom 0 og 50°C, og hvis den fremstilte forbindelse med den generelle formel I inneholder en basisk rest, overføres denne eventuelt med uorganiske eller organiske syrer til syreaddisjonssaltene derav.where Y is as indicated above, in water or in an organic solvent at temperatures between 0 and 100°C, preferably between 0 and 50°C, and if the prepared compound of the general formula I contains a basic residue, this is optionally transferred with inorganic or organic acids to the acid addition salts thereof. 4. Anvendelse av en forbindelse med den generelle formel I ifølge krav 1 eller 2 til fremstilling av antibakterielt aktive 4-spectinomycylaminer.4. Use of a compound with the general formula I according to claim 1 or 2 for the production of antibacterially active 4-spectinomycylamines.
NO784297A 1977-12-21 1978-12-20 SPECTINOMYCIN DERIVATIVES FOR USE IN THE PREPARATION OF THERAPEUTIC ACTIVE 4-SPECTINOMYCYLAMINE NO784297L (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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